2002, Vol.86, Issues 3, Dementia

Med Clin N Am 86 (2002) xi–xiii
Preface
Dementia
James D. Bowen, MD
Guest Editor
Dementia is one of the most important yet difficult conditions that phy-
sicians are asked to manage. It takes an enormous toll on patients, even-
tually robbing them of the accumulated wealth of their life experiences,
destroying the very essence of their beings. Families likewise suffer from
the loss of patriarchs and matriarchs while communities lose the guidance
and wisdom of seasoned leaders. With 6% to 10% of those over 65 years of
age affected, dementia takes a staggering economic toll that will only worsen
as the population ages. Though dementia is common, and despite the sever-
ity of its impact, physicians and families often overlook the diagnosis.
Recognizing dementia is not the only challenge because identifying the cor-
rect diagnosis may be difficult. Finally, the management of these patients
can be daunting even for skilled geriatricians.
This issue of Medical Clinics of North America is devoted to dementia. It
is divided into three sections discussing clinical aspects, recent scientific
insights, and treatments. The first article provides an overview of the diag-
nosis of patients with dementia. The clinical history, examination, labora-
tory evaluation, and differential diagnosis are reviewed. The next five
articles review specific dementing diseases that are of particular importance
today. Vascular dementia is reviewed in the second article. This represents
the second most common cause of dementia, after Alzheimer’s disease.
The third and fourth articles review frontotemporal dementia and dementia
with Lewy bodies. These two conditions have recently been distinguished
from other types of dementia. New criteria have been proposed, allowing
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xii Preface / Med Clin N Am 86 (2002) xi–xiii
them to be distinguished from other dementing illnesses. Correctly diagnos-

ing frontotemporal dementia and dementia with Lewy bodies can explain
otherwise baffling behaviors and can provide important prognostic informa-
tion to patients and families. These diagnoses also carry important implica-
tions for treatment. The fifth article is devoted to AIDS dementia. Dementia
in patients with HIV infections can be the result of a number of different
causes. Correctly identifying the cause is key to providing optimal treat-
ment. The sixth article rounds out the discussion of specific diseases with
a review of human prion diseases. Prion diseases represent a new class of
infectious agents that have had dramatic effects on public health policy
because of their link to specific food sources. Understanding and recogniz-
ing the conditions described in these opening articles should provide the
practitioner with valuable tools in evaluating dementia patients.
The next section of this issue reviews some of the scientific findings
that have advanced our understanding of dementing diseases. The epide-
miology of dementia is discussed in the seventh article. Epidemiology stud-
ies drive many of the public health care decisions that must be made in
caring for the elderly because the incidence and prevalence of dementia
point toward society’s present and upcoming healthcare needs. Epidemiol-
ogy also identifies risk factors for dementia that may provide additional
insight into the pathogenesis of dementing diseases. The eighth article
describes the many advances in the genetics of dementia that have
occurred during the past few years. Many families with genetic risks of
dementia have now been recognized. In many cases, the responsible genes
have been identified. These genes and the proteins that they encode
increase our understanding of dementia at the molecular level, not only
for familial dementias, but also for nongenetic dementias. Genetic
advances merge into the recent advances in our understanding of the
molecular basis of Alzheimer’s disease. We are beginning to understand
the molecular causes of two of the prominent pathologic changes found
in Alzheimer’s disease: neurofibrillary tangles and plaques. The role of
tau in the formation of neurofibrillary tangles and Alzheimer’s disease
is described in the ninth article. The role of beta-amyloid in the formation
of plaques and Alzheimer’s disease is described in the tenth article.
The final two articles address the treatment of patients with dementia.
The eleventh article describes some of the nonpharmacologic treatments
that may be used to manage the symptoms of dementia. Successful manage-
ment of these symptoms can greatly reduce the burden on patients and
families. In addition, these treatments can avert or delay the need for expen-
sive care in assisted living facilities or nursing homes. The final article
describes pharmacologic treatments of dementia. These relatively new med-
ications are the first treatments that can improve cognitive function.
I hope this issue will provide the practitioner with the tools needed to
diagnose and manage patients with dementia in their clinical practices. It
should also provide a basis for understanding the recent scientific advances
Preface / Med Clin N Am 86 (2002) xi–xiii xiii
that have added so much excitement to this field, and that provide such hope
for the future.
James D. Bowen, MD
Guest Editor
Department of Neurology
University of Washington
Box 356465, Room RR650
1959 N.E. Pacific Street
Seattle, WA 98195-6465, USA
E-mail address: [email protected]

Med Clin N Am 86 (2002) 455–476
The diagnosis and differential diagnosis

of dementia
G. Webster Ross, MDa,*, James D. Bowen, MDb
a
Honolulu Department of Veterans Affairs, and John A. Burns School of Medicine,
University of Hawaii, Pacific Health Research Institute,
846 South Hotel Street, Suite 307, Honolulu, HI 96813, USA
b
Department of Neurology, University of Washington School of Medicine,
Box 356465, Seattle, WA 98195, USA
Dementia is one of the most costly and disabling diseases associated with
aging. The emotional impact of the disease on patients and families is devas-
tating, and the cost to society is staggering. Annual costs for caring for a
single patient with Alzheimer’s disease (AD) are reported to be between
$35,000 and $47,000, totaling more than $140 billion dollars per year in the
United States assuming there are 4 million people with AD [1–3]. This figure
is projected to rise as the proportion of the population older than the age
of 65 years increases. As treatments for AD and other dementias that can
extend the period individuals have reasonably good cognitive and physical
functioning become available, the accurate and early diagnosis of these dis-
orders becomes more crucial.
This article provides an overview of the bedside and clinic evaluation of
patients with complaints of forgetfulness or other cognitive or behavioral
disturbances and reviews distinguishing features of dementia and other con-
ditions that may be confused with dementia. The laboratory and imaging
evaluation of the patient with dementia and the various causes of dementia
are described. Current clinical practice guidelines and practice parameters
are reviewed as relevant for the primary care practitioner. For the most part,
these guidelines are similar; however, there are important inconsistencies
that are discussed.
* Corresponding author.
E-mail address: [email protected] (G.W. Ross).
This work was supported by National Institute on Aging contract NO1-AG-4-2149, US
Department of the Army grant DAMD17-98-1-8621, and Department of Veterans Affairs
medical research funds. The information contained in this article does not necessarily reflect the
position or the policy of the US government, and no official endorsement should be inferred.
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456 G.W. Ross, J.D. Bowen / Med Clin N Am 86 (2002) 455–476
Dementia is a clinical syndrome characterized by acquired impairment in

multiple neuropsychologic and behavioral domains, including memory, lan-
guage and speech, visuospatial ability, cognition (the ability to manipulate
previously learned information), and mood/personality [4]. Most definitions,
such as that of the fourth edition of the Diagnostic and Statistical Manual of
Mental Disorders (DSM-IV) [5], require that the intellectual deficits be of suf-
ficient severity to impair social or occupational functioning. These definitions
necessarily draw an arbitrary line between no dementia and dementia.
Patients most often pass through stages of intellectual decline that may or
may not progress to dementia. These include cognitive deficits thought to
occur with normal aging; mild cognitive impairment (MCI), a term used
to recognize a transitional phase from normal aging to dementia; and early
dementia. In practice, it is often difficult to recognize when a patient with
memory complaints has a process that is likely to progress to further intellec-
tual and functional decline. Because there is no diagnostic test to identify
dementia, the clinician must rely on a careful and accurate history from the
patient and a reliable informant as well as a good mental status examination.
As effective treatments are developed for the common causes of dementia,
it is important to diagnose patients in the earliest phases of disease, perhaps
even before affected individuals recognize that a memory problem exists.
According to one recently published population-based study, approximately
20% of family informants failed to recognize memory problems in elderly
subjects who were found to have dementia on a comprehensive standardized
examination [6]. Another study found that more than 75% of patients in a
primary care group practice found to have dementia on cognitive screening
had no documentation of cognitive impairment in their medical record [7]. It
is thus essential that clinicians inquire about cognitive and functional
changes in their elderly patients and administer a brief mental status exam-
ination if changes exist so as to identify cognitive decline as early as possible.
Clinical evaluation of patients with memory complaints

History of cognitive impairment
Patients who complain of memory problems and those suspected to have
memory problems should give a thorough and detailed history, taken from
the patient as well as from a relative or close friend. Even in the early stages
of dementia, such as AD or frontotemporal dementia, patients may be unable
to recall important aspects of their medical history and may even deny or not
recognize significant memory deficits because of lack of insight. Family mem-
bers can provide information regarding the time and character of onset as
well as the pattern of progression of the memory complaints. For example,
the onset of AD is insidious, and the course is slowly progressive, whereas
vascular dementia (VsD) may begin abruptly and be associated with a step-
wise decline [5,8,9]. Although there are exceptions to these rules, they do
G.W. Ross, J.D. Bowen / Med Clin N Am 86 (2002) 455–476 457
provide useful information for distinguishing these two common dementia

syndromes. It is also helpful to inquire about life events temporally related
to the onset of the memory complaints, such as hospitalization, stroke, head
injury, new medications, or the loss of a spouse or other family member.
Inquiry should be made regarding ability to learn and recall new informa-
tion. Examples include recall of recent conversations and events, telephone
messages, short shopping lists, appointments, and use of new appliances or
electronic devices. Patients may forget to pay their bills, become lost in
familiar surroundings, lose items (eg, mail or keys), or exhibit repetitive beha-
viors (eg, asking the same question over and over). Standardized informant-
based questionnaires regarding memory and cognitive decline may be
administered by trained interviewers, providing a base for a more focused
history taken by the primary physician. One of these tools is the Informant
Questionnaire on Cognitive Decline in the Elderly [10,11].
History of behavioral disturbances

It should be recognized that memory impairment, although a hallmark of
the dementia syndrome, is not always the presenting feature. Behavioral dis-
turbances and decline in functional ability are often the triggers that lead
family members to seek medical attention [6]. Behavioral disturbances
include delusions, hallucinations, changes in mood (eg, depression), and
changes in personality (eg, disinhibition, impulsivity, loss of interest in usual
activities, excessive anxiety, uncharacteristic anger or agitation). Standard-
ized assessments of behavioral complications are also available, such as the
Neuropsychiatric Inventory [12] or the Behave-AD [13]. These assist the
clinician in screening for a range of behavioral complications associated
with dementia and in measuring the effect that these complications have
on the caregiver’s well-being.
History of functional impairment

An important component of the history is assessing the impact that the
intellectual decline and behavioral disturbances are having on the patient’s
social and basic functioning ability. This may be a difficult task in the
elderly, especially when physical ailments also contribute to inactivity or
decline in functional ability. As a result, some knowledge of the patient’s
previous activities is necessary. Standardized instruments, such as the
informant-rated Blessed Dementia Scale [14], the Functional Activity Ques-
tionnaire [15], or the Instrumental Activities of Daily Living Scale [16], may
be used for functional assessment. These scales assess activities of daily
living (personal maintenance activities essential for good health and well-
being), including dressing, bathing, eating, and toileting, as well as instru-
mental activities of daily living (higher order skills required for
independent living), including managing money, preparing meals, taking
medication, and performing household tasks. More detailed discussions of

these topics are available in recently published guidelines and reviews [17–20].
A review of the patient’s past medical and psychiatric history for condi-
tions that may contribute to cognitive decline is always necessary. This
should include questions regarding cardiovascular disease, remote head
trauma, alcohol use, prescription and nonprescription medications, dietary
supplements, and treatment for depression. Family history is important,
because many dementing diseases have a familial component. Thorough
reviews of systems and a general physical examination, including a detailed
neurologic examination, are needed to identify clues to the diagnosis. A car-
diac murmur or dysrhythmia along with focal neurologic signs may suggest
a vascular etiology, whereas bradykinesia, rigidity, and tremor suggest one
of the parkinsonian syndromes.
Mental status examination

The bedside mental status examination should include assessment of level
of consciousness, orientation, attention, speech and language, recent and
remote memory, cognition, visuospatial skills and mood/personality. Atten-
tion refers to the patient’s ability to maintain focus on the appropriate stimu-
lus while avoiding distraction from irrelevant stimuli. This may be tested by
digit repetition or by subtracting serial 7’s or 3’s from 100. In general, atten-
tion is preserved until late in most dementias. Language assessment begins
with listening to the patient’s spontaneous verbal output and includes word
list generation, confrontation naming, repetition, and comprehension. Apha-
sia may suggest dominant hemisphere disease; however, impoverished spon-
taneous verbal output with paraphasic errors (word substitutions) may also
be an early indication of AD [21]. Recent memory may be tested by asking
the patient to recall a list of words after 3 to 5 minutes. The minimum is three
words; however, longer lists, such as eight words, allow the generation of a
learning curve. During the recall phase, category or multiple choice cues may
be given to determine if the words have been learned. These techniques can be
helpful for differentiating the forgetfulness (ie, intact learning, impaired
retrieval) of normal aging and certain subcortical dementia syndromes from
the amnesia (ie, impaired learning and retrieval) of AD and other cortical
syndromes [4]. Visuospatial function is tested at the bedside by asking the
patient to copy two- and three-dimensional geometric shapes. Cognition or
the ability to manipulate previously learned information includes assessment
of abstracting ability by interpretation of similarities, proverbs, and mental
arithmetic. Performance of these tasks is highly dependent on educational
level. Executive function refers to judgment and motivation as well as plan-
ning, performing, and monitoring complex behaviors. Impairment in this
area is characteristic of subcortical dementia syndromes. The reader is direc-
ted to several references with excellent descriptions of the mental status
examination for more detail [4,22]. The bedside mental status examination
provides valuable qualitative information in multiple cognitive domains;

however, the time and expertise to administer the full examination may make
it impractical in the average primary care setting. Clinicians may prefer a
brief standardized cognitive assessment instrument such as the Mini-Mental
State Examination [23], the Cognitive Abilities Screening Instrument [24], the
Alzheimer’s Disease Assessment Scale [25], or the Neuropsychological Assess-
ment of the Consortium to Establish a Registry for Alzheimer’s Disease [26].
These all have the advantage of being quantitative and easy to administer.
When used along with the other components of the history and examination,
they are useful for determining if a patient has dementia. Because of the vari-
able sensitivity and specificity in different populations and the effects of edu-
cation on performance, a specific cutoff score cannot be the sole method of
diagnosing dementia. Scores are useful for measuring change over time
[18,19]. The Mini-Mental State Examination is the most commonly used cog-
nitive screening instrument (Table 1). It has the advantages of being brief,
easy to administer, and inclusive of multiple domains, including orientation,
attention, language, memory, and visuospatial ability. Published normative
data allow interpretation of scores according to the patient’s age and edu-
cation [27].
In addition to age and education, impairment in hearing and vision as
well as cultural and language background may affect performance on cogni-
tive testing [18,28]. Nonnative English speakers may have difficulty with
Table 1
Mini-mental state examination
Maximum score
What is the (year)(season)(date)(day)(month)? 5
Where are we (state)(country)(town)(hospital)(floor)? 5
Registration
Name three objects. Give 1 second to say each. 3
Ask the patient all three after you have said them.
Give 1 point for each correct answer.
Repeat them until the patient learns all three count trials and record.
Attention and calculation
Serial 7’s. Give 1 point for each correct. Stop after five answers. 5
Alternatively, spell ‘‘world’’ backwards.
Recall
Ask for the three objects repeated previously. Give 1 point for each 3
correct answer.
Language
Names a pencil and watch. 2
Repeat the following: ‘‘No ifs, ands, or buts.’’ 1
Follow a three-stage command: ‘‘Take a paper in your right hand, 3
fold it in half, and put it on the floor.’’
Read and obey the following: CLOSE YOUR EYES. 1
Write a sentence. 1
Copy design [two overlapping pentagrams]. 1
cognitive function tests given in English. Individuals relatively fluent in

English may still perform at a higher level in their native language given the
stress of cognitive function tests. Cognitive screening instruments translated
into the native language should be used when available. Even when assessing
cognition in the language most comfortable for the patient, culturally biased
items on the screening test used may still affect performance, requiring inter-
pretation of the test results within culture-specific norms [18,28].
Formal neuropsychologic testing may be necessary when the bedside
assessment fails to differentiate between changes associated with normal
aging and early dementia. These tests may also assist with narrowing the dif-
ferential diagnosis of the dementia syndrome.
Diagnostic evaluation of dementia

Neuroimaging
Although the literature regarding indications for neuroimaging in the
evaluation of dementia remains inconclusive, most dementia specialists sug-
gest that a structural brain image be obtained for a newly diagnosed patient
to assess cerebrovascular lesions, neoplasms, subdural hematomas, or hydro-
cephalus [17]. The recent report from the Quality Standards Subcommittee
of the American Academy of Neurology on the diagnosis of dementia
recommends neuroimaging at the time of initial dementia assessment ‘‘under
most circumstances’’ [20]. Earlier published guidelines state that neuro-
imaging is optional [29], and some offer prediction rules that dictate when
imaging is indicated [19,30]. A recent evaluation of six published sets of pre-
diction rules for neuroimaging in the evaluation of dementia found that the
sensitivity of these rules for identifying potentially reversible causes of de-
mentia, such as subdural hematomas, neoplasm, or hydrocephalus, ranged
from 12.5% to 100%. Depending on the rules used, it was estimated that
12% to 88% of patients with a potentially reversible cause of dementia would
not be imaged [31]. Another study evaluating the usefulness of the predic-
tion rules from the American Academy of Neurology guidelines published
in 1994 [30] found that 5% of cases with a meaningful lesion found on neu-
roimaging had none of the clinical predictors [32]. Although the guidelines
support the use of either a non-contrast-enhanced CT scan or MRI, MRI
is more sensitive than CT for identifying small cerebrovascular lesions and
space-occupying lesions that could cause cognitive impairment. The clinical
significance of multiple small white matter changes seen on T2-weighted
MRI images in the elderly is often uncertain, however.
Neuroimaging is essential for the diagnosis of cerebrovascular dementia.
Clinically silent (ie, no recognized focal event) lacunar infarcts, ischemic
white matter changes, and even cortical infarctions that affect cognition may
be present. Imaging analysis techniques that quantify the volume of brain
structures or lesions may be useful in the future for diagnosing AD [33].
Presently, these techniques are expensive and time-consuming. Neither sin-

gle photon emission CT nor positron emission tomography is recommended
for routine use in the diagnostic evaluation of dementia [20]. These studies
can be useful diagnostic adjuncts, however.
Laboratory tests
Laboratory tests should be performed to identify infectious, metabolic,
toxic, and inflammatory disorders that can cause neuropsychologic impair-
ment. Required tests include a complete blood cell count; tests of electrolyte,
serum glucose, vitamin B12, and folate levels; tests of liver, renal, and thy-
roid function; and a serologic test for syphilis [19,20]. In a recent study, the
use of these tests affected patient management in 13% of consecutive patients
being evaluated for dementia [32].
Further diagnostic testing should be based on clinical suspicion. This
includes serum or urine tests for toxins, drugs, or heavy metals when expo-
sure is suspected; sedimentation rate for suspected infectious or inflam-
matory disorders; and human immunodeficiency virus antibody testing.
Genetic testing may be useful in those with three or more first-degree rela-
tives with a dementing illness. Assuming that mass lesions are absent, a lum-
bar puncture may help to diagnose metastatic cancer, infection, vasculitis,
encephalitis, meningitis, syphilis, or hydrocephalus. Lumbar puncture may
be particularly useful in dementia patients less than 55 years of age or in
those with rapid progression, unusual dementia, or immunosuppression
[30]. Specific tests on cerebrospinal fluid (CSF), although not standard, may
be helpful for diagnosis. For example, elevation of the normal brain protein
14-3-3 in the CSF of patients with progressive dementia without CSF pleo-
cytosis has been reported to be 96% sensitive and 99% specific for Creutz-
feldt-Jakob disease [20,34]. An electroencephalogram may identify the
periodic sharp wave complexes associated with Creutzfeldt-Jakob disease and
may be helpful in distinguishing depression or delirium from dementia [30].
Differential diagnosis of memory and cognitive impairment

Not all patients with complaints of memory loss have dementia. Some
have no memory loss at all, whereas others have a mild degree of impair-
ment insufficient for a diagnosis of dementia. When evaluating the patient
with complaints of memory loss, the physician must first determine whether
true memory loss is present. A number of conditions can lead to memory
complaints or cognitive impairment. These are listed in Table 2.
Cognitive changes with normal aging

Cognitive decline related solely to aging remains a controversial topic.
Normative data from cross-sectional studies examining neuropsychologic
Table 2
Problems presenting as memory loss
Dementia
Worried well
Normal aging
Depression
Delirium
Stroke syndromes
Bradykinesia
Abulia
Seizure
Excessive daytime somnolence
Amnestic syndrome
performance demonstrate declines in memory with age. Specifically, it has

been reported that new learning ability or acquisition declines with age,
whereas cued recall remains stable [35]. The pattern and severity of deficits
across cognitive domains vary widely depending on the population studied,
the tests used, and whether the data are cross-sectional or longitudinal [35–
37]. A clear conclusion from studies of neuropsychologic function in the
elderly is that aging-related declines are not inevitable, and that when they
do occur, it is age-related diseases that are often responsible [36,38]. It
should be emphasized that all patients with memory complaints need a care-
ful evaluation. It is not appropriate to assume that memory complaints, at
any age, are caused by senescence.
Mild cognitive impairment

One of the more important clinical concepts to emerge recently in the
field of cognitive disorders is MCI. Although exact definitions vary, MCI
exists in patients with memory complaints and objective memory impair-
ment. Because the activities of daily living are intact in these patients, they
do not meet the criteria for dementia. This condition is considered to be a
transitional stage between normal aging and dementia. The significance of
MCI lies in the identification of patients at high risk for developing demen-
tia and in the potential for treating these patients so as to prevent further
decline. Guidelines for the detection and management of this condition have
been published recently [39]. It is reported in this evidence-based review that
subjects with MCI followed for up to 4 years have a high risk of progressing
to dementia, with an annual conversion rate ranging from 6% to 25%. The
recommendations are made that persons with MCI be recognized and mon-
itored for cognitive and functional decline because of their increased risk of
progressing to dementia and that general cognitive screening instruments be
considered for identifying dementia in patients with MCI [39]. Arguments
countering these recommendations question the benefit of clinical monitor-
ing considering the fact that not all those with MCI evolve to dementia and
suggest that the stigma attached to this label could actually work to the
patient’s detriment [40].
Depression
Memory impairment is commonly associated with major depression in the
elderly and may be the presenting symptom of this common and treatable dis-
order [41]. In fact, memory complaints in the elderly may be more related to
depression than to objective memory impairment [42]. The essential features
of major depression are sadness that is persistent or anhedonia (loss of inter-
est in usual activities) [5]. In addition to memory impairment and poor con-
centration, depressed patients experience sleep and appetite disturbances, loss
of energy, psychomotor retardation, feelings of worthlessness or guilt, or
recurrent thoughts of death. Clinical screening tools for depression are avail-
able, such as the Hamilton Scale or the Geriatric Depression Scale [43,44].
Patients with depression generally have impaired recall with relative spar-
ing of recognition memory. The cognitive and mood symptoms can resolve
completely with treatment, although response to treatment may be difficult
to assess when dementia and depression coexist. Additionally, because de-
pression with cognitive impairment may presage the development of demen-
tia, it is important to follow patients so as to assess treatment effectiveness
and track progression of cognitive deficits [45].
Delirium
Delirium or acute confusional state is another condition that is common
in the elderly. According to the DSM-IV [5], delirium requires the following:
1. Disturbance of consciousness (ie, reduced clarity of awareness of the
environment) with reduced ability to focus, sustain, or shift attention.
2. A change in cognition (eg, memory deficit, disorientation, language dis-
turbance) or the development of a perceptual disturbance that is not
better accounted for by a preexisting, established, or evolving dementia.
3. The disturbance develops over a short period (usually hours to days)
and tends to fluctuate during the course of the day.
Illusions and hallucinations may be seen, speech may be incoherent at
times, sleep-wake cycles are often disturbed, and psychomotor activity is
increased or decreased. Delirium is associated with a variety of systemic
illnesses, infections, and toxic and metabolic disturbances. Hospitalized
patients in general and surgical patients in particular are prone to delirium.
Features that help to differentiate delirium from dementia include rapid
onset, short duration, and disturbance of consciousness that often waxes
and wanes between agitation and lethargy. It is important to recognize that
patients with dementia are at increased risk for delirium and that delirium
and dementia may coexist [46].
Amnestic syndromes
Amnesia is defined as an inability to learn new information and is an early
sign of AD. Unlike AD, however, the amnestic syndromes are characterized
by isolated amnesia with preservation of other areas of neuropsychologic
function, such as language and visuospatial ability. Amnestic syndromes are
generally associated with conditions that affect the mesial temporal lobes
and their connections with the fornix, mamillary bodies, and thalamus.
Causes of amnesia include Korsakov’s syndrome associated with alcohol
abuse and thiamine deficiency, herpes encephalitis, and head trauma [47].
It is important to recognize that patients with isolated memory loss with-
out apparent cause are at high risk for developing dementia and should be
closely monitored [48].
Aphasia
Language disturbance or aphasia complicates the evaluation of the cog-
nitively impaired patient. An aphasic patient may be unable to participate in
memory testing because of an inability to comprehend instructions, repeat
words or phrases, or read. Aphasia is associated with dysfunction in the
dominant hemisphere, usually the left hemisphere. Anterior lesions cause
nonfluent aphasia with sparse verbal output, whereas posterior lesions in
Wernicke’s area are associated with fluent verbal output with word substitu-
tions or paraphasias and impaired comprehension [49]. Dominant hemi-
sphere strokes are the most common cause of aphasia; however, anomia
may be the earliest feature of AD or frontal lobe degenerative dementia [21].
Etiology of dementia
Once it has been determined that a patient’s complaints of memory loss
are the result of dementia, the physician must determine the nature of the
dementing disorder. Table 3 provides a partial list of the many causes of
dementia. The following discussion highlights some of the more common
and reversible causes. Detailed information on some of these conditions may
be found in other articles in this issue. Comprehensive reviews of the causes
of dementia are also available [4,18].
Identifying less common causes of dementia

Although AD is the most common cause of dementia, the physician must
be vigilant to less common causes. Clues to diagnosing less common condi-
tions include the presence of focal neurologic findings that suggest focal
structural lesions, such as stroke, tumor, or subdural hematoma. The early
onset of behavioral abnormalities, language dysfunction, rigidity, or apraxia
suggests frontotemporal dementia. Parkinsonian features in early stages of
the disease suggest the presence of Parkinson’s disease or dementia with
Table 3
Causes of dementia
Cortical degenerative dementias Dementias associated with parkinsonism
Alzheimer’s disease Parkinson’s disease
Frontotemporal dementia Dementia with Lewy bodies
Vascular dementias Progressive supranuclear palsy
Multiple large vessel infarcts Multiple systems atrophy
Single strategic infarct Cortical-basal ganglionic degeneration
Lacunar state Idiopathic basal ganglia calcifications
Binswanger’s disease Parkinsonism-dementia complex of Guam
CADASILa Other extrapyramidal disorders
Toxic/metabolic conditions Wilson’s disease
Medication-induced dementia Huntington’s disease
Alcohol-related dementia Hallervorden-Spatz disease
Dementia related to heavy metal Dementias related to infections
exposure Prion diseases
Vitamin B12 deficiency Creutzfeldt-Jakob Disease
Folate deficiency Gerstmann-Straussler-Scheinker Disease
Hypo- or hyperthyroidism Kuru
Hypo- or hyperparathyroidism New-variant Creutzfeldt-Jakob Disease
Hypo or hypermagnesemia Neurosyphilis
Hypo or hypercalcemia AIDS dementia
Cushing’s disease Chronic meningitis
Addison’s disease Fungal
Renal failure Tuberculosis
Liver failure Lyme disease
Porphyria Viral encephalitis
Domoic acid poisoning Whipple’s disease
Paraneoplastic syndromes Trauma-related dementias
Limbic encephalitis Dementia related to closed-head injury
Autoimmune/inflammatory disorders Chronic subdural hematoma
Multiple sclerosis Dementia pugilistica
Behcet’s disease Miscellaneous disorders
Lupus erythematosus Normal pressure hydrocephalus
Sarcoidosis Hippocampal sclerosis
Temporal arteritis and other central Central nervous system tumors
nervous system vasculitides Mitochondrial encephalopathies
a
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalo-
pathy.
Lewy bodies. Fluctuations in performance, often over a period of minutes,

or the presence of visual hallucinations also suggests dementia with Lewy
bodies. Age of onset less than 50 years or the presence of three or more
first-degree relatives with dementia suggests a genetic dementing disorder.
Alzheimer’s disease
AD is the most common cause of dementia, comprising over two thirds
of all cases in most studies [50]. There is no confirmed biologic marker for
AD; however, standardized clinical criteria have improved the accuracy of
diagnosis to greater than 85% [8,51]. Onset is insidious, and progression
slow. Language disturbances may be an early feature, with anomia progres-

sing to fluent aphasia with word substitutions or paraphasias and impair-
ment in comprehension. Recent memory and the ability to learn new
information are also impaired early in AD. Other common disturbances
in cortical function include apraxia (impaired ability to perform motor
activities despite intact motor function), agnosia (inability to recognize
objects despite intact sensory functioning), and alexia (inability to compre-
hend the written word). Patients with AD commonly lack knowledge of
their memory problems. Delusions and hallucinations are common and
occur in up to 50% of patients [52]. The results of the elementary neurologic
examination are remarkably normal in most cases. Subtypes of AD include
those with isolated cognitive impairments that later progress to more wide-
spread cognitive deficits. In addition, another type presents with rigid or
bradykinetic symptoms resembling Parkinson’s disease. When present early,
extrapyramidal signs suggest a more rapid decline [53]. In those patients
with three or more first-degree affected family members, familial AD must
be suspected, and appropriate testing should be undertaken.
Vascular dementia
The concept of (VsD) is evolving as it becomes increasingly recognized
that in addition to causing cognitive decline alone, vascular lesions modify
the expression of Alzheimer pathologic findings [54]. VsD is clinically recog-
nized in patients with a prior history of strokes, focal neurologic findings, or
strokes on neuroimaging. The classic sudden onset with stepwise deteriora-
tion of VsD probably occurs in less than half of cases. Because of these clini-
cally silent cases, it is important to obtain neuroimaging in all cases of
dementia. The cognitive deficits associated with VsD depend on the lesion
location. Large vessel strokes cause cortical deficits, such as aphasia and
focal neurologic deficits, such as hemianopia and hemiparesis. Multiple
small vessel strokes cause a subcortical clinical presentation with forgetful-
ness and prominent executive function deficits. Pseudobulbar palsy, gait dis-
turbances, and urinary incontinence are also common. Although several sets
of criteria exist for VsD [5,9,55], the clinician should be concerned with
stroke prevention in any dementia patient with cerebrovascular risk factors
or vascular lesions on neuroimaging.
Frontotemporal dementia
Frontotemporal dementia consists of a clinically and pathologically
heterogeneous group of disorders, including Pick’s disease. These have in
common degeneration of the frontal and temporal lobes. Diagnostic criteria
for frontotemporal dementia are listed in Table 4 [56]. Behavioral changes,
including disinhibition, impulsiveness, social inappropriateness, apathy, and
withdrawal, are early and prominent features. These behavioral changes pro-
vide the most important clue allowing the differentiation of this condition
Table 4
Criteria for the diagnosis of frontotemporal dementia
A. Dominant deficits in behavior and conduct appearing early in the course
Loss of personal awareness (neglect of hygiene and grooming)
Loss of social graces and awareness
Disinhibition (sexually provocative or demanding, inappropriate jocularity), overactivity,
or restlessness, often with a stereotyped repertoire
Impulsivity, distractibility
Hyperorality (dietary changes, excessive eating, smoking, or alcohol consumption,
preference for sweet foods or food fads, oral exploration of objects)
Withdrawal from social contact, apathy or inertia
Stereotyped or perseverative behaviors (wandering, repetitive clapping, humming or
singing, ritualistic toileting, dressing)
B. Speech output changes
Progressive reduction of speech (late mutism, economy of speech)
Stereotypy of speech (few repeated phrases or themes), perseveration
Echolalia
C. Physical signs
Early or prominent primitive or ‘‘frontal’’ reflexes
Early incontinence
Late akinesia, rigidity, tremor
D. Deficits in social comportment, behavior, judgment, or language are out of proportion to
memory deficit. Memory loss is variable, often seems to result from lack of concern or effort;
frontal lobe impairments most notable: abstraction, planning, self-regulation of behavior
from AD. Language disturbances may also appear early, whereas visuospatial
function remains intact until later in the illness [57]. Neuroimaging may allow
the visualization of focal atrophy, but the disease can often be recognized
clinically before changes on routine imaging are apparent [58]. Single photon
emission CT imaging demonstrates hypoperfusion in the frontal and temporal
lobes before atrophy in these regions is evident on structural imaging [58].
Dementias associated with parkinsonism

Parkinsonism is a syndrome of disturbed motor function character-
ized by bradykinesia, muscle rigidity, rest tremor, and postural instability.
Dementia is often a secondary feature. There are many diseases that cause
parkinsonism. The most common of these is Parkinson’s disease, which is
characterized by loss of dopaminergic neurons in the substantia nigra of the
midbrain. The presence of Lewy bodies, target-shaped inclusions with a
dense eosinophilic core, within the degenerating neurons of the substantia
nigra confirms the diagnosis of Parkinson’s disease; however, these lesions
may also occur in the cortex. Dementias associated with Lewy bodies
comprise a spectrum of diseases, including Parkinson’s disease with Lewy
body pathologic changes limited to the brain stem, dementia with Lewy
bodies associated with Lewy bodies in the cerebral cortex, and AD
associated with cortical Lewy bodies as well as typical Alzheimer pathologic
findings. Dividing lines between these conditions are somewhat arbitrary;
however, the practitioner should be familiar with the basic clinical distinc-
tions, because the correct diagnosis affects patient management.
Dementia occurs at some time during the course of the illness in approxi-
mately 40% of patients with Parkinson’s disease [59]. Cognitive decline begins
at least 1 year after the onset of the movement disorder and is associated with
impaired recall that is aided with recognition cues, prominent executive func-
tion deficits, and intact language [60]. Dementia with Lewy bodies, in contrast
to Parkinson’s disease, is identifiable by fluctuating cognitive performance,
well-formed visual hallucinations unrelated to dopaminergic therapy, and
parkinsonism that emerges simultaneously with the cognitive impairment.
These features allow it to be differentiated from AD and Parkinson’s disease.
It is particularly important to recognize dementia with Lewy bodies because of
the severe adverse reactions that these patients may have to neuroleptic med-
ications used to treat behavioral problems. Because of this, neuroleptics
should be avoided in the treatment of this disease [61]. Diagnostic criteria for
identifying dementia with Lewy bodies are listed in Table 5 [62]. Other degen-
erative parkinsonian syndromes are much less common. Progressive supra-
nuclear palsy begins at the age of 40 years or older and is characterized by a
rigid-akinetic form of parkinsonism, dementia, supranuclear gaze palsy,
severe dysarthria, neck rigidity (usually in extension), minimal tremor, and fre-
quent falls [63]. Multisystem atrophy refers to a group of adult-onset progres-
sive neurodegenerative disorders (ie, striatonigral degeneration, Shy-Drager
syndrome, olivopontocerebellar atrophy) characterized by parkinsonism that
Table 5
Criteria for diagnosing Lewy body dementia
A. The central requirement is progressive cognitive decline of sufficient magnitude to interfere
with normal social or occupational function. Prominent or persistent memory impairment
may not necessarily occur in the early stages but is usually evident with progression. Deficits
on tests of attention and frontal-subcortical skills and visuospatial ability may be especially
prominent.
B. Two of the following are required for a probable diagnosis, and one for a possible diagnosis
of dementia with Lewy bodies:
Fluctuating cognition with pronounced variations in attention and alertness
Recurrent visual hallucinations that are typically well formed and detailed
Spontaneous motor features of parkinsonism
D. Features supportive of the diagnosis are as follows:
Repeated falls
Syncope
Transient loss of consciousness
Neuroleptic sensitivity (deterioration in cognitive function, parkinsonism, drowsiness,
and some features of so-called neuroleptic malignant syndrome)
Systematized delusions
Hallucinations in other modalities
E. A diagnosis of dementia with Lewy bodies is less likely in the presence of the following:
Stroke disease, evident as focal neurologic signs or on brain imaging
Evidence on physical examination and investigation of any physical illness or other brain
disorder sufficient to account for the clinical picture
is poorly responsive to levodopa and is associated with cerebellar dysfunction,

pyramidal dysfunction, or symptomatic autonomic failure as well as dementia
[64]. Vascular parkinsonism is characterized by the stepwise progression of an
akinetic-rigid syndrome in the setting of clinical strokes or other vascular risk
factors, such as hypertension, diabetes, or lipid abnormalities. Clinical signs
may improve without the use of levodopa [65]. Cortical-basal ganglionic
degeneration is characterized by a chronic progressive akinetic-rigid parkin-
sonian syndrome resistant to levodopa and is associated with dystonic limb
posturing and focal myoclonus. There is also evidence of higher cortical
dysfunction (apraxia, cortical sensory loss, or alien limb) [66].
Dementia related to chronic subdural hematoma

The presenting features of chronic subdural hematoma include focal
symptoms, headache, or cognitive/personality changes. Without neuroim-
aging, the diagnosis is rarely straightforward. A history of trauma is absent
in one third of patients. The onset may be sudden with a fluctuating course
or may extend over weeks to months. Seventy percent of chronic subdural
hematomas occur in patients more than 60 years old, and men are more
commonly affected than women [67–69]. Patients may have lethargy or agita-
tion. Cognitive deficits involve multiple domains, including recent memory,
language, abstract thinking, calculations, and judgment [68,69]. A contrast-
enhanced brain CT scan may be required to recognize chronic subdural hema-
toma, because the density of the lesion may be the same as that of brain
parenchyma. Medical management is recommended for small lesions with
minimal clinical signs [70]. Surgical management is indicated for the rest.
Either burr holes or twist-drill craniotomy is effective and associated with
relatively few complications [71].
Dementias associated with infectious disease

The prion diseases, including Creutzfeldt-Jakob disease and dementia sec-
ondary to human immunodeficiency virus infection, are covered elsewhere in
this issue. Creutzfeldt-Jakob disease usually presents with a dementia that
progresses over weeks or months. In addition to cognitive impairment, many
patients experience depression or emotional lability. Myoclonus, especially in
response to stimuli, is seen later in the course of the disease in three fourths of
patients. Ataxia is often seen as a late manifestation of the disease. Gait and
vision may be affected. The dementia is often rapidly progressive, with the
median time from onset of symptoms to death being 4.5 months. Diagnosis
may be aided by the electroencephalographic finding of 1- to 2-Hz triphasic
sharp waves that are often asymmetric. Elevated levels of the 14-3-3 protein
in CSF in the absence of pleocytosis also support the diagnosis. Recently,
variant Creutzfeldt-Jakob disease has been found after consumption of beef
infected by bovine spongiform encephalopathy. These variant cases generally
affect younger patients and have a more prolonged course.
General paresis refers to the dementia associated with parenchymatous

neurosyphilis. Once a common cause of institutionalization, general paresis
is now rarely seen, causing some to question the utility of routinely screening
for treponemal infection [20]. Onset may occur many years after the initial
infection. Patients exhibit memory impairment with confabulation, dys-
arthria, impaired judgment, psychosis, and grandiosity [4]. Treponemal
serology tests, such as the micro hemagglutination assay for treponema palli-
dum (MHA-TP), have fewer false-negative results than nontreponemal tests,
such as the venereal disease research laboratory slide test (VDRL). Cases
screening positive by serologic testing should undergo lumbar puncture. The
CSF VDRL test is highly specific; however, the results may be negative in some
cases. Patients with positive serology and elevated white blood cells in their
CSF should be treated. Aqueous penicillin G remains the treatment of choice.
Toxin-related dementias
Wernicke’s encephalopathy, characterized by delirium, ophthalmoplegia,
and ataxia, is related to thiamine deficiency and is associated with pro-
longed heavy use of alcohol. Prompt thiamine replacement may reverse the
delirium and other signs, although some patients still evolve to Korsakoff’s
syndrome, an amnestic disorder that may be permanent [72]. Although the
DSM-IV recognizes alcohol-induced dementia that persists after heavy
drinking, the lack of pathologic findings in the brain related to alcohol abuse
has called into question the direct toxic effect of alcohol on the brain [5,73].
The increased risk of head injury and association of heavy prolonged alco-
hol use with blood disorders that can lead to stroke may also cause persis-
tent cognitive impairment.
Medications are a common cause of delirium and cognitive decline in the
elderly and may be responsible for 1.5% to 10% of all clinically diagnosed
dementias [74]. Patients with dementia may be particularly susceptible to
further cognitive impairment with medication use [75–77]. Sedatives and
hypnotics (eg, benzodiazepines), anticholinergic drugs (eg, trihexyphenidyl
and meclizine), antidepressants (eg, amitriptyline), analgesics, and antihy-
pertensives (eg, beta-blockers) are all commonly prescribed medications that
can cause cognitive impairment reversible on withdrawal of the medication
[18]. Medications used to treat the behavioral complications of dementia,
such as the antipsychotics haloperidol and thioridazine, may worsen the
memory impairment. The lowest possible dose should be used to control the
target symptoms, and the need for continued use of the medication should
be assessed at regular intervals.
Dementia associated with metabolic disturbance

Neurologic symptoms related to vitamin B12 deficiency occur most com-
monly in the fourth through sixth decades and include paresthesias of the
feet and hands, loss of vibratory and position sensation, ataxia, extremity
weakness, and neuropsychiatric disturbances. Confusion, memory loss, para-
noia, hallucinations, depression, and irritability are all features of the neuro-
psychiatric syndrome that has been described as megaloblastic madness
[78,79]. Importantly, among those with cognitive and behavioral symptoms
and vitamin B12 deficiency, as many as one fourth do not have the megalo-
blastic anemia that is classically associated with pernicious anemia [80].
Focal areas of cerebral demyelination characterize the brain pathologic find-
ings much like the loss of myelin in the posterior and lateral columns of the
spinal cord associated with this syndrome. Treatment consists of intramus-
cular administration of vitamin B12. This usually results in improvement in
the motor and sensory deficits and has been reported to improve language
and frontal function in individuals with vitamin B12–related cognitive
impairment [81]. Folate deficiency may cause a similar syndrome that can
be treated with oral folic acid supplements.
Dementia associated with hypothyroidism is characterized by inatten-
tion, memory impairment, and impaired abstraction. Psychosis may occur
[4]. Owing partly to the common assessment of thyroid function, the myx-
edema syndrome of edema, weight gain, thick skin, cold intolerance, consti-
pation, and psychomotor slowing is rarely seen. More often, clinicians
encounter patients with elevated thyrotropin levels, normal thyroid hor-
mone levels, and absent or mild symptoms [82]. Evidence from community-
based studies demonstrates an association between this condition known as
subclinical hypothyroidism and cognitive impairment [83]. Furthermore,
treatment with thyroxine has been associated with significant improvement
in cognitive function [82].
Normal pressure hydrocephalus

Normal pressure hydrocephalus is a rare condition characterized by the
triad of dementia, gait disturbance, and urinary incontinence. Onset is rare
before 60 years of age. Typically, the gait disturbance develops first, followed
by dementia. Incontinence may not occur until the later stages of the disease.
The gait is associated with slow and small steps akin to parkinsonism, with slow
initiation giving the appearance that the feet are stuck to the floor–hence, the
term magnetic gait. The dementia syndrome is mild, with forgetfulness,
psychomotor slowing, and impaired executive function being the predomi-
nant symptoms. The cause is unknown but is thought to be related to ischemic
demyelination in periventricular white matter secondary to a combination of
vascular insufficiency and intermittent slight increases in CSF pressure [84].
The diagnosis is made by neuroimaging in patients with the appropriate clin-
ical picture. MRI or CT demonstrates ventricular dilatation, especially of the
frontal horns, that is out of proportion to the amount of cortical sulcal widen-
ing. Radionuclide cisternography, once the diagnostic test of choice, is an
unreliable predictor of treatment response and is unlikely to contribute to the
diagnostic certainty beyond a good history, examination, and structural brain

imaging. If hydrocephalus is a serious consideration, neurologic or neurosur-
gical consultation is recommended for several invasive tests that do have prog-
nostic value, such as serial lumbar punctures, continuous CSF drainage, and
continuous intracranial pressure monitoring. Approximately 30% to 40% of
patients have improvement in cognitive function after shunt surgery [85,86].
The elderly, however, are susceptible to complications of shunt surgery, which
occur in 30% to 40% of patients, with 6% to 8% having serious complications
such as death or residual neurologic deficits. Predictors of good response to
shunting include a short history of mental decline, known cause of hydro-
cephalus (eg, subarachnoid hemorrhage or meningitis), predominant gait dis-
order, and clinical improvement after serial lumbar CSF taps or continuous
drainage [86].
Summary
The initial approach to the patient with memory complaints should consist
of a focused history, mental status examination, and functional assessment.
Patients with MCI should be monitored every 6 to 12 months for conversion
to dementia. Delirium, depression, amnestic disorders, and aphasias should
be considered in the differential diagnosis of memory impairment. Once a
diagnosis of dementia is made, patients should have a brain CT or MRI scan
and laboratory tests to assist with determining the cause.
It is crucial that dementia be recognized and evaluated at the earliest
stage so as to begin appropriate therapy and allow the patient to have a role
in management decisions. In the future, therapies for MCI may prevent con-
version to dementia. The need for early recognition makes the development
of diagnostic tools, such as quantitative or functional neuroimaging, and
genetic or clinical biologic markers essential.
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Med Clin N Am 86 (2002) 477–499
Vascular dementia revisited:

Diagnosis, pathogenesis, treatment,
and prevention
Gustavo C. Román, MD*
Department of Medicine/Neurology, University of Texas Health Science Center
at San Antonio, and Audie L. Murphy Memorial Veterans Hospital,
7703 Floyd Curl Drive, San Antonio, TX 78284-7883, USA
Vascular dementia (VaD) is an etiologic category that includes clinical

forms of dementia caused by ischemic or hemorrhagic cerebrovascular dis-
ease (CVD) or by ischemic-hypoxic brain lesions of cardiovascular origin
[1,2]. VaD is the most common cause of dementia after Alzheimer’s disease
(AD) [3]. Among other recent developments, the recognition of the adjuvant
role of vascular factors in AD, the recent identification of genetic forms of
VaD, and progress in the understanding of pathogenetic mechanisms as well
as new possibilities of early diagnosis, treatment, and prevention, have made
VaD one of the most controversial, challenging, and rapidly evolving areas
in the field of dementia.
History
Thomas Willis first described postapoplectic dementia in the seventeenth
century [4]. In 1894, Otto Binswanger and Alois Alzheimer separated VaD
from dementia paralytica (neurosyphilis), a common cause of dementia at
that time, and identified at least four different clinicopathologic forms of
VaD [5]. Based on their work, Kraepelin concluded in 1910 that arterio-
sclerotic insanity, also known as cerebral arteriosclerosis, was the most fre-
quent form of senile dementia [4]. This unwarranted simplification of the
complexity of the field implied that progressive narrowing and blockage
of large cerebral arteries led to decreased cerebral blood flow, neuronal
death, brain atrophy, and dementia. This concept persisted until the late
1970s, when the importance of AD as the main cause of senile dementia was
* E-mail address: [email protected] (G.C. Román).
0025-7125/02/$ - see front matter 2002, Elsevier Science (USA). All rights reserved.
PII: S 0 0 2 5 - 7 1 2 5 ( 0 2 ) 0 0 0 0 8 - 1
478 G.C. Román / Med Clin N Am 86 (2002) 477–499
recognized. Concurrently, Tomlinson, Blessed, and Roth demonstrated that

the loss of more than 50 to 100 mL of brain tissue from stroke resulted in
dementia [6]; the term multi-infarct dementia (MID) was then coined for this
condition [7]. Nevertheless, as described later in this article, VaD includes
more than MID, because a single strategic stroke may also result in VaD.
Likewise, with the advent of new-generation CT and MRI of the brain, the
important role of ischemic-hypoxic white matter lesions in the pathogenesis
of VaD has been recognized.
Pathogenesis
VaD may be caused by a number of vascular lesions and pathogenetic
mechanisms as listed in Table 1 [8]. Of particular importance in the elderly
is small vessel disease, which causes lacunes and white matter ischemic
lesions. These ischemic lesions may interrupt the recently described frontal
Table 1
Pathological lesions capable of producing vascular dementia
1. Multi-infarct dementia
Multiple large complete infarcts, cortico-subcortical in location, usually with perifocal
incomplete infarction involving the white matter
2. Strategic infarct dementia
A single brain infarct, often lacunar in size, damages functionally critical areas of the brain
(angular gyrus, thalamus, basal forebrain, posterior cerebral artery and anterior cerebral
artery territories)
3. Small-vessel disease with dementia
Subcortical
Binswanger’s disease
CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy)
Lacunar dementia or lacunar state (état lacunaire)
Multiple lacunes with extensive perifocal incomplete infarctions
Cortical and subcortical
Hypertensive and arteriolosclerotic angiopathy
Amyloid angiopathies (including British dementia)
Collagen-vascular disease with dementia
4. Ischemic-hypoxic dementia (hypoperfusive)
Diffuse anoxic-ischemic encephalopathy
Restricted injury due to selective vulnerability
Incomplete white-matter infarction
Border-zone infarction
5. Hemorrhagic dementia
Traumatic subdural hematoma
Subarachnoid hemorrhage
Cerebral hematoma
Venous thrombosis
6. Other mechanisms
Modified from Brun A. Pathology and pathophysiology of cerebrovascular dementia: pure
subgroups of obstructive and hypoperfusive etiology. Dementia 1994;5:145–7; with permission.
G.C. Román / Med Clin N Am 86 (2002) 477–499 479
cortical-subcortical circuits that underlie executive functions, motivation,

and socially responsive behaviors [9,10].
There are five parallel anatomic circuits that link regions of the frontal
cortex to the striatum (caudate nucleus), globus pallidus/substantia nigra,
and thalamus, with thalamocortical connections closing the loop [11–15].
These frontal circuits originate in the supplementary motor area, frontal eye
fields, dorsolateral prefrontal region, lateral orbitofrontal area, and anterior
cingulate cortex [11,16,17]. The last three are the primary behaviorally rele-
vant circuits [12–15,18], as follows (Table 2): (1) interruption at any portion
of the loop of the dorsolateral prefrontal subcortical circuit results in execu-
tive dysfunction, (2) orbitofrontal subcortical circuit lesions are manifested
by disinhibited behaviors and obsessive-compulsive disorders, and (3) me-
dial-frontal (anterior cingulate) cortex subcortical circuit lesions often result
in apathy. Each segment of the circuit has different neurotransmitters, modu-
lators, and receptor subtypes that may provide the basis for pharmacologic
intervention [18]. Not surprisingly, executive dysfunction, apathy, mood
changes, and uninhibited behaviors are frequently observed in patients with
VaD [19–22].
Table 2
Behavioral manifestations of subcortical vascular dementia caused by lesions interrupting
prefrontal-subcortical circuits
1. Dorso-lateral prefrontal circuit lesions
Lesions
May include cortical strokes involving dorsolateral prefrontal cortex, infarctions at head
of the caudate nucleus, lacunar lesions in putamen or thalamus, or ischemic white
matter lesions involving loop segments, such as capsular genu lacunes
Manifestations
Executive dysfunction, poor word list generation and decreased verbal fluency, impaired
motor programming, perseveration, impersistence, and difficulty with set shifting (loss
of Luria’s kinetic melody)
2. Orbito-frontal-subcortical circuit lesions
Lesions
May include anterior cerebral artery strokes involving lateral orbitofrontal cortical
territories, or subcortical circuit lesions interrupting connections at the level of caudate,
basal ganglia, thalamus or white matter loop links
Manifestations
Disinhibited behaviors, mania, and obsessive-compulsive disorder
3. Medial-frontal (cingulate) cortex-subcortical circuits
Lesions
May include anterior cerebral artery strokes involving medial frontal cortical territories,
or subcortical circuit lesions interrupting connections at the level of caudate, basal
ganglia, thalamus or white matter loop links
Manifestations
Apathy, slowing of information processing, mood changes, or vascular depression
Modified from Cummings JL. Frontal-subcortical circuits and human behavior. Arch
Neurol 1993;50:873–80; and Cummings JL. Anatomic and behavioral aspects of frontal-
subcortical circuits. Ann NY Acad Sci 1995;769:1–13; with permission.
Vascular and circulatory lesions

In addition to acute ischemia from embolic and atherothrombotic large
vessel occlusions, the elderly are also susceptible to ischemic lesions of small
vessels, resulting in lacunes, cortical microinfarcts (granular atrophy), and
ischemic periventricular leukoencephalopathy of the Binswanger type. Re-
peated episodes of brain ischemia from chronic hypoperfusion affect
the deep white matter territories that are perfused by small vessels (medul-
lary arterioles) [23]. Ageing produces tortuosity and elongation of these
arterioles [24–26], leading to dilatation of the perivascular spaces of Virchow-
Robin [27] and état criblé. Also, narrowing of the lumen is produced by
senile arteriolosclerosis [28], diabetes, and hypertension. The end result
of these morphologic changes is the loss of the normal autoregulation of
cerebral blood flow [29] and hypoperfusion of gray matter and white
matter [30].
For these reasons, orthostatic hypotension, cardiac arrhythmias, and
congestive heart failure in the elderly increase the risk for the development
of cognitive loss and eventual VaD [31–33]. Other mechanisms responsible
for VaD include cortical disconnection from ischemic white matter lesions
[34], such as those present in Binswanger’s disease (BD) [21], and diaschisis.
For instance, a single small thalamic stroke may cause extensive hypometab-
olism and decrease of blood flow in the frontal cortical territories and cer-
ebellum as a result of diaschisis [35–37].
The multiple mechanisms capable of producing VaD, and the syndromes
resulting therein, represent a major challenge when formulating diagnostic
criteria for VaD as well as for case ascertainment in epidemiologic studies
and recruitment of subjects participating in controlled clinical trials.
Epidemiology
AD and VaD are the most common causes of senile dementia, with VaD
ranking second after AD [3,38–40]. Cerebrovascular pathologic findings and
heart disease are common in the elderly, and their prevalences increase with
age; as a result, histologic changes of AD in the elderly often coexist with
stroke and vascular pathologic changes [41,42]. Somewhat more unexpected
was the observation of the adjuvant role of cerebral infarction in AD [43],
whereby elderly subjects with the presence of one or two lacunar strokes
seem to require a lesser amount of senile plaques and neurofibrillary tangles
to manifest signs of dementia.
Recently, Hénon and her colleagues [44,45] demonstrated that careful
questioning can separate patients with preexisting memory loss and prob-
able AD from pure cases of poststroke VaD. About one third of poststroke
VaD patients harbor this dual pathologic profile. These cases should be
classified as ‘‘AD plus CVD’’ instead of the commonly used but incorrect
denomination of ‘‘mixed’’ dementia. Hénon et al [44] found a 16% preva-

lence of prestroke dementia in possible cases of poststroke dementia.
Prevalence
Jorm et al [40] performed a meta-analysis of 47 international studies on
VaD prevalence and found that prevalence increases exponentially with age
up to the age of 95 years. Prevalence rates double every 5.3 years compared
with every 4.5 years for AD. Prevalence rates range from approximately 1.5
per 100 persons from the age of 70 to 75 years to 14 to 16 per 100 persons at
the age 80 years and above. In Europe, VaD was more prevalent than AD in
85-year-olds in Italy and Gothenburg (Sweden) [46]. VaD seems to be more
common in men in contrast to AD, which predominates in women. Also,
VaD has a peculiar geographic (racial) variation, being more prevalent in
Asian populations than in white populations. This is probably a result of the
preponderance of small vessel disease in Oriental races. The prevalence of
AD versus VaD tends to increase among ethnic Japanese who migrated to
Hawaii, however, indicating environmental interaction on genetic suscep-
tibility [47].
Incidence
Incidence data for VaD from longitudinal cohort studies are rather lim-
ited. Jorm and Jolley [48] performed a meta-analysis of 11 studies of VaD
with age-specific incidence data. More recently, Dubois and Herbert [49] used
age-based standardized incidence ratios to analyze data from 10 incidence
studies of VaD in comparison to the Canadian Study of Health and Aging.
Age-based standardized incidence ratios ranged from 0.42 to 2.68, confirming
the geographic variation of VaD. These variations may be a result of genetic,
environmental, or methodologic differences between studies.
Poststroke dementia
The most common form of VaD is probably poststroke dementia (also
known as MID when dementia develops after multiple strokes). The inci-
dence of poststroke dementia is relatively easy to ascertain when cognitive
tests are performed after stroke (typically, at 3 months after ictus). There are
methodologic variations that depend on the definition of dementia and test
cutoffs used. In Helsinki [50], the figures ranged from 6% to 25.5%, whereas
in New York City [51,52], poststroke dementia ranged between 27% and
41%. This means that in the United States alone, approximately 125,000
new cases of VaD after ischemic stroke occur every year (approximately one
third of the estimated 360,000 incident cases of AD) [39,53]. Based on these
figures, the prevalence of poststroke VaD would be above 1 million elderly
people currently suffering from poststroke VaD [53]. It should be noted,
however, that most cases of poststroke VaD remain undiagnosed.
Risk factors for vascular dementia

One of the long-time paradoxes of VaD has been why it is that some
patients develop dementia after a single stroke, whereas others seem to tol-
erate large or recurrent strokes without decline of intellectual function.
Risk factor quantification in case-control studies of poststroke dementia
have begun to provide an answer [54,55]. Pohjasvaara and colleagues [50]
confirmed that the most important risk factors for poststroke VaD are older
age, lower educational level, recurrent stroke, and left hemisphere stroke
(associated with a fivefold increase in the risk of developing poststroke
dementia, an effect not explained by aphasia) as well as the presence of dys-
phagia, gait limitations, and urinary impairment. Demented patients were
more often current smokers and had lower blood pressure and orthostatic
hypotension. Larger periventricular white matter ischemic lesions as detec-
ted by MRI are also predictive of poststroke dementia [56,57].
Moroney et al [58] recently found that hypoxic and ischemic complica-
tions of acute stroke (eg, seizures, cardiac arrhythmias, aspiration pneu-
monia) are strong and independent risk factors for poststroke dementia,
increasing more than fourfold the risk of developing poststroke dementia
(odds ratio ¼ 4.3 and 95% confidence interval: 1.9–9.6, after adjustment for
demographic factors, recurrent stroke, and baseline cognitive function).
Hypoxic and ischemic complications of acute stroke may result in border
zone infarcts [59] but also cause Binswanger-type ischemic periventricular
white matter lesions [60]. Orthostatic hypotension has been correlated with
these lesions in a large population-based MRI study of elderly subjects [61].
Consequently, dementia is a predictor of poor outcome in patients with
stroke [52].
Clinical forms of vascular dementia

Román [62] has simplified the clinical syndromes of VaD into two main
groups, acute and subacute, according to the temporal profile of clinical pre-
sentation.
Acute-onset vascular dementia

This group includes patients with new-onset dementia after a clinically
eloquent acute ischemic event as a single ‘‘strategic stroke’’ resulting from
occlusion (or rupture) of a large-sized vessel, from recurrent strokes (MID),
or after a symptomatic lacunar stroke caused by small vessel disease.
Poststroke multi-infarct dementia

The risk factors for poststroke MID have been presented and are sum-
marized in Table 3.
Table 3
Principal risk factors for poststroke vascular dementia
1. Age: older age
2. Education: lower educational level
3. Personal factors: lower-income, current smokers
4. Genetic factors: family history of dementia
5. Stroke type: recurrent strokes
6. Stroke location: left-sided lesions, ‘‘strategic strokes’’ (ie, posterior association areas such as
gyrus angularis; posterior cerebral artery territories including paramedian thalamic artery
territory, inferomedial temporal lobes, and hippocampus; watershed or border-zone infarcts
mainly involving superior frontal and parietal regions; bilateral anterior cerebral artery
territories, anterior choroidal artery strokes, and basal forebrain lesions; and frontal white
matter lesions); inferior capsular genu stroke producing diaschisis of frontal lobes and
cerebellum
7. Stroke volume: lesions larger than 50–100 ml of tissue destruction, larger peri-lesional
incomplete ischemic areas involving white matter, larger periventricular white matter
ischemic lesions
8. Stroke complications: hypoxic and ischemic complications of acute stroke (ie, seizures,
cardiac arrhythmias, aspiration pneumonia, hypotension)
9. Stroke manifestations: dysphagia, gait limitations, urinary impairment
Dementia caused by a single cortical-subcortical infarction

A single large vessel stroke in the following locations may produce VaD:
1. Posterior cerebral artery territory involving the ventral-medial temporal
lobe, hippocampus, occipital structures, and thalamus and presenting
with anterograde amnesia, aphasia, visuospatial difficulties, or construc-
tional apraxia [63].
2. Infarction in the anterior cerebral artery territory and medial-frontal
lobe lesions, often from an anterior communicating artery aneurysm
rupture [64].
3. Infarctions of the left angular gyrus presenting with right-to-left dis-
orientation, finger agnosia, acalculia, dysgraphia, aphasia, and con-
structional difficulties and on the right side with hemispatial neglect
and visuospatial or visuoconstructive disturbances [65].
4. Bilateral involvement of the basal ganglia and thalamus. This is the so-
called thalamic dementia of vascular origin [66] caused by butterfly-
shaped bilateral paramedian thalamic polar infarcts [66,67].
Some cases of caudate stroke may also result in VaD [68].
Dementia from capsular genu infarction

In 1992, Tatemichi and his colleagues [69,70] called attention to this char-
acteristic—although relatively uncommon—syndrome manifested by sudden
change in cognitive function and often associated with fluctuating attention,
memory loss, confusion, abulia, striking psychomotor retardation, inatten-
tion, and other features of frontal lobe dysfunction but with mild focal find-
ings, such as hemiparesis or dysarthria. The usual cause is a lacune involving
the inferior genu of the internal capsule, causing ipsilateral blood flow reduc-
tion to the inferomedial-frontal cortex by a mechanism of diaschisis [71]. This
is considered a thalamocortical disconnection syndrome [69]. An unusual
case of subcortical dementia resulting from a giant lacune with a unilateral
left-sided mammillothalamic tract lesion has been recently reported [72].
Subacute (subcortical) vascular dementia

The temporal profile of presentation of these forms of VaD is typically
subacute, with a chronic course marked by fluctuations and progressive
worsening. This group is characterized clinically by a subcortical dementia
(subcortical VaD) with frontal lobe deficits, executive dysfunction, slow
information processing, impaired memory, inattention, depressive mood
changes, motor involvement, parkinsonian features, urinary disturbances,
and pseudobulbar palsy. As mentioned previously, this is one of the most
common forms of VaD and results from small vessel disease with lacunes
and white matter lesions that damage structures (caudate nucleus, globus
pallidus, thalamus, and connecting fibers) of the prefrontal subcortical cir-
cuits [22]. The main forms of subacute subcortical VaD are lacunar state
(état lacunaire), BD, cerebral autosomal dominant arteriopathy with sub-
cortical infarcts and leukoencephalopathy (CADASIL), and some forms
of cerebral amyloid angiopathy (CAA). Diagnostic criteria for subcortical
VaD have been proposed recently [73].
Lacunar state (état lacunaire)

In 1901, Pierre Marie [74] described this clinical syndrome in the elderly,
emphasizing the presence of multiple lacunes in the basal ganglia, pons, and
white matter. In addition to lacunes, ventricular dilatation and Binswanger-
type lesions of the white matter caused by recurrent ischemia-hypoxia fre-
quently coexist. The latter are also called leukoaraiosis (Greek for ‘‘white
rarefaction’’) [75].
Senile dementia of the Binswanger type

In 1894, Binswanger [76] described as the hallmark of this condition the
presence of an ischemic periventricular leukoencephalopathy that typically
spares the arcuate subcortical U fibers [21]. Small vessel disease and multiple
lacunes often coexist in BD, and it has been postulated that this condition
and the so-called lacunar dementia of patients with a lacunar state may
represent a single entity [77]. Their clinical manifestations are similar,
[21,76–79] and are discussed jointly.
A lacunar state and BD produce a cognitive and motor syndrome with
characteristics of subcortical dementia, including executive dysfunction, loss
of verbal fluency, slowing of motor function with perseveration, impersis-
tence, inattention, difficulties with set shifting, and abnormal Luria’s kinetic
melody test results [12,13,17–21,78–80]. Memory loss is characterized by
poor retrieval and intact recognition. Apathy, depression, and behavioral

problems are common. Mild residual hemiparesis or other discrete focal
findings are often found as well as a peculiar short-stepped gait (marche à
petits pas), dysarthria, pseudobulbar palsy, and, in some cases, astasia-aba-
sia. Extrapyramidal features, such as inexpressive facies, slowness of move-
ment, axial rigidity, loss of postural reflexes, frequent falls, increased urinary
frequency, and nocturia are also common findings [80,81].
Cerebral autosomal dominant arteriopathy

with subcortical infarcts and leukoencephalopathy
One of the most important recent developments in the field of VaD has
been the clinical and genetic description of CADASIL [82–84]. Originally
called familial BD [85], this condition offers a natural model for the study
of subcortical subacute forms of VaD, particularly BD. Numerous pedigrees
have been described in Europe and North America [82,84,86,87].
CADASIL is an autosomal dominant disorder of cerebral small vessels
mapped to chromosome 19q12 [83]. Clinical manifestations include tran-
sient ischemic attacks and strokes (80%), cognitive deficits and VaD (50%),
migraine with focal deficits (40%), mood disorders (30%), and epilepsy
(10%). Onset is usually in early adulthood (mean age of 46 years) [87] in the
absence of risk factors for vascular disease, culminating in dementia and death
usually approximately 20 years after the onset of symptoms [82,84,87]. The
dementia is slow in onset, subcortical, frontal in type, and accompanied by gait
and urinary disturbances and pseudobulbar palsy clinically identical to that of
sporadic BD. MRI reveals a combination of small lacunar lesions and diffuse
white matter abnormalities; these are often present in asymptomatic relatives
[88]. Also, cerebral blood flow reactivity to inhaled carbon dioxide is impaired.
The underlying vascular lesion is a unique nonamyloid and nonathero-
sclerotic microangiopathy involving arterioles (100–400 lm in diameter) and
capillaries, primarily in the brain but also in other organs. The diagnosis
may be established by skin biopsy [89] and confirmed by immunostaining
with a Notch3 monoclonal antibody [90].
The vessels show deposits of eosinophilic periodic acid–Schiff-positive
material in the arterial media that consists of granular osmiophilic deposits
and accumulation of the ectodomain of the Notch3 receptor in the basal
lamina of degenerated smooth muscle cells on electron microscopy. The
brain lesions are ischemic infarcts, mainly lacunar strokes, localized in the
basal ganglia, thalamus, centrum ovale, and pons, and are associated with
extensive confluent areas of frontal ischemic leukoencephalopathy, particu-
larly in periventricular regions.
The disease is caused by highly stereotyped mutations in the Notch3 gene,
which encodes a phylogenetically old transmembrane cell surface receptor
that regulates cell fate during embryonic development. The large extracellular
domain of Notch3 contains 34 tandem epidermal growth factor–like repeats,
where the mutations result in gain or loss of a cysteine residue [91].
Cerebral amyloid angiopathy

This is a heterogeneous group of disorders characterized by deposition of
amyloid in the walls of leptomeningeal and cerebral cortical blood vessels
and demonstrated clinically by recurrent or multiple lobar hemorrhages,
cognitive deterioration, and ischemic strokes. MRI displays diffuse white
matter abnormalities along with ischemic or hemorrhagic focal brain le-
sions. On histologic examination, the vessels show amyloid deposition,
microaneurysms, and fibrinoid necrosis.
There are several autosomal dominant forms of CAA with differences in
their clinical, genetic, biochemical, and pathologic findings. Amyloid b, the
major amyloid component in the Dutch, Flemish, and Iowa type of familial
CAA, is also the major amyloid component in sporadic CAA and AD.
Familial British dementia with amyloid angiopathy (FBD) is an autosomal
dominant condition characterized by VaD, progressive spastic paraparesis,
and cerebellar ataxia with onset in the sixth decade [92]. A point mutation in
the BRI gene has been shown to be the genetic abnormality. On brain MRI,
Binswanger-type deep white matter hyperintensities and lacunar infarcts are
seen, but no intracerebral hemorrhages are apparent. The corpus callosum is
severely affected and atrophic plaques and tangles are present, but the amy-
loid subunit found in FBD brains is entirely different and unrelated to other
amyloid proteins. FBD combines neurodegeneration and dementia with sys-
temic amyloid deposition [93].
Diagnosis of vascular dementia

Although a number of diagnostic criteria for VaD have been proposed,
the National Institute of Neurologic Disorders and Stroke-Association
Internationale pour la Recherche et l’Enseignement en Neurosciences
(NINDS-AIREN) criteria [94] (Table 4) offer an operative approach to the
three basic elements needed to reach a diagnosis of VaD: cognitive loss, fre-
quently a subcortical form of dementia; cerebrovascular lesions demon-
strated by brain imaging (CT, MRI); and exclusion of other causes of
dementia, such as AD. These criteria also require a logical link between the
vascular lesions and the dementia. A temporal relation (ie, development of
dementia within 3 months after stroke) has proven to be more difficult to
fulfill, particularly in patients with silent strokes.
The NINDS-AIREN criteria require objective proof of dementia vali-
dated by neuropsychologic tests. In practical terms, internists usually have
suspected patients perform a Mini-Mental State Examination (MMSE)
[95]. This test is more suitable for patients with cortical forms of dementia,
particularly AD. VaD requires the use of tests for subcortical dysfunction,
including executive function testing [22]. Some of the bedside tests available
include clock drawing [96], the Trail Making Test Part B [97], and the Beha-
vioral Dyscontrol Scale [98] based on Luria’s kinetic melody.
Table 4
NINDS-AIREN diagnostic criteria for vascular dementia
I. The criteria for the diagnosis of probable VaD include all of the following:
1. Dementia: Impairment of memory and two or more cognitive domains (including
executive function), interfering with ADLs and not due to physical effects of stroke
alone. Exclusion criteria: Alterations of consciousness, delirium, psychoses, severe
aphasia or deficits precluding testing, systemic disorders, Alzheimer’s disease, or other
forms of dementia.
2. Cerebrovascular disease: Focal signs on neurological examination (hemiparesis, lower
facial weakness, Babinski sign, sensory deficit, hemianopia, dysarthria) consistent with
stroke (with or without history of stroke, and evidence of relevant CVD by brain CT or
MRI including multiple large-vessel infarcts or a single strategically placed infarct
(angular gyrus, thalamus, basal forebrain, or PCA or ACA territories), as well as
multiple basal ganglia and while matter lacunes or extensive periventricular white matter
lesions, or combinations thereof. Exclusion criteria: Absence of cerebrovascular lesions
on CT or MRI.
3. A relationship between the above two disorders is manifested or inferred by the presence
of one or more of the following:
A. Onset of dementia within 3 months following a recognized stroke.
B. Abrupt deterioration in cognitive functions or fluctuating, stepwise progression of
cognitive deficits.
II. Clinical features consistent with the diagnosis of probable VaD include the following:
1. Early presence of gait disturbances (small step gait or marche à petits pas, or magnetic,
apraxic-ataxic or parkinsonian gait).
2. History of unsteadiness and frequent, unprovoked falls.
3. Early urinary frequency, urgency, and other urinary symptoms not explained by
urologic disease.
4. Pseudobulbar palsy.
5. Personality and mood changes, abulia, depression, emotional incontinence, or other
deficits including psychomotor retardation and abnormal executive function.
III. Features that make the diagnosis of VaD uncertain or unlikely include:
1. Early onset of memory deficit and progressive worsening of memory and other cognitive
functions such as language (transcortical sensory aphasia), motor skills (apraxia), and
perception (agnosia), in the absence of corresponding focal lesions on brain imaging.
2. Absence of focal neurological signs, other than cognitive disturbances.
3. Absence of CVD on CT or MRI.
Abbreviations: ACA, anterior cerebral artery; ADLs, activities of daily living; CT, com-
puterized tomography; CVD, cerebrovascular disease; MRI, magnetic resonance imaging;
PCA, posterior cerebral artery; VaD; vascular dementia.
From Román GC, Tatemichi TK, Erkinjuntti T, et al. Vascular dementia: diagnostic criteria
for research studies. Report of the NINDS-AIREN International Workshop. Neurology 1993;43:
250–60; with permission.
Demonstration of the presence of vascular lesions by brain MRI or CT

is required. Lesions range from a single strategic lacunar stroke, to multiple
cortical-subcortical strokes, to periventricular ischemia. Mungas et al [99]
determined by MRI that hippocampal atrophy, volume of cortical gray mat-
ter, and volume of white matter lesions (but not lacunes) were strong and
independent predictors of vascular cognitive impairment. The neuropatho-
logic substrate of these lesions in patients with VaD seems to be widespread
ischemia from microvascular disease, including ischemic hippocampal injury
pathologically resembling mesial temporal lobe sclerosis [100]. By definition,

absence of vascular lesions by brain imaging excludes VaD. Inclusion and
exclusion criteria as well as stratification into levels of diagnostic certainty
are also provided in Table 4. Chui [39] has recently reviewed other available
diagnostic criteria for VaD. The different criteria are not interchangeable,
and the criteria for subcortical VaD are yet to be validated.
Separating Alzheimer’s disease from vascular dementia

A practical problem that frequently confronts the internist is the elderly
patient with cognitive and behavioral disturbances presenting with an
abnormal MMSE and the presence of vascular lesions on brain imaging.
Does the patient have MID, AD plus CVD, or simply AD?
The ischemic score (Table 5) may provide additional elements for the
diagnosis of the MID form of VaD [101]. A score greater than or equal
to 7 is consistent with MID, a score less than or equal to 4 is consistent with
AD, and a score of 5 to 6 is suggestive of AD plus CVD. In a recent meta-
analysis [101], the following features were found more often in VaD than in
AD: stepwise deterioration, fluctuating course, history of hypertension, his-
tory of stroke, and focal neurologic symptoms.
As discussed previously, it is possible to successfully diagnose prestroke
dementia by means of a careful interview of relatives and caregivers [45].
In most instances, probable AD is a likely etiology for the progressive mem-
ory loss occurring before the ictus.
Another related method is the application of the concept of mild cogni-
tive impairment [102]. The amnestic form of MCI is easily identifiable and
carries a risk of conversion to clinically probable AD at a rate of 10% to
15% per year compared with 1% to 2% per year in healthy age-matched
Table 5
Items of the ischemic score
Item Score (total: 18)
Abrupt onset 2
Stepwise deterioration 1
Fluctuating course 2
Nocturnal confusion 1
Preservation of personality 1
Depression 1
Somatic complaints 1
Emotional incontinence 1
History of hypertension 1
History of stroke 2
Associated atherosclerosis 1
Focal neurological symptoms 2
Focal neurological signs 2
Modified from Hachinski VC, Zilhka E, DuBoulay GH, McAllister VL, Marshall J.
Cerebral blood flow in dementia. Arch Neurol 1975;32:632–7; with permission.
control subjects. The frequency and severity of CVD in older patients with
AD point to the possibility that vascular risk factors may predispose not
only to VaD but to the development of AD [103]. Population-based epide-
miologic data [104,105] have shown that vascular risk factors, such as hyper-
tension, carotid artery wall thickness, cholesterol, and peripheral vascular
disease, often occur in patients who develop AD. The vascular role of the
apolipoprotein E e4 allele [105,106], a risk factor for AD, may partially
explain this interaction.
Treatment and prevention

Secondary prevention
Patients with VaD have higher morbidity and mortality than age-matched
control subjects and patients with AD [52]. Coronary artery disease and
recurrent strokes are among the common complications in these patients.
Secondary prevention of recurrent stroke must be undertaken in patients
with poststroke VaD. Although age, gender, ethnicity, and genetic factors
are nonmodifiable stroke risk factors, there is clear class I evidence that treat-
ment of hypertension reduces the risk of recurrent stroke by 28% [107]. Like-
wise, the use of statins to decrease low-density lipoprotein cholesterol by 25%
reduces stroke risk up to 30% [108]. Antiplatelet medications reduce the risk
of recurrent stroke by 17% with aspirin and 25% with ticlopidine. Clopido-
grel is a safe and effective alternative to ticlopidine but is not superior to
aspirin; dipyridamole in combination with aspirin seems to be superior to
aspirin alone [109]. Anticoagulation with warfarin [International Normal-
ized Ratio (INR): 2–3] in patients with atrial fibrillation is highly efficacious
in preventing recurrent stroke (approximately 70% risk reduction) [110]. For
patients with more than 75% carotid artery stenosis, surgery reduces recur-
rent stroke by 51% [111].
Primary prevention
Of significant public health interest are the observations that the treat-
ment of hypertension [112–115] and the use of statins [116–119] have been
associated with decreased incidence of dementia in the elderly.
Other risk factors

Treatment of other risk factors for subcortical VaD is also indicated; these
risk factors include smoking, hyperfibrinogenemia, orthostatic hypotension,
cardiac arrhythmias, congestive heart failure [32,33,120], and obstructive
sleep apnea [121]. Not infrequently, nocturnal hypertension (‘‘nondippers’’),
a risk factor for Binswanger-type VaD, frequently occurs in patients with
obstructive sleep apnea. Finally, control of hemorheologic factors that
increase blood viscosity becomes important in subjects with small vessel
disease and disturbances of the microcirculation. Blood glucose control

in patients with diabetes and lowering of fibrinogen and lipids should be
beneficial. In patients with hyperhomocystinemia, the use of oral folate is
recommended. Increased homocysteine levels may have a role in the patho-
genesis of CADASIL [122].
Drug treatments for vascular dementia

A large number of medications of purported efficacy for VaD have been
available for many years [123]. These drugs responded to prevailing notions
about pathogenesis, however, and have been found to be ineffective. For
instance, vasodilators (nicotinic acid, cyclandelate, papaverine, isoxsuprine,
cinnarizine, buflomedil, naftidrofuryl, and ergoloid mesylates among others)
were widely used to counteract ‘‘hardening of the arteries.’’ As pointed out
by Cochrane [124], their alleged efficacy was based on open-label trials that
lacked masking, controls, randomization, clear inclusion and exclusion cri-
teria, and appropriate outcome measures and endpoints. A comprehensive
review by Román [125] of pharmacologic agents for VaD is available else-
where. Here, only those agents with demonstrated efficacy in randomized
controlled clinical trials (class I evidence) are presented.
Calcium channel blockers

Nimodipine (Nimotop) and nicardipine have demonstrated moderate
efficacy in tests of attention and psychomotor performance in the subcorti-
cal (small vessel) form of VaD [126,127]. These agents have effects on auto-
regulation of cerebral blood flow and block L-type calcium receptors,
providing some degree of neuroprotection.
Neuroprotective (Nootropic) agents

Piracetam [128], oxiracetam [129], and nicergoline [130] seem to be safe
and modestly effective in the MID form of VaD as well as in elderly hyper-
tensive patients with leukoaraiosis [131]. Citicoline has been shown to have
positive short-term effects on memory and behavior in patients with VaD
[132,133]. Citicoline activates the biosynthesis of structural phospholipids
in the neuronal membranes, increases cerebral metabolism, and increases
noradrenaline and dopamine levels in the central nervous system [134].
Memantine
This agent is a potent noncompetitive antagonist of the N-methyl-D-
aspartate receptor with nootropic properties [135]. Memantine has been
shown to be well tolerated and useful in severe dementia [136]. A recently
completed pivotal 28-week trial of memantine in patients with mild to mod-
erate VaD enrolled 321 patients who received 2 · 10 mg/d or placebo. The
study demonstrated good tolerance and improvement in cognitive tests,
including the Alzheimer’s Disease Assessment Scale–Cognitive Subscale
(ADAS-Cog) and MMSE [137].
Pentoxifylline (Trental)
This is a xanthine derivative with hemorheologic and immunomodula-
tory properties [138]. The multicenter European Pentoxifylline Multi-infarct
Dementia Study demonstrated significant cognitive improvement in the
MID form of VaD in comparison with placebo [139]; these findings con-
firmed previous results [140]. Recently, Solerte et al [141] described hemor-
heologic alterations in patients with AD but not in age-matched controls or
in patients with VaD. Abnormalities included hyperviscosity, increased sedi-
mentation rate, hyperfibrinogenemia, and increased acute-phase reactants;
these changes were correlated with increased levels of tumor necrosis fac-
tor-a and interferon-c. Pentoxifylline treatment lowered fibrinogen and
tumor necrosis factor-a levels and corrected these abnormalities.
Antiplatelet agents
Aspirin [142], triflusal [143], and Ginkgo biloba [144] have been used in
patients with MID or with AD plus CVD with modest positive results. It
should be noted that the MMSE was the primary endpoint for cognitive
evaluation in most of these patients.
Cholinesterase inhibitors
The encouraging results obtained with the use of cholinergic agents in
VaD may give some clinicians the mistaken impression that VaD is really
AD or, at best, a mixed dementia [145]. It seems clear that (at least in the old-
est patients) both vascular and degenerative mechanisms contribute to AD
dementia [146]. This overlap occurs, however, only in one third of patients
diagnosed with VaD [147]. Sometimes, such as in the case of an anterior chor-
oidal artery occlusion, the patients fulfill the criteria for AD [148].
Cholinergic drugs are effective in VaD because these patients have choli-
nergic deficits related to ischemic involvement of basal forebrain neurons
(nucleus basalis of Meynert) or their projections. Wallin et al [149] found
pronounced disturbances of the serotoninergic and cholinergic systems in
subcortical and cortical gray matter at postmortem brain examination of
patients with VaD. These widespread neurotransmitter deficits probably
are not caused by localized brain infarcts per se. Likewise, Tohgi et al [150]
found acetylcholine concentrations in the cerebrospinal fluid of patients with
BD and MID to be significantly lower than in controls, whereas choline
concentrations were higher than in controls or AD patients. Recently, using
postmortem brain tissue materials, Martin-Ruiz et al [151] demonstrated the
relative integrity of nicotinic receptors in definite cases of VaD. Nicotinic
receptors control cerebral vasodilatation.
Of the available cholinergic agents approved for the treatment of AD,
donepezil hydrochloride (Aricept), rivastigmine tartrate (Exelon), and gal-
antamine hydrobromide (Reminyl) have been used in patients with VaD.
A large, 24-week, multicenter, randomized, placebo-controlled interna-
tional trial of donepezil in VaD has been completed recently [152]. The trial
randomized 1219 subjects with mild to moderate VaD selected according to

the NINDS-AIREN criteria. Patients were randomized to placebo (n ¼ 330),
to low-dose donepezil at 5 mg/d (n ¼ 329), or to high-dose donepezil at
10 mg/d (n ¼ 310). Compared with placebo, significant improvement was
noted on the ADAS-Cog and MMSE cognitive tests, with beneficial effects
on activities of daily living and global scores. Patients on the 5-mg/d dose tol-
erated the drug better than those on the high dose of 10 mg/d.
Rivastigmine tartrate was evaluated in patients with mild to moderately
severe AD with or without concurrent vascular risk factors [153]. Patients
were randomized to placebo (n ¼ 235), low-dose rivastigmine (1–4 mg/d,
n ¼ 233), or high-dose rivastigmine (6–12 mg/d, n ¼ 231) for 26 weeks. Sig-
nificant improvement was found on the ADAS-Cog and MMSE in patients
treated with high-dose rivastigmine compared with controls treated with
placebo. Rivastigmine has also been found to be effective and safe in a study
of 16 patients with subcortical VaD [154].
Galantamine is also being tested in a large, multicenter, controlled clin-
ical trial of patients with VaD identified by NINDS-AIREN criteria [155].
The results of the trial are awaited with interest.
Other agents
Atypical antipsychotic drugs, such as risperidone and olanzapine, have
been useful in the treatment of agitation and disruptive behaviors. The use
of cholinergic medications often controls these problems.
For some patients with depression and anxiety, the use of antidepres-
sants, such as the selective serotonin reuptake inhibitors citalopram or ser-
traline, may be required. The use of tricyclic antidepressants in the elderly
patient with VaD is discouraged because of anticholinergic effects and
orthostatic hypotension.
Summary
VaD is the second most common cause of dementia in the elderly after
AD. VaD is defined as the loss of cognitive function resulting from ischemic,
ischemic-hypoxic, or hemorrhagic brain lesions as a result of CVD and car-
diovascular pathologic changes. Diagnosis requires (1) cognitive loss (often
predominantly subcortical), (2) vascular brain lesions demonstrated by imag-
ing, and (3) exclusion of other causes of dementia, such as AD. VaD is
excluded by brain imaging showing no evidence of vascular lesions. VaD
may be caused by multiple strokes (MID or poststroke dementia) but also
by single strategic strokes, multiple lacunes, and hypoperfusive lesions such
as border zone infarcts and ischemic periventricular leukoencephalopathy
(Binswanger’s disease). Primary and secondary prevention of stroke and
cardiovascular disease decreases the burden of VaD. Genetic advice is
needed in patients with familial forms, such as CADASIL. Treatment
involves control of risk factors (ie, hypertension, diabetes, smoking, hyper-

fibrinogenemia, hyperhomocystinemia, orthostatic hypotension, cardiac
arrhythmias). Anticholinergic medications used for AD are also useful in
VaD, and atypical antipsychotic agents and antidepressants (eg, selective
serotonin reuptake inhibitors) may be required in some patients.
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Med Clin N Am 86 (2002) 501–518
Andrew Kertesz, MD, FRCPCa,*,
David G. Munoz, MD, FRCPCb,c
a
Department of Clinical Neurological Sciences, St. Joseph’s Hospital,
University of Western Ontario, 268 Grosvenor Street, London,
Ontario N6A 4V2, Canada
b
Department of Pathology and Clinical Neurological Sciences,
University of Western Ontario, London, Ontario, Canada
c
Banco de Tejidos para Investigacion Neurológica, Universidad Autonoma, Madrid, Spain
Frontotemporal dementia (FTD) is a new name for clinical Pick’s disease

(PiD). The eponymic PiD has been increasingly restricted to the pathologic
variant with Pick bodies. The clinical picture of frontal lobe dementia
(FLD) or, as later renamed, FTD, has been described with emphasis on the
personality and behavioral changes [1–3]. The Lund and Manchester
Groups [4] described the core symptoms as personality change, apathy,
blunting of emotions, lack of insight, and disinhibition. The pathologic pro-
file was characterized by gliosis, neuronal loss, and spongiform degeneration
in a superficial area of the frontal and temporal cortex [5]. Similar cases were
described as ‘‘dementia lacking distinctive histology’’ (DLDH) [6]. Less than
25% of the patients with this syndrome had Pick bodies [5]. Neuropsycholo-
gic testing showed poor performance on tests of mental flexibility and execu-
tive function. Nevertheless, most clinicians make the diagnosis on the basis
of the striking behavioral and personality changes, neuroimaging evidence
of often asymmetric frontal and temporal atrophy, or decreased activity
on isotope single photon emission CT [3,7].
At the same time, when dementia of the frontal lobe type was described
as a behavioral and personality disorder, cases of primary progressive apha-
sia (PPA) were distinguished as a unique entity [8]. Subsequently, it was
recognized that PPA is related to FTD, and it was also suggested that cor-
ticobasal degeneration (CBD) belongs to this group of various overlapping
clinical presentations and underlying pathologic findings called Pick com-
plex [9]. Later, a consensus meeting agreed that PPA and semantic dementia
E-mail address: [email protected] (A. Kertesz).
PII: S 0 0 2 5 - 7 1 2 5 ( 0 2 ) 0 0 0 1 1 - 1
502 A. Kertesz, D.G. Munoz / Med Clin N Am 86 (2002) 501–518
should be part of the frontotemporal lobar degenerations [2]. It was recog-

nized that FTD or Pick complex could have a number of pathologic sub-
strates, including PiD, CBD, and motor neuron type inclusions [10,11].
The recent discovery of autosomal dominant inherited chromosome 17–
linked FTD with parkinsonism (FTDP-17) and subsequent description of
tau mutations in several families with this linkage created considerable inter-
est [12,13]. The phenotypic and pathologic variations of these mutations
closely match sporadic disease and provide powerful evidence for the cohe-
sion of the complex. FTD is still underdiagnosed and underestimated, partly
because the individual components of the complex are considered separately
or considered ‘‘heterogeneous,’’ a favorite and sometimes misleading adjec-
tive in many descriptions. In this review, the considerable overlap is empha-
sized in addition to the distinctive features.
Pick’s disease
Arnold Pick [14] described behavioral and aphasic symptoms associated
with frontotemporal atrophy more than 100 years ago. Several of his subse-
quent articles dealt with progressive aphasia and progressive apraxia on the
basis of focal atrophy. Pick’s initial cases only had gross examination with-
out any microscopic data, but the clinical pattern and its relation to focal
atrophy are the basis of the syndrome. Gans [15] suggested the eponymic
term and considered a predilection for the phylogenetically younger frontal
and temporal lobes in the etiology. Subsequently, PiD was defined on the
basis of histology as initially described by Alzheimer [16]. Onari and Spatz
[17] re-examined the cases of Pick and cases from others emphasizing Pick
bodies and Pick cells (large ballooned neurons). Later, it became apparent
that cases of clinical PiD with frontal lobe and temporal lobe symptomatol-
ogy often do not show this typical histologic picture on autopsy [18–20].
Most series of PiD were based on postmortem examination, and the clinical
features were often incompletely described because of the retrospective na-
ture of these studies. A dichotomy of nosology arose, because some people
use the term Pick’s disease on the basis of histologic criteria, whereas others
describe the clinical picture of focal atrophies as Pick did originally. This
gave rise to the notion that PiD is difficult to diagnose in vivo.
Many of the clinical descriptions had dramatic frontal lobe deficits.
Schneider [21,22] described several stages of PiD: first, a ‘‘disturbance of
judgement and asocial behaviour,’’ followed by aphasia and, later, by more
generalized dementia. The temporal lobe variety of PiD presenting with pro-
gressive aphasia was described quite early [14,18,23–26], and these descrip-
tions are similar to those of PPA appearing later. Caron [27], in his review of
PiD, stated that the most common form is characterized by early develop-
ment of aphasia, and others also emphasized early speech disturbance or
aphasia in PiD [28–30].
A. Kertesz, D.G. Munoz / Med Clin N Am 86 (2002) 501–518 503
There have been several case descriptions of PiD in which the patients
had prominent extrapyramidal features [19,24,31,32]. Ferraro and Jervis
[33] stated that extrapyramidal symptoms were common in PiD. Sometimes,
unilateral rigidity and parkinsonism were the first symptoms to attract
attention. It was recognized that subcortical changes occur in PiD even
without extrapyramidal symptomatology [19]. Constantinidis et al [20]
described extrapyramidal involvement particularly in ‘‘group B’’ patients,
and Mann et al [34] described extrapyramidal involvement in 8 of 12 of FLD
patients. Changes in the basal ganglia, especially in the striatum and sub-
stantia nigra in addition to cortical pathologic changes, occurred in most
of 30 cases in one review [35]. Many of the subcortical varieties of PiD are
similar to corticonigral and CBD clinically and pathologically.
Munoz-Garcia and Ludwin [36] differentiated the ‘‘generalized’’ variety
of PiD from the cortical variety because of the subcortical extent of the
pathologic findings. The clinical description of these patients is quite similar
to the description of the cortical variety of PiD. None of these patients had
prominent extrapyramidal symptoms, but some had features of the Klüver-
Bucy syndrome [37]. The relatively early age of patients has been observed
by authors describing the subcortical or generalized varieties of PiD
[19,36,38]. PiD generally has a presenile onset below the age of 65 years
in contrast to the age at onset of most AD patients. In addition, familial
cases tend to have an even earlier onset.
It was recognized that the disease sometimes occurred in families [39].
More than half of autopsy-diagnosed cases of PiD were familial [40]. A large
family with PiD, where 25 of 51 examined members were affected [41] with a
mostly behavioral presentation, was subsequently found to have a genetic
linkage to chromosome 17 [42]. Several other families were described with
various tau mutations with classic PiD pathologic findings [43–46].
There were larger series of PiD described in the literature in the early 1950s
from Europe [47–50]. Frontotemporal atrophy was the most common form
of the disease (54%). Frontal atrophy only occurred in 25% of cases, and tem-
poral atrophy only occurred in 17% of cases. The brunt of the atrophy was
most often in the medial orbital, the inferior frontal gyri, and the anterior
third of the superior temporal gyrus. More than half of the cases showed
atrophy on the left side more than on the right side, and in 20% of the cases,
right frontal atrophy was more prominent than left frontal atrophy. Con-
stantinidis et al [20] classified PiD as (1) with Pick bodies, (2) only with
swollen neurons, and (3) only gliosis. They believed that ‘‘in spite of the dis-
similarities between these forms, considering the absence of sufficient knowl-
edge about pathogenesis, it seems prudent at present to maintain the
uniqueness of Pick’s entity’’ [20]. They thought the clinical differences
between these forms were not related to the nature of histologic alterations
but rather to the temporal lobe or frontal predominance of the abnormality.
With the development of neuroimaging, frontotemporal lobe atrophy
was demonstrated with increasing frequency in vivo, first, with air studies;
then, with CT scans in the 1970s; and more recently, with MRI and single
photon emission CT scans. The in vivo diagnosis of PiD continued to be
made sporadically on the basis of frontal and temporal symptomatology
supported by the focal atrophy on imaging and a normal electroencephalo-
gram [51]. Instead of shifting the diagnosis of PiD back to the clinic, how-
ever, the in vivo studies applied new labels, such as FLD, FTD, and PPA, to
clinical PiD, while reserving the diagnosis of PiD to increasingly restricted
histologic criteria.
The pathologic definition of PiD, as defined by pathologists, is character-
ized as round argyrophilic inclusions in the neuronal cytoplasm called Pick
bodies. They are best demonstrated with traditional silver stains, such as
Bodian or Bielchowsky stain, but do not stain with the Gallyas method
[11]. There is variable labeling with tau antibodies, ubiquitin, and chromo-
granin A. Electron microscopy has revealed bodies made up of 15-nm
straight fibrils [36,52] and long-period twisted fibrils [53]. Neocortical Pick
bodies are preferentially located in small neurons, and they are pathognomo-
nic in the dentate gyrus [53], whereas traditional silver stains and tau anti-
bodies identify scattered Pick bodies in the neocortex in CBD as well [54].
Large ballooned neurons (Pick cells), superficial cortical spongiosis neuro-
nal loss, and gliosis occur in the atrophied areas, and these features are com-
mon in CBD, DLDH, and other forms of the Pick complex. Complement
proteins and complement inhibitors are detected in the neuronal cytoplasm,
suggesting that complement activation is interrupted before reaching comple-
tion and causing neuronal lysis [55]. Additionally, Pick body–bearing neurons
(but not Pick cells) are surrounded by activated microglial cells and T lympho-
cytes [56].
Progressive subcortical gliosis [38,57] is clinically similar to PiD but, so
far, only remains a pathologic diagnosis. More than 30 cases have been
described in the literature, with the largest series being those of Verity and
Wechsler [58] and Bergeron et al [59]. Because white matter gliosis is com-
mon in other varieties of Pick complex pathologic entities, the separation
of this variation is hardly justified [11].
In the second half of the 1980s, two European groups described FLD as a
distinct entity and contrasted the clinical features with those of AD [1–3,5].
They estimated its relative incidence to be 15% to 20% of degenerative
dementias. Both groups recognized that even though some of the cases had
Pick bodies and most did not, the clinical syndrome was the same. They
called the pathologic entity without Pick bodies ‘‘frontal lobe dementia
type,’’ which consisted of neuronal loss and gliosis in the frontal cortex with
or without spongiform changes or ballooned neurons [5]. At the same time,
Knopman et al [6] described a similar clinicopathologic picture as DLDH.
The groups that described dementia of the frontal lobe type changed the
terminology to FTD [4]. The term frontotemporal degeneration or frontotem-
poral dementia [60] does not include the frequent subcortical involvement,
parietal pathologic findings, or extrapyramidal symptomatology. Further-
more, it does not distinguish between the clear-cut behavioral presentation
of FTD and aphasic presentation of PPA, which is one of the most valuable
contributions of the recent descriptions of the clinical picture in these con-
ditions. It does reflect, however, the frequent combination of frontal and
anterior temporal atrophy originally described by Pick.
The striking alterations in personality and behavior have become synon-
ymous with FTD. The hallmark of this distinctive form of dementia is the
combination of disinhibition with apathy, although at different stages of
the disease, one or the other symptom may be predominant. Disinhibition
often refers to social inappropriateness ranging from childish rude behavior
to exposure and kleptomania. It overlaps with impulsivity, poor judgment,
irresponsibility, and irritability. Other manifestations, such as restlessness,
pacing, wandering, and aggression, are also seen.
One of the characteristic groups of behaviors is characterized by persevera-
tion of words, gestures, and actions as well as obsessive stereotypic routines.
These patients are inflexible, insisting on eating, buying, or doing the same
thing at the same time; hoarding objects, clothes, or even garbage; perseverat-
ing with stories; and telephoning people inappropriately. Patients may be pre-
occupied with germs, pills, money, sex, types of clothing, or clock watching
while they carry out their stereotypic routines. If attempts are made to restrain
these behaviors, anger and violent resistance often occur. In more advanced
stages, echolalia, incessant clapping, singing, and laughing are observed.
Other disinhibition phenomena, such as hypersexuality, hyperorality, and
utilization behavior, are sometimes grouped under the term Klüver-Bucy
syndrome, which originated from the observation of monkeys with bilateral
temporal lobectomy [37]. The hypersexuality may be only verbal and gestural
in middle-aged or older individuals. Hyperorality often manifests in gluttony
and overeating, and many patients develop food fads, particularly for
sweets. Patients may consume large quantities of candy or cookies in one sit-
ting. We had patients who would eat in the same chicken restaurant day in
and out. Others insisted on a diet of milk and bananas or had plum sauce
with everything. Some patients grab food off the serving plate before any-
body else starts or even take food off the plates of others. The compulsive eat-
ing and drinking sometimes extends to inedible objects as in coprophagia.
Utilization behavior is the need to touch, feel, examine, or pick up objects
within reach and sight, similar to what others called ‘‘environmental depen-
dence’’ or ‘‘hypermetamorphosis’’ [61]. The final stages of disinhibition mani-
fest in urinary and stool incontinence, although this may occur early in FTD
patients who are still oriented.
There is a group of behaviors that can be characterized as ‘‘negative,’’
consisting of apathy, aspontaneity, indifference, and emotional flatness.
Patients are unable to recognize the extent of their own behavioral distur-
bance and most often insist there is nothing wrong. A striking disinterest
in family matters or in the plight of others is sometimes the presenting fea-
ture. More apparent extremes of indifference and apathy culminate in perso-
nal neglect, for example, not washing or changing underwear. Another
negative behavior is the lack of ability to plan complex activity or pay atten-
tion in a sustained manner so as to complete a task, which is often called the
‘‘dysexecutive syndrome.’’ Decreasing language and communication is also
part of this negative cluster of symptoms, which may eventually resemble
progressive aphasia resulting in mutism.
Lately, several anatomic correlations with the behavioral variants of
FTD have been attempted. Snowden et al [62] distinguished the ‘‘disinhib-
ited overactive’’ variety of FTD. These patients are impulsive and distracti-
ble. Their social and personal disinhibitions are embarrassing to families.
The pathologic changes tend to be in the orbital surface of the frontal lobes
and the temporal neocortex. The ‘‘apathetic inert subtype’’ may be seen at
presentation or subsequent to the disinhibited behavior. These patients have
pathologic changes in the dorsal lateral convexity as well as in the temporal
neocortex. The ‘‘stereotypic rigid subtype’’ of FTD is associated with perse-
verative and ritualistic behavior and tends to be associated with akinesia and
rigidity early in the disease. Pathologic changes are considered to involve the
basal ganglia and temporal neocortex, with relative sparing of the frontal
lobes. Others emphasize the ‘‘loss of self,’’ a serial criminal behavior, and
obsessive copying or coloring behavior with right temporal atrophy [63].
Progressive aphasia was also renamed the left temporal variety of FTD.
In our experience, these variants tend to overlap a great deal, and their
separation may not be clinically or pathologically feasible.
Patients may perform surprisingly well on neuropsychologic tests,
although impulsiveness, distractibility, and lack of cooperation tend to inter-
fere with testing rather early in the disease. Sometimes, only the results of
complex executive tests of shifting sets, such as the Wisconsin Card Sorting
Test, interference (the Stroop Test), or planning (the Tower of Hanoi), are
abnormal. There are patients, however, whose behavior is grossly abnormal,
yet they can perform well on the traditional frontal lobe tests. A behavioral
inventory, such as that designed in our clinic, seems to be more helpful in the
clinical diagnosis and even in the quantitation of severity of the illness [64].
Similar behavioral inventories for FTD have been used at other centers
[65,66]. The more general Neuropsychiatric Inventory has also been used
to differentiate AD from FTD but has less specific items for FTD [67].
The pathologic profile of FTD was originally described as a separate
entity, consisting of focal atrophy with superficial cortical spongiosis, glio-
sis, and neuronal loss, but this is generic to all the varieties of Pick complex
pathologic findings [11]. Several families with FTD have been described with
linkage to chromosome 17 [68]. The combination of phenotypes in these
families suggests that the various clinical manifestations in the much more
common sporadic illness are also related. Some of these families have tau-
positive pathologic findings and tau mutation, but tau-negative families with
motor neuron type inclusions are also described [69].
An association of FTD with motor neuron disease (MND) has been
increasingly recognized [70,71]. Ubiquitin-positive and tau-negative inclu-
sion bodies in the dentate gyrus and nonmotor cortex were described as a
marker of this MND type of FTD [72,73]. Strong et al [74] reviewed the neu-
ropsychologic deficit in amyotrophic lateral sclerosis, which tends to be the
frontal type. When MND supervenes, however, the rapid course precludes
development of full-blown FTD.
Primary progressive aphasia

PPA was described as a distinct clinical entity [8]. It is defined as progres-
sive language impairment without dementia for at least two years [75],
although it is recognized that other modalities are affected subsequently,
particularly behavioral changes suggesting frontal deficit. In the original
series, only one patient had a biopsy showing ‘‘nonspecific’’ pathologic
changes with lipofuscinosis. Many subsequent (and preceding) cases of PPA
were described with classic PiD [9,23,25,26,76], however. Other cases had
histologic findings characterized by gliosis, neuronal loss, layer II and III
spongiosis in the cortex [77] identical to that described in FLD, and sub-
cortical involvement with neuronal achromasia similar to that in CBD
[9,78]. Although much has been made of the heterogeneity of the underlying
pathologic changes, Mesulam and Weintraub [79] found that most cases have
a PiD or Pick variant pathologic profile. If one includes the cases with only
focal atrophy and superficial cortical spongiform degeneration or those with
motor neuron type inclusions in this group, the pathologic findings become
far less heterogenous. There are a few cases with underlying focal AD, but
the pathologic or clinical features may not be typical [80]. Mesulam [81] also
recently argued that the syndrome is connected to FTD clinically, pathologi-
cally, and genetically.
Several varieties of PPA have been described, with the more common
nonfluent variety leading to mutism (most of the published cases), the aphe-
mic variety with verbal apraxia and stuttering initially, and semantic aphasia
(dementia) in which speech output remains preserved, whereas the naming
and comprehension of objects seem to be lost [82]. The major distinction
is the early loss of comprehension in semantic dementia and the early loss
of fluency in primary nonfluent aphasia. It must be kept in mind that the
fluency-nonfluency distinction is relative and greatly depends on when the
patient is seen in the course of the illness. Progression of the illness results
in eventual mutism in all varieties, but even those patients who are mute
may have relatively well-preserved memory and visuospatial orientation and
may function surprisingly well in the community if they do not develop
the behavioral disturbance in contrast to aphasia in AD, which is usually

superimposed on memory and visuospatial loss. Sometimes, isolated pro-
gressive aphasia can be seen for a decade before other symptoms develop.
Semantic dementia or aphasia deserves to be described separately,
although the features overlap with primary progressive nonfluent aphasia
and FTD. These cases often begin with difficulty in naming and compre-
hending single nouns—in other words, losing the meaning of words; thus,
the term semantic dementia [82,83]. Similar cases were described as ‘‘loss
of semantic memory’’ [84]. Affected patients retain good articulation and
syntax, and their speech remains quite fluent, but they begin asking stereo-
typic questions, such as ‘‘What is a steak?’’ or ‘‘What is a vehicle?’’ At first,
this occurs for relatively low-frequency words, but common words seem to
be involved later on. The loss of comprehension and naming and the
retained fluency and repetition are distinct and could be classified as trans-
cortical sensory aphasia. Some cases have associated visual agnosia, indicat-
ing a multimodality loss of meaning for objects. Patients with semantic
dementia become nonfluent later in their illness, and they also develop
behavioral disturbances relatively frequently.
At times, extrapyramidal complications [9,85,86] and even MND super-
vene in PPA [87]. The variety associated with MND tends to be more rapidly
progressive [87]. FTD and CBD, in turn, frequently have a progressive lan-
guage disturbance. As a result, not only the pathologic findings but the symp-
tomatology of PPA overlaps among the entities belonging to the Pick complex.
Corticobasal degeneration
When Rebeiz et al [88] described corticodentatonigral degeneration, they
considered it to be a distinct entity characterized by an akinetic extrapyra-
midal syndrome, apraxia, ‘‘alien hand,’’ and vertical gaze palsy, but they
recognized the similarity of the pathologic findings to those of PiD (alien
hand refers to one hand interfering with the other among other phenomena).
The syndrome was ignored for 20 years and then resurrected using the term
corticobasal degeneration or corticobasal ganglionic degeneration [89,90].
Most of the literature concerning this condition acknowledges the clinical
and pathologic overlap between CBD and PiD [91–93].
In addition to the ballooned neurons (Pick cells) and superficial layer
(cortical spongiosis), CBD has certain distinctive features. The cortical neu-
ronal inclusions are positive by Gallyas stain, and the hippocampus is usual-
ly spared. Most of the pathologic changes are subcortical, and the inclusions
often have a ring or kidney shape and are less homogenous than in Pick
bodies; however, without the Gallyas stain, they may be difficult to distin-
guish. The abundance of tau-positive oligodendroglial inclusions and astro-
cytic plaques is characteristic.
CBD patients suffer from a dichotomy similar to that of PiD patients in
that the pathologic and clinical descriptions do not fully overlap. There are
some case reports describing patients who presented clinically with CBD as
defined by unilateral rigidity, apraxia, and alien hand syndrome but had the
pathologic findings of PiD with Pick bodies [31,94,95]. Other cases, patholo-
gically typical of CBD, have a frontal type of dementia without the present-
ing extrapyramidal features [91,96,97]. Typical CBD pathologic findings can
be seen with a clinical picture of PPA [9,78,98–100]. In a recent study, we
suggested that the clinical syndrome of prominent apraxia unilateral extra-
pyramidal syndrome with the alien hand phenomenon should be designated
as CBD syndrome, regardless of the pathologic findings. Further evidence of
the clinical and neuropathologic overlap between CBD, FTD, and PPA has
been accumulated. The evidence is overwhelming that CBD is also part of
the Pick complex [101].
There is also a significant overlap between CBD and progressive supra-
nuclear palsy (PSP) clinically and pathologically, suggesting that PSP may
be considered in the same biologic spectrum as CBD [102–105]. Typically,
unilateral presentation of extrapyramidal symptoms in combination with
apraxia leads to the diagnosis of CBD; axial dystonia, falls, and bilateral
rigidity are considered more typical of PSP [106]. Nevertheless, these dis-
tinctions are not mutually exclusive. The increasingly frequent recognition
of gaze palsy in CBD also contributes to the clinical similarities of these
entities.
The Pick complex

Because FTD is used to designate the behavioral abnormality of disinhi-
bition dementia in most instances and the use of PiD has been accepted by
many to designate a specific histopathologic profile with Pick bodies, we
suggested the term Pick complex to avoid the confusion that continues to
surround the term Pick’s disease [9]. Pick complex designates both the
pathologic and clinical overlap between the variations. It has an advantage
over FTD in that it avoids the restriction of pathologic and clinical sympto-
matology to the frontotemporal cortex and acknowledges the relation of
PiD. Pick complex is a unifying concept of the overlapping clinical syn-
dromes of FTD, PPA, and CBD with the underlying neuropathologic find-
ings, emphasizing the commonalities rather than differences between them.
An alternative is to use the lengthy and redundant term frontotemporal lobar
degeneration [62], but this term does not consider the extrapyramidal or sub-
cortical manifestations or CBD [107]. The third alternative is to return to the
term Pick’s disease; however, to date, this has been done with a degree of
equivocation [108].
Conditions combining several features of the Pick complex continue to
be published under different names, such as dementia with nonspecific patho-
logic findings, atypical presenile dementia or DLDH [6], hereditary dys-
phasic dementia [85], and disinhibition dementia–parkinsonism–amyotrophy
complex [109], with a variable amount of discussion and reference to the clin-
ical and pathologic overlap. Table 1 summarizes the terms used to describe
similar conditions.
If one considers all the cases of FTD, PPA with and without MND, and
CBD as part of the Pick complex, the entity becomes much less of a rarity.
According to some estimates, including all pathologic variants, the incidence
of FTD may be as high as 20% of degenerative dementias [2,40,110], and
PPA reports may represent another 10%, even considering the substantial
overlap with FTD. The percentage is higher if only presenile cases are con-
sidered [108]. This number would be further increased by the inclusion of
CBD cases. We have now examined over 150 patients with Pick complex
in our clinic compared with 600 patients with probable AD, and we fre-
quently continue to see suspected cases. Approximately half of these
patients have FTD (behavioral), half have PPA (language) presentation, and
a smaller number (7%) start with the movement disorder of CBD. The num-
bers match or surpass those of patients with vascular dementia. The ratio of
Pick complex to AD may turn out to be 1:4 or approximately 25% of degen-
erative dementias rather than the estimates of PiD based on autopsy mate-
rial using restrictive histologic criteria. Admittedly, epidemiologic studies
are lacking, and a selection bias is playing a role in centers with an interest
in the disease. Nevertheless, a revision of the mistaken belief that the disease
is rare and difficult to diagnose should result in increased recognition; hope-
fully, successful treatment will follow.
Table 1
Glossary of Pick complex
1. Circumscribed cerebral atrophy
2. Pick’s disease (PiD)
3. Lobar atrophy
4. Progressive subcortical gliosis (PSG)
5. Corticodentatonigral degeneration
6. Generalized Pick’s disease
7. Frontal lobe dementia (FLD)
8. Primary progressive aphasia (PPA)
9. Corticobasal degeneration (CBD)
10. Dementia lacking distinctive histology (DLDH)
11. Semantic dementia
12. Frontal lobe dementia with motor neuron disease
13. Frontotemporal dementia (FTD)
14. Primary progressive apraxia
15. Nonspecific familial dementia
16. Atypical presenile dementia
17. Spongiform encephalopathy of long duration
18. Hereditary Dysphasic Dementia
19. Pallido-Ponto-Nigral Degeneration
20. Disinhibition-Dementia-Parkinsonism-Amyotrophy
Neuropathologic findings
The underlying commonality of Pick complex neuropathologic findings is
the initially asymmetric focal atrophy of the frontotemporal regions. There
is also underlying neuronal loss, gliosis, and superficial linear spongiosis in
affected cortical areas. Ballooned neurons or Pick cells occur with variable
frequency in all varieties. They appear swollen pink on hematoxylin-eosin
staining, lack Nissl substance (neuronal achromasia) of the cytoplasm, and
express phosphorylated neurofilament episodes. There is tau reactivity in the
oligodendroglial cells and astrocytic processes. The superficial layer spon-
giosis is seen in layers II and III of the cortex in contrast to the spongiform
changes of Creutzfeldt-Jakob disease, which tend to be visible throughout.
Various distinctive features, such as Pick bodies, astrocytic plaques in CBD,
tufted astrocytes in PSP, and ubiquitin-positive and tau-negative inclusions
in MND type dementia, have been described, but they, in turn, can occur
with each of the other clinical varieties. Cases lacking any of these distinctive
features are often labeled ‘‘dementia lacking distinctive histology,’’ but we
have found ubiquitin-positive and tau-negative inclusions of the amyo-
trophic lateral sclerosis type in many of these cases previously considered
to represent DLDH [69]. There is substantial overlap between all varieties
of the Pick complex, although their distinctiveness is also argued [111]. As
mentioned previously, the clinical varieties do not predict the histologic vari-
ety, but they strongly predict the complex.
Biochemistry
Pathologic tau proteins (PTPs) are biochemical markers of various forms
of degenerative dementia, including AD, PiD, CBD, PSP, the parkinsonism-
dementia of Guam (Lytico-Bodig), and dementia pugilistica, which are col-
lectively called tauopathies. Tau mutations have been discovered only in
FTDP-17, however. Neurofibrillary tangles of AD contain all six human tau
isoforms. Abnormally phosphorylated PTPs form three bands on Western
blot studies with a molecular weight of 55, 64, and 69 kd using certain
immunologic probes in AD. Other monoclonal antibodies label other bands
indicating variously phosphorylated amino acids [112]. PiD has 64-kd and
55-kd doublets, and CBD and PSP have 69-kd and 64-kd doublets. The
amount of abnormal tau can be low in FTD, and PTP is sometimes absent.
At times, FTD has a tau triplet as in AD [112]. Sometimes, different band
compositions are obtained from different parts of the brain [113]. In some
studies, two bands were seen in brain stem neurons, and triplets were seen
in the hippocampal neurons of PSP.
Tau-negative ‘‘hereditary dysphasic disinhibition dementia’’ and some
sporadic cases of DLDH with prominent language and behavioral deficits
have been more recently attributed to the loss of tau in the brain, with the
same effect as the tauopathies with tau-positive pathologic findings [114].
Genetics
Wilhelmsen et al [12] discovered a linkage to chromosome 17 q21–22 in a
large family with variable symptomatology of FTD, aphasia, parkinsonism,
and amyotrophy [109]. A consensus conference summarized the clinical fea-
tures of 12 families and the pathologic characteristics resembling those of
the sporadic cases. Although each family was described under different ter-
minology (see Table 1), the term frontotemporal dementia with parkinsonism
linked to chromosome 17 was accepted [68]. The microtubular-associated
protein tau was suspected as the candidate gene for mutation. A few years
later, several tau mutations were discovered [13,115,116]. Normal tau pro-
teins contribute to axonal transport by binding to microtubular protein. Six
tau isoforms are created by the differential splicing of exon 10, making three
or four repeats of the microtubular binding domain of tau.
To date, more than 20 tau mutations in more than 50 families have
been identified [117]. The exon 10 splice mutations alter the ratio of four-
repeat to three-repeat tau isoforms, most often resulting in pathologic find-
ings resembling those of CBD or PSP. The phenotypes range from FTD, to
PiD, to CBD, with the same mutation often resulting in a different clinical
presentation [43]. The missense mutations disrupt the interaction between
tau and microtubules, and unbound tau becomes abnormally phosphory-
lated and polymerized into filaments and inclusions. Mutations in exons
9, 12, and 13 lead to accumulation of all six isoforms of tau, resulting in
Alzheimer-type tangles, or to a predominance of three-repeat tau and Pick
body dementia. Although different tau mutations differentially alter bio-
chemical properties of tau isoforms [118], these mutations do not predict the
clinical presentations, but they do predict the overall clinical morphologic
picture resembling sporadic FTD or Pick complex.
Tau polymorphisms from the two main haplotypes of tau were also asso-
ciated with various phenotypes. The AO allele is overrepresented in both
PSP and CBD [119]. The allele is more common in AD with an interaction
with apolipoprotein E4; a similar interaction was found in FTD, but the
association of apolipoprotein E4 with FTD is controversial [120].
Treatment
There is evidence that cholinergic receptor binding is decreased in PiD in
affected cortical regions [121–123]. Serotonin and Imipramine binding were
decreased in the hypothalamus and frontal and temporal lobes associated
with PID [124]. The decreased serotonin binding could correlate with the
overeating and weight gain observed in some patients with PiD/FTD/Pick
complex. Other behavioral impairments, such as depression, irritability, and
apathy, with relative preservation of memory are also compatible with sero-
toninergic dysfunction [125]. Selective serotonin reuptake inhibitors and
Trazodone have been tried in an off-label application in FTD patients and

did result in improvement of some of the symptoms [126].
We have tried Lithium, Selegiline, Donepezil, and Cerebrolysin for pos-
sible disease-modifying properties in a few patients without observable effect.
Lithium has been shown to dephosphorylate tau in vitro, but the few patients
we have tried to treat tolerated it poorly. Trazodone may help agitation and
compulsive behavior, and antipsychotics may have to be used for aggressive
behavior when behavioral modification fails. Patients may become aggres-
sive when their disinhibited, stereotypic, perseverative behavior is opposed
by caregivers or if they are restrained in any manner. Distracting patients
and providing them with alternative routines to socially unacceptable behav-
ior seems to work better than verbal attempts to dissuade them. The disease
is often misdiagnosed and treated with excessive sedation, however.
Acknowledgment
The authors thank Bonita Stevenson for secretarial assistance.
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Med Clin N Am 86 (2002) 519–535
Dementia with Lewy bodies

James B. Leverenz, MDa,b,c,*,
Ian G. McKeith, MD, FRCPsychd
a
Department of Veterans Affairs, Northwest Network Mental
Illness and Parkinson’s Disease Research, Education and Clinical Centers,
116MIRECC, 1660 S. Columbian Way, Seattle, WA 98108, USA
b
Department of Neurology, University of Washington,
1959 NE Pacific Street, Box 356465, Seattle, WA 98195, USA
c
Department of Psychiatry and Behavioral Sciences, University of Washington,
1959 NE Pacific Street, Box 356560, Seattle, WA 98195, USA
d
Department of Old Age Psychiatry, Institute for the Ageing and Health,
Wolfson Research Centre, Newcastle General Hospital,
Westgate Road, Newcastle upon Tyne, NE4 6BE, UK
Historical perspective
Parkinson’s disease
James Parkinson’s classic monograph of 1817 is generally considered the
first full description of the clinical disorder now bearing his name, Parkin-
son’s disease (PD) [1]. Physicians prior to Parkinson had described various
patients with components of the syndrome, such as tremor and gait distur-
bance, but his description was significant in bringing together the major
motor manifestations of this disease. Interestingly, his initial description
of PD specifically notes ‘‘…the senses and intellects being uninjured.’’ This
failure to recognize any intellectual impairment may have been, in part,
caused by the fact that three of his six cases were ‘‘…noticed casually in the
street’’ or were ‘‘…only seen at a distance.’’
The French physicians Trousseau and Charcot appear to have been the
first to recognize the cognitive impact of PD. Trousseau noted, in his Lec-
tures on Clinical Medicine, that ‘‘The intellect is at first unaffected, but gets
* Corresponding author. Department of Veterans Affairs, Northwest Network Mental

Illness and Parkinson’s Disease Research, Education and Clinical Centers, 116MIRECC, 1660
S. Columbian Way, Seattle, WA 98108, USA.
E-mail address: [email protected] (J. Leverenz).
This work was supported by NIA U01AG06781, RO1-AG10845, Department of Veterans
Affairs (JBL), and University of Newcastle upon Tyne, and NNNT Mental Health NHS Trust
(IGM).
PII: S 0 0 2 5 - 7 1 2 5 ( 0 2 ) 0 0 0 1 2 - 3
520 J.B. Leverenz, I.G. McKeith / Med Clin N Am 86 (2002) 519–535
weakened at last; the patient loses his memory …precocious caducity set in’’
[2]. Charcot also recognized that in the later stages of disease ‘‘…the mind
becomes clouded and memory is lost’’ [3,4]. The English physician Sir
Edward Gowers later noted that there could be ‘‘mental weakness’’ and ‘‘loss
of memory’’ [5]. In addition, he reported a tendency to ‘‘delusions,’’ perhaps
the first description of the now well-recognized propensity for psychotic
symptoms in patients with PD and dementia with Lewy bodies (DLB).
Lewy bodies (LB) are the characteristic pathology associated with idio-
pathic PD. Friederich H. Lewy first described these intracytoplasmic inclu-
sions in the basal forebrain (substantia innominata) [6]. He did not describe,
however, any LB pathology in other regions such as the substantia nigra or
cortex. Tretiakoff appears to have been the first to describe LB in the substan-
tia nigra [7]. Subsequent reports by Foix, Hassler, Klaue, and Greenfield and
Bosanquet fully characterized the substantia nigra lesions in the brains of PD
patients, including neuronal loss, gliosis, and LB inclusions [8–11].
LB in the substantia nigra and other brainstem nuclei, such as the locus
coeruleus, have a characteristic spherical appearance with an eosinophilic
core and clear halo on standard hematoxylin and eosin staining (Fig. 1a).
In extra-brainstem regions, such as the cortex, LB are often elliptical or ir-
regularly shaped and are without a halo. This appearance of extra-brainstem
LB makes them difficult to identify using standard pathological stains, such
Fig. 1. Lewy body inclusion (arrow) in a pigmented neuron of the substantia nigra (a,
hematoxylin and eosin). Immunohistochemical staining of multiple Lewy body inclusions
(arrows) in substantia nigra neurons using antibodies to ubiquitin (b) and alpha-synuclein (c).
Lewy neurites detected by antibody to alpha-synuclein (c, small arrows). Lewy body inclusions
detected using alpha-synuclein antibodies in CA-3 neurons of the hippocampus (d, arrows).
J.B. Leverenz, I.G. McKeith / Med Clin N Am 86 (2002) 519–535 521
as hematoxylin and eosin. Many neuropathologists now use antibodies

to protein components of LB, such as ubiquitin or alpha-synuclein, to de-
tect extra-brainstem LB (Fig. 1d) [12,13]. Research utilizing biochemical
analysis and highly specific antibodies have found a number of potential
protein constituents of LB [14–17]. Antibodies raised against neurofila-
ments, ubiquitin, and alpha-synuclein have been found to label inclusions
and other LB-associated pathologies, such as neurites (Fig. 1b, c, and d),
throughout the nervous system. The discovery of alpha-synuclein mutations
in familial Parkinson’s disease and the finding of distinct alpha-synuclein
pathology in diseases such as multiple system atrophy and DLB has sug-
gested to many investigators that these comprise a group of disorders char-
acterized by synuclein abnormalities, and they have been classified as
‘‘synucleinopathies’’ [18].

As previously noted, nineteenth-century French and English physicians
recognized that late-stage PD patients often developed neuropsychiatric
symptoms. Subsequent reports by Lewy in 1923, Hassler in 1938, and Wood-
ard in 1962 also noted dementia or psychiatric disorders associated with
LB pathology [10,19,20]. In fact, Woodard labeled cases with LB and psy-
chiatric disease as having ‘‘Lewy body disease’’. The Japanese in the 1960s
were the first to recognize that some patients who present with a dementia
syndrome have a predominant LB pathology at autopsy [21,22]. Because
of the diffuse distribution of LB pathology in these cases, both in brainstem
and cortical regions, the cases were diagnosed with ‘‘Diffuse Lewy body dis-
ease’’. These cases often had only modest, and occasionally no, AD pathol-
ogy (senile plaques and neurofibrillary tangles) to account for the dementia.
Clinical parkinsonism was also variably present.
In the 1970s, several groups reported significant numbers of clinically
diagnosed AD cases as having clinical parkinsonism. Subsequent neuro-
pathological reports confirmed a seemingly high frequency of LB pathology
in cases of AD [23,24]. Because most of these cases had concomitant AD
pathology, these cases were frequently interpreted as being patients with a
variant of AD, the ‘‘Lewy body variant’’ [25]. Others found, however, that
these cases with AD and LB pathology generally had less severe AD pathol-
ogy than that observed with AD alone [26]. In addition, the report of ‘‘Lewy
neurites’’ in the CA2 region of the hippocampus of only LB-containing
dementia cases suggested that these cases with combined pathology were pa-
thologically different and therefore a pathophysiologically unique and sepa-
rate disorder from Alzheimer’s disease, ‘‘Diffuse Lewy body disease’’ [27].
Although it was suggested that the difference in the diagnostic labeling of
these cases with combined AD and LB pathology was semantic [28], the cor-
rect classification of cases has important implications for research on the
fundamental pathogenesis of the disorders characterized by LB pathology.
In 1995, the First International Workshop of the Consortium on Demen-

tia with Lewy Bodies met in the United Kingdom. The results of this
conference were published in 1996 by McKeith et al, who outlined the con-
sensus guidelines for the clinical and pathological diagnosis of DLB [13].
Pathologically, DLB required only the presence of LB pathology with a his-
tory of dementia. Some of these cases would also fulfill pathological criteria
for AD and thus would have that additional classification. Because of the
unclear pathophysiological relationship between DLB and AD, the consen-
sus group was unable to come to an agreement on a single disease classifica-
tion of cases with both LB and AD pathology. The clinical criteria for DLB
will be reviewed in the next section.
It is an ongoing research objective to more fully understand the patho-
physiology of DLB and thus improve the appropriate diagnostic classifica-
tion scheme. Despite the lack of diagnositic clarity inherent in any disease
process that is not yet fully understood, it is clear that the pathology and
clinical symptoms of DLB comprise a large proportion of dementia cases,
second perhaps only to AD [13]. Thus, DLB is an important focus for both
research and clinical care.
Clinical diagnosis of DLB

Clinical-pathological studies have revealed a complex set of clinical signs
and symptoms in DLB. We will outline the cognitive, behavioral, and motor
signs and symptoms observed in pathologically confirmed cases of DLB
patients and will then review the current consensus criteria used by many
researchers to make a clinical diagnosis of DLB.
Cognitive
The primary clinical feature of DLB is progressive loss of cognitive func-
tion and associated decline of social or occupational function [13]. This pro-
gression generally occurs over years, although it may proceed more rapidly
than typically observed in AD. The cognitive profile of patients with DLB,
however, can be very similar to AD and in fact accounts for the frequent
misdiagnosis of DLB patients as having AD [29]. Similar to AD, memory
impairment can involve loss of ability to encode new memories (short-term
or recent memory), although this type of memory impairment is generally
less severe than that observed in AD patients [30,31]. Loss of the ability
to retrieve already encoded information (long-term memory) may be more
severe in DLB than AD [30]. DLB patients will also generally have more
severe visuospatial dysfunction than observed in AD patients [30,31]. Clini-
cally, this can manifest as the loss of the ability to navigate in well-known
locations (eg, getting lost in one’s own neighborhood) or on examination
by the inability to perform tasks such as clock drawing or copying figures.
Similar to patients with Parkinson’s disease, patients with DLB can also
have significant problems with frontal lobe-associated cognitive skills such
as executive function. This latter problem might present clinically with loss
of ability to problem-solve or plan and successfully execute a task. On neu-
ropsychological testing, this may appear as a decline in the ability to per-
form tests such as the Wisconsin Card Sorting and Trail Making Tests
[30,31]. Although there is some overlap with the cognitive impairments in
AD, this pattern of neuropsychological dysfunction should increase the clin-
ician’s suspicion of DLB. Thus, although the bedside neuropsychological
testing (eg, Mini-Mental State Exam, Short Blessed) is important, formal
neuropsychological testing can provide a more detailed profile of cognitive
deficits that may be helpful in differentiating DLB from other disorders such
as AD. Finally, it is important to recognize that these cognitive differences
may be most evident in the early stages of disease. Neuropsychological dis-
tinctions between DLB and other neurodegenerative dementias are less clear
as a patient moves into a more severe stage of disease and cognitive deficits
become much broader.
Besides specific neuropsychological deficits, patients with DLB can exhi-
bit marked fluctuation in attention and cognition with cognitive impairment
alternating from near-normal performance to severe confusion within peri-
ods ranging from minutes to days and weeks [13,32]. This is distinct from
normal variations in function observed in all patients with neurodegenera-
tive disorders in which the severity of the fluctuations are less severe and
more predicable. In addition to fluctuations in cognition, alterations in
levels of attention and vigilance are also seen. Patients with DLB can have
episodes of severely reduced levels of arousal and also may have histories of
increased somnolence. Recent work with computerized attention and vigi-
lance tasks in DLB patients have confirmed this increased frequency of fluc-
tuation in performance on some tasks on a second-by-second basis [33]. For
clinicians, it is worth noting that these fluctuations can be helpful diagnos-
tically and can also account for visit to visit variability in patient cognitive
and functional performance.
Behavioral
Behavioral and psychiatric disturbances in dementia are a significant
source of morbidity and increase the risk for institutionalization [34]. Psy-
chotic symptoms are more frequent, persistent, and tend to occur earlier
in DLB patients, when compared with patients with AD [35–37]. Recurrent
visual hallucinations (VH) are one of the hallmarks of DLB and are one of
three core symptoms in the consensus criteria for DLB (Table 1). VH are
characteristically well formed in DLB, with patients able to describe fine
details. Emotional responses can vary, ranging from indifference to signifi-
cant distress and agitation. Level of insight may be an important factor in
the emotional response. As will be discussed in the treatment section, the
Table 1
Consensus criteria for the clinical diagnosis of probable and possible DLB
1. The central feature required for a diagnosis of DLB is progressive cognitive decline of
sufficient magnitude to interfere with normal social or occupational function. Prominent or
persistent memory impairment may not necessarily occur in the early stages but is usually
evident with progression. Deficits on tests of attention and of frontal-subcortical skills and
visuospatial ability may be especially prominent.
2. Two of the following core features are essential for a diagnosis of probable DLB, and one is
essential for possible DLB:
a. Fluctuating cognition with pronounced variations in attention and alertness
b. Recurrent visual hallucinations that are typically well formed and detailed
c. Spontaneous motor features of parkinsonism
3. Features supportive of the diagnosis are:
a. Repeated falls
b. Syncope
c. Transient loss of consciousness
d. Neuroleptic sensitivity
e. Systematized delusions
f. Hallucinations in other modalities
4. A diagnosis of DLB is less likely in the presence of:
a. Stroke disease, evident as focal neurologic signs or on brain imaging
b. Evidence on physical examination and investigation of any physical illness or other brain
disorder sufficient to account for the clinical picture
From McKeith IG, et al: Consensus guidelines for the clinical and pathologic diagnosis of
dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop.
Neurology 1996; 47:1114.
emotional response can be used as a guide to help determine whether psy-

chotropic medications are required. Unlike VH in delirium, those in DLB
are recurrent and not associated with a systemic illness [37]. Other types
of hallucinations, such as auditory hallucinations, are less frequent and less
specific for DLB. Delusions are also less unique to DLB than VH. When
delusions occur, however, they are frequently complex and bizarre, in con-
trast with AD where delusions are less well formed or related to misidenti-
fication or memory impairment (eg, delusions of theft) [13].
Other behavioral symptoms are also common in DLB. A large cross-
sectional study of behavioral symptoms in DLB has revealed high frequency
of apathy, anxiety, and depression [38]. As with other dementias, these
symptoms are important as a source of morbidity and effects on caregiver
burden. It is not clear, however, that these latter behavioral symptoms are
sufficiently unique to DLB to warrant use in diagnosis.
Motor
The four major motor symptoms of PD (resting tremor, rigidity, brady-
kinesia, and postural instability) can be observed in DLB, but with lesser
frequency and with a distribution of symptoms that differs from typical
PD [39]. In particular, patients with DLB can be bradykinetic, rigid, and
have significant gait disturbance, whereas resting tremor is a compara-

tively uncommon motor symptom. The gait disturbance can include slow
shuffling steps, en bloc turns, and decreased arm swing, in addition to pos-
tural instability. Unlike PD, these motor symptoms may be less responsive
to dopaminergic agents [39]. The reasons for this discrepancy in patterns of
motor symptoms and response to treatment are unclear, although differ-
ences in the nigrostriatal dopaminergic systems in DLB and PD may be
important [40].
It is worth noting that PD symptoms are relatively common in the later
severe and terminal stages of several other dementias including AD and
fronto-temporal dementia. Thus, the timing of onset of motor symptoms
may be an important feature in helping to distinguish DLB from other de-
mentias. On the other hand, it has also been reported that some autopsy-
confirmed DLB patients never exhibited motor symptoms of PD [41]. Good
prospective studies of the parkinsonian symptoms in DLB and other degen-
erative disorders are needed to further our understanding of the timing of
these motor symptoms and their diagnostic utility.
Consensus criteria for the diagnosis of DLB

Currently, most investigators utilize the consensus guidelines provided by
the First International Conference on Dementia with Lewy Bodies for the
clinical diagnosis of DLB [13]. In these guidelines, the clinical diagnosis of
DLB is based on a set of required ‘‘core’’ symptoms and assisted by the pre-
sence of supportive signs and symptoms (Table 1). The first required feature
is the presence of dementia. Second, two of three core features are also
required for a diagnosis of probable DLB, and one of three for a diagnosis
of possible DLB. These core features include fluctuating cognition with pro-
nounced variations in attention and alertness, VH, and spontaneous motor
features of parkinsonism. Included in the consensus guidelines are a series of
supportive features, such as falls and neuroleptic sensitivity, whereas other
clinical features such as a focal neurological deficit or stroke make a diagno-
sis of DLB less likely. Supportive symptoms have not, as yet, been shown to
clearly improve on the diagnostic accuracy of DLB [13].
Multiple studies have examined the diagnostic accuracy of the published
clinical criteria for DLB [42–49]. Most of these studies have demonstrated
high specificity and positive predictive value of the criteria for the diagnosis
of DLB. Thus, when a case of dementia is clinically diagnosed with DLB,
there is a high likelihood (greater than 80%) that there will be LB pathology
at autopsy. In most retrospective studies, and one recent prospective study,
however, the consensus criteria were found to have a relatively low sensitiv-
ity (the clinical criteria correctly identifying pathologically confirmed DLB
cases) [42–45,48,49]. Two other prospective studies have found higher sensi-
tivity rates for the diagnostic criteria, though still lower than the specificity
rates [46,47]. These results would suggest that the consensus DLB criteria
are, in general, very good at correctly identifying patients who will have LB
pathology at autopsy (high positive predictive value). The lower sensitivity
values would suggest that DLB is under-diagnosed clinically. This lower sen-
sitivity is likely, in part, because of the inconsistent presence of clinical parkin-
sonism and is exacerbated by the criteria’s exclusion of patients who present
with parkinsonism more than 12 months before dementia (these patients are
currently classified as PD with dementia). Exclusion of these latter patients
lowers the ability of the presence of this core feature to identify patients with
dementia and LB pathology [13,50]. Additionally, reliable identification of
fluctuating confusion and cognition may also be a problem, as these symp-
toms are difficult to operationalize. More systematic approaches to identify-
ing fluctuating cognition may improve the clinical diagnosis of DLB.
At this point, additional prospective investigations into the clinical char-
acteristics of DLB should help improve our ability to accurately diagnosis
DLB. Ancillary studies including special imaging studies (eg, PET and
SPECT imaging) may be particularly helpful in the future. Several MRI stud-
ies have emphasized the relative preservation of medial temporal lobe
volume in DLB compared to AD [51,52], although there is no significant dif-
ference in the overall rate of brain atrophy in DLB compared with other
dementia syndromes [53]. Postmortem pathological assessment of temporal
lobe volume provides a clear correlate of this with in vivo imaging data [54].
PET and SPECT studies show consistent evidence of occipital hypometabo-
lism (reduced O2 uptake and reduced glucose utilization) compared with AD
[55,56]. The degeneration of the nigrostriatal dopaminergic projection in
DLB is demonstrable by FP-CIT SPET imaging of the pre-synaptic dopa-
mine uptake site [57,58]. This investigation has been proposed as a diagnos-
tic procedure to distinguish DLB from AD [59]. Whether other ancillary
studies such as spinal fluid testing will be helpful is less clear [60]. From a
clinician’s point of view, it is important to look prospectively for the core
and supportive signs and symptoms of DLB and to know that once a patient
fulfills these criteria, the patient is likely to have DLB pathologically.
Clinical management of DLB

Clinical management of DLB patients can be very challenging. In addi-
tion to their dementia, patients develop frequent behavioral disturbances
that are a source of significant morbidity for patients and are quite problem-
atic for their caregivers. Appropriate clinical management can lead to sub-
stantial improvement in the quality of life for both the patient and caregiver.
Dementia
A focus of treatment of dementia in AD has been the reversal of the well-
characterized loss of cholinergic activity in the brain. In the United States,
there are currently four medications (three of these in Great Britain) avail-
able to clinicians for treatment of the cholinergic deficit in mild to moderate
AD (see also Bonner and Peskind, in this issue) [97]. All are cholinesterase
inhibitors that increase availability of central nervous system acetylcholine
by blocking its metabolism by the cholinesterases. Tacrine was the first avail-
able cholinesterase inhibitor approved for use in AD in the United States in
1993. Since that time, three additional cholinesterase inhibitors (donepezil,
rivastigmine and galantamine) have become available with improved ease
of administration and more favorable side effects profiles than tacrine [61].
All of these ‘‘second generation’’ cholinesterase inhibitors have been shown,
in double-blind placebo-controlled studies, to have significant positive cog-
nitive and behavioral effects in AD (see Bonner and Peskind, Chapter 12).
Examination of the cholinergic system in DLB has also demonstrated a
significant reduction in activity that appears to be more severe than that
observed in AD [62]. These findings in DLB suggest that this group of
patients may also respond well to cholinesterase inhibitors [63]. Several
open-label trials have suggested that patients with DLB can tolerate choli-
nesterase inhibitors, with few reports of worsened parkinsonism, and can
have a positive clinical response [64–72]. In the first and, thus far, only
double-blind study of cholinesterase inhibitor treatment in DLB, McKeith
et al found a significant positive treatment effect of rivastigmine [73]. DLB
patients treated with rivastigmine had significantly better performance on
a computerized cognitive assessment system examining attention, working
memory, and episodic memory. Neuropsychological tests for executive func-
tion and planning also showed significant improvement with treatment. The
Neuropsychiatric Inventory (NPI), a systematic behavioral assessment scale,
was administered as a primary outcome measure and demonstrated signifi-
cant improvement with rivastigmine treatment on ratings of apathy, indiffer-
ence, anxiety, delusions, hallucinations, and aberrant motor behavior. Given
the significant morbidity associated with behavioral disturbance in dementia
and the high frequency of these symptoms in DLB, this latter finding has
particular importance in the treatment of patients with DLB. Further
evaluation of the cholinesterase inhibitors for patients with DLB and PD
with dementia will hopefully be available in the future.
Psychiatric features
Psychotic symptoms present a common and challenging clinical problem
in the treatment of DLB. As with other behavioral disturbances, psychotic
symptoms are associated with significant morbidity and early nursing home
placement. Double-blind placebo-controlled treatment trials of psychotic
symptoms in DLB are nonexistent (however, note rivastigmine trial in pre-
vious section [73]). Only case reports or small case series are available. There
does exist, however, a more extensive literature investigating treatment of
psychosis in PD, which suggests that the newer atypical antipsychotic agents
may be the most useful ones [74–77]. Unfortunately, studies in PD suggest

that even some atypical antipsychotic agents, such as risperidone and olan-
zepine, can have significant associated extrapyramidal and cognitive side
effects [74,78]. Treatment of psychotic DLB patients with atypical antipsy-
chotics can be successful but can also be associated with either significant
side effects, such as confusion or parkinsonism, or a lack of response. Based
primarily on the PD literature, clozapine may be the most effective atypical
antipsychotic medication available for patients with psychosis and parkin-
sonism, whereas quetiapine needs further study [76].
The results from the rivastigmine trial would suggest that treatment with
cholinesterase inhibitors might be an effective treatment for not only cogni-
tive but also behavioral disturbances in DLB [73]. The Lewy body ‘‘cluster’’
of symptoms from the NPI (delusions, hallucinations, apathy, and depres-
sion) was significantly improved with treatment. In contrast with most anti-
psychotics, rivastigmine was not associated in treatment with a significant
increase in extrapyramidal symptoms (except for the appearance of new trem-
or in 4 of 59 subjects). In addition, cognitive symptoms were improved with
treatment, rather than impaired, as can be observed with antipsychotic use.
Despite the encouraging findings in the rivastigmine study, the treatment
of psychosis in DLB remains problematic. Further blinded and controlled
studies of atypical antipsychotic medications and cholinesterase inhibitors
are needed to guide treatment strategies. As a final caveat, in some patients,
psychotic symptoms do not appear to be a significant stressor to the patient
or caregivers. In this latter circumstance, it generally wise to avoid medi-
cations that specifically target psychotic symptoms.
Motor symptoms
As with psychosis, treatment of parkinsonian motor features in DLB has
been incompletely studied. Motor symptoms in DLB patients are somewhat
unique, in that there tends to be less resting tremor than observed in PD,
while there are similar levels of rigidity, bradykinesia, and postural instabil-
ity [39]. In addition, the clinical response of motor symptoms to levodopa is
modest in DLB, in comparison with the almost universal response in PD
[39]. A randomized and blinded prospective study of levodopa, or other
antiparkinsonian agents, in DLB has not been performed and is clearly
needed. Unfortunately, given the unique motor profile of DLB patients, stud-
ies of treatments in PD are not necessarily applicable.
Research in DLB
Clinical
The focus of much of the clinical research in DLB has been on diagnostic
and clinical characterization. As elaborated in previous sections, the consensus
criteria for DLB have been successful in accurately identifying patients with
DLB pathology, but not as successful in identifying clinically subtle cases.
This latter problem has led to continued efforts to improve characterization
of the clinical symptoms of DLB patients and to identify biomarkers that
may help in improving diagnostic sensitivity of DLB clinical criteria.
Pathological
Pathological characterization of DLB using new histological techniques
has been a major focus of recent clinical-pathological studies [79–81]. The
clinical and pathophysiologic significance of the high frequency of alpha-
synuclein lesions in the amygdala of AD patients remains unclear. Further
evaluation of alpha-synuclein pathology and examination of other patholo-
gical markers are needed (See also Neurobiology below).
Neurobiological
Neurochemistry
Neurobiological investigations have focused on understanding the patho-
physiological basis of the unique clinical symptomatology of DLB. As
already mentioned, it has been established that DLB patients have substan-
tial loss of cholinergic function [62]. Recent evidence suggests that specific
alterations in cholinergic receptors also occur in DLB and that regionally
specific alterations in receptor density are associated with delusions and hal-
lucinations [82,83]. The well-established cholinergic disturbance in DLB and
the beneficial response to cholinesterase inhibitors are important findings
and clues to future directions of DLB research.
As would be expected, alterations in the substantia nigra-based dopami-
nergic system have been demonstrated in DLB, with reduction in dopamine
transporter sites and dopamine levels in the striatum [40,84,85]. There is
some evidence that dopaminergic changes in DLB differ from those ob-
served in PD and may account for the differential clinical response of DLB
patients to dopaminergic agents [40]. Of course, alterations in the dopamine
system have been implicated in psychotic disorders, and disruption of this
system in DLB may also be important in the development of hallucinations
and delusions.
In addition to the abnormalities of the dopaminergic and cholinergic sys-
tems in DLB, the locus coeruleus and its neurotransmitter norepinephrine
are also affected. Neuronal counts of the locus coeruleus in DLB show a
substantial loss of neurons [86]. Norepinephrine levels are also significantly
reduced in the striatum of DLB, and receptors for norepinephrine are
abnormally increased in locus coeruleus projection sites [85,86].
Neurotransmitter system alterations in dementia, and particularly in
DLB, are complex and incompletely understood. Understanding of the
alterations of these systems including potential compensatory mechanisms
will be important, however, in advancing the understanding of the patho-

physiology of clinical symptoms.
Biology of alpha-synuclein
The discovery of alpha-synuclein mutations in a subset of cases with famil-
ial PD and the presence of this protein in LB has led to an exploration of sy-
nuclein biology in both normal brain function and in disease. Alpha-synuclein
appears to play an important role in normal vesicular function in the pre-
synaptic terminals of neurons [87]. Mutation in the gene is associated with a
form of familial PD characterized by LB inclusions [88,89]. Interestingly, in
at least one of these families with an alpha-synuclein mutation, PD motor
symptoms are also associated with a dementing syndrome [90]. Further work
in PD and DLB has also suggested a more widespread dysfunction of all of
the synuclein proteins (alpha-, beta- and gamma-synuclein) [91]. There may,
in fact, be critical interactions between alpha- and beta-synucleins that influ-
ence the development of LB pathology [92]. Interactions between alpha-synu-
clein and other proteins implicated in the synucleinopathies, such as parkin
and synphilin, may also play a role in the development of LB pathology
[93]. Additional recent investigations have suggested an abnormal post-
translational modification of alpha-synuclein in synucleinopathies [94].
Transgenic mouse models are currently under development; these mice
have the mutated form of alpha-synuclein inserted into their genome and
have shown associated alpha-synuclein abnormalities in the brain [95]. It
is unclear at this time whether these animals will serve as useful models for
the clinical-pathologic components of DLB; however, they certainly should
provide important, more general, insights into the pathophysiology of the
synucleinopathies.
Genetics
Mutations in alpha-synuclein and parkin genes in familial PD would
appear to be important in helping understand the pathophysiology of PD
and its relationship to DLB. In these families with alpha-synuclein and par-
kin mutations, individuals have presented with PD symptoms and/or
dementia, suggesting that the same mutation can lead to a variety of clinical
phenotypes [90]. These findings also appear to blur the distinctions between
DLB and PD. The frequent presence of AD and LB pathology together in
familial AD would also suggest a possible pathophysiologic connection
between AD and DLB [80]. In contrast to PD and AD, only a few families
with familial DLB have been described [96]. In these families, dementia was
the predominant presenting symptom and LB pathology was confirmed at
autopsy. At this time, there is no mutation that has been associated with
DLB. Identification of additional cases of familial DLB and of mutations
could be critical to our understanding of the etiologic processes that lead
to the development of this disease.
Summary
DLB is a complex disorder with important associations with PD and AD.
As clinicians, it is important for us to identify these patients because of their
unique responses to medical interventions and to help patients and care-
givers more fully understand this disease process and its implications.
Further research is needed to improve our understanding of the pathophy-
siology of this important dementing disorder, with the ultimate goal of
improving clinical management of this disease.
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Med Clin N Am 86 (2002) 537–550
AIDS dementia
David B. Clifford, MD*
Department of Neurology, Washington University School of Medicine, Box 8111,
660 South Euclid Street, St. Louis, MO 63110, USA
Human immunodeficiency virus type 1 (HIV-1)–associated complications

were first reported in 1981, and the virus was identified in 1983 [1]. The sub-
sequent scientific battle that has been a major part of medicine in the past
20 years has expanded knowledge in many areas of medicine, including but
not limited to infectious diseases, oncology, immunology, nephrology, gas-
troenterology, ophthalmology, metabolism, and neurology. Worldwide, this
infection affects in excess of 36 million people, and its rapid growth in the
poorest parts of the world, notably in Africa and Asia, threatens profound
economic and political consequences while causing unthinkable human suf-
fering. A detailed understanding of the manifestations of the infection is
thus of considerable importance. This tragic epidemic also represents an
opportunity for mankind. As a model of the interaction between viral infec-
tions and hosts, it provides insights into human pathobiology that may
assist in the development of treatments for many other afflictions. Further,
the complicated ramifications of this infection in society seem to require that
broad societal improvements be included in the response to the infection.
Improvements in general health care and in the social and economic status
of the world’s peoples are required to control this epidemic.
The neurologic impact of HIV-1 has been recognized since quite early in
the development of the clinical description of HIV infection [2] and includes
opportunistic complications as well as those primarily associated with the
HIV infection itself. Clinical diagnosis of HIV-infected subjects must always
include careful exclusion of opportunistic complications. Cryptococcal
meningitis, toxoplasma encephalitis, cytomegalovirus (CMV) encephalitis
and radiculomyelitis, progressive multifocal leukoencephalopathy, neurosy-
philis, and primary central nervous system (CNS) lymphoma are the most
prominent of the serious secondary neurologic complications. Primary
HIV-associated conditions include peripheral neuropathy, myelopathy, and
* E-mail address: cliff[email protected] (D.B. Clifford).
PII: S 0 0 2 5 - 7 1 2 5 ( 0 2 ) 0 0 0 0 5 - 6
538 D.B. Clifford / Med Clin N Am 86 (2002) 537–550
encephalopathy. The latter is associated with clinical dementia that has been
called AIDS dementia complex (ADC) [3]. Other names for this condition
are HIV-associated cognitive motor complex and HIV-associated dementia.
A milder clinical presentation that may be a precursor of full-blown dementia
is minor cognitive motor disorder, which is recognized by a complaint of
neurologic dysfunction accompanied by changes in neuropsychologic test
performance. Systematic classification of these HIV-associated cognitive
processes is most widely performed using the American Academy of Neurol-
ogy criteria [4].
Human immunodeficiency virus

HIV-1 is an RNA virus that is spread by person-to-person tissue transfer,
most commonly during sexual intercourse, during blood transfusion, from
mother to child, in maternal milk, or on contaminated needles. Although the
epidemic in the United States began with a preponderant cohort of male
homosexuals, globally, the infection is spread predominantly through het-
erosexual contacts and by contaminated needles most commonly used in il-
licit intravenous drug abuse. In the United States, the spread of the virus has
gradually been decreasing in the initial male homosexual cohort and more
heavily affecting drug abusers and persons of both sexes. The social stigmas
of homosexual lifestyles and drug abuse have compounded the medical
problems associated with the disease. Behavior modification in the face of
drug abuse has been particularly challenging, and this sector of the epidemic
has been especially hard to stem.
HIV-1 has several important characteristics that have an impact on the
natural history of the infection. After introduction of the virus, most hosts
experience a viral illness, including fever, myalgia, headaches, and some-
times a rash. As the host immune response develops, serologic tests for HIV
become positive, and viral load in the serum declines to a variable degree.
The success of the host immune response governs the course of untreated
infection. Where hosts generate a good immune response, viral loads fall
to low levels, and clinical progression is absent or slow, leading to more than
a decade of asymptomatic infection in some ‘‘nonprogressors.’’ In others,
less complete control of the infection results in higher viral loads and more
rapid onset of clinical symptoms associated with increasing immunodefi-
ciency. The CD4 lymphocyte count declines over time in infected hosts and
is a useful indicator of the degree of immunosuppression. When this count
falls below 200 cells per cubic millimeter, a notable increase in opportunistic
infections is more commonly encountered, and clinical signs with weight
loss, diarrhea, fever, and thrush often develop. Characterization of the clin-
ical state and outlook has been refined by the development of routine mon-
itoring of CD4 counts and HIV RNA viral loads in the plasma. Effective
therapy generally results in significant increases in CD4 counts (rarely to
D.B. Clifford / Med Clin N Am 86 (2002) 537–550 539
normal levels, however) and decline of viral loads to levels that are not
detectable by current RNA assays.
A second important aspect of HIV is the rapid and persistent rate of viral
replication that typifies this infection [5]. The virus has a half-life of only a
few days in the plasma compartment, implying that the large amount of
virus correlates with a huge synthesis rate estimated at 109 to 1010 virions
per day. Replication requires a viral reverse transcriptase step in which viral
RNA is transcribed to DNA, which may then be inserted into the host
DNA. This step is a critical target for antiretroviral therapy. Also important
is a high mutation rate that allows rapid change in the genetics of the virus
even in the same individual over time. With the high mutation rate and high
turnover rate, it is possible for this virus to generate resistant versions in a
distressingly rapid and efficient manner. Presumably, this modulating char-
acteristic of the virus explains in part why the immune response alone is
unable to control the infection and why antiviral medications cannot eradi-
cate it.
Clinical characteristics of acquired immunodeficiency syndrome

dementia complex
The full manifestations of ADC are characteristic of a subcortical demen-
tia in which cognitive decline and motor slowing are the predominant char-
acteristics, colored by a variable degree of behavioral change. Cognitive
decline is subacute with a course of at least 6 months in most cases. Abrupt
changes in cognition are generally not attributable to HIV itself. In ques-
tioning subjects, one finds that there is often insight into the progressing
cognitive decline. Patients often discover that they have increased problems
with concentration interfering with their ability to perform tasks, enjoy
reading, and eventually concentrate on hobbies and avocations. Language
involvement is variable but generally not prominent. Patients often compen-
sate by writing reminders and making lists. Motor slowing is a virtually uni-
form feature of this process, to the extent that clinical trial testing can be
heavily weighted to timed motor tasks that reliably monitor the severity
of the disorder. Motor slowing affects patients’ ability to get around and
to accomplish tasks as well as their independence. It generally involves the
arms and legs. Symmetric involvement is typical of ADC, and any major
degree of lateralized asymmetry should arouse serious suspicion that addi-
tional opportunistic processes are involved. Behavioral changes are variable.
A depressed affect may be particularly pronounced in this setting, but the
performance deficits can generally be clearly separated from an affective dis-
order. Rarely, frank psychotic changes are observed, generally for relatively
brief intervals. Other neurologic manifestations that accompany ADC in-
clude some increase in the frequency of seizures and increased complaints of
headache.
Epidemiology
ADC is seen primarily in advanced HIV patients in whom immunodefi-
ciency has developed. Although it may be the presenting complaint leading
to the diagnosis of AIDS, this is rarely the case. Instead, it complicates the
disease course of subjects who often have multiple medical problems be-
cause of the broad impact of immunodeficiency. Before effective antiviral
therapy was developed, ADC developed in more than 60% of patients devel-
oping AIDS [3]. The introduction of zidovudine (ZDV) therapy and, subse-
quently, dual nucleoside therapy resulted in a decline in ADC to the range of
20% [6]. The more recent introduction of highly active antiretroviral therapy
(HAART) has further reduced the incidence to considerably less than 10%
of AIDS patients. In HAART-treated patients, ADC has declined less than
other complications, however, now representing a greater proportion of
AIDS-defining clinical events [7]. Further, it is notable that ADC is now
encountered more commonly in patients with a higher CD4 count. Dore
et al [7] report that the median CD4 count in subjects with ADC rose from
70 to 170 cells per cubic millimeter after the introduction of HAART. Addi-
tional factors that are associated with an increased risk of dementia include
anemia, constitutional symptoms, and wasting [8]. Advancing age has been
suspected as a risk but has not been clearly demonstrated as such. Similarly,
it has not been clear that exposure through intravenous drug use is asso-
ciated with a risk different from that of sexual exposure for the development
of ADC [9]. The impact of viral replication is clearly important; this is sup-
ported by the declining incidence of ADC with increasingly effective treat-
ment and by the observation that ADC patients have a higher HIV viral
load in the cerebrospinal fluid (CSF) than patients without ADC [10].
Pathologic characteristics and mechanisms

The pathologic characteristics of HIV infection in the brain often seem to
be less impressive than the functional impact would predict, but careful anal-
ysis of the brain reveals many pathologic changes [11–13]. The onset of neu-
rocognitive dysfunction in HIV is likely associated with modification of
synaptic architecture in the cortex [14,15]. In the hippocampus, a stereologic
study demonstrated cell atrophy without loss of cell numbers [16]. Cortical
atrophy develops as HIV infection progresses. In advanced stages, this is
grossly apparent and is obvious in loss of thickness of the cortical mantle
[17]. Quantitatively, neuronal cell loss has been demonstrated in frontal [18]
and temporal regions [19]. Not all neuronal types are equally likely to be killed
[17,20,21]. Apoptosis [22,23] is probably a common pathway for cell loss and
is somehow accelerated in the setting of HIV.
Because ADC has the appearance of a subcortical dementia, it is not sur-
prising that there is ample evidence of involvement in subcortical structures.
From the earliest descriptions of the brain in HIV, notable involvement of

the subcortical white matter has been described, with the presence of multi-
nucleated giant cells often loaded with the virus and change in the staining
characteristics of white matter being prominently described. The subcortical
gray matter also seems to be preferentially involved. Early positron emission
tomography scans demonstrated the earliest stages of ADC associated with
hypermetabolism in deep gray structures [24], and this is followed by loss of
volume that is notable in MR scans when basal ganglia atrophy develops in
association with ADC [25].
HIV is primarily replicated in monocytes and macrophages in the brain
[26]. In groups, the presence and severity of ADC correlates with the levels
of productive HIV replication within the brain [27]. In individual cases,
however, high viral load is sometimes found without dementia, and some
patients with dementia have low brain viral loads. In ADC, there is an asso-
ciation with multinucleated macrophages and leukoencephalopathy seen on
pathologic examination, but, again, these findings are not uniformly seen in
patients with ADC. Although astrocytes may be infected, they do not seem
to be a source of replicative infection. This does not mean that viral-induced
changes in astrocytic function, so critical to maintaining the brain environ-
ment, may not be an important aspect of the clinical syndrome. Neurons are
rarely, if ever, infected. It is thus implied that the changes in neuronal per-
formance that must underlie behavioral changes are indirect rather than
direct. Indirect mechanisms that may be responsible for this changed neuro-
nal behavior are probably myriad. Portions of the HIV virus have been pos-
tulated to have critical importance, with most evidence accruing to the
impact of the envelope glycoprotein, gp120 [28]. Recent evidence has linked
Tat with neurotoxicity by a number of mechanisms [29–31], including a
recent report linking it to the metabolic balance of low-density lipoprotein
receptor–related protein ligands as well as to direct activation of neuronal
genes [32]. Cytokines have also been implicated in the indirect mechanisms
resulting in neuronal dysfunction in ADC. When messenger RNA was
analyzed in brains of ADC patients, tumor necrosis factor-a message was
found to be most closely associated with the development of dementia [33].
b2-microglobulin [34,35], neopterin [36,37], and quinolinic acid [38] have
been demonstrated to be elevated in CSF in proportion to progressing
ADC when other causes of activation are excluded.
Although therapeutic drug activity within the CNS seems to be of critical
importance to understanding AIDS dementia treatment, it has been surpris-
ing that even with regimens that penetrate the CNS and CSF compartments
relatively poorly, the protective CNS benefits for HIV therapy remain. The
hypothesis that the development of dementia may be initiated outside the
brain would be consistent with this observation. Pulliam et al [39] reported
significant elevations of peripheral CD14/CD16 and CD14/CD69 mono-
cytes associated with the development of AIDS dementia. Gartner [40] has
proposed the hypothesis that peripheral events may be primary in triggering
AIDS dementia. It could be that bone marrow populations are activated in

late-stage disease, leading to the development of monocyte subsets asso-
ciated with ADC. The activated cells probably transmigrate into the brain,
readily setting up the physiologic changes leading to dementia. If this were
true, peripheral control of the disease should protect subjects from demen-
tia. The alternative scenario that remains of great concern to investigators is
that the CNS represents a distinct compartment in which HIV infection can
develop less impeded by drug treatments and that it becomes the nidus of
treatment failure, manifesting neurologic complications particularly in late
disease. Longitudinal data to assess the peripheral and CSF compartments
(and the brain after death) are critical to a more certain understanding of
the dynamic interaction between peripheral and central viral infection in the
genesis of neurologic disease.
Diagnosis and monitoring

Diagnosis of ADC is made by recognition of a compatible clinical picture
in the setting of HIV infection and exclusion of alternative causes for these
clinical changes. Research criteria have been articulated in the report of the
American Academy of Neurology AIDS Task Force [4]. Ideally, an infor-
mant should assist in corroborating the change in cognitive and motor func-
tions typifying ADC, whereas neuropsychologic testing may be used to
quantify performance measures. Most HIV neurology studies have used
widely available neuropsychologic tests, including representative measures
of attention/working memory, speed of information processing, learning,
and motor skills.
Ancillary measures that are essential include brain imaging studies and
CSF evaluation. Brain imaging is not diagnostic, but it is a critical means
of helping to rule out alternative diagnoses. MR brain scanning detects
more lesions than CT, with its greater sensitivity for pathologic changes,
particularly in the white matter. Recent reports suggest that focusing on
white matter by the use of diffusion tensor imaging might further enhance
the ability of MR to detect the subtle white matter changes caused by HIV
[41]. MR scanning is optimal for screening for other diagnoses, although CT
scanning allows reliable exclusion of most mass lesions, including toxo-
plasma encephalitis and lymphoma. CNS complications such as toxoplasma
encephalitis, progressive multifocal leukoencephalopathy, and primary CNS
lymphoma have notable abnormalities on MRI that should turn the clini-
cian’s attention to these alternative causes of neurologic abnormality.
Absence of massive space-occupying CNS lesions also augments the safety
of performing lumbar puncture. CSF evaluation is important. Cryptococcal
meningitis may mimic ADC and is best excluded when cryptococcal antigen
is absent from the CSF. CMV encephalitis is one of the most serious consid-
erations in the differential diagnosis, and it can be excluded by absence of
CMV DNA on polymerase chain reaction testing of CSF [42]. Neurosyphilis

should also be considered when sexually transmitted disease–related demen-
tia is being considered. CSF testing for syphilis is important in excluding this
consideration.
CSF cannot confirm the diagnosis of ADC, because findings are nonspe-
cific. Typically, a few mononuclear cells are found (as they are throughout
HIV infection), and CSF protein may be slightly elevated, although glucose
is generally in the normal range. Oligoclonal bands may be found in the CSF
in the setting of HIV infection but are not limited to ADC patients. In
advanced disease, elevations of neopterin and b2-microglobulin correlating
with increasing dementia have been reported [37]. HIV viral loads have been
studied in the CSF. Overall, ADC subjects have higher viral loads than unde-
mented controls [10,43], but elevated viral loads are not necessarily asso-
ciated with dementia, and dementia is sometimes seen in the absence of
elevated viral loads. Correlates of ADC in the CSF include b2-microglobulin
[34,35], neopterin [36,37], and quinolinic acid [38]. Elevated levels of soluble
Fas and Fas ligand in the CSF [44] were recently described. These elevated
levels associated with ADC declined with successful treatment and decreas-
ing viral loads. Fas is involved in the execution of apoptotic programs and
thus may be a rationale link to neuronal loss causing neurologic impairment.
One of the promising means of tracking HIV brain involvement uses MR
spectroscopy [45–47]. This MR-based technique allows noninvasive mea-
surement of several brain metabolites reflecting neurons and glia. Advancing
ADC has been accompanied by declining N-acetylaspartate and early eleva-
tions in choline reflecting neuronal loss and gliosis, respectively [48]. Recent
studies with perfusion MR scanning also suggest that MR techniques allow
monitoring of cerebral blood flow, which seems to diminish as ADC pro-
gresses [49].
Therapy
HIV therapy has evolved rapidly over the past decade, propelled by the
urgent need to address this devastating viral disease. Improvements in gen-
eral therapy for HIV have led to marked improvements in life expectancy
and quality of life and have been accompanied by improvements in the
neurologic complications. The unique aspects of the brain and CSF com-
partment, which involve barriers to drug penetration and a different immu-
nologic milieu, make it critical to maintain additional vigilance for
incongruity of response in these compartments compared with plasma,
where most observations informing drug development occur. Further,
inability to completely clear this viral infection and the potential of indirect
mechanisms to cause complications even when the replicative viral infection
is largely controlled make it critical to continue to study the evolution of
ADC in the HAART era.
HIV therapy is rapidly evolving. Some of the drugs required have com-
plicated and important drug interactions. It is thus best for HIV patients
to be managed by clinicians with extensive practice in this area. HIV specia-
lists have the incentive and opportunity to stay abreast of current therapeu-
tic knowledge. Without this investment, care is often suboptimal, leading to
inferior clinical outcomes.
The best point after infection for initiation of therapy remains uncertain.
This therapeutic decision must balance the rational desire to treat infections
early when involvement may be minimal and complications have not
occurred with the recognition that current therapy has substantial long-term
toxicities, is expensive, and inevitably results in evolution of resistant virus
over long periods of use. The current trend in academic centers is moving
toward delayed initiation of drug therapy because of these concerns. Current
recommendations suggest initiation of therapy in acute infection or sympto-
matic infection. For asymptomatic subjects, therapy should be offered when
viral loads are high (>55,000 copies per milliliter) or the CD4 count has fallen
to levels less than 350 cells per cubic millimeter. Evolving recommendations
may be studied as they are developed by a panel of experts working with the
International AIDS Society—USA (http://www.hivatis.org).
Once therapy is undertaken, the goal is to achieve maximal viral suppres-
sion with minimal toxicity. Most subjects should reach undetectable levels of
HIV virus in the plasma with currently available HAART therapy. Ongoing
research probes the ability of resistance testing to improve drug selection by
genotypic or phenotypic techniques, the role of therapeutic drug monitoring
in dose selection, and tools to enhance compliance, which is absolutely
essential to therapeutic success.
Currently, three classes of antiretroviral medications are approved, with
15 approved drugs available as follows:
Nucleoside reverse transcriptase inhibitors (NRTIs)
• Abacavir (Ziagen)
• Didanosine (Videx)
• Lamivudine (Epivir, Combivir)
• Stavudine (Zerit)
• Zalcitabine (Hivid)
• Zidovudine (Retrovir, Combivir)
Nonnucleoside reverse transcriptase inhibitors (NNRTIs)
• Delavirdine (Rescriptor)
• Efavirenz (Sustiva)
• Nevirapine (Viramune)
Protease inhibitors (PIs)
• Amprenavir (Agenerase)
• Indinavir (Crixivan)
• Lopinavir / ritonavir (Kaletra)

• Nelfinavir (Viracept)
• Saquinavir (Fortovase)
• Ritonavir (Norvir)
The first class of drugs developed was the NRTI class, which includes
ZDV (also known as AZT), didanosine (ddI), zalcitabine (ddC), lamivudine,
stavudine (d4T), and abacavir (ABC). These drugs are important compo-
nents of most standard treatment combinations, and exploration of a triple-
nucleoside HAART regimen also seems to be acceptable [50]. Because resis-
tance tends to develop within classes of drugs, delaying exposure to other
classes of drugs has a significant theoretical benefit. Major toxicity of NRTI
drugs includes bone marrow toxicity (ZDV), pancreatitis (d4T, ddC, ddI),
rashes (most serious hypersensitivity reaction with ABC), distal sensory per-
ipheral neuropathy (ddI, d4T, ddC), and lactic acidosis. Other less common
neurologic toxicities include myopathy (ZDV) and headache (especially
ZDV).
The second class of drugs developed was the NNRTI class. These drugs
specifically block the active site of HIV-1 reverse transcriptase. These are
potent compounds that are highly specific for HIV-1 alone. They are drugs
useful only in combinations, because resistance develops quite rapidly in
monotherapy. They are extremely important components of HAART, how-
ever. The chief toxicities of this class are hypersensitivity reactions with
rashes, and hepatic toxicity. Approved drugs in this class include nevirapine,
delavirdine, and efavirenz. Neurologic toxicity has been the most common
issue with efavirenz, with more than half of subjects reporting a detectable
change in sleep, dreaming, attention, or alertness [51]. Fortunately, this is
mild in most cases and tolerated well enough to allow continuation of the
therapy. Symptoms tend to recede over the initial weeks of therapy.
The third class of antiretroviral agents is the PI class. These drugs, includ-
ing saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, and lopinavir,
revolutionized HIV therapy when they were introduced. Their marked effi-
cacy when combined with NRTI drugs vastly increased the ability to achieve
prolonged viral inhibition, resulting in fewer opportunistic complications,
longer life, and improved quality of life. The combination therapies origi-
nally including PIs were referred to as HAART. As potent NNRTI and
NRTI drugs have been introduced, the concept of HAART has been broad-
ened to include the numerous triple or more drug-containing regimens that
typically can achieve undetectable HIV RNA viral loads.
Improvements in the overall health of HIV patients associated with
HAART are not without a price in toxicity. Long-term complications asso-
ciated with these drugs in conjunction with the other antiretroviral agents
are a growing source of concern. Gastrointestinal toxicity with nausea,
diarrhea, and hepatic toxicity has been seen with drug regimens that contain
PI drugs. Metabolic complications, including insulin resistance and the
development of diabetes, elevated cholesterol, and elevated triglycerides as

well as osteopenia and lipodystrophies, are active areas of research asso-
ciated with the use of HAART. Some of these complications may combine
to accelerate atherosclerosis with the risk of premature cardiovascular and
cerebrovascular disease.
Because ADC seems to be triggered by HIV replication in the CNS, selec-
tion of optimal antiretroviral therapy is an important consideration. Com-
parative trials of different antiviral regimens have not been undertaken for
neurologic disease. At present, optimizing the efficacy of the treatment for
full control of the plasma viral load would appear to be the primary goal
of therapy. Many neuroAIDS specialists are monitoring the response of
HIV viral load in the CSF as a part of such therapy. Generally, a successful
response in plasma is accompanied by a decline in CSF viral load as well
[52]. If this did not occur and ADC were suspected, efforts to enhance CSF
and CNS penetration would be appropriate. PIs are highly protein bound
and enter the CSF and CNS only in low concentrations. The least protein
bound of these drugs is indinavir, and its CNS efficacy is better established
than that of the other PI drugs [53]. Use of NNRTI drugs may be of advan-
tage in the setting of neurologic disease. Nevirapine seems to cross the
blood-brain barrier quite effectively [54], whereas efavirenz has been docu-
mented to at least achieve therapeutic free drug concentrations in the CSF
[55]. In the NRTI class, ZDV has the best evidence of efficacy against ADC
[56], but d4T [52] also seems to be efficacious in lowering viral load in the
CSF [52]. ABC is potent, has good CSF penetration, and thus is seen as a
good drug to use in this situation. Nevertheless, a placebo-controlled trial
of this drug in patients with ADC failed to demonstrate efficacy when it was
added to optimal therapy in the setting of ADC. The study did provide evi-
dence of ABC antiretroviral activity in CSF studies, however [57]. Conse-
quently, construction of a treatment program with these specific drugs is
probably optimal.
Design of antiviral therapy for ADC should consider other criteria as
well. Achieving strict compliance with therapy is crucial to success for HIV
therapy, because the rapid turnover of the virus means that even brief lapses
of therapeutic efficacy allow time for viral replication and selection of resis-
tant mutants. With cognitive function impaired, the needed focus on com-
pliance goals may threaten therapeutic success. A supportive environment
designed to ensure compliance should be sought for ADC patients. As with
other patients, simplified drug regimens are easier to follow and may be of
particular value with cognitively impaired populations or where directly
observed therapy is tried. Extended-release forms of some of the drugs are
in development, and the once-a-day dosing of efavirenz should make these
formulations of particular value if they are otherwise satisfactory. Finally,
side effects routinely encourage noncompliance; thus, working closely with
patients to achieve the most tolerable set of medications may also pay hand-
some dividends in clinical success.
At present, clinical evidence primarily supports efforts to optimize anti-

retroviral therapy without clear evidence that other forms of therapy
improve the outcome for patients with ADC. The belief that indirect
mechanisms are important in developing the neurotoxicity underlying ADC
suggests that other forms of therapy might be quite helpful. Mechanisms of
toxicity for which there is at least in vitro evidence include calcium-mediated
toxicity, excitotoxicity mediated by N-methyl-D-aspartate, oxidative stress,
cytokine-mediated damage, platelet activating factor–mediated neuronal
injury, nitric oxide–mediated toxicity, and toxicity of viral components,
including gp120 and Tat [28,58–60]. A substantial group of small clinical
trials have explored some of these mechanisms, including trials of nimodi-
pine [61], lexipafant [62], peptide T [63], selegiline [64,65], CPI-1189 [66], and
memantine [67]. The most promising results to date have been seen in the
small trials of selegiline, and a larger trial is currently enrolling subjects
sponsored by the Neurologic AIDS Research Consortium and the AIDS
Clinical Trials Group to further investigate this drug. Selegiline is to be
administered transdermally in this trial (A5090). Updates on clinical trials
for ADC may be obtained by consulting the web site of the Neurologic
AIDS Research Consortium (www.neuro.wustl.edu/narc).
Major questions
HIV infection has resulted in many opportunities to learn more about
medicine and neurology. The treatments devised have already resulted in
longer and healthier lives for our patients. We still are challenged by an
incomplete understanding of the pattern of trafficking of the virus across the
blood-brain barrier and by the potential pathologic mechanisms resulting in
ADC and other neurologic consequences of infection. Because the CNS
compartment represents a challenge to treatment, it remains a concern that
over the extended survival time now achieved by our patients, the brain may
become a recurrent source for infection or that accelerated degenerative pro-
cesses may result in more serious and common neurologic disease later in the
course of infection. Ongoing studies focusing on the CNS and CSF are con-
tinuing to unravel the virology, pharmacology, and pathologic conse-
quences in the brain and CSF.
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Med Clin N Am 86 (2002) 551–571
Human prion diseases

Man-Sun Sy, PhDa,*, Pierluigi Gambetti, MDb,
Boon-Seng Wong, PhDb
a
Division of Neuropathology, Institute of Pathology, and Cancer Research Center,
Room 933 Biomedical Research Building, School of Medicine,
Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44120-1712, USA
b
Division of Neuropathology, Institute of Pathology, School of Medicine,
Case Western Reserve University, 10900 Euclid Avenue,
Cleveland, OH 44120-1712, USA
Transmissible spongiform encephalopathy (TSE) is a group of rare,

subacute, fatal neurodegenerative diseases in human beings and animals
[1–3]. In human beings, TSE includes Creutzfeldt-Jakob disease (CJD),
Gerstmann-Sträussler-Scheinker disease (GSS), fatal familial insomnia (FFI),
and kuru. CJD and GSS have been known since the 1920s [2]. Kuru, a disease
confined to the Fore linguistic group, a tribe in Papua–New Guinea, was
first reported in the 1950s by Gajdusek [1]. In Fore language, kuru means
‘‘to tremble or shake’’ and graphically describes a symptom of the disease.
FFI is a much more recent disease that was first described in 1986 by Gold-
farb and colleagues [4]. From the onset, it was recognized that some of these
spongiform diseases, such as GSS, occur in clusters in an inherited familial
manner [2].
Some histopathologic features of this group of diseases are spongiform
vacuolation, astrocytic proliferation, and neuronal loss [2]. GSS has a
unique phenotype with the presence of multicentric amyloid plaques. The clin-
ical presentations of these diseases as well as the levels of histopathologic
lesions and their distribution in the central nervous system (CNS) vary from
case to case. It has been suggested that there are variants in each disease [5,6].
These variations hampered earlier histopathologic and clinical diagnose of
these diseases.
In recent years, human TSE diseases have been classified on the basis
of pathogenic mechanisms instead of histopathologic and clinical observa-
tions [2]. Human TSE diseases were divided into three basic categories: the
E-mail address: [email protected] (M.-S. Sy).
PII: S 0 0 2 5 - 7 1 2 5 ( 0 2 ) 0 0 0 0 4 - 4
552 M.-S. Sy et al / Med Clin N Am 86 (2002) 551–571
familial form, as in GSS and FFI cases and some CJD cases; the infectious
form, as in kuru and iatrogenic CJD; and the sporadic form, as in 85% of
human TSE cases, which occurs sporadically via unknown mechanisms
(Table 1). In animals, major TSE diseases include scrapie in sheep and goats,
transmissible mink encephalopathy in mink, bovine spongiform encephalop-
athy (BSE) in cattle, and chronic wasting disease (CWD) in deer and elks (see
Table 1). TSE has also been found in captive animals in the zoo as well as in
domestic cats.
A major breakthrough in our understanding of these diseases was the ser-
endipitous discovery of histopathologic similarities between the brains of
kuru patients and the brains of sheep and goats with scrapie, a TSE disease
[1]. Scrapie has been known in the United Kingdom for more than 200 years.
It was commonly thought to be a genetic disease [7], that is, some herds of
sheep were susceptible, whereas others were resistant. In 1936, however,
Cuille and Chelle demonstrated that scrapie was a transmissible disease [8].
Based on this lead, Gibbs and Gajdusek demonstrated the transmissibility of
kuru and then of CJD in the 1960s, followed by that of GSS in 1981, from
human beings to primates [1,3]. Experimental transmission was most effi-
ciently achieved by injecting homogenates into the brain of recipient ani-
mals. The homogenates were prepared using brains from affected subjects.
Subsequent studies revealed that the natural transmission of kuru most
likely occurred through cannibalism, which was practiced as part of the
funereal ceremony common to the Fore linguistic group [1]. The incubation
period of kuru could be as long as four to five decades [1]. Cessation of
Table 1
Transmissible spongiform encephalopathy diseases in human beings and animals
Form Phenotype
Human beings
Sporadic Creutzfeldt-Jakob disease
Fatal familial insomnia
Inherited Creutzfeldt-Jakob disease
Fatal familial insomnia
Gerstmann-Sträussler-Scheinker disease
Undefined or mixed
Acquired by infection ‘‘Iatrogenic’’ Creutzfeldt-Jakob disease (tissue grafts,
surgical instruments, hormones)
Kuru (contaminated food)
Variant Creutzfeldt-Jakob disease (contaminated food?)
Animals
Probably all acquired Scrapie
by infection Bovine spongiform encephalopathy
Chronic wasting disease
Transmissible mink encephalopathy
Transmissible spongiform encephalopathy
of domestic and captive animals
M.-S. Sy et al / Med Clin N Am 86 (2002) 551–571 553
cannibalism since the 1950s has gradually eliminated the disease. Like other
infectious diseases caused by microbes or viruses, kuru can be acquired exo-
genously, specifically by the ingestion of contaminated foods. The infectious
agent spreads from the digestive tract to the CNS, a process known as neu-
roinvasion. The mechanisms of neuroinvasion are not clear. It is believed
that the infectious agent can travel from the peripheral to the CNS either via
the peripheral nervous system or via the circulatory system [3].
Scrapie has a 200-year history in the United Kingdom and is endemic [7].
No transmission of scrapie to human beings has yet been reported, however.
In the past, experimental animal models showed that the infectious agent is
highly species specific [3]. Hence, transmission of scrapie was thought to be
impossible because of the existence of this ‘‘species barrier’’ between the
agent and the host. It is now clear that this species barrier can be violated
in experimental animals, and it can also be penetrated outside the laboratory
[8]. The barrier is not permanent, because the agent of TSE can cross the
species barrier after repeat passages in the host.
Recently, a novel form of CJD called variant CJD (vCJD) that is believed
to be acquired from cattle affected by BSE (commonly known as mad cow
disease) has emerged in the United Kingdom [9]. The development of BSE in
England in the 1980s has been traced to the consumption of meat and bone
meal fed to cattle [9]. This dietary supplement was contaminated by scrapie-
infected ovine. It became infectious in the 1980s when rendering plants aban-
doned the use of organic solvents that inactivated the infectious agent. By
jumping the species barrier, the infectious agent has transmitted scrapie from
sheep to cattle and from cattle to human beings. Dietary supplement contami-
nated with scrapie-infected ovine is also the culprit for transmissible mink
encephalopathy in mink and for most of the TSE cases in captive animals
in the zoo. Despite the relative rarity of the cattle-to-human transmission
route, TSE diseases have captured considerable attention because of their
unique pathogenic mechanism and their potential threat to public health.
Overall, TSE diseases are rare in human beings. The annual rate is
approximately 1.5 per 1 million people per year, a rate that has remained
stable over the last few decades [2,10]. Many case-control studies have
attempted to identify the risk factors in these diseases [8]. So far, there is
no conclusive evidence to suggest that the frequency of the disease is linked
to gender, occupation, geographic location, or environmental factors. The
exception occurs in cases where there is a familial link between affected indi-
viduals. These cases represent the familial form of the TSE diseases.
All patients with sporadic TSE diseases suffer from cognitive deficits,
including psychiatric and behavior abnormalities. For sporadic diseases, the
onset of disease most frequently occurs between the fifth and seventh de-
cades of life. Clinical laboratory results reveal no evidence of inflammation,
abnormal blood chemistry, or malfunctions of hepatic or renal systems.
Immune responses also have not been detected in affected individuals. The
mean survival time for patients with sporadic diseases is approximately
5 months, and most patients die within 1 year. The inherited form of the dis-
eases has an earlier age of onset and a more protracted disease course than
the sporadic form [2].
At variance with other neurodegenerative diseases, human TSE diseases
have been acquired via infectious mechanisms, as most vividly demonstrated
by kuru. Physicians have also inadvertently transmitted the disease to pa-
tients as a result of medical procedures. These cases are commonly referred
to as iatrogenic CJD [2]. Human transmission was most convincingly
demonstrated when TSE disease developed in two young patients who
underwent stereotactic electroencephalographic exploration with silver elec-
trodes. The electrodes had previously been implanted in a patient with TSE
disease [2]. The electrodes were ‘‘sterilized’’ with 70% alcohol and formalde-
hyde vapor, which was sufficient to eliminate microbes and viruses but did
not destroy the TSE agent. Furthermore, more than 80 cases of iatrogenic
diseases have been reported after neurologic transplants of human cadaver-
derived dura mater. More than 100 cases of iatrogenic diseases have also been
linked to injection of cadaver-derived growth hormone and gonadotropic
hormone [2]. It is presumed that the dura maters and the hormones were
harvested from donors who might have died of unrecognized TSE diseases.
More recently, a cluster of seven TSE cases surfaced in a small village
with a population of approximately 70,000 in Australia (C.L. Masters, per-
sonal communication, 2001). All seven patients are unrelated, and the com-
mon feature of the group is that three of the seven patients have visited the
same ophthalmologist. It is clear that TSE can be transmitted by invasive med-
ical procedures under some conditions. Nevertheless, based on the number of
surgical procedures that have been carried out and the number of iatrogenic
TSE cases that have been reported, the risk of contracting TSE as a result of
surgery must be low.
The onset, frequency, and duration of the iatrogenic form of the diseases
are much more variable than those of either the sporadic form or the inher-
ited form. The incubation period for iatrogenic diseases ranges from
6 months to 19 years. These variations reflect differences in the levels of
exposure as well as in the route of infection. Intracranial infections, as in the
cases of electrode implantation or dura mater transplants, have a shorter
incubation period. Extracranial infections, as in the cases of growth hor-
mone injection, tend to have a much longer incubation period. Similar to
patients with sporadic disease, patients with iatrogenic disease develop
ataxia and movement disorders followed by dementia.
Human TSE is clearly transmissible, but the rate of transmission from
human beings to primates varies from disease to disease. Based on studies
carried out over a span of 30 years involving 300 cases of human TSE and
close to 2000 primates, Brown and colleagues [11] found that the transmis-
sion rates were higher for iatrogenic CJD (100%), kuru (95%), and sporadic
CJD (sCJD) (90%) and lower for the familial form of diseases (68%). Trans-
mission best correlated with the presence of spongiform pathologic findings
(80%). The absence of spongiform change was a better indicator of non-

transmissibility, however.
The brain, spinal cord, and eye consistently have the highest infectivity [11].
In contrast, infectivity in other tissues was much lower and was only detect-
able in a limited number of inoculated animals. No infectivity has ever been
detected in any body fluids, including the transfusion of full units of blood
from CJD donors into chimpanzees, the most susceptible host. This observa-
tion is consistent with the findings of epidemiologic studies, which have failed
to uncover any link between blood transfusion and human TSE to date [9].
Neither patients with hemophilia nor intravenous drug users have increased
risk. A number of CJD patients have been known to donate blood over
extended periods of time. The tracking of the blood recipients has failed to
uncover any development of CJD in this group so far [9]. Therefore, although
the infectious agent has been reported to be present in non-CNS locations,
including blood, in experimentally infected animals, there is no evidence to
suggest that the agent is present in the blood of affected human beings.
It has been known since 1936 that scrapie is a transmissible disease. The
nature of the etiologic agent remained elusive and controversial until the
mid-1980s, however. Many attempts to isolate the pathogen were unsuccess-
ful, and many positive reports were never confirmed [3]. The infectious agent
was too small to carry nucleic acid and tended to copurify with proteins [3].
Accumulated evidence suggested that the infectious agent in scrapie was
highly unusual. It was resistant to agents that destroy nucleic acids but was
sensitive to agents that destroy protein [3]. The confusion and frustration are
best summarized by the names assigned to this elusive pathogen (eg, slow
virus, virino, virods [plant virus] or, simply, unconventional viruses) [3].
Prion concept and protein-only hypothesis

In 1967, Griffith [12] was the first to propose that the agent for TSE is a
self-replicating protein rather than a bacteria or virus. Prusiner [3] made the
fundamental discovery that led to our current understanding of these dis-
eases, however. In 1982, Stanley Prusiner and his colleagues isolated and
tentatively identified the infectious pathogen, which they termed a proteina-
ceous infectious particle or prion. Since then, the name prion disease has been
used synonymously with TSE. Later, the same group found that the prion is
an aberrant isoform of a protein that is normally expressed and highly con-
served in all mammals [13].
The normal human cellular prion protein (PrPC) is encoded by a single
gene in the short arm of chromosome 20 [13]. All three forms of prion dis-
eases (hereditary, sporadic, and infectious) are believed to share the same
pathogenic mechanism, which is based on the conversion of the normal
PrPC into the pathogenic prion protein (PrP), commonly called scrapie PrP
(PrPSc). As a result, PrPSc has the unique and fundamental property of being
a self-replicating and infectious agent that lacks nucleic acid. Although the
conversion hypothesis provides a mechanism for the propagation of PrPSc,
the mechanisms by which PrPSc causes neurodegeneration remain unclear.
In addition to the CNS, PrPC is expressed at high levels in many non-CNS
tissues, including the heart, lymphoid tissues, and muscle [3]. In all human
prion diseases, with the exception of vCJD, no PrPSc has ever been detected
in non-CNS tissues. Therefore, the brain is the only site where the conver-
sion from PrPC to PrPSc could occur. Alternatively, conversion may occur
in other tissues, but only the CNS has the capacity to accumulate PrPSc. The
mechanism by which PrPSc targets the CNS is not known.
Two different lines of evidence provide the strongest support for the prion
concept. The first line of evidence came from studies in transgenic animals.
PrPC knockout mice that do not express PrPC are resistant to infection [14].
Therefore, the presence of the PrPC is essential for PrPSc propagation. The sec-
ond line of evidence came from clinical studies in human beings. It has been
known for decades that some human spongiform diseases, such as GSS and,
more recently, FFI, can be inherited in an autosomal dominant fashion [2].
The identification of the prion gene suddenly permits investigators to deter-
mine whether any of the inherited forms of human prion disease are linked
to the PrP gene. Indeed, more than 20 pathogenic mutations have been found
in the coding sequence of the PrP gene in patients with the inherited form of the
diseases [3]. Pathogenic mutation represents approximately 15% of the human
prion diseases. Pathogenic mutations are broadly divided into those that cause
point mutations and those that cause insertion mutations in the coding region.
Whereas it is generally accepted that normal cellular PrPC is critical for
the pathogenesis of prion diseases, it should be noted that the prion concept
or the ‘‘protein-only hypothesis’’ is not universally accepted. Some skeptical
investigators still question whether prion by itself is sufficient for the patho-
genesis of the diseases [15].
Normal cellular prion protein

In human beings, PrPC is a small glycoprotein bound to the cell surface
by a glycosyl-phosphatidyl-inositol (GPI) anchor [16]. The full-length PrPC,
which includes 209 amino acids (residues 23–231), can be arbitrarily divided
into three subregions: (1) the N-terminus region, which encompasses ap-
proximately the first 90 amino acids and has a highly conserved motif of
five repeating octapeptides; (2) the central region, which is located approxi-
mately between amino acids 110 and 125; and (3) the C-terminal region,
which has two highly conserved nonobligatory N-linked glycosylation sites
and a disulfide bridge between residues 179 and 214 (Fig. 1) [3].
In the human brain, PrPC is expressed in three glycoforms [5]. It is
believed that these three glycoforms represent: (1) the diglycosylated form,
which migrates at 33 to 42 kd; (2) the monoglycosylated form, which mi-
grates at 29 kd; and (3) the unglycosylated form, which migrates at 27 kd
Fig. 1. Diagrammatic representation of human prion protein after posttranslational modifica-

tions. The normal cellular prion protein can be divided into three regions: the N-terminus
region, the central region, and the C-terminus region. Most of the secondary structure elements,
the a-helices, and b-sheet structures are located in the C-terminus as well as two potential N-
linked glycosylation sites and the disulfide bonds.
(Fig. 2). The N-link glycans are complex, as exemplified by the murine
PrPSc, which has over 60 different carbohydrate structures [17]. This variety
indicates that the glycans play a complex role in the physiology of PrPC and
may be important in the pathogenesis of the diseases [18].
Nuclear magnetic resonance analysis of recombinant PrPC shows that the
N-terminus region is highly flexible. It also shows that the central region is
partially structured and hydrophobic. In contrast, the C-terminus region
includes three a-helices and two short antiparallel b-strands, which form a
well-structured core domain when combined (see Fig. 1) [19,20]. PrPC knock-
out mice are normal; thus, expression of PrPC is not obligatory for survival
in mice [21]. Recent in vitro and in vivo studies suggest that PrPC is a metal-
binding protein and may be important in oxidative stress responses [22].
Pathogenic mechanism: conversion of normal cellular

prion protein to scrapie prion protein
The PrPC-to-PrPSc conversion is based on a conformational change from
the predominantly a-helical structure of PrPC to the predominantly b-sheet
structure of PrPSc (see Fig. 2) [23]. PrPC has 42% a-helix content and 3%
b-sheet content. In contrast, the b-sheet content of infectious PrPSc increases
to 43%, and the a-helix decreases to 30%. According to the most recent
model, the PrP is inherently unstable, fluctuating between the dominant
native state, PrPC, and other intermediate conformers, one or more of which
can self-associate to produce a supramolecular structure, PrPSc. This struc-
ture then acts as a ‘‘seed,’’ recruiting the unstable PrP forms, which leads to
the formation of new PrPSc through an autocatalytic process [3].
The exact cellular compartment where the conversion processes takes
place is not clear. The initial interaction between infectious PrPSc and PrPC
Fig. 2. Ribbon models of the tertiary structures of hamster cellular prion protein (PrPC) (A)
and scrapie prion protein (PrPSc) (B) based on nuclear magnetic resonance studies of PrP108–
231 and major biochemical differences between PrPC and PrPSc. The PrPC-to-PrPSc conversion
is based on the change in conformation from the predominantly a-helical form of PrPC (light
ribbons) to the predominantly b-sheet structure of PrPSc (dark ribbons). (From Prusiner SB. An
introduction to prion biology and diseases. In: Prusiner SB, editor. Prion biology and diseases.
Cold Spring, NY: Cold Spring Harbor Press; 1999. p. 1–68; with permission.)
is believed to occur first in the plasma membrane and then in the endosome
[24]. The presence of the GPI anchor is important for the conversion pro-
cesses to occur [16]. The GPI anchor may be needed, because GPI-anchored
proteins occupy microdomains on the cell membrane known as detergent-
insoluble complex in a concentrated and multimeric form, and the deter-
gent-insoluble complex may facilitate the initial interaction [25]. Disulfide
bonding is also important in the conversion process [26] and seems to be
inversely related to the glycosylation in PrPC [18]. Extensive cell model stud
ies support this interpretation [27]. Indirect evidence suggests that the con-
version process requires PrPSc to interact with PrPC either directly or through
the ‘‘help’’ of protein X or chaperones [28]. To date, a molecular chaperone
has not been identified. Conversion of PrPC by exogenous PrPSc has been
demonstrated in vitro in a cell-free system [29]; however, the process is ineffi-
cient because of the absence of cofactors or the chaperone protein [30].
The conformational changes in PrPSc also result in drastic alterations in
its biochemical properties. Some of these changes are summarized in Table 2.
One of the consequences of the conformational change is that although the
N-terminal region of PrPSc remains sensitive to treatment with proteases,
the C-terminal region from residues 80 to 231, also known as PrP27–30,
becomes protease resistant. In contrast, the entire PrPC is protease sensitive.
The accumulation in the brain of PrPSc that is resistant to proteases has
Table 2
Differences between normal human cellular prion protein and scrapie prion protein
PrPC PrPSc
Monomer Oligomeric or polymeric
More a-helix More b-sheet
Relatively more soluble in detergent Less soluble in detergent
Sensitive to in vitro digestion with proteinase K Relatively more resistant to proteinase K
Noninfectious Infectious
Present in CNS and many non-CNS tissues Only in CNS
Abbreviations: PrPC, normal human cellular prion protein; PrPSc, scrapie prion protein;
CNS, central nervous system.
provided a useful diagnostic test for prion diseases [6,31]. The commonly
used protease is proteinase K (PK) (Fig. 3). Resistance to PK is the only
in vitro test by which one can distinguish PrPSc from PrPC. Sensitivity to
PK in vitro is relative rather than absolute, and the levels of PK-resistant
PrPSc vary greatly between different prion diseases. In a small number of
cases, no PK-resistant PrPSc was detected [32]. Therefore, the presence of PK-
resistant PrPSc might not be required for pathogenesis in some situations.
Brown and colleagues [11] have also evaluated the relation between trans-
missibility of diseases and the presence of PK-resistant PrPSc in human
Fig. 3. Resistance of scrapie prion protein (PrPSc) but not cellular prion protein (PrPC) to
proteinase K (PK) digestion in vitro. Brain homogenates were prepared from two non-
Creutzfeldt-Jakob disease (CJD) cases and two confirmed CJD cases. Each sample was divided
into two tubes: one sample was either not treated (lanes 1 and 2 from non-CJD, lanes 5 and
6 from CJD) or treated with PK (lanes 3 and 4 from non-CJD, lanes 7 and 8 from CJD). After
treatment, all samples were separated by sodium dodecyl sulfate polyacrylamide gel elec-
trophoresis and immunoblotted with an anti-PrPC monoclonal antibody as described [47]. No
immunoreactivity is detected in non-CJD samples after PK digestion (lanes 3 and 4). In
contrast, strong immunoreactivity remained detectable after PK treatment of samples from
CJD cases (lanes 7 and 8) (unpublished results) [47].
prion diseases. Approximately 80% of the transmissible cases contain PK-

resistant PrPSc. This discrepancy may be a result of the presence of variable
amounts of PrPSc in the different parts of the brain that were used for in vivo
transmission and in vitro immunoblots. Alternatively, the in vivo bioassay
may be much more sensitive than the in vitro immunoblots, a fact that has
been demonstrated in animal models. Although resistance to PK is a reliable
diagnostic test for human prion diseases, it is time-consuming and techni-
cally demanding. Only laboratories with the necessary expertise can perform
the test.
All three forms of prion diseases (hereditary, sporadic, and infectious) are
believed to share the same fundamental pathogenic mechanism, which is
based on the conversion of the endogenous PrPC (or its conformational var-
iants) into PrPSc [2]. Accumulated evidence also suggests that the conversion
involves one or more intermediate conformers [32].
In the hereditary form, which represents about 15% of human prion dis-
eases, the disease is believed to be triggered by the presence of a germline
mutation in the PrP gene. This mutation destabilizes the mutant PrP and
facilitates its inevitable conversion to PrPSc [2]. More than 20 pathogenic
mutations have been found in the human PrP gene. Most of the point muta-
tions are located in the C-terminal regions of the PrP protein (Fig. 4). A
pathogenic point mutation in residue 145 has been found to result in the
generation of the stop codon and in premature termination of the PrP.
Another pathogenic mutation has been identified in the GPI anchor signal-
ing peptide at residue 231. This residue is normally removed during the
Fig. 4. Diagram of prion protein (PrP), including mutations, polymorphisms, secondary

structures, and posttranslational modifications. Mutations resulting in Creutzfeldt-Jakob
disease and fatal familial insomnia as well as polymorphisms (long arrows) are indicated above
the diagram. Mutations resulting in the heterogeneous and Gerstmann-Sträussler-Scheinker
disease phenotypes are indicated below the diagram. b ¼ b-sheets, H ¼ a-helix, S-S ¼ disulfide
bond, CHO ¼ N-glycans. (From Gambetti P, Petersen RB, Parchi P, Chen SG, Capellari S,
Goldfarb L, et al. Inherited prion diseases. In: Prusiner SB, editor. Prion biology and diseases.
Cold Spring, NY: Cold Spring Harbor Press; 1999. p. 1–68; with permission.)
attachment of the GPI anchors to the protein and is absent in the mature
protein. Collectively, these results suggest that there are multiple pathways
in the pathogenesis of the inherited form of human prion diseases.
Sixty percent of pathogenic mutations found in human prion diseases
involve residue 200, which results in a change from glutamine (E) to lysine (K).
Microsatellite analysis searching for E200K mutation–associated haplotypes
reveals that this mutation is derived from two families, one in Spain and the
other in Slovakia. All E200K cases reported in the United States and Canada
are descendants of the Slovakia family, whereas the Spanish family is the
origin of the cases in Europe (L.G. Goldfarb, personal communication, 2001).
Conversely, insertion mutations have only been found in the octapeptide
repeat region [33]. The number of insertions ranges from one to nine octa-
peptide repeats. It is interesting to note that although insertion mutations in
the octapeptide repeat region cause diseases, deletion mutation in the same
region does not. As a matter of fact, a single octapeptide repeat deletion is a
polymorphism in 1% to 2.5% of the population [2]. Also noteworthy, trans-
genic mice lacking the N-terminus are susceptible to infectious PrPSc, albeit
at a reduced efficiency [34].
One of the most intriguing findings regarding the inherited form of prion
diseases comes from studies revealing that a common polymorphism in amino-
acid residue 129 of the human PrP gene can greatly modulate disease
phenotypes [4]. An individual can be homozygous with methionine (M/M)
or valine (V/V) or heterozygous (M/V). Two groups of patients were identi-
fied with an identical mutation in residue 178 with a change from aspartic
acid to asparagine. The clinical presentations and histopathologies of the
two groups differed dramatically, however. In the group with the 129 V/V
genotype, the phenotype was more consistent with CJD, with extensive
spongiosis, neuronal loss, and astrogliosis in the cerebral cortex region.
Lesions were less severe in the thalamus. In the group with the 129 M/M
genotype, the phenotype was that of FFI, with preferential thalamic and oli-
vary atrophy. These findings show that a difference in one amino acid can
drastically alter disease phenotype. The mechanisms by which residue 129
influences the disease phenotype are not clear.
Experimental mutations of the PrP gene in some transgenic mice have led
to neurodegeneration in the absence of detectable PrPSc [35]. It is unclear
whether PrPSc is solely responsible for all aspects of the pathogenesis and
whether all hereditary prion diseases share the same pathogenic mechanism.
It should be noted that another transgenic mouse line bearing the same
human pathogenic mutation failed to develop neurodegeneration [36]. The
reason for this discrepancy is not known. These results suggest that a muta-
tion in the PrP gene may not be sufficient to cause neurodegeneration and
that other factors unique to human brain may be required for the manifes-
tation of the disease.
Sporadic prion diseases are thought to be triggered by a rare and stochas-
tic change of the PrPC conformation, which leads to the formation of PrPSc.
Even so, one cannot rule out the possibility that some sporadic prion diseases
may be caused by non-germline mutations or by unrecognized infectious
mechanisms. Interestingly, the 129 polymorphism also influences the incidence
of sCJD in Caucasian patients. Most of the sCJD patients are homozygous
with M/M or V/V [10]. In the general population, the frequency of M/M is
37%, V/V represents 12% of cases, and the remaining 51% of cases are hetero-
zygous (Table 3). Accumulated results suggest that homozygosity at residue
129 predisposes an individual to prion diseases. Homozygosity presumably
provides more PrPC substrates with similar conformation for conversion.
In contrast, heterozygous individuals have two different PrPCs with different
conformations. If this interpretation is correct, it suggests that residue 129 is
important either directly or indirectly in the overall conformation of PrPC.
Prion diseases contracted by an infectious mechanism are believed to
result from exposure to exogenous PrPSc, which binds to endogenous PrPC,
causing its conversion to PrPSc [3]. Accumulated evidence in animal models
suggests that the successful transmission of a prion disease depends on sev-
eral factors: (1) the degree of homology between the exogenous PrPSc and
the PrPC of the recipient, which may be necessary for the initial binding;
(2) the dose of the PrPSc; and (3) the expression of PrPC at the portal entry
of the exogenous PrPSc as well as in the various intermediate stations
between the portal entry and the CNS of the recipient. The mechanism by
which the PrPSc travels from the peripheral to the CNS is not clear. Some
investigators believe that the peripheral nervous system is the route of PrPSc
entry into the CNS. Other investigators believe that blood cells are involved
in the process. Once the initial conversion occurs, it is the endogenous PrPSc
that propagates and accumulates, causing the disease. Interestingly, all vCJD
cases so far were from individuals homozygous with M/M at residue 129 [9].
Either individuals with M/M are uniquely susceptible to vCJD or other geno-
types are also susceptible but with a much longer incubation period.
Rise of variant Creutzfeldt-Jakob disease

BSE was first reported in 1986 in England [9]. The first confirmed vCJD
case was reported in 1996, suggesting an incubation period of approximately
Table 3
Polymorphism at amino-acid residue 129 and incidences of sporadic Creutzfeldt-Jakob disease
129 Genotype M/M M/V V/V
Normal 37% 51% 12%
Sporadic 71.6% 11.7% 16.7%
Abbreviations: M, methionine; V, valine.
Data from Parchi P, Giese A, Capellari S, Brown P, Schulz-Schaeffer W, Windl O, et al.
Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic
analysis of 300 subjects. Ann Neurol 1999;46:224–33; with permission.
10 years in vCJD. Since 1996, close to 100 confirmed cases of vCJD have
been reported, most of which occurred in the United Kingdom with a few
exceptions [9]. The origin of the infection in vCJD has not been firmly es-
tablished, but considerable evidence points to BSE [37]. Four major lines
of evidence associate vCJD with BSE: (1) the outbreak of vCJD with a time
delay from and in the same geographic location as the BSE epidemic; (2) the
distinct clinical features of vCJD, which set this disease apart from conven-
tional CJD; (3) the similar histopathologic lesion profile in mice inoculated
with either BSE or vCJD preparations; and (4) the similar ‘‘molecular signa-
tures’’ shared between BSE and vCJD.
The histopathologic changes seen in the vCJD cases are reminiscent of
those seen in kuru, suggesting that similar pathologic mechanisms are
involved in these two diseases (ie, consumption of contaminated meat or
meat products). Early on, it was recognized that the clinical signs, age at
onset of the disease, and CNS pathologic findings seen in patients with vCJD
differed greatly from those seen in patients with conventional CJD. The un-
usual clinical signs of vCJD patients are prominent behavior changes at the
time of clinical presentation, followed by ataxia, dementia, and myoclonus
at the terminal stage of disease. In addition, PK-resistant PrPSc is detectable
in non-CNS tissues (eg, tonsils, appendix) of vCJD patients but not in
patients with conventional CJD [8,38]. Interestingly, PK-resistant PrPSc is
detectable in tonsil before the manifestation of clinical signs. Some of the dif-
ferences between vCJD and conventional CJD are summarized in Table 4.
No vCJD has been reported in the United States; however, four cases of
prion disease in unusually young patients have been reported [39]. At least
three of these patients (whose tissue has been examined by us) had regularly
consumed deer or elk meat. Available evidence does not indicate that the
prion disease was acquired via exposure to CWD through the consumption
of contaminated deer or elk meat, however. CWD was first recognized as
a prion disease in deer and elks in 1980. CWD is endemic in north central
Colorado and southeastern Wyoming.
Table 4
Differences between sporadic Creutzfeldt-Jakob disease and variant Creutzfeldt-Jakob disease
sCJD vCJD
Residue 129 genotype M/M, M/V, or V/V M/M only
Disease onset (mean age) 60 years old 29 years old
Mean duration of disease 5 months 14 months
CNS histopathology No ‘‘daisy’’ plaques Plaques with
‘‘daisy’’-like feature
PrPSc type Type 1 or 2 Type 2 only
PrPSc outside of CNS None In tonsil and appendix
Abbreviations: sCJD, sporadic Creutzfeldt-Jakob disease; vCJD, variant Creutzfeldt-Jakob
disease; M, methionine; V, valine; CNS, central nervous system; PrPC, normal human cellular
prion protein; PrPSc, scrapie prion protein.
Can sCJD also be caused by ingestion of infected meat? Case-control stud-

ies involving 206 cases of sCJD disease identified between 1990 and 1997 in
England have provided statistical evidence that the risk of CJD increases with
the frequency of consumption of certain types of meat [40]. The greatest odds
ratio is for venison (odds ratio ¼ 7.94), with individuals who eat venison at
least once per year having an eightfold increased risk of sCJD compared with
individuals who never eat venison (P ¼ 0.004). Because of the small sample
size, this study should be duplicated before drawing any definitive conclusion.
Molecular and biochemical typing of human prion strains

Early on, it was recognized that the infectious agent of scrapie exists in
multiple strains in a manner similar to microbes and viruses. When inoculated
into susceptible animals, each strain of scrapie produces characteristic patho-
logic lesions and has a distinct incubation time. Recent reports indicate that
the size of the PK-resistant PrPSc fragment and the ratio of the three glyco-
forms vary depending on the type of prion diseases or the strain of prion. Two
major types of PrPSc have been identified in human prion diseases based on
electrophoretic mobility; which, in turn, reflects the size of the main PrPSc
fragment generated by PK digestion in vitro [6]. After electrophoresis, type
1 PrPSc migrates at 21 kd and type 2 PrPSc migrates at 19 kd (Fig. 5).
Fig. 5. Molecular typing of human prion stains. (A) Brain lysates were prepared and separated
by sodium dodecyl sulfate polyacrylamide gel electrophoresis. Separated proteins were then
transferred onto nitrocellulose membranes and blotted with anti-prion protein (PrP) mono-
clonal antibody 8H4 as described [47]. PrP from four of the sporadic Creutzfeldt-Jakob disease
cases was indistinguishable from that of the control sample. (B) Aliquots of lysates were treated
with 50 lg/mL of proteinase K (PK), and immunoblots were carried out as described. After PK
treatment, the unglycosylated form of scrapie prion protein type 1 migrated at approximately 21
kd, whereas that of type 2 migrated at approximately 19 kd. (From Wong BS, Chen SG, Colucci
M, Xie Z, Li R, Pan T, et al. Aberrant metal binding by prion protein in human prion disease.
J Neurochem, in press; with permission.)
Microsequencing shows that PrPSc type 1 is cleaved by PK at (or around)

residue 82 and that PrPSc type 2 is cleaved at (or around) residue 97 [6]. This
difference in size is likely caused by conformational differences between these
two prion strains, which results in the exposure of different PK cleavage
sites. Both PrPSc type 1 and type 2 have been transmitted to transgenic mice
and are considered to represent human prion strains. The differences in the
size of the PK-resistant fragments along with differences in glycosylation
may account for some of the heterogeneity seen in the clinical presentation
of the human prion diseases.
The type of PrPSc also correlates with the 129 genotype [6,10]. Approxi-
mately 95% of the subjects with PrPSc type 1 are homozygous for methio-
nine at 129 (M/M), whereas 86% of those with the type 2 are either
homozygous for valine (V/V) or heterozygous (M/V) (Table 5). Parchi and
colleagues analyzed the physiochemical properties of PrPSc in conjunction
with the 129 genotype. They subdivided 300 cases of the most common
sporadic diseases into six phenotypic variants, five distinct subtypes of CJD,
and the sporadic form of FFI. This analysis provides a classification of dis-
ease variants based on biochemical analysis rather than on histopathologic
and clinical evaluations. Some of the clinical and pathologic features of
these six phenotypic variants are summarized in Table 6.
Oxidative stress, metals, and prion diseases

It is clear that PrPC and PrPSc are important in the pathogenesis of prion
diseases. Nevertheless, the biochemical pathways that lead to neurodegen-
eration remain unknown. It has been speculated that metallochemical
alterations, which result in oxidative stress, play a critical role in the patho-
genesis of neurodegenerative diseases, such as Alzheimer’s disease and
Parkinson’s disease, as well as in experimental prion diseases [41].
Oxidative stress is an abnormal physiologic condition caused by overpro-
duction of reactive oxygen species (ROS) [41]. Hydrogen peroxide (H2O2) is
the most common ROS. ROS is generated during normal metabolic
processes such as the reduction of oxygen to water by the mitochondrial
Table 5
Preferential association of type 1 diseases with methionine/methionine homozygous and Type 2
diseases with valine/valine homozygous
129 genotype M/M M/V V/V
Type 1 94.9% 3.7% 1.4%
Type 2 14.0% 31.4% 54.6%
Abbreviations: M, methionine; V, valine.
Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic anal-
ysis of 300 subjects. Ann Neurol 1999;46:224–33; with permission.
Table 6
Some of the clinical features at presentation and immunohistochemical staining patterns of the
five subgroups of sporadic Creutzfeldt-Jakob disease and sporadic fatal familial insomnia cases
based on 129 genotype and type of scrapie prion protein
Subtypes of sporadic human prion diseases

MM1/MV VV1 MM2-C MM2-sFI MV2 VV2
Number of cases 186 3 6 6 23 43
Age of onset (years) 65.5/62.1 39.9 64.3 52.3 59.4 61.3
Duration (months) 3.9 6.5 17.1 15.6 15.7 15.3
Cognitive loss 75/50% 100% 100% 67% 74% 27%
Myoclonus 18/12% 0% 0% 0% 0% 0%
Aphasia 23/25% 33% 33% 0% 11% 0%
Insomnia 8/0% 0% 0% 17% 15% 9%
PrPSc staining pattern
in immunostaining
Synaptic 100% 100% 0% 33.3% 100% 100%
Cerebellar kuru plaques 0% 0% 0% 0% 100% 0%
Plaque-like deposits 0% 0% 0% 0% 100% 100%
Abbreviations: M, methionine; V, valine; PrPSc, scrapie prion protein.
The MM, MV, VV represent 129 genotype. MM1 and MV1 cases have similar phenotypes;
thus, they were grouped together. The numbers (1 or 2) are the PrPSc types as determined by
immunoblots. MM2-C represents a subgroup with cortical involvement, and MM2-T represents
sporadic fatal familial insomnia with prominent thalamus involvement.
Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic anal-
ysis of 300 subjects. Ann Neurol 1999;46:224–33; with permission.
electron transport chain. Because of their highly reactive nature, ROS are
potentially quite toxic to cells. They can readily combine with other mole-
cules, such as proteins, lipids, and nucleic acids. Attack by ROS can result
in breakage of proteins and nucleic acids. ROS can also chemically modify
proteins and lipids, which results in the loss of their normal functions. In
normal conditions, two families of molecules tightly regulate the levels of
ROS: the pro-oxidants and the antioxidants. Overproduction of ROS may
be attributed to either an increase in pro-oxidant activity or a decrease in anti-
oxidant availability. One of the most important antioxidants is superoxide-
dismutase (SOD). This family of enzymes converts damaging superoxide
anion free radicals to H2O.
Both recombinant PrP and brain-derived PrP have been reported to have
SOD-like activity when they carry bound copper (Cu) [42]. In contrast, this
SOD-like activity is lost when Cu is replaced with manganese (Mn) [43].
Protein oxidation and lipid peroxidation are two of the best-characterized
markers of oxidative stress. Recently, we investigated whether these markers
are detectable in sporadic human prion diseases. We found that the levels of
protein oxidation and lipid peroxidation were greatly increased in the brain
of all sCJD cases [44]. More interestingly, we observed a striking elevation
of Mn accompanied by a significant reduction of Cu bound to PrP in all
sCJD patients. These metal imbalances varied according to the PrP 129
genotype and PrPSc type [44]. Cu and Mn changes were pronounced in sCJD
subjects homozygous for methionine at codon 129 and carrying PrPSc type 1
(sCJD M/M1). Furthermore, correlating with the increases in the markers of
oxidative stress, the PrP-associated SOD-like activity was reduced by
approximately 85% in each of the sCJD variants. The loss of antioxidant
function associated with increased oxidative stress suggests a change in the
metal-ion occupancy of PrP. This change might play a pivotal role in
the pathogenesis of prion diseases. Because the metal change is different
in the sCJD variants, it may also contribute to the diversity of PrPSc and dis-
ease phenotype in sCJD [44]. Whether alteration in metal binding is the
cause of the diseases or the consequence of the diseases remains to be deter-
mined. Recent studies in an animal model suggest that alterations in metal
binding can be observed in experimentally infected mice at a presymptom-
atic stage (Wong et al, manuscript submitted).
Diagnosis and surveillance of human prion diseases

Currently, the diagnosis of human prion diseases is based on a set of
established clinical, immunohistochemical, and biochemical criteria [2,10].
Advances in molecular biologic techniques have allowed rapid screening
of individuals with pathogenic mutations. This screening can be carried out
with non-CNS tissues (eg, peripheral blood). In contrast, the diagnosis
is much more cumbersome for the most common sporadic human prion
diseases. PrPSc detection by histochemistry or Western blot analysis is
nonquantitative, time-consuming, and technically demanding. It also relies
exclusively on the availability of brain tissues. No diagnostic test based on
PrPSc detection in peripheral tissues (eg, blood) is available for human or
animal prion diseases. This is because the infectious agent, PrPSc, is not pre-
sent in the peripheral tissues or the level of PrPSc in peripheral tissues may be
much too low for currently available assays [9,31].
Since the discovery of vCJD in 1996, the need for a rapid, effective, and
relatively early diagnostic test for the detection of human and animal prion
diseases is of obvious importance. Human prion diseases should be diag-
nosed as early as possible so as to avoid the potential transmission of infec-
tious prions through the donation of blood, other tissues, and organs. The
British experience indicates that unchecked animal prion diseases may be
transmitted to human beings. As a result, it is just as important to develop
tests that can detect PrPSc in animals before the animals reach the food chain.
Recently, a diagnostic test for the presence of a family of proteins known
as 14-3-3 proteins was introduced [45]. The sensitivity and specificity of this
test was reported to be greater than 90%. Because the 14-3-3 proteins are
essentially markers of brain parenchymal damage, they are also present in
a variety of conditions other than prion diseases. For example, they are pre-
sent in conditions that affect the CNS both focally (eg, neoplasm, infarct)
and with widespread distribution (eg, Alzheimer’s disease). Furthermore, it

is currently unclear whether the 14-3-3 protein test is positive in all five var-
iants of sCJD and in sporadic FFI or only in typical CJD [46].
In addition to diagnosis, monitoring disease incidence is important in
public health. After the discovery of vCJD in the United Kingdom, many
European counties have established surveillance centers to monitor the
appearance and spread of vCJD, and other prion diseases. In 1997, we
established a National Prion Diseases Pathology Surveillance Center in the
United States. The major purposes of this center are to monitor the inci-
dence of prion diseases in the United States, to identify any potential case
of human prion disease that might have been transmitted from animals; and
to collect and provide human tissues for research on the pathogenesis of
prion diseases. Since then, we have received and diagnosed more than 326
cases of human prion diseases (Table 7). So far, we have not uncovered any
vCJD case in the United States.
Future challenges
Like all other human diseases, the challenge for human prion diseases is
in the diagnosis, cure, and eventual prevention of the diseases. Of these three
challenges, the development of a more reliable and rapid diagnostic test is
the easiest task. Since the appearance of vCJD, significant progress has been
made in the diagnosis of prion diseases. Conversely, like all other neurode-
generative diseases, finding a cure for prion diseases is likely to be difficult.
This is because most patients with sCJD do not have obvious clinical signs
until they are close to the terminal stage of the diseases. Many attempts have
been made to identify compounds that might interfere with the PrPC-to-
PrPSc conversion in in vitro and in vivo experimental models. Only time can
tell whether any of these approaches reaches clinical application.
To find a cure and prevent human prion diseases, we must focus on a bet-
ter understanding of the molecular mechanisms that are responsible for the
diseases. Human prion diseases belong to a group of heterogeneous diseases.
Identification of the infectious agent is only the first step in a long and ardu-
ous process. We must endeavor to unravel the mechanisms by which this
Table 7
Cases of human prion diseases received and diagnosed by the National Prion Diseases
Surveillance Center at Case Western Reserve University
Human prior diseases
Year Sporadic Familiar Iatrogenic Total
1997 54 4 0 58
1998 45 5 1 51
1999 65 9 0 74
2000 97 12 2 111
2001 (3/1) 31 1 0 32
small protein causes diseases. The control and containment of prion diseases
is likely to remain a major challenge for scientists, clinicians, and public
health officials in the days ahead.
Acknowledgment
Dr. Sy dedicates this manuscript to Pearl Ling.
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Med Clin N Am 86 (2002) 573–590
Dementia epidemiology
Walter A. Kukull, PhDa,*, James D. Bowen, MDb
a
Department of Epidemiology, University of Washington, Box 357236, Seattle,
WA 98195-7286, USA
b
Department of Neurology, University of Washington School of Medicine,
Box 356465, Seattle, WA 98195-7286, USA
Dementia has become one of the leading public health concerns facing
our society. The past few decades have seen remarkable success in treating
some acute illnesses and in reducing the incidence of others, such as stroke.
Epidemiology has played a central role in identifying the risk factors and
potential causes of these acute illnesses, whereas clinical medicine has pro-
vided new and more effective treatments. This has allowed us to develop a
wide array of interventions, such as antibiotics, safer working conditions,
and improved sanitation. Our success in preventing and controlling the
acute diseases that strike between childhood and early middle age has led
to greater longevity and the aging of our population. In the developed
world, chronic diseases are the leading causes of morbidity and mortality.
Of these chronic illnesses, dementia is one of the most common, extracting
an enormous social, emotional, and economic burden on society. At least
6% to 10% of persons in the United States aged 65 years or older may suffer
from some form of dementia [1]. Approximately 2.32 million persons in the
United States were estimated to be living with Alzheimer’s disease (AD) in
1997 [2]. The enormous burden that dementia inflicts on individuals,
families, and society underlies the increased emphasis medical science has
placed on the study of these diseases. As with other scientific fields, there
is great interest in studying causes and risk factors for dementia with all the
tools that epidemiology can bring to bear. The epidemiologic study of
dementia has some unique challenges, however.
Case detection and identification (or diagnosis) are critical to the epide-
miologic study of dementia. In other words, how are new dementia cases
found, and once found, how accurately are they diagnosed? The diagnosis
of dementia is difficult because specific antemortem biologic markers for
E-mail address: [email protected] (W.A. Kukull).
PII: S 0 0 2 5 - 7 1 2 5 ( 0 2 ) 0 0 0 1 0 - X
574 W.A. Kukull, J.D. Bowen / Med Clin N Am 86 (2002) 573–590
most dementias, and specifically for AD, do not exist. Instead, the diagnosis
must be made on the basis of clinical evidence. There can be considerable
variation in making the diagnosis of dementia based on a clinical examina-
tion, potentially leading to diagnostic heterogeneity and misclassification of
those patients with dementia. Fortunately, some of this heterogeneity has
been reduced by the recent introduction of clinical criteria for the diagnosis
of various types of dementia. Standardization of clinical criteria can limit
the amount of misclassification; however, in practice, standardization is dif-
ficult to achieve.
Case detection is a further problem for most epidemiologic studies. Cases
identified using death certificates alone are simply not comparable to those
identified by direct patient examination; there are too many extraneous fac-
tors affecting whether dementia might or might not be entered as a cause of
death. The method of identifying and including cases, if associated with expo-
sure history, could cause serious selection bias and lead to spurious conclu-
sions. Can all identified cases from a particular study base be enrolled in a
study? Usually, this does not happen, because many persons (or their families)
decline to participate in research studies. Frailty, age, ethnicity, gender, edu-
cation, and a host of other factors also influence participation. If any of these
participation factors is systematically related to exposure status, an uncon-
trolled bias may result. Case identification methods are also critical to cohort
studies (and intervention trials). Failure to start with a cohort that is free of
the disease of interest can potentially bias results. Lack of sensitivity or spec-
ificity in screening or diagnosing disease during follow-up leads to incorrect
estimates of incidence and to distorted risk factor relations.
Exposure measurement (valid determination of risk factor information) is
critical for analytic risk factor studies. For dementia, determining when,
relative to disease onset, an exposure may have been able to influence dis-
ease is complicated by the often insidious and indeterminate onset of dis-
ease. Long past exposure histories are difficult to construct and validate,
especially in diseases that affect memory. Self-reported histories and those
obtained from proxies are often the basis for risk factor inference but may
be flawed by distorted recollection or recall bias. Actual records, for exam-
ple, of medication history or occupational exposures are seldom available.
Biologic markers of exposure (except for genotype) are difficult to obtain;
and some may be affected by the disease itself. For example, low serum cho-
lesterol levels in existing/prevalent cases may be a function of the impact of
disease on diet or may be influenced by physical wasting. Potential markers
obtained from analysis of peripheral blood may not correspond to marker
exposure levels in neuronal tissue. Biopsy of the affected tissue is not avail-
able in most dementia diagnoses, and autopsy, which is the gold standard
for the diagnosis of many dementias, may reflect cumulative disease pro-
cesses, leaving the picture additionally confusing.
As one leaves major research institutions or attempts to begin epidemio-
logic research studies in less developed countries, the problems grow in mag-
W.A. Kukull, J.D. Bowen / Med Clin N Am 86 (2002) 573–590 575
nitude. Differences in available facilities and local practices are likely the
easiest to overcome. Addressing political concerns and suspicions to gain the
cooperation necessary to begin a study may take additional time and pre-
paration. Case detection, case identification, and risk factor exposure mea-
surement remain critical to valid research in these settings, but the difficulty
in obtaining acceptable levels of each is increased substantially.
Clinical overview
Dementia can sometimes occur suddenly as the result of a stroke. More
often, it presents with a slowly progressive loss of cognitive function as with
AD. Cognitive loss may begin with mild memory problems, language diffi-
culties, or problems with activities of daily living that many might ascribe to
aging but progress to more serious socially and functionally debilitating cog-
nitive impairment. Memory may not always be the first domain affected.
The usually insidious nature of most dementia makes it difficult to deter-
mine the point of disease onset. Moreover, it is especially difficult to deter-
mine whether dementia is present in people with only some mild indications
of cognitive impairment and whether that mild impairment is benign and
nonprogressive or a prodrome of the progressive disease. Valid early identi-
fication of true disease would be most helpful in linking exposures and risk
factors to the disease. Behavioral changes may be prominent, including
agitation, wandering, personality change, and depression. In late stages,
patients may be completely dependent on others. Various definitions of
dementia have been used in past research studies, but that of the Diagnostic
and Statistical Manual: Edition IV (DSM-IV) is the most commonly used
now [3]. The DSM-IV criteria for dementia require memory impairment and
one or more additional cognitive disturbances. These include aphasia (lan-
guage disturbance), apraxia (impaired ability to carry out motor activities
despite intact motor function), agnosia (failure to recognize or identify
objects despite intact sensory function), and disturbances in executive func-
tioning (ie, planning, organizing, sequencing, abstracting). The cognitive
deficits must be severe enough to cause significant impairment in social or
occupational functioning and represent a significant decline from a previous
level of functioning. Dementia must be differentiated from delirium (eg,
caused by illness, medications, or intoxicants). The causes of dementia are
listed in Table 1. There is some controversy concerning whether memory
loss should be the cardinal feature of dementia (ie, ‘‘necessary’’ for the diag-
nosis) or whether loss in a combination of other cognitive domains, without
memory loss, should be considered sufficient for diagnosis. Leaders in the
study of vascular dementia have raised interest and debate concerning this
question. Beyond the umbrella category of ‘‘dementia,’’ there are clinical
and sometimes histopathologic criteria for differentiation of dementia
subtypes. To date, diagnostic criteria have been developed for ‘‘mild cogni-
tive impairment,’’ AD, vascular dementia, dementia with Lewy bodies,
Table 1
Causes of dementia
Idiopathic
Frontal temporal dementia
Focal/central nervous system pathologic findings
Multi-infarct dementia
Binswanger’s disease
Multiple sclerosis
Mass lesions
Tumors, multiple sites
Tumors, single site
Gliomatosis cerebri
Abscess
Subdural malformation
Hydrocephalus
Infections
AIDS (HIV)
Chronic meningitis
Encephalitis
Progressive multifocal leukoencephalopathy
Subacute sclerosing panencephalitis
Syphilis
Lyme disease
Prion disease (kuru, Creutzfeldt-Jacob)
Toxins
Drugs
Alcohol
Heavy metals
Industrial toxins
Domoic acid
Inherited disease
Huntington’s disease
Gerstmann-Sträussler syndrome
Porphyria
Propionic aciduria
Adult-onset lysosomal storage diseases
Hexosaminidase
Arylsulfatase (metachromatic leukodystrophy, or MLD)
Kuf disease
Adrenoleukodystrophy
Others
Myotonic muscular dystrophy
Down’s syndrome
Hereditary ataxias
Hereditary spastic paraplegias
Cerebrotendinous xanthomatosis
Systemic disease
Cardiac
Pulmonary
Renal
Renal failure
(continued on next page)
Table 1 (continued )
Dialysis dementia
Hepatic
Hepatic failure
Hepatocerebral degeneration
Wilson’s disease
Endocrine
Hyper/hypothyroid
Hyper/hypoparathyroid
Hyper/hypoadrenalism
Syndrome of inappropriate secretion of antidiuretic hormone (SIADH)
Rheumatologic
Vasculitis (including systemic lupus erythematosus, or SLE)
Giant cell arteritis
Sarcoid
Amyloid
Neoplastic
Metastasis
Carcinomatous meningitis
Paraneoplastic (limbic encephalitis)
Associated movement disorder
Parkinsonian diseases
Parkinson’s disease
Progressive supranuclear palsy
Postencephalitic dementia
Posttraumatic (dementia pugilistica)
Diffuse Lewy body disease
Myoclonus
Creutzfeldt-Jakob disease
Metabolic derangement
Other movement disorder
Hereditary ataxias
Hereditary spastic paraplegia
Kuru
Wilson’s disease
Seizures
Kuf disease
Deficiency
Vitamin B12 deficiency
Thiamine
Niacin (Pellagra)
frontotemporal dementia, and HIV dementia. Unfortunately, for the re-

searcher seeking a common standardized definition, there is often more than
one diagnostic criteria set for each condition; often, too, they do not agree.
Although AD is the most common form of dementia, many other disor-
ders must be considered, including drug-induced conditions, alcoholism,
stroke, Parkinson’s disease, Huntington’s disease, subdural hematoma, brain
tumors, hydrocephalus, vitamin B12 deficiency, hypothyroidism, neurosyphilis,
and HIV infection. Two commonly used criteria for the diagnosis of AD
have been proposed [3,4].
Vascular dementia is difficult to differentiate from AD because of the
common occurrence of cerebrovascular disease and stroke with AD in the
elderly. The more sophisticated the search for stroke, the more likely it is
that some strokes are found. The clinical identification of stroke is surpassed
by CT, which is surpassed by MRI. The false-positive identification of
stroke also increases, however. Many different criteria have been developed
to diagnose vascular dementia [3,5,6]. Much of the pioneering work in the
definition and recognition of vascular dementia can be attributed to
Hachinski and his colleagues [7–15].
Recently, two additional types of dementia, dementia with Lewy bodies
[16] and frontotemporal dementia [17], have been separated from AD based
on their clinical presentations and pathologic characteristics. Dementia with
Lewy bodies presents with cognitive losses. In addition, fluctuating cognitive
performance, visual hallucinations, and parkinsonism are suggestive of this
disease. Memory impairment may not necessarily be prominent in the early
stages of the disease. Deficits in attention, frontal subcortical skills, and
visuospatial ability predominate.
In frontotemporal dementia, changes in behavior dominate the early
course of the disease These include loss of personal awareness, loss of social
graces, disinhibition, overactivity, restlessness, impulsivity, distractibility,
hyperorality, withdrawal from social contact, apathy or inertia, and stereo-
typed or perseverative behaviors. Speech output changes occur, including
progressive reduction of speech, stereotypy of speech, perseveration, and
echolalia. Physical signs include early or prominent primitive or ‘‘frontal’’
reflexes, early incontinence, late akinesia, rigidity, and tremor. Deficits in
social comportment, behavior, judgment, or language are out of proportion
to the memory deficit. The memory loss is variable and often seems to be
caused by lack of concern or effort. Frontal lobe impairments are notable,
including abstraction, planning, and self-regulation of behavior. There are
several pathologic findings that may lead to frontotemporal dementia, includ-
ing some with dominantly inherited mutations related to the protein tau.
Current cases versus risk of dementia and Alzheimer’s disease

The prevalence of dementia is the proportion of persons in a population
suffering from dementia at a particular time. It represents a cross-sectional
picture of the population—the burden of that disease on society. Prevalence
is useful in determining the needs for resources and societal burden from a
disease. The prevalence of dementia is affected by differences in length of
survival, effectiveness of treatment, emigration, and institutionalization as
well as by the occurrence of new disease cases. The incidence of dementia
(ie, risk or rate) is calculated as the new cases per population at risk per time
period. Often, incidence is presented as a ‘‘cumulative’’ figure (eg, 15 new
cases per 1000 persons older than 65 years of age in 1999) or as a ‘‘density’’
or instantaneous rate (eg, 12 new cases per 1000 person-years). Incidence is
less useful in determining societal burden, and prevalence is not useful in
determining disease risk, but kept in their own arena, they are useful
descriptors of disease occurrence, and they are linked by disease duration.
Evans et al [18] reported the results of a community study in East Boston.
The prevalence estimates for dementia and AD were based on a complex
community sampling scheme [19]. Because of the diagnostic criteria and
screening procedures, the results of this study have been somewhat contro-
versial, but they are widely accepted as an observed but high estimate of the
potential dementia prevalence in East Boston. Prevalence proportion rose
from 3% among those 65 to 74 years of age to 47% in those older than 85 years
of age. More than 80% of the observed dementia cases were classified as AD.
Evans later applied the observed rates to census data, projecting that 10.3
million persons would have AD in the year 2050. Recently, a meta-analysis
of prevalence studies worldwide was conducted [20], which concluded that
the prevalence proportions and incidence rates observed across studies were
geographically consistent, except for variations caused by methodologic dif-
ferences. Prevalence proportions rose from 0.3% to 1.0% in 60- to 64-year-
olds to 43% to 68% in persons aged 95 years or older. As a summary figure,
prevalence is often reported as 6% to 10% among persons aged 65 years or
older in North America [1]. Brookmeyer et al [2] have estimated that if disease
age-specific incidence curves could be shifted generally to delay onset by
2 years, that would result in 2 million fewer cases in the future.
The dementia prevalence proportion in the population is a function of
disease incidence and disease duration (or survival). Jorm and Jolley [21]
gathered data from 23 studies and produced a meta-analysis of dementia in-
cidence. Incidence was estimated for Europe, the United States, and East
Asia; dementia, AD, and vascular dementia incidence rates were computed.
Incidence rates for the United States and Europe were quite similar: ‘‘mod-
erate’’ dementia incidence rose from 3.6 per 1000 person-years (in persons
aged 65–69 years) to 37.7 per 1000 person-years (in persons aged 85–89 years)
in Europe and from 2.4 to 27.5 per 1000 person-years for the same age groups
in the United States. ‘‘Mild’’ AD incidence was also computed, ranging from
2.5 per 1000 person-years (in persons aged 65–69 years) to 46.1 per 1000
person-years for Europe compared with 6.1 to 74.5 per 1000 person-years for
the United States and 0.7 to 39.7 per 1000 person-years for East Asia.
Rocca et al [22] reanalyzed dementia and AD incidence data for 1975
through 1984 based on charted data from the Rochester Epidemiology
Project at the Mayo Clinic. The results showed dementia incidence overall
as 2.2 per 1000 person-years in 65- to 69-year-olds rising to 40.8 per 1000
person-years in those aged 90 years or more. Similarly, for AD, rates rose
from 1.2 to 33.9 per 1000 person-years. These investigators noted that
annual incidence seemed to stay rather stable during the 1975 to 1984 time
interval. After disaggregating the data for the oldest people, Rocca et al [22]
also reported that rates seemed to continue to rise with age after the age of
84 years. They also noted that rates were similar for men and women.
The combined analysis of four large ongoing European cohort studies of
dementia and AD was recently reported by Launer et al [23]. Cohorts
enrolled in Denmark, France, the Netherlands, and the United Kingdom
totalled more than 16,000 members aged 65 years or older at enrollment.
After a mean follow-up of 2.2 years (comprising approximately 28,600
person-years), the overall incidence of dementia was 14.6 per 1000 person-
years. Approximately two thirds of these cases were attributed to AD. In-
cidence of dementia was 2.5 per 1000 person-years in 65- to 69-year olds and
rose to 85.6 per 1000 person-years in those aged 90 years and older. Simi-
larly, AD rose from 1.2 per 1000 person-years to 63.5 per 1000 person-
years across the same age groups. The report by Launer et al [23] is one
of the first using data from the large cohort studies that are now underway
in Europe and the United States. As more cohort studies begin to report inci-
dence, consistent estimates are likely to emerge.
Most of the difference between dementia and AD incidence rates reported
here likely represents the next most common form of dementia, vascular
dementia. We cannot be sure of this at present, however. Despite the com-
pilation of several competing diagnostic criteria for vascular dementia [5,6],
this syndrome remains an area of controversy and uncertainty [24–29].
Application of the diagnostic criteria has been shown to be difficult and
unreliable in practice, even by experienced research investigators [30]. Many
of the reliability and validity problems experienced by investigators in clas-
sifying a case as ‘‘vascular’’ or AD may stem from the mutual exclusion of
the two conditions imposed principally by the DSM-IV diagnostic criteria.
There is a growing realization that a vascular component can contribute to
the dementia seen in AD [26,31–36].
Late-stage dementia and AD hold little hope for treatment or the identifi-
cation of consistent risk factors; as a result, interest has continued to shift
toward early and valid identification of disease. Early forms of pre-AD or
predementia are difficult to distinguish from the relatively benign cognitive
decline associated with aging. Nevertheless, when mild cognitive decline can
be identified, it seems that perhaps 50% of such cases may progress to become
dementia [37–41]. Distinguishing between normal persons, those with mild
cognitive impairment, and those with incipient dementia/AD may provide
important clues about risk factors and critical periods of exposure before dis-
ease onset. Reliable and valid distinctions may also help to determine whether
mild cognitive impairment is a treatable and reversible phenomenon.
Exposures associated with the onset of Alzheimer’s disease

Studying dementia and its relevant exposures presents many methodologic
and logistic challenges. Careful, consistent, and valid case identification and
detection (discussed previously) must always be addressed by researchers.
Comparison groups must also be carefully defined and enrolled to avoid

spurious associations as a result of bias. In the absence of a biologic marker
identifying all cases of AD, there is considerable difficulty in ascertaining all
cases and in ensuring that everyone identified as having AD truly does as
well as in ensuring that all who clinically do not show symptoms truly do
not have the disease. If a case series includes substantial misclassification
of disease, the ability to recognize risk factors is reduced. In other words,
the observed relative risk estimate tends to be biased toward the null (assum-
ing the misclassification is nondifferential). Exposure to risk factors for AD
could possibly occur many years before the recognition of clinical disease or
rather close to recognition. The relevant time window may vary for each
exposure; some exposures could cause a disease change immediately after
a single exposure, whereas others may take years of sustained exposure,
either by themselves or in combination with one or more other factors, to
cause disease changes. The later in the clinical course a patient is identified
as having dementia, the more remote the risk factor exposure must be, and
the more difficulty there is in recognizing it. Complicating the situation is the
lack of verifiable records for most exposures coupled with the patient’s and
patient proxy’s difficulty in recalling a specific exposure or the details sur-
rounding it. The use of caregivers as proxies is an imperfect solution to the
patient’s loss of recall, but it is sometimes the best we have to work with.
Most early analytic observational studies of AD were based on a case-
control design. In this design, cases of disease were identified, and their
exposure histories were compared with those of persons without the disease.
The design itself is well accepted and valid as a method of study. It is subject
to bias if not judiciously applied, however. In the case of AD (and demen-
tia), problems with case identification and detection, case selection for study,
and exposure measurement may have caused at least some results to be
biased or spurious. Now, as cohort studies of AD and dementia are begin-
ning to emerge, findings that were viewed as consistent in case-control stud-
ies are being questioned or refuted. One example of a potential bias
concerning a potential protective effect for AD associated with cigarette
smoking was addressed in a recent article [42]. The argument for that poten-
tial bias is described as an example that could apply to risk factors other
than smoking. A meta-analysis of studies of smoking and AD showed a con-
sistent decreased risk associated with smoking [43]. Most of these studies
were of the case-control design. When case-control studies rely on cross-
sectional samples to obtain cases, they are more likely to encounter those
patients with the longest survival after diagnosis [44–46]. Also, when
decreased postdiagnosis survival among patients is associated with the
exposure of interest (eg, smoking), a potential spurious excess of exposure
among controls may be observed. Wang et al [47] conducted a cross-sec-
tional and longitudinal study to observe the relation between smoking and
AD. They found that although mortality between smokers and nonsmoking
control subjects was rather similar, AD case smokers had a threefold
increase in risk of death compared with AD nonsmokers. As a result of mor-

tality, smoking would be less common in a cross-sectional sample of AD
patients than among controls. Cohort studies where this selection bias is
minimized now report either ‘‘no association’’ or a potential increased risk
of AD associated with smoking [23,47–49].
Head trauma has also been shown to be a relatively consistent risk factor
for AD, primarily based on case-control studies [50,51]. Here, selective recall
or recall bias may be more important than the effect of survival, even though
risk of death or continued cognitive impairment immediately resulting from
the injury is substantial [52]. Several recent longitudinal studies now show a
negligible risk of AD associated with head injury [23,53,54], although others
still find some potentially increased risk [55,56].
Higher educational level has been proposed as influencing a decreased
risk of AD, but the relation between education and AD may be quite com-
plex [1,57–65]. Educational level influences a subject’s likelihood of partici-
pating in epidemiologic studies. Educational level influences the diagnostic
process, at least in the early stages of disease, because of the individual’s
ability to respond correctly in testing situations. Education may influence
health care use and may result in greater income or a higher occupational
level. The idea that higher education confers greater ‘‘cognitive reserve’’
to be accessed when disease strikes is tantalizing, although biologically
unsubstantiated. Recently, an important idea was raised concerning the
importance of early life development in increasing susceptibility to AD
[42]. The biologic plausibility of this association has been reviewed [66].
Several ‘‘protective’’ factors for AD have been raised in the past 10 years.
These factors include anti-inflammatory medications [1,67–73], estrogen
replacement therapy [74–88], and antioxidants such as vitamin C and vitamin
E [89]. Although the initial associations seemed relatively consistent across
studies, designs differ, and conclusions are still tentative. Randomized trials
to test the observed associations are either proposed or underway. In the case
of estrogen as a potential treatment for AD, results have shown no indication
that estrogen replacement therapy is an effective treatment for AD [78,81].
This result does not address estrogen as a preventive measure, however.
AD is likely to be heterogeneous both diagnostically and etiologically.
What results in the AD phenotype may be the sum or product of aging,
environmental factors, genetic constitution, and sociodemographic experi-
ences. Aside from the observable effect of aging dramatically increasing the
risk of dementia and AD, success in finding environmental risk factors has
been limited and potentially related to design and selection factors.
Genetics and Alzheimer’s disease

Great progress has been made in the genetics of AD. Most of the strict
genetic ‘‘causes’’ of disease have been limited to familial AD, however. Famil-
ial AD behaves similar to an autosomal dominant genetic pattern and predom-
inantly tends to affect persons younger than 60 years of age. Familial AD,
so defined, seems to account for less than 5% of all AD, but important clues
may be learned from the study of familial disease, which may apply to the
more common form (often called sporadic, but it may also have undiscovered
genetic causes). Several current reviews of AD genetics are available [90–99].
The largest proportion of familial AD is attributed to mutations in the
presenilin 1 gene (chromosome 14), and the next largest known contribution
is from mutations in a homologous gene on chromosome 1, presenilin 2. A
small proportion of cases are caused by specific mutations in the amyloid
precursor protein gene (chromosome 21). It is abnormal cleavage of the
amyloid precursor protein that results in the formation of amyloid-b pro-
tein(1–42). Amyloid-b protein aggregates in the brain, forming the charac-
teristic plaques of AD. Recently, important work has been published
concerning the identification of enzymes that cleave the precursor protein
abnormally, forming the amyloid-b 1–42 protein. This work may ultimately
help to identify sites for drug intervention not only for familial AD but for
nonfamilial AD [93,100–105]. Perhaps one quarter to one half of the genes
for familial AD have yet to be identified [95–98].
Arguably, the strongest and most consistent risk factor for nonfamilial
AD (other than age) is apolipoprotein E (APOE) genotype. The association
was first described from Allen Roses’ laboratory [106–111]. ApoE naturally
occurs as three different alleles (e2, e3, and e4), which pair to form one of six
genotypes for each individual. Genotypes containing the e4 allele are asso-
ciated with an increased risk of AD; homozygous e4 greatly increases the
risk (>8-fold). Since the initial description of increased risk associated with
the e4 allele, many investigators have observed the association. Discussion
of ApoE genotype is now included in most risk factor studies of AD either
as a focus or as a potential confounder/effect modifier of an association.
Farrer et al [112] provided a meta-analysis of the age and gender effects, and
Mayeux et al [113] later described caveats for the potential value of ApoE
genotype in AD diagnosis. Despite the huge volume of studies that include
ApoE genotyping, relatively little is known concerning how the e2, e3, and
e4 alleles actually work to influence the risk of AD.
Evidence for the effects of other genes on AD has also been presented. a2-
Macroglobulin was first shown as a potential risk factor by Blacker et al
[117], but a number of other investigators failed to replicate the association
[114–116,118]. Other genetic associations have been studied but with limited
impact to date [96,119–129]. Progress continues, and there is considerable
hope for the discovery of important genes that may provide indications for
prevention or therapy.
Summary
Determining the incidence and prevalence of dementia is an inexact
science. Dementia is difficult to define and detect in the population. Even
with the difficulties of determining prevalence and incidence, it is clear that

dementia causes a substantial burden on our society. Problems with diag-
nostic inaccuracy and insidious disease onset influence our ability to observe
risk factor associations; factors related to survival may be mistaken for risk/
protective factors. Current studies suggest that factors influencing brain
development or cognitive reserve may delay the onset of AD, perhaps
through a protective mechanism or a delay in diagnosis caused by improved
performance on cognitive tests.
The recent identification of genes that cause dementia suggests that these
genes or their biochemical pathways may be involved in the pathogenesis of
nonfamilial cases. The contribution of genes that cause disease in and of
themselves may be smaller than that of genes that act to metabolize or po-
tentiate environmental exposures. The interaction between gene and environ-
ment should be increasingly well studied in the future. Epidemiology must
take advantage of these molecular advances. The tasks of public health and
epidemiology should still involve prevention, the nonrandom occurrence of
disease, and its environmental context in addition to heredity. The tools to
address these tasks should continue to be refined.
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Med Clin N Am 86 (2002) 591–614
Genetics of dementia
Debby W. Tsuang, MD, MSca,b,c,*,
Thomas D. Bird, MDb,c,d
a
Departments of Psychiatry and Behavioral Sciences and Epidemiology,
University of Washington, Seattle, WA, USA
b
Alzheimer’s Disease Research Center, University of Washington, Seattle, WA, USA
c
Veterans Affairs Puget Sound Health Care System, Mental Illness Research, Clinical, and
Education Center, 116MIRECC, 1660 South Columbian Way, Seattle, WA 98108, USA
d
Departments of Neurology, Medical Genetics, and Psychiatry and Behavioral Sciences,
University of Washington, Seattle, WA, USA
This article reviews seven of the most prominent examples of dementing

disorders for which genes have been identified. These disorders comprise the
most common causes of dementia in the elderly; however, this list is not
exhaustive. Interested readers should refer to the texts by Pulst [1] and Terry
et al [2] for detailed descriptions regarding specific disorders.
Clinical features
Alzheimer’s disease (AD) is the most common cause of dementia [2]. It is
a slowly progressive disease that initially presents with short-term memory
loss. Additional symptoms include executive dysfunction, confusion, apha-
sia, gait, and behavioral disturbances. The typical age of onset is older than
65 years. The average duration of illness ranges from 4 to 20 years. More
women than men are affected even after adjustment for the greater longevity
of women.
Pathologic features
Pathologically, AD is characterized by diffuse cerebral atrophy associated
with b-amyloid (Ab) neuritic plaques, neurofibrillary tangles, and amyloid
* Corresponding author. Veterans Affairs Puget Sound Health Care System, Mental Illness
Research, Clinical, and Education Center, 116MIRECC, 1660 South Columbian Way, Seattle,
WA 98108, USA.
E-mail address: [email protected] (D.W. Tsuang).
PII: S 0 0 2 5 - 7 1 2 5 ( 0 2 ) 0 0 0 0 3 - 2
592 D.W. Tsuang, T.D. Bird / Med Clin N Am 86 (2002) 591–614
angiopathy as first described by Alois Alzheimer in 1911 [3]. Senile plaques

are complex structures consisting primarily of a core of abnormal aggregates
of a small protein molecule known as Ab. Neurofibrillary tangles are dense
bundles of helically wound abnormal fibers composed of a modified form of
a normally occurring neuronal protein, the microtubule-associated protein
tau. The presence of either senile plaques or neurofibrillary tangles is not
pathognomic of AD [4]. They are both known to occur in other neurodegen-
erative disorders as well as in normal aging. A higher density of these lesions
in specific brain regions along with the presence of a clinical history of
dementia consistent with AD confirms the diagnosis of AD.
Epidemiology
The risk for AD increases with advancing age. Approximately 10% of the
white population over the age of 70 years have dementia, and more than half
of these patients have AD [5]. In addition, approximately 20% to 40% of
individuals older than 85 years have clinically significant dementia.
The next most important risk factor for AD is family history. Epidemio-
logic studies show that individuals who have an affected first-degree relative
with AD have an approximately fourfold greater risk of developing AD and
a total lifetime risk of 23% to 48% [6], although more recent European stud-
ies do not report such high estimates [7]. To date, reports on monozygotic
and dizygotic twin pairs have suggested higher concordance rates in mono-
zygotic twins than in dizygotic twins [8]. Although the sample sizes are
small, they suggest that genetic components play an important role. The
lack of complete concordance in monozygotic twins suggests that environ-
mental components are also important in the etiology of AD.
The risk for AD is even higher if there are individuals in more than one
generation with the disease, especially when the disease is of early onset (age
<65 years). In some of these rare families, AD occurs as a single-gene auto-
somal dominant trait. Further proof for a genetic basis in AD is that all per-
sons with trisomy 21 (Down syndrome) who survive beyond the age of
40 years invariably demonstrate the neuropathologic features of AD [9].
These observations led to the finding of mutations in the amyloid precursor
protein (APP) gene on chromosome 21, the first documented genetic cause
of AD [10]. Although there are fewer than 20 families worldwide with APP
mutations, the discovery of these mutations confirmed that genetic factors
are important in AD.
Familial Alzheimer’s disease

Although there is no universally accepted definition of familial AD
(FAD), a working definition is three or more affected first-degree relatives
(with at least one individual’s diagnosis confirmed at autopsy). The clinical
features of FAD are typically indistinguishable from nonfamilial (or spo-
radic) AD [11]. Disease duration is usually 6 to 10 years but can range from
D.W. Tsuang, T.D. Bird / Med Clin N Am 86 (2002) 591–614 593
2 to 20 or more years. Familial AD is typically divided into early-onset (<65

years old) and late-onset (>65 years old) types. Thus far, three causative
genes have been found in early-onset families. Although these genes account
for less than 2% of all cases of AD, the discovery of these genetic mutations
has been critical in designing studies to investigate the underlying pathophy-
siology in AD. A fourth gene, the apolipoprotein E (APOE) e4 is a major
genetic risk factor for both early- and late-onset AD. Other important ge-
netic and environmental risk factors remain to be discovered.
Amyloid precursor protein

The APP gene maps to the long arm of chromosome 21. It encodes for a
precursor protein that is proteolytically cleaved to form Ab protein. Ab is a
39 to 43 amino-acid peptide that is the major component of the neuritic
plaque, one of the neuropathological hallmarks of AD. Two proteolytic
pathways for APP processing have been shown to occur normally (Fig. 1).
The first is cleavage within the Ab sequence by a protease referred to as
a-secretase [12]. Ab is destroyed by this cleavage, meaning that this pathway
does not contribute to Ab formation. The second cleavage is on either side of
the Ab sequence. Enzymes called b- and c-secretase cleave APP to form the N
(amino) and C (carboxy) termini of Ab peptide, respectively. b-secretase
cleaves APP first, followed by c-secretase cleavage, which can result in Ab
peptides of different lengths [13]. Two b-secretases have been identified and
are referred to as BACE 1 and BACE 2 [14]. c-secretase cleavages occur
within the predicted transmembrane domain of APP, resulting in the Ab40
and Ab42 species. The predominant species, Ab40, is formed by cleavage
after the fortieth amino acid of Ab. Conversely, Ab42 only accounts for 10%
of the totally secreted Ab. It is hypothesized that Ab42 is the pathogenic
Fig. 1. Schematic representation of the amyloid b (Ab) peptide portion of the amyloid
precursor protein (APP) demonstrating mutation sites associated with familial Alzheimer’s
disease (positions 670-671 and 717) and hereditary cerebral hemorrhagic amyloidosis of the
Dutch type (positions 692 and 693). The three normally occurring sites for processing this
portion of the APP are also indicated by the a-, b-, and c-secretases. Note that cleavage by the
a-secretase interrupts the Ab peptide, whereas cleavage by only the b- and c-secretases allows
the Ab peptide to remain intact. (From Levy-Lahad E, Bird TD. Genetic factors in Alzheimer’s
disease. Ann Neurol 1996;40:829–40; with permission.)
species in FAD, because plasma exhibits a selective increase in Ab42

and because Ab42 is the major constituent of amyloid plaque deposits in
the brain [13,15]. b- and c-secretases are potential therapeutic targets, be-
cause inhibition of their activity would decrease Ab production. There is
evidence that presenilin-1 has c-secretase activity and may be the major
c-secretase [16].
In 1990, a mutation in the APP gene was first discovered in the rare
condition called cerebral hemorrhagic amyloidosis of the Dutch type [17]. Be-
cause cerebral amyloidosis is also a hallmark of AD, this led to the search for
APP mutations in FAD. In 1991, it was discovered that a valine-to-isoleucine
substitution existed at codon 717 (Val717Ile) in two families [10]. Sub-
sequently, more than 20 different families have been identified with disease-
causing APP mutations. APP mutations are a rare cause of early-onset FAD
(which is itself uncommon). They account for probably less than 10% of
early-onset FAD and certainly less than 1% of all AD. Clinically, APP muta-
tions result in autosomal dominant early-onset AD, which is typically fully
penetrant by the time an affected individual reaches his/her early sixties. In
the Val717Ile mutation, age of onset ranges from 41 to 64 years (mean ¼ 50
50 years). There is no evidence that APP mutations are responsible for late-
onset FAD. There is no commercially available test for APP mutations.
Presenilin 1/chromosome 14 gene

In 1992, genetic linkage of FAD to a chromosome 14 locus was established
and confirmed [18]. The gene, presenilin 1 (PS-1), was subsequently discov-
ered in 1995 [19]. This gene is predicted to encode a 467–amino acid protein
with 7 to 10 hydrophobic transmembrane domains (Fig. 2). More than 70 dif-
ferent mutations in PS-1 have been identified worldwide [20]. Most of the
mutations are missense mutations (ie, a single base-pair change that results
in a single amino acid substitution). However, very few of these mutations
result in a truncated normal protein, however, suggesting that the mutations
likely cause a change or gain in protein function rather than a loss of function.
The function of PS-1 remains unknown, but it may have c-secretase–like
activity [16,21].
Of the three genes known to cause FAD, PS-1 mutations are associated
with the earliest age of onset and cause the most rapidly progressive disease.
Disease onset ranges from 35 to 55 years of age. Penetrance is nearly com-
plete by the age of 65 years. Disease duration is usually short (5.8–6.8 years)
[6]. PS-1 mutations are more common than APP mutations, representing
approximately 30% to 60% of early-onset FAD and less than 5% of all
AD [6]. A commercial test is available for PS-1 mutations. It is critical that
genetic counseling take place before genetic testing in asymptomatic indivi-
duals, however [22].
The clinical picture associated with PS-1 mutations is typically character-
ized by severe dementia associated with language disturbance and myoclo-
Fig. 2. Schematic representation of one possible form of the transmembrane proteins encoded
by the presenilin-1 (PS-1) gene on chromosome 14 and presenilin-2 (PS-2) gene on chromosome 1.
This diagram shows eight transmembrane domains, but other configurations remain possible.
Several known mutations are indicated, including PS-1 (filled circles) and PS-2 (open circles).
Not all mutations are shown. The arrow at the top left of the figure points to the Volga German
PS-2 N141I mutation, the first PS-2 mutation discovered. The arrow at the bottom of the figure
points to a PS-1 mutation (an exon 9 deletion) that is often associated with early spasticity.
nus, which appear relatively early in the course of the disease [23,24]. One
mutation in the PS-1 gene (an exon 9 deletion) is often associated with early
spasticity (see arrow in Fig. 2) [25].
Presenilin 2/chromosome 1 gene

The third AD gene was discovered shortly after the discovery of the PS-1
gene. It was found in FAD kindreds with Volga German (VG) ancestry [26].
These families are ethnic Germans who migrated to Russia but remained
separated from the native Russian population. Many of these families sub-
sequently immigrated to the United States, and eight of these families were
found to have FAD presumably on the basis of a genetic founder effect (ie,
a single common affected ancestor). The presenilin 2 (PS-2) gene was cloned
through its homology with the PS-1 gene [27]. It was also called STM-2
(seven-transmembrane domains), although the exact number of transmem-
brane domains remains unknown. PS-2 is predicted to encode a 448–amino
acid protein that is 67% identical to PS-1 (see Fig. 2). The highest degree of
conservation is within the hydrophobic/transmembrane domains, suggesting
that these regions are important in the normal functioning of the protein.
Furthermore, the genomic similarity between PS-1 and PS-2 suggests that
they arose by duplication. To date, only four or five mutations in PS-2 have
been discovered, making this the least common known genetic cause of AD
[20]. A single mutation (N141I) occurs in all the reported early-onset VG
pedigrees, which is consistent with the founder effect hypothesis. All PS-2
mutations are also missense mutations.
Clinical features associated with PS-2 mutations have been reported pri-
marily in the VG families. The mean age of onset in these families is
54.9 ± 8.5 years, and mean disease duration is 7.6 ± 3.2 years. Within the
VG families, there is high variability in age of onset, ranging from 40 to
75 years [26]. Ths PS-2 mutation is highly penetrant (>95%). The dementia
in PS-2 AD is clinically and neuropathologically indistinguishable from that
of sporadic AD.
Apolipoprotein E
The APOE gene was initially identified as a genetic risk factor in AD by
genetic linkage analysis of late-onset FAD pedigrees [28]. Because APOE
was known to be present in amyloid plaques and neurofibrillary tangles,
these observations made APOE a plausible candidate gene. A strong allelic
association between APOE e4 and AD was established in 1993 [29,30]
and was rapidly confirmed in autopsy-proven sporadic and familial late-
onset AD cases. AD risk associated with APOE is dose dependent
[29,31]. The presence of the e4 allele seems to modify the age of onset of
AD [32]. Compared with the most common APOE genotype (e3/e3), odds
ratios range from 2.8 to 4.4 for AD subjects with one e4 allele compared
with normal controls; the odds ratio increases from 7.0 to 19.3 for subjects
with two e4 alleles [33,34]. These risk estimates are not as strongly observed
in blacks or Hispanics (reviewed by Farrer et al [33]), although Hispanics
with an e4 allele and blacks who are e4 homozygous remain at increased
risk for developing AD [35]. Studies suggest a different e4 allele effect in
men than in women. In men, only e4/e4 homozygotes have a younger age
of onset; whereas one e4 allele is sufficient to reduce the age of onset in
women [36]. The APOE e4 risk seems to be more pronounced in women
[32]. This study reported that women with the e4/e4 genotype (approxi-
mately 1% of the general population) have a 40% risk of developing AD
by the age of 73 years. Not all studies support these findings, however. In
addition, several studies suggest a reduced frequency of the APOE e2 allele
in AD patients [37,38].
Apolipoprotein E genetic testing in Alzheimer’s disease

APOE genotyping is not recommended in asymptomatic persons without
dementia, because the presence or absence of e4 is not highly predictive of
future AD. Individuals with an e4 allele may not develop AD, whereas those
without an e4 allele sometimes develop AD. Some have advocated APOE
testing as an adjunct in the diagnostic evaluation of demented persons
[39]. A community-based study suggests that such testing only adds a small
amount of certainty to diagnostic accuracy [40].
Late-onset Alzheimer’s disease

More than 50 genes have been implicated in late-onset AD [41]. Linkage
studies suggest that chromosome 12 contains such candidate genes, includ-
ing the a-2 macroglobulin gene [42] and low-density lipoprotein receptors
[43]. Neither has been clearly established as an AD gene, however [44,45].
Other studies requiring further evaluation have suggested the involvement
of genes on chromosome 10 [46,47]. Numerous association studies have
implicated other potential genetic factors in AD, but most have not been
confirmed or replicated. These factors include interleukin-6, human leuko-
cyte antigen, a1-antichymotrypsin, and angiotensin converting enzyme [41].

Dementia with Lewy bodies (DLB) [48] encompasses any case that exhi-
bits clinical dementia and has Lewy bodies (LBs) on autopsy, thereby includ-
ing (1) diffuse LB disease, (2) LB variant of AD, as well as (3) dementia
associated with classic Parkinson’s disease (PD). As anticipated, there is sub-
stantial clinical overlap between DLB and AD as well as PD. Clinically,
DLB is characterized by progressive and fluctuating cognitive impairment,
parkinsonism (either de novo or neuroleptically induced), and psychosis with
prominent visual hallucinations. Over half of the patients with autopsy-
proven DLB have hallucinations or systematized delusions during the course
of their illness [49]. Behavioral disturbances (ie, systematized delusions or
hallucinations) that require neuroleptic treatment, which can worsen parkin-
sonian signs and symptoms, present therapeutic challenges for clinicians.
Neuropathologically, DLB is characterized by the presence of LBs, which
is also the hallmark of PD. Twenty to fifty percent of cases with neocortical
LBs also have substantial AD pathologic findings, namely, Ab deposition
[49]. The boundaries of DLB are still far from being clearly defined because
of its shared clinical and neuropathologic features with PD and AD.
Although most cases with DLB are considered sporadic, there are several
reports in which LB disease seems to be familial [50,51]. To date, no genes
have been identified that cause DLB, and additional genetic and neuro-
pathologic studies are necessary to further investigate the role of genetic fac-
tors in DLB. Two genes have been shown to cause rare genetic types of PD:
a-synuclein and parkin. Families with a-synuclein mutations have LB patho-
logic findings and may develop dementia [52,53]. Patients with parkin muta-
tions do not necessarily have dementia or LB pathologic findings [54].
Vascular dementia
Clinical features
Binswanger (1894) and Alzheimer (1911) described behavioral disorders
related to arteriosclerosis. Initially, these conditions were categorized as
subcortical arteritis; later, they were classified as Binswanger’s disease. With

newer neuroimaging techniques, small vessel ischemic disease is now com-
monly observed in geriatric patients. The contribution of small vessel
atherosclerotic disease to clinical dementia remains controversial. Vascular
dementia typically does not have a distinct genetic risk factor, although mul-
tiple cerebrovascular risk factors are heritable (eg, hyperlipidemia, hyperten-
sion). The genetics of vascular dementia is likely multifactorial. As a result,
assessing the genetic contributions of each of the risk factors is extremely
complicated. For the purposes of this article, we focus on a rare cerebrovas-
cular disease associated with dementia for which a gene has been discovered.
An autosomal dominant syndrome of hereditary multi-infarct dementia
has been described with subsequent gene identification [55]. This disorder
is called cerebral autosomal dominant arteriopathy with subcortical infarcts
and leukoencephalopathy (CADASIL). Although this is a rare form of vas-
cular dementia, it is the first genetic form of geriatric dementia and depres-
sion to be identified. As a result, this disorder should be considered in the
differential diagnosis of geriatric patients presenting with these symptoms.
Clinically, patients with CADASIL can have dementia (80%), depression
(30%–50%), and migraine with an aura (30%) during the course of their dis-
ease. The typical age of onset is in the 50s or 60s; the typical age at death is
64.5 years. Cognitive impairment in CADASIL is best characterized as fron-
tal lobe disturbance, including inattention, perseveration, apathy, and pseu-
dobulbar affect. On T2-weighted MRI, patients with CADASIL have areas
of high signal in the periventricular and deep white matter as well as in the
basal ganglia. These abnormalities may be observed while patients are in their
20s, asymptomatic, and are initially similar to patients with multiple sclerosis.
Hyperintensities increase over the next two decades of life until confluent areas
of high signal in the subcortical white matter are observed. Transient ischemic
attacks begin to occur when patients are in their 40s and 50s, with some
cases showing extensive lacunar infarcts. The patients are not hypertensive.
Pathologically, there is a narrowing of small arteries throughout the brain
caused by smooth muscle layer hypertrophy, with electron microscopy show-
ing osmophilic densities in the arteriolar media. The diagnosis of CADASIL
can sometimes be confirmed by skin biopsies showing the arteriolar patholo-
gic changes. False-negative skin biopsies have been reported, however.
Notch3
Linkage analysis mapped the CADASIL gene to the short arm of chro-
mosome 19. Mutations in the Notch3 gene were first reported in 1996.
Subsequent studies reported that these mutations may be present in indivi-
duals without a positive family history [56]. The frequency of Notch3 muta-
tions in sporadic and familial cases with vascular dementia remains unclear
but seems to be rare. In addition, mutations in the APP and cystatin-b genes
are rare causes of cerebral amyloid angiopathy and hemorrhagic strokes.
Regardless of their prevalence, the discovery of these mutations provides an

opportunity to explore the genetics of cerebrovascular disease.
The interaction of the multitude of risk factors related to stroke remains
unclear. Each of these risk factors is influenced by diverse pathogenetic
mechanisms. In the future, additional knowledge regarding the genetic and
environmental risk factors related to conditions such as atherosclerosis, dia-
betes mellitus, and hypertension should result in prevention of and interven-
tion in dementia associated with cerebrovascular disease in the future.
Clinical features
The clinical triad in HD includes chorea, cognitive impairment, and beha-
vioral disturbances. Chorea is the main motor sign in HD. These involuntary
movements are present only during waking hours. Typically, they cannot
be voluntarily suppressed and can increase with stress. Some patients may
develop bradykinesia, rigidity, and dystonia. Aspiration secondary to dys-
phagia is the most common cause of mortality and morbidity. A typical pat-
tern of cognitive decline includes slowness of thought and impaired ability
to integrate new knowledge, particularly new motor skills, and a lack of aware-
ness of one’s own disability. Visuospatial memory is particularly affected,
whereas verbal memory remains preserved until late in the course of the dis-
ease. Patients may be able to remember facts, stories, and words but have dif-
ficulty copying designs on the Mini-Mental State Examination. Orientation
to time and place remains intact until late in the illness. Changes in mood and
personality are common, ranging from irritability to prolonged periods of
depression as well as psychosis [57]. Suicide is more common in patients with
HD than in the general population. Psychiatric symptoms may precede motor
signs and symptoms by many years and do not necessarily relate to the sever-
ity of chorea or dementia. Other symptoms commonly observed include
apathy, aggressive behavior, sexual disinhibition, and alcohol abuse.
The diagnosis of HD is indicated by the presence of a positive family his-
tory of an autosomal dominant degenerative disorder consistent with HD;
presence of progressive motor disability, including voluntary and involun-
tary movements; cognitive decline; and behavioral disturbances. Caudate
atrophy on CT or MRI provides additional support for the diagnosis. Finally,
DNA analysis confirms the diagnosis. The mean age of onset in HD is
approximately 40 years [58], although the age of onset ranges from 2 to
80 years. The duration of HD is typically 15 years, with the age of death
ranging from 51 to 63 years.
Pathologic features
The primary pathologic feature in HD is neuronal loss in the corpus stria-
tum, occurring first in the caudate and later in the globus pallidus. Caudate
atrophy is evident on MRI, with characteristic concavity of the ventrolateral

aspect of the lateral ventricles. A neuropathologic grading system rates the
macroscopic and microscopic appearance of the striatum [59]. The neuronal
loss seems to be selective, with the medium spiny neurons being preferen-
tially lost. Neurons containing gamma-aminobutyric acid and enkephalin
are the most severely affected, and the most consistent neurochemical find-
ings suggest low levels of these two neurotransmitters. The discovery of
intranuclear inclusions in HD brains that contain the protein encoded by the
HD gene (huntingtin) [60] has resulted in new avenues of animal research.
Whether these inclusions interfere with nuclear function or whether they are
markers for neurodegeneration remains unknown.
Epidemiology
Many epidemiologic studies have been performed worldwide. There is
general agreement that the prevalence of HD in Western European coun-
tries is between 3 and 10 cases per 100,000 persons. The rates are lower in
Japan, China, and Finland as well as in African black populations. George
Huntington, who first described the syndrome in 1872 [61], noted clear
familial aggregation in HD.
Genetics
HD is inherited as an autosomal dominant trait. In 1983, HD became the
first genetic disorder to be linked by restriction fragment length polymor-
phism markers to a locus on chromosome 4. [62] Ten years later, an interna-
tional research consortium reported the successful cloning and sequencing of
the HD gene [63]. A novel gene containing a trinucleotide repeat (CAG) that
is repeated beyond the normal range is associated with HD. This highly poly-
morphic CAG repeat is located in the 5¢ region of the HD gene (Fig. 3).
Individuals with symptomatic HD have more than 36 CAG repeats in the
HD gene. Individuals with the greatest number of repeats (>60) are more likely
to have juvenile-onset illness. Most adult-onset HD cases have 38 to 50 CAG
repeats. A significant correlation between the number of CAG repeats and age
of onset of HD has been demonstrated [64–67]. The association was the great-
est in patients with higher CAG repeats (>60), who tended to have a lower age
of onset. But the number of CAG repeats is not useful in predicting the age
of onset or type of symptoms at presentation in individual patients, however.
HD is the first of numerous neurodegenerative disorders associated with a
trinucleotide repeat expansion. Several other neuropsychiatric disorders (eg,
fragile X mental retardation, hereditary ataxias) that exhibit anticipation are
also trinucleotide repeat disorders [68,69]. Genetic testing issues in HD are
complex and require careful thought and counseling [70,71].
Interestingly, the discovery of dynamic repeat mutations helps to account
for the long-observed clinical phenomenon of anticipation. Anticipation is
Fig. 3. The Huntington’s disease (HD) gene on chromosome 4. Genetic markers are indicated
at the top of the figure. D4S10 was the initial marker linked to HD. The bold lines indicate the
HD gene, which was called Interesting Transcript-15. This novel gene contains highly
polymorphic trinucleotide repeats, (CAG)n, at the 5¢ end of the HD gene. Individuals with
symptomatic HD have more than 36 CAG repeats at this locus. (Courtesy of Elisabeth
Almqvist, PhD, Stockholm, Sweden).
the observation that a disease becomes more severe and appears earlier with
each successive generation. As in other trinucleotide repeat disorders, this is
a result of the unstable expansion of the CAG trinucleotide repeats when the
disorder is passed from parent to offspring. In addition, paternal HD alleles
are more likely to undergo significant expansion than maternal alleles,
resulting in the observation that those individuals with larger repeat sizes are
more likely to have affected fathers.
Clinical features
Initially, Pick described a clinical syndrome with dementia, progressive
aphasia, and frontal cortical atrophy [72]. Neuronal cytoplasmic inclusions
(Pick bodies) were observed later in neuropathologic studies of some cases.
Because most patients with dementia and prominent frontal lobe dysfunction
do not have Pick bodies, confusion has reigned in the nosology of frontotem-
poral dementia (FTD). Terminology has included Pick’s disease, Pick com-
plex, non-AD dementia, disinhibition-dementia-parkinsonism-amyotrophy
complex, and frontal lobe degeneration with spinal motor degeneration.
In the 1970s, clinical and pathologic studies helped to solidify consensus
diagnostic criteria for FTD [73–75]. Specifically, the discovery of genetic
mutations in some FTD families with taupathies (eg, FTD, parkinsonism-
linked to chromosome 17 [FTDP-17]) has resulted in new diagnostic cate-
gories (see below).
Typically, the clinical presentation of FTD includes personality or behav-
ioral change (often disinhibition) with a relatively intact memory. Later in the
course of disease, there may be marked confusion, mutism, and parkinsonian
features. There are at least three subtypes of FTD, including progressive
aphasia, semantic dementia, and frontal lobe degeneration [76]. Patients

with progressive aphasia have progressively nonfluent speech with agraphia,
alexia, and acalculia with preservation of word meaning. Patients with seman-
tic dementia have predominantly temporal lobe abnormalities with progres-
sive loss of word meaning but a preserved ability to read and write regular
words. Patients with frontal lobar degeneration have a marked loss of person-
al and social awareness with hyperorality, distractibility, and task impersis-
tence. In general, patients with inferior-frontal lobe involvement tend to be
more disinhibited, whereas patients with involvement of dorsolateral-frontal
regions tend to be abulic.
Pathologic features
Pathologically, there is frontal or temporal lobar atrophy. Many cases
have only gliosis and neuronal loss without distinctive features. Other
cases have cytoplasmic inclusions that may be typical Pick bodies or other
varieties of tau-positive material, sometimes resembling neurofibrillary tan-
gles. Classic Pick’s disease with Pick bodies is considered a subtype of FTD.
Some cases also have anterior horn cell loss in the spinal cord.
Epidemiology
Incidence and prevalence estimates of FTD are not well established,
partly due to the clinical heterogeneity of the disorder. The only available
sample estimating disease incidence is based on clinician referrals. In this
study [77], the prevalence rises from 1.2 to 28 cases per 1 million persons from
the third decade to the sixth decade. But because this was not a population-
based study, this is probably an underestimate. Among all patients with
dementia, FTD is thought to comprise approximately 10% of cases (and prob-
ably more in younger age groups).
FTD is the most common syndrome with prominent frontal lobe degen-
eration. It is commonly misdiagnosed as AD, and less commonly as DLB
or AD with vascular disease. Most FTD cases are misdiagnosed as AD. In
the Consortium to Establish a Registry for Alzheimer’s Disease neuropatho-
logic studies, FTD-like pathologic findings were observed in 3% to 9% of
patients with a clinical diagnosis of AD [78]. The frequency of FTD in
autopsy case series with dementia varies from 0% to 15% [79].
Genetics
Familial aggregation was the first feature of FTD suggesting that there
may be an underlying genetic cause. Several groups reported a positive
family history in 10% to 60% of cases [77,80]. Segregation analyses have sug-
gested that first-degree relatives of FTD patients are 3.5 times more likely to
develop dementia than first-degree relatives of normal controls. It has also
been suggested that age of onset in relatives of FTD patients is, on average,
11 years younger than in other dementia patients [77]. There are clearly a
few large families with multiple affected individuals in which FTD seems
to segregate in a highly penetrant and autosomal dominant fashion. The
success of gene identification (see below) in families with atypical dementia
not only confirmed the genetic basis of FTD but established it as a distinct
clinical and pathologic entity.
Frontotemporal dementia and parkinsonism-linked to chromosome 17

The first systematic linkage study of FTD families mapped the causative
gene to chromosome 17 [81]. Subsequently, many other families with FTD-
like features also showed linkage to the same region. Interestingly, several
other clinically distinct syndromes also mapped to 17q21-22, including par-
kinsonism [82] and schizophreniform features [83].
At the consensus meeting on chromosome 17-linked dementia in 1996,
these syndromes were classified as FTD and FTDP-17 [84]. Even though
many clinical differences exist, pathologic similarities between the various
syndromes include tau protein aggregates in the absence of amyloid plaques.
Some of these aggregates have similar morphology to the neurofibrillary
tangles (NFTs) seen in AD. Because tau is a major component of NFTs and
the tau gene is located in the critical region, it has been considered an impor-
tant candidate gene for FTDP-17. After some failed attempts to identify
mutations in this gene, the first tau mutation was identified in a family with
familial presenile dementia with psychosis [85] and was confirmed in addi-
tional studies [86,87]. This mutation (V337M) is located in exon 12 of the
tau gene (Fig. 4). Since then, more than 20 tau mutations have been identi-
fied in FTDP-17 families [88,89]. Other families not linked to chromosome
17 have been identified, however, and linkage to chromosome 3 has been
reported in one such family [90]. The causative gene in this family is yet
to be identified.
Tau gene
The modified product of the tau gene is a major component of NFTs seen
in AD. The tau gene is large, with 100,000 base pairs of DNA and 15 exons.
It also exhibits complex splicing (see Fig. 4). There are commonly six alter-
natively spliced isoforms of the tau gene involving exons 2, 3, and 10. All but
one of the currently identified mutations affect microtubule binding do-
mains. Most of these mutations are missense, appearing in the coding re-
gions as well as in the noncoding regions (introns). Some mutations are
believed to cause disease by producing functional changes that interfere with
the normal binding of microtubules, whereas other mutations appear to
change the ratio of tau isoforms in the brain (3 and 4 repeat tau). The discov-
ery of tau mutations in families with FTDP-17 has confirmed the fact that
genetics plays a role in a subgroup of FTD cases. More work needs to be
done to determine the range of tau mutations in FTD and related disorders.
Fig. 4. The tau gene on chromosome 17 has a complex genomic structure with more than 15
exons spread over 100,000 base pairs of genomic DNA (top of figure). It undergoes complex
differential splicing. Exons 2, 3, and 10 are alternatively spliced, making up six commonly
alternatively spliced isoforms of the tau gene. The large bold arrow points to the first tau
mutation (V337M) associated with frontotemporal dementia, which was discovered in exon 12.
(Courtesy of Parvoneh Poorkaj, PhD, Seattle, WA).
Tau mutations have not been found in AD or sporadic cases of FTD. In

conditions with tau aggregate pathologic findings, such as Guamanian-
amyotrophic lateral sclerosis-parkinsonism-dementia complex and progres-
sive supranuclear palsy, there are genetic association data that suggest that
tau may play a role in the disease process [91–93]. Explanations for these
various clinical, pathologic, and molecular findings are necessary to better
understand the role of tau and the frontal lobes in behavior and cognition.
Understanding the in vivo processing of the tau gene is likely to be impor-
tant in the eventual development of therapeutic treatments. But most FTD
cases are sporadic and are not associated with mutations in the tau gene
[94,95]. If FTD is familial and affected individuals have tau-related neuro-
pathologic findings, the frequency of tau mutations increases to as high as
30% to 40%.
Prion disease
Although prion diseases are relatively uncommon, they exemplify both
transmissible and heritable forms of dementia. What we now know as prion
diseases were first described in the 1800s, with reports of scrapie in sheep.
Scrapie was shown to be experimentally transmissible in 1936 [96]. Human
prion diseases were recognized in the 1920s by Creutzfeldt and Jakob and
were called spongiform encephalopathies [97,98]. In the 1960s, kuru (a

deadly neurodegenerative disorder transmitted through ritualistic cannibal-
ism) was recognized to be similarly transmissible. In the 1990s, the occur-
rence of bovine spongiform encephalopathy (mad cow disease) further
increased the recognition of these disorders. The prevalence of Creutzfeldt-
Jakob disease (CJD) is approximately 1 case per 1 million persons.
Prions are small proteinaceous particles that resist inactivation by con-
ventional proteinases. The normal cellular prion protein (PrPC) is a mem-
brane protein primarily expressed in astrocytes [99–101]. The mechanisms
by which PrPC converts to the scrapie isoform (PrPSc) remain unclear, but
the protein structure undergoes a three-dimensional configuration change.
Six human diseases associated with prions have been described, including
kuru, CJD, Gerstmann-Sträussler-Scheinker syndrome (GSS), fatal familial
insomnia (FFI), atypical prion disease, and new variant CJD (Fig. 5).
The identification of the prion protein (PRNP) gene that encodes the prion
protein (PrP) [102] has rapidly transformed neurobiologic and genetics
research in this area. Although some families have mutations in the PRNP
gene that are transmitted in an autosomal dominant fashion and other
cases are caused by known exposure to contaminated tissue, most sporadic
cases have no known cause. Interestingly, some prion diseases (eg, CJD,
new variant CJD) can be both vertically (heritable) and horizontally
Fig. 5. The human prion diseases include Creutzfeldt-Jakob disease, kuru, Gerstmann-
Sträussler-Scheinker disease, and fatal familial insomnia. The animal prion diseases include
scrapie, transmissible mink encephalopathy, and bovine spongiform encephalopathy. Because
these diseases all share the property of transmissibility and the characteristic pathologic finding
of spongiform changes, they are often collectively referred to as transmissible spongiform
encephalopathies.
(infectious) transmitted. In this section, we review the genetics of CJD, GSS,

and FFI. Current nosology may be replaced in the future by specific DNA
mutations, such as ‘‘familial prion disease with a P102L mutation and
predominant ataxia.’’
Creutzfeldt-Jakob disease
Sporadic CJD most often affects patients in their 50s and 60s. The typical
clinical presentation includes rapid progressive cognitive decline (<2 years to
death) accompanied by a variety of neurologic signs (most commonly rigid-
ity, ataxia, and myoclonus) and characteristic synchronous spikes on the
electroencephalogram in an afebrile individual. The classic symptoms occur
in less than 60% of cases, however. Other clinical features may include psy-
chotic symptoms resembling schizophrenia as well as extrapyramidal and
cerebellar dysfunction or akinetic mutism.
The diagnosis of CJD should be entertained in individuals with rapidly
progressive neuropsychiatric disorders. Clinical diagnostic criteria have
been established by a large CJD surveillance group in Europe [103],
although definitive diagnosis can only be made on neuropathologic or bio-
chemical examination of the brain. The neuropathologic hallmarks of CJD
include spongiform degeneration, neuronal loss, and astrocytic gliosis.
PrPSc-positive kuru plaques and other PrP-containing amyloid plaques are
pathognomic of prion disease. They are almost exclusively found in familial
CJD cases with PRNP mutations. A cerebrospinal fluid test for the 14-3-3
protein has been found to be diagnostically useful.
Prion protein mutations

The human PRNP gene is located on the short arm of chromosome 20.
This gene is highly conserved throughout many species, suggesting that its
function is critical. The cellular function of PrPC remains unknown, how-
ever. In families with inherited prion diseases, more than 15 types of muta-
tions have been described [104]. There are no systematic studies that provide
frequency estimates of known mutations in different patient samples.
The most common PRNP mutation associated with familial prion disease
is the E200K (glutamic acid [GAG] to lysine [AAG]) mutation. This muta-
tion has been found in more than 50 families worldwide. Up to 50% of
familial cases have this mutation. The largest known cluster is a group of
Libyan Jews living in Israel, who have an incidence of CJD 100-fold greater
than the population worldwide [105].
Another missense mutation (D178N) in the PRNP gene has been
reported in a number of different families. Surprisingly, the phenotype
depends heavily on the genotype present at an entirely different codon
(codon position 129). In families with the D178N mutation and valine at
position 129, the presentation is that of fairly typical CJD with memory loss,
ataxia, and myoclonus. The age of onset is in the 50s and 60s, with the dis-
ease duration ranging from 9 months to 4 years. The electroencephalogram
shows generalized slowing rather than periodic triphasic waves. Neuro-
pathologic findings include diffuse spongiform degeneration in the cerebral
cortex and basal ganglia with relative sparing of the thalamus.
Alternatively, in families with the same D178N mutation but with
methionine at position 129, the phenotype is that of FFI. These patients
often present with insomnia and dysautonomia. They may later show signs
of ataxia, dysarthria, myoclonus, and pyramidal tract dysfunction. In the
later stages, patients exhibit complete insomnia, dementia, rigidity, dysto-
nia, and mutism. The duration of illness is short (mean ¼ 13 months).
Neuropathologically, FFI is characterized by neuronal loss and astrocy-
tic gliosis preferentially affecting the thalamus. At least 21 families with FFI-
D178N mutations have been reported [106]. It is unclear why the codon
129 genotype dramatically influences the phenotype associated with the
D178N mutation, but it presumably affects the three-dimensional structure
of PrP.
Another phenotype, the GSS syndrome, is caused by several different
mutations in the PRNP gene [107]. Clinical symptoms include early ataxia,
dementia, dysphagia, dysarthria, and hyporeflexia. Patients with GSS are
more likely to exhibit ataxia than patients with CJD. Conversely, patients
with CJD are more likely to have dementia and myoclonus. Clinical symp-
toms often overlap, however, and do not always ‘‘breed true’’ within families.
As such, family members with the same PRNP mutation may have either
phenotype. GSS is always considered to be solely genetic and often has a
longer disease duration than CJD. Neuropathologically, GSS is distinct from
CJD in that GSS is characterized by the presence of large multicentric PrP-
containing amyloid plaques with variable spongiform changes.
The most common mutation associated with GSS is the P102L mutation.
More than 30 affected families in the Northern Hemisphere have been
described to date [108]. This was the first mutation to be formally linked
to a human prion disease and is the causative mutation originally described
by Gerstmann, Straüssler, and Scheinker [109].
The clinical and neuropathologic characteristics of these families are indis-
tinguishable from those of sporadic CJD. Interestingly, when infected brain
tissue from CJD E200K patients was injected into primates, the disease was
transmitted in most trials, but transmission has not been demonstrated in
other families with different mutations [110]. This finding is similar to the
results observed in experiments using brain tissue from sporadic CJD cases.
Mitochondrial disorders
Mitochondrial disorders are clinically diverse and are defined by structu-
ral or functional abnormalities in the mitochondria or mitochondrial DNA
(mtDNA). Because mtDNA has a poorly developed repair system, muta-

tions are rarely repaired. Although infrequent, an increasing number of
mtDNA mutations have been described in several neurologic disorders. The
characteristics of inherited mitochondrial disorders include maternal inheri-
tance, heteroplasmy, mitotic segregation, and the threshold effect. Because
mtDNA is almost exclusively maternally inherited, all mtDNA mutations
are passed on by mothers. Because of the clinical heterogeneity associated
with mitochondrial disorders, analysis of large families is often necessary
to establish the pattern of maternal inheritance. Heteroplasmy refers to the
mixture of both mutant and wild-type molecules within mitochondria. In
normal cells, all mtDNA molecules are identical. As heteroplasmic cells
undergo cell division, the proportions of mutant and normal mtDNA allo-
cated to daughter cells shift. As a result, some clinical symptoms may
improve as a child ages. Mitotic segregation explains the markedly different
levels of mutant mtDNA in members of the same family as well as among
different tissues in a single individual. The threshold effect is the observation
that a certain level of mutant mtDNA must be achieved before a cell
expresses a defect. Variability in onset and severity of clinical manifestations
results from a changing balance between the energy supply and oxidative
demands of different organ systems.
Mitochondrial disorders have been implicated in prevalent neurodegene-
rative disorders (eg, AD, PD) as well as in aging itself, but the evidence is
controversial. Aging is associated with an increase in mtDNA mutations.
These are not specifically germline mutations but accumulating mutations
that may increase over time in any organ, including the brain. The precise
effects of these mutations are not known. These mutations are not genetically
transmitted to the next generation but may cause dysfunction of the organs in
which they occur. It has been hypothesized that several different mutations
may ultimately contribute to functional impairment. There is evidence that
mtDNA mutations may be involved in neurodegenerative conditions such
as AD. In AD, it is postulated that mtDNA mutations may lower the oxida-
tive efficiency of critical neuronal populations early in life [111]. An increase
in oxidative damage to mtDNA in AD brains has been reported. In addition,
younger AD patients (<75 years old) are more likely to have an increased
level of common mtDNA mutations than age-matched controls. Neverthe-
less, the data need to be confirmed. It remains unclear whether these observa-
tions are the consequences of the disease or whether they contribute to the
pathophysiology. Screening for mtDNA mutations is not recommended for
any neurodegenerative conditions until these frequency of these mutations
is better established [112].
Summary
Many neurodegenerative diseases are exceedingly complex disorders
(Fig. 6). In the past decade, we have made tremendous advances in our under-
Fig. 6. This diagram demonstrates the concept that the Alzheimer’s disease (AD) phenotype (as
well as the other neurodegenerative conditions) is phenotypically heterogeneous. On the left are
the four known genetic factors associated with AD. There are likely other early-onset as well
as late-onset genes yet to be discovered. On the right are four potential nongenetic causes of
AD that presently remain speculative. In summary, the bottom arrow shows that most cases of
AD in the general population may be the result of a complex interplay between environment,
genetic predisposition, and aging.
standing of the genetic basis of these disorders. One common characteristic

of these disorders is the existence of rare families in which a given disease is
inherited as a Mendelian trait. In this article, we have reviewed the genetics
of several common neurodegenerative disorders that are associated with
cognitive disturbances and for which causative genes have been identified.
Further genetic analysis should clarify the roles of known genes in the
pathogenesis of common sporadic forms of these various diseases. Investiga-
tion of the normal and aberrant functions of these genes should provide
insight into the underlying mechanisms of these disorders. Such research
should facilitate new strategies for therapeutic interventions.
Although molecular genetics has helped to clarify the etiology of these
disorders, clinicians have played a critical role in the careful identification
and classification of many families who were involved in the eventual map-
ping and cloning of causative mutations. The role of the clinician should not
be underestimated. Future clinical and molecular genetics findings hold
many clinical implications. It is likely that new diagnostic and therapeutic
strategies for dementing disorders are just on the horizon.
Acknowledgements
The authors thank Lillian DiGiacomo, BA, and Charisma Eugenio,
BS, for their editorial assistance and Molly Wamble, BA, for her technical
assistance.
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Med Clin N Am 86 (2002) 615–627
The role of tau in Alzheimer’s disease

John Q. Trojanowski, MD, PhD*,
Virginia M.-Y. Lee, PhD
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory
Medicine, University of Pennsylvania School of Medicine, Maloney Building,
3rd Floor, HUP, Philadelphia, PA, 19104, USA
Growing evidence over the past decade has led to the realization that
many sporadic and familial neurodegenerative diseases are characterized
by distinct hallmark brain lesions formed by filamentous deposits of abnor-
mal brain proteins, and a group of heterogeneous disorders characterized
neuropathologically by prominent intracellular accumulations of abnormal
tau filaments may share common disease mechanisms (for recent reviews,
see [1–3]). Despite their diverse phenotypic manifestations, these disorders
are collectively known as neurodegenerative tauopathies (Table 1), and the
absence of other disease-specific neuropathological abnormalities in several
tauopathies provided circumstantial evidence implicating tau abnormalities
in the onset/progression of neurodegeneration [1–3]. However, this was con-
troversial until 1998 when multiple tau gene mutations were discovered in
families with frontotemporal dementia and parkinsonism linked to chromo-
some 17 (FTDP-17) and provided unequivocal evidence that tau abnormal-
ities alone are sufficient to cause neurodegenerative disease [4–8]. This
opened up new avenues for investigating the role of tau abnormalities in
mechanisms of brain dysfunction and degeneration in Alzheimer’s disease
(AD) and related neurodegenerative disorders [1–3]. Indeed, these dramatic
discoveries re-focused attention on the role of tau pathologies in mecha-
nisms of brain degeneration in AD, and here we review recent insights into
these aspects of the pathobiology of AD.
Normal tau biology and functions

Tau proteins are low Mr microtuble associated proteins (MAPs) that
are expressed predominantly in axons of central nervous system (CNS)
E-mail address: [email protected] (J.Q. Trojanowski).
PII: S 0 0 2 5 - 7 1 2 5 ( 0 2 ) 0 0 0 0 2 - 0
616 J.Q. Trojanowski, V.M.-Y. Lee / Med Clin N Am 86 (2002) 615–627
Table 1
Neurodegenerative disease with tau pathology
Amyotrophic lateral sclerosis/parkinsonism-dementia complex*
Argyrophilic grain dementia*
Corticobasal degeneration*
Dementia pugilistica*
Diffuse neurofibrillary tangles with calcification*
Down’s syndrome
Frontotemporal dementia with parkinsonism linked to chromosome 17*
Multiple system atrophy
Myotonic dystrophy
Neurodegeneration with brain iron accumulation type 1 (formerly Hallevorden-Spatz disease)
Niemann-Pick disease, type C
Pick’s disease*
Post-encephalitic parkinsonism
Prion diseases
Progressive subcortical gliosis*
Progressive supranuclear palsy*
Subacute sclerosing panencephalitis
Tangle only dementia*
* Diseases in which tau pathologies are the most predominant neurodegenerative brain
lesions.
neurons, and they also are found in axons of peripheral nervous system
(PNS) neurons, but they are barely detectable in CNS astrocytes and oligo-
dendrocytes [9,10–14]. Human tau is encoded by a single gene consisting of
16 exons on chromosome 17q21, and the CNS isoforms are generated by
alternative mRNA splicing of 11 exons [15–17]. In the adult human brain,
alternative splicing of exons (E) 2 (E2), 3 (E3) and 10 (E10) generates six tau
isoforms ranging from 352 to 441 amino acids in length which differ by the
presence of either three (3R-tau) or four (4R-tau) carboxy-terminal tandem
repeat sequences of 31 or 32 amino acids that are encoded by E9, E10, E11
and E12 [15,18,19]. Additionally, the three 3R-tau and 4R-tau isoforms dif-
fer due to alternative splicing of E2 and E3 that results in tau isoforms with-
out (0N) or with either 29 (1N) or 58 (2N) amino acid inserts of unknown
functions. In the adult human brain, the ratio of 3R-tau to 4R-tau isoforms
is 1, but the 1N, 0N and 2N tau isoforms comprise about 54%, 37% and 9%
of total tau, respectively [20,21]. Further, tau is developmentally regulated
leading to expression of only the shortest tau isoform (3R/0N) in fetal brain,
but all six isoforms are expressed in the adult human brain. In the PNS,
inclusion of E4a in the amino-terminal half results in the expression of the
largest tau isoform [12,22,23].
Several functions of tau have been extensively characterized (for review
[1–3]). For example, tau binds to and stabilizes microtubules (MTs), in addi-
tion to promoting MT polymerization through MT binding domains in
the carboxy-terminal half of tau that are composed of highly conserved
J.Q. Trojanowski, V.M.-Y. Lee / Med Clin N Am 86 (2002) 615–627 617
18-amino acid long binding elements separated by less conserved 13-14

amino acid long inter-repeat sequences [1–3,11,24–27]. The binding of tau to
MTs is a complex process mediated by several MT binding sites distributed
throughout the MT binding repeats and the inter-repeat sequences as well as
sequences flanking the repeats [1–3,20,24,26,28–30]. The 4R-tau isoforms are
more efficient at promoting MT assembly and have a greater MT binding
affinity than 3R-tau isoforms, but the inter-repeat sequence between the 1st
and 2nd MT binding domains has >2 times the binding affinity of any of the
MT binding repeats, and this region is unique to 4R-tau, which may account
for the higher MT binding affinity of 4R-tau versus the 3R-tau isoforms.
Tau phosphorylation is developmentally regulated and fetal tau is more
highly phosphorylated in the embryonic compared to the adult CNS, while
the degree of phosphorylation of the six adult tau isoforms decreases with age
[1–3,31–35]. The tau phosphorylation sites are clustered in regions flanking
the MT binding repeats, and 79 potential serine (Ser) and threonine (Thr)
phosphate acceptor residues are present in the longest tau isoform, while
phosphorylation at 30 of these sites has been reported in normal tau, the
increasing phosphorylation of tau negatively regulates MT binding [1–3,
31,36,37]. Although the relative importance of individual sites for regulating
the binding of tau to MTs is unclear, phosphorylation of Ser-262 has been
reported to play a dominant role in reducing the binding of tau to MTs
[38], but a similar role has been ascribed to phosphorylation of Ser-396
[31], while other studies suggest that neither of these sites dominantly regulate
binding of tau to MTs [39]. However, both sites are phosphorylated in fetal
tau and they are hyperphosphorylated in all six adult human brain tau iso-
forms that form paired helical filaments (PHFs) in AD neurofibrillary tangles
(NFTs). Further, it has been suggested that a sequence of residues amino-
terminal to the MT binding domains (224KKVAVVR230) promotes MT
binding in combination with the repeat regions, and it is likely that phos-
phorylation at multiple phosphate acceptor sites regulates the binding of tau
to MTs.
Although the kinases and protein phosphatases that regulate tau phos-
phorylation are the focus of intense investigation, and a large number of
Ser/Thr protein kinases have been suggested to play a role in regulating tau
functions in vivo, this aspect of tau biology remains controversial (reviewed
in [1–3]). The major candidate tau kinases include mitogen-activated protein
kinase [36,40,41], glycogen synthase kinase 3b (GSK-3b) [42–45], cyclin-
dependent kinase 2 (cdk2) [46], cyclin-dependent kinase 5 (cdk5) [46,47] ,
cAMP-dependent protein kinase [48], Ca2þ/calmodulin-dependent protein
kinase II [49], MT-affinity regulating kinase [50], and stress-activated protein
kinases [51–53]. However, recent data suggest that GSK-3b and cdk5 plausi-
bly regulate the in vivo phosphorylation of tau. For example, GSK3b is a Ser/
Thr kinase that is abundant in brain and associates with MTs, and cell culture
studies indicate that GSK3b induces hyperphosphorylation of tau followed
by dimished MT binding [45,54–57]. In cultured neuronal cells, GSK3b
mediated tau phosphorylation is inhibited by insulin and IGF-1 via a phos-

phatidylinositol 3-kinase and protein kinase B dependent pathway, and in-
hibition of GSK-3b by lithium salts or ATP inhibitors reduces tau
phosphorylation and affects MT stability [43,44,58–61]. On the other hand,
cdk5 is a Ser/Thr protein kinase highly enriched in neurons that colocalizes
with the cytoskeleton and contributes to the phosphorylation of tau, and it
is activated by regulatory subunits such as p35 [46,47,54,62,63]. Moreover,
cdk5 complexes with tau and anchors cdk5 to MTs while cdk5-mediated tau
phosphorylation stimulates further phosphorylation of tau by GSK3b [64–
66]. However, the relative contributions of individual kinases to tau phos-
phorylation in vivo remain to be elucidated.
Protein phosphatases also have been the focus of research on tau since they
counterbalance the effects of tau kinases, and studies have implicated protein
phosphatse (PP) 1 (PP1), 2A (PP2A), 2B (PP2B) and 2C (PP2C) in regulating
tau phosphorylation, although their role in vivo is unclear (reviewed in [1–3]).
Both PP2A and PP2B are present in human brain tissue and they dephos-
phorylate tau in a site-specific manner. For example, both enzymes dephos-
phorylate Ser396, but PP2A also dephosphorylates tau at additional sites,
and PP2A shows the major activity in brain on tau phosphorylated by a num-
ber of kinases [41,67–69]. PP1 and PP2A bind to tau, possibly mediating an
association with MTs, and PP2A also binds directly to MTs [70–72]. Finally,
although inhibition of PP1 and PP2A by okadaic acid in cultured human neu-
rons was followed by increased tau phosphorylation, decreased tau binding
to MTs, selective destruction of stable MTs and rapid axonal degeneration
of axons [73], the specific role of individual phosphatases in the in vivo regu-
lation of tau phosphorylation remains to be determined.
Pathological tau in AD
In contrast to tauopathies, wherein filamentous neuronal and/or glial tau
inclusions are the only defining neuropathological features in affected brain
regions, tau-rich NFTs and neuropil threads co-occur with deposits of Ab
fibrils in the extracellular space as diffuse and senile plaques as well as in
blood vessel walls of AD brains (reviewed in [1–3]). The neurofibrillary tau
lesions in AD brains were first shown to be stained with anti-tau antibodies
more than 15 years ago [74,75], but more than 20 years earlier [76] electron
microscopical (EM) studies had revealed that the major structural compo-
nents of NFTs were PHFs and to a lesser extent straight filaments (SFs).
Subsequent EM studies demonstrated that PHFs contain two strands of
fibrils twisted around one another with a periodicity of 80 nm and a width
varying from 8 to 20 nm, while SFs do not demonstrate a similar helical
periodicity [77]. However, after the appearance of a number of conflicting
reports on the composition of these filaments in the early 1980s, the building
block subunits of both PHFs and SFs were shown to be abnormally phos-
phorylated tau proteins [16,68,78–83]. For example, biochemical analysis of
PHFs purified from AD brains revealed three major bands of approximately

68-, 64- and 60-kDa, in addtion to a minor 72-kDa band, but after enzy-
matic dephosphorylation, six protein bands corresponding to the six adult
human brain tau isoforms were evident. Indeed, the relative abundance of
each of the six tau isoforms in AD PHFs (PHFtau) was indistinguishable
from the six soluble tau isoforms in the normal adult human brain
[3,21,84,85]. Moreover, most phosphorylated residues in PHFtau also were
found in tau isolated from biopsies of normal human brain [69], but relative
to normal, soluble adult brain tau isoforms, PHFtau was more extensively
phosphorylated (ie, hyperphosphorylated) at these sites [85–88].
Numerous kinases and protein phosphatases were implicated in the aber-
rant phosphorylation tau in the AD brain (for detailed reviews see [1–3]),
but cdk5 abnormally activated by p25, a truncated form of p35, may play
a mechanistic role in the conversion of normal tau into PHFtau in AD
[89–92]. While the role of tau phosphorylation in AD brain degeneration
remains uncertain, it is possible that hyperphosphorylation of tau disen-
gages tau from MTs, thereby increasing the pool of unbound tau which then
may aggregate into insoluble filamentous inclusions, although there is no
consenus on this at this time [1–3,93–95]. Nonetheless, since increasing the
ability of pathological tau to intereact with MTs may be beneficial, the
organic osmolytes trimethylamine N-oxide (TMAO), betaine or related
compounds could have therepeutic potential in AD and related tauopathies
because they appear to increase tau mediated MT assembly and restore the
ability of phosphorylated tau to promote this assembly [96,97]. Nonetheless,
while tau hyperphosphorylation is likely an early step in the generation of
PHFtau from normal soluble tau [98], it is unclear if it directly mediates
tau fibrillogenesis in vivo. Indeed, a number of early studies of tau fibrillo-
genesis showed that PHF-like filaments can be assembled in vitro from bac-
terially expressed non-phosphorylated 3R-tau fragments, although PHFs
from AD brain consist of full-length tau [99–101]. In subsequent studies,
sulphated glycosaminoglycans (GAGs) were shown to stimulate phosphor-
ylation of tau by a number of protein kinases and induce fibrillization of full
length tau [102–104], while a short amino acid sequence (VQIVYK) in the
third MT-binding repeat was suggested to be essential for heparin-induced
filament assembly [105]. Further, tau fibrillization may occur in a nucleation-
dependent manner [106]. Moreover, RNA [107,108] and arachidonic acid
[109] also were shown to induce fibrillization of full-length recombinant tau,
and the detetion of GAGs and RNA co-localized with PHFtau in NFTs
suggests that these in vitro findings may be relevant to tau fibrillization in the
AD brain [103,110–112].
Implications of other neurodegenerative tauopathies for AD

Despite controversies about the role of tau pathology in AD, indirect evi-
dence of a causative role for tau protein abnormalities in brain degeneration
comes from studies of pure tauopathies wherein there is abundant filamen-

tous tau pathology and brain degeneration in the absence of extracellular
amyloid deposits or other brain lesions (Table 1), and this is exemplified
by sporadic tauopathies such as progressive supranuclear palsy and cortico-
basal degeneration (for which specific tau haplotypes appear to be genetic
risk factors), and Pick’s disease (reviewed in [1–3]). However, more compel-
ling evidence for this notion came from studies of a group of syndromes
known as FTDP-17 that are autosomal-dominantly inherited neurodegen-
erative diseases with diverse, but overlapping, clinical and neuropathologi-
cal features, and these disorders are characterized neuropathologically by
prominent filamentous tau inclusions in neurons and/or glial cells (for recent
reviews, see [1–3]). For example, in 1998, several groups identified patho-
genic mutations in the tau gene that segregated with FTDP-17 [4–8], and
within three years more than 20 distinct pathogenic mutations in the tau
gene have been identified in a large number of new FTDP-17 families. As
reviewed elsewhere [1–3], these include 11 missense mutations in coding
regions of the tau gene involving E9 (K257T, I260V, G272V), E10
(N279K, P301L, P301S, S305N), E12 (V337M, E342V) and E13 (G389R,
R406W), three silent mutations in E10 (L284L, N296N, S305S) and a dele-
tion mutation (DK280), while five substitutions in six different positions of
the intron following E10 have been identified (at positions þ3, þ12, þ13,
þ14, þ16) and other mutations have been reported in recent meetings.
Further, studies of FTDP-17 brains from several laboratories add increasing
support to the hypothesis that FTDP-17 mutations lead to tau dysfunction
and neurodegenerative disease by one or more distinct mechanisms includ-
ing losses of tau functions and gains of toxic properties, while experimental
confirmation of this notion is emerging from studies of a number of trans-
genic mouse and other model systems of tauopathies (see [1–7,21,113] for
further details, reviews of other studies, and additional citations).
Summary
Despite earlier uncertainties about the role of tau patholgy in AD, the
discovery of multiple mutations in the tau gene that lead to the abnormal
aggregation of tau and the onset/progression of FTDP-17 demonstrates that
tau dysfunction is sufficient to produce neurodegenerative disease. The
mutations lead to specific cellular alterations, including altered expression,
function and biochemistry of tau. The finding that specific tau gene mu-
tations lead to diverse FTDP-17 phenotypes raises the possibility that the
clinical and pathological expression of hereditary and related sporadic
tauopathies may be influenced by tau gene polymorphisms, other genetic
factors and epigenetic events. However, the precise mechanisms whereby tau
assembles into filaments and causes neurodegeneration in the human brain
remain to be elucidated, but further investigation into the mechanisms of
tau dysfunction, as well as the identification of potential disease-modifying
factors, will provide additional insight into novel strategies for the treatment
and prevention of AD and related disorders. Moreover, development of
additional animal models of tauopathies that more closely recapitulate
human diseases will facilitate this undertaking, and this is likely to have
implications for other neurodegenerative disorders since the aggregation
of tau in AD and and related tauopathies is an example of abnormal pro-
tein–protein interactions resulting in the intracellular accumulation of fila-
mentous proteins that is a common feature of many fatal CNS diseases
characterized by relentlessly progressive brain degeneration [1–3]. Thus, the
fibrillization and aggregation of proteins in the brain is a common theme in
a diverse group of neurodegenerative disorders and insight into the patho-
genesis of any one of these disorders may have implications for understand-
ing the mechanisms that underlie all these diseases as well as for the
discovery of better strategies to treat them [1–3].
Acknowledgements
V.M.-Y.L. is the John H. Ware 3rd Chair of Alzheimer’s disease research
at the University of Pennsylvania. Work done in the laboratories of the
authors is supported by grants from the National Institute of Aging of the
National Institutes of Health and the Alzheimer’s Association. We also
thank our many collaborators and past as well as current members of the
Center for Neurodegenerative Disease Research (CNDR) for contributions
to the research from CNDR summarized here. Finally, the support of the
families of our patients have made this research possible.
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Med Clin N Am 86 (2002) 629–639
The role of beta-amyloid in

Sukanto Sinha, PhD*
Elan Biopharmaceuticals, 800 Gateway Boulevard,
South San Francisco, CA 94080, USA
Alzheimer’s disease pathology

Alzheimer’s disease (AD) is characterized, upon postmortem analyses of
the brain, by the presence of two major pathologic lesions, the senile or neu-
ritic plaque, and neurofibrillary tangles, both identified by Alois Alzheimer
in 1906. Neuritic plaques are composed of extracellular fibrillar deposits of
the beta-amyloid peptide, Ab, and are often associated with dystrophic neu-
rites, activated microglial cells, and activated astrocytes. They are found
widely in the limbic and association areas of the temporal cortex, as well
as in the hippocampus, a structure that is affected dramatically in the disease
[1]. Neurofibrillary tangles, or NFTs, which have been shown to be com-
posed of the abnormally phosphorylated microtubule-associated protein tau
[2], are found extensively in all of the brain areas affected in AD. They occur
as intraneuronal, cytoplasmic inclusions, ultrastructurally shown to occur as
interwound paired-helical filaments (PHF), remarkably resistant to solubili-
zation even in strong chaotropic agents. Although both of these prominent
pathologic lesions often occur simultaneously in the majority of AD cases,
NFTs are sometimes found in diseases other than AD, especially some of
the ‘‘taupathies’’ without coincidental beta-amyloid plaques. But all cases
of clinical AD that have been analyzed for neuropathology have been shown
to have Ab deposits, although the nature and extent of these varies widely in
both sporadic and familial forms of the disease.
Amyloid precursor protein (APP) and its metabolism

Remarkable progress in understanding the underlying pathology of this
disease has been made over the last fourteen years, dating approximately
* E-mail address: [email protected] (S. Sinha).
PII: S 0 0 2 5 - 7 1 2 5 ( 0 2 ) 0 0 0 2 2 - 6
630 S. Sinha / Med Clin N Am 86 (2002) 629–639
from the time that the protein precursors to the Ab peptides, collectively
called APP, were cloned [3] and subsequently expressed in cell culture.
Studies of the metabolism of the APP from various laboratories have
conclusively established that following maturation of the protein in the
secretory pathway, proteolytic cleavages take place in the extracellular or
luminal domain of the protein, which leads to the release (secretion) of the
bulk of the N-terminal ectodomain of the protein as sAPP [4], which is
detected not only in the culture medium of cells expressing APP, but also
in physiologic fluids such as plasma and cerebrospinal fluid (CSF). It turns
out that most of the sAPP generation takes place as a consequence of cleav-
age of the membrane-bound protein approximately 12 amino acids N-termi-
nal to the membrane interface [5]. This ‘‘a-secretase’’ cleavage also leads to
the loss of the intact Ab peptide region, the site of endoproteolysis being 16
aa C-terminal to the start of the Ab peptide sequence. The early identifica-
tion of this pathway, and its recognition as the major, ubiquitous pathway
of mature APP processing, led to the dogma that this represents ‘‘normal’’
APP metabolism, and that alternate, pathologically triggered pathways
must be responsible for the aberrant generation of the Ab peptides, which
are then subsequently deposited as insoluble amyloid during the disease
process.
The recognition that the Ab peptides are actually normal metabolites of
APP came about as the consequence of the discovery that primary human
neuronal cells release Ab peptides, Ab1-40, as well as Ab11-40, in their cul-
ture medium [6], and that tissue culture cell lines, such as HEK293 that are
transfected with APP also release Ab peptides into their culture medium as
well. Shortly thereafter, it was shown that a subset of sAPP is generated by
an alternate ‘‘b-secretase’’ activity that cleaves the full-length membrane-
bound APP immediately N-terminal to the Ab peptide sequence. This
cleavage takes place between Met671-Asp672 (using the APP770 codon
numbering), releasing a b-sAPP [7] that is C-terminally truncated compared
with a-sAPP, and also generating a cell-associated 99 aa long C-terminal
fragment (CTF) which starts with Asp672 (¼Ab1) (Fig. 1).
This alternate secretory cleavage was found to be far more prevalent in
primary neuronal cultures than in peripherally derived tissue culture cells;
the b-sAPP made up as much as 40–50% of total sAPP derived from culture
medium of the neuronal cells, compared with 5% or less as found in culture
medium from HEK293 cells transfected with APP. It therefore appeared
that b-secretase cleavage of APP, enriched in neuronal cells, could initiate
the normal production of Ab by the cellular turnover of the 99 aa b-CTF.
Familial Alzheimer disease mutations and genetic risk factors

Concurrent with the elucidation of these cellular pathways of APP
metabolism that lead to the release of Ab peptides into the extracellular
milieu came the identification of rare missense mutations in APP that lead
S. Sinha / Med Clin N Am 86 (2002) 629–639 631
Fig. 1. The a- and b-secretase cleavage pathways for APP.
to the familial inheritance of AD. These classified into two groups, one
in which Val717 was found to be mutated into either Ile [8], Phe or Gly
(‘‘London’’ mutations, APP717), and a second pedigree [9] with a double
mutation, changing the Lys670Met671 sequence of the b-secretase cleavage
site to a Asn670Leu671 motif (‘‘Swedish’’ mutation, APPNL). The identifi-
cation of such disease-causing mutations that framed the Ab peptide region
suggested that they somehow alter the metabolism of APP, leading to
increased Ab production.
This was demonstrated dramatically on transfection of the Swedish APP
forms into HEK293 cells, which led to a five to sixfold overproduction of
the Ab peptides compared with Wt APP [10]. The increased Ab peptide
release was accompanied by increased levels of b-sAPP as well, indicating
that the Swedish double mutation at the b-secretase site leads to an
increased cleavage of the full-length APP molecule at the altered sequence.
The higher levels of the cell-associated b-CTF generated as a consequence of
this gives rise to the higher levels of Ab peptide released.
Although missense mutations in APP account for a very small number of
total AD cases, epidemiologic data have long pointed to the strong contri-
bution of genetic factors to the overall population risk for AD. For example,
there is an increased age-dependent risk for AD among primary relatives of
patients with AD [11], consistent with either incompletely penetrant single-
gene defects, or with a more complex interaction among multiple hereditary
and extrahereditary factors, such as possible environmental modifiers.
Approximately 10% of AD cases, however, appear to be transmitted in
familial pedigrees in a classical Mendelian autosomal dominant manner,

and the identification of the genes that account for the predominant
numbers of such cases have provided key insights into the etiology of AD.
With the exception of the small number of families that map to APP on
chromosome 21, the majority of cases of familial Alzheimer’s disease (FAD)
were found to map to chromosome 14, to a locus that was identified as a
new gene, S182 [12]. The protein product of the S182 gene, named preseni-
lin-1 (PS-1), was predicted to traverse the membrane multiple times (poly-
topic) and was shown to be widely expressed in all cells and tissues
surveyed. A homologous gene, STML2, called presenilin-2 (PS-2), was con-
currently mapped to chromosome 1, in a Volga-German family [13]. More
than 80 separate missense mutations have been cataloged in PS-1, and 5 in
PS-2, inheritance of any of which leads to fully penetrant AD at an early age
(35–65 age of onset).
Distinct from these autosomally inherited single gene defects in PS or APP
that lead to early onset AD, genetic linkage studies of other familial pedigrees
led to the identification of the apolipoprotein E (apo E) locus on chromo-
some 19 as a potential AD susceptibility gene [14]. Apo E in humans is a poly-
morphic protein, with three commonly occurring variants, e2 (10%), e3
(75%) and e4 (15%), the numbers in parentheses indicating their approximate
prevalence in a Caucasian population. Multiple studies have gone on to
establish that the e4 allele is over-represented in patients with late-onset
AD (40% in postmortem or clinically diagnosed AD). The inheritance of
two e4 alleles correlates with an earlier age of onset in patients with AD than
with a single allele [15], although it appears that the apo E polymorphism
remains a risk factor and is not causative for AD. Current estimates suggest
that the apoe4 allele may account for only 7–9% of all AD cases.
Ab42 and AD pathogenesis

Although the analysis of Ab isoforms from primary cells, transfected
cells, and CSF indicate that the predominant form of Ab is Ab1-40, it has
turned out that a relatively minor form, Ab1-42, is the primary constituent
of the amyloid burden in AD [16]. As demonstrated in vitro, the additional 2
amino-acid extension at the C-terminus renders this form much more prone
to aggregation, consistent with its increased presence in insoluble amyloid
plaques. The generation of antibodies specific to this form of the Ab peptide,
and also to the shorter Ab40 peptide, made possible the development of sen-
sitive and specific assays for both of these forms [17]. The utilization of such
assays in the analysis of the effect of the various FAD mutations in PS-1,
PS-2, and the ‘‘London’’ mutations in APP, has led to the emergence of a
central hypothesis for the cause of AD.
Immunohistochemical analyses of AD brain sections with such antibod-
ies have revealed that the majority of diffuse plaques, and most senile plaques,
label strongly with antibodies specific to the 42 form of the peptide,

although the mature, senile plaques label with antibodies to Ab40 as well
[16]. At this level of analysis, the Ab42 appears to be a preponderant
constituent of neuropil amyloid in AD, even though it makes up a relatively
small proportion of normally secreted Ab peptides. Biochemical analyses of
AD brain plaque composition have provided more quantitative confirma-
tion of this as well. That said, it has been a difficult proposition to precisely
nail down the exact composition of senile plaques in AD, and the heteroge-
neity of the Ab forms that have been identified from AD brain, using a vari-
ety of different methodologies, renders the biochemical problem quite
formidable. The concurrent presence of cerebral amyloid angiopathy, vessel-
associated amyloid, has also confounded the issue of what forms of the Ab
peptides make up the senile plaque [17]. A roundabout approach to this
problem has evolved as a consequence of careful analysis of Ab forms
deposited in the various FAD families and the analysis of brains from indi-
viduals with Down’s syndrome.
Down’s syndrome is accompanied, essentially without exception, with the
progressive acquisition of AD-like pathology, and the availability of post-
mortem brain tissue from trisomy 21 individuals at various ages has enabled
the ‘‘reconstruction’’ of the likely temporal progression of AD. Trisomy 21
theoretically leads to an extra copy of the APP gene, and the translation of
this increased gene dosage at the protein level has been confirmed by analyz-
ing for APP levels in the body fluids of persons with Down’s syndrome. The
increased APP levels, not surprisingly, leads to increased levels of circulating
Ab peptides [18]. The earliest amyloid deposits seen in very young individ-
uals, approximately 12 years old, with DS have a diffuse morphology, and
although these diffuse ‘‘plaques’’ label readily with Ab42 antibodies, they
show no reactivity with either antibodies to Ab40, or with antibodies specific
to the N-terminal region of the Ab peptide [19]. More Ab42 reactive plaques,
accompanied by dystrophic neurites and activated microglial cells, show
up in DS individuals who are 20–30 years old, with neurofibrillary tangles
being evident by age 30. Plaques at this time label prominently with anti-
bodies to the N-terminus of Ab, as well as with antibodies to Ab40.
Effect of FAD APP mutations on Ab42

As described earlier [8], the first FAD mutation identified was the ‘‘Lon-
don’’ mutation, which resulted in the substitution of an Ile for a Val at codon
717 of APP. Inheritance of this led to an autosomally dominant, early onset
form of AD. Postmortem examination of brains from a Japanese family with
this mutation showed dramatic and extensive presence of both diffuse and
neuritic amyloid plaques, which prominently labeled with antibodies specific
to the Ab42 epitope. Other APP717 mutations have since been identified,
leading to substitution of Phe and Gly for the naturally-occurring Val at
that position. The observation that a single point mutation in APP can lead
to AD provided the first direct genetic evidence for Ab as a causative factor
in AD.
The pathologic observation of the preponderance of Ab42 plaques, in
both sporadic as well as in this first FAD disease, prompted the analysis
of the mechanism by which APP717 leads to disease. Analysis of Ab species
derived on transfection of the mutated APP717 form into 293 cells showed
that a small yet significant change in the composition of the Ab species
secreted into the conditioned medium. Compared with cells transfected with
Wt APP, an increased level of Ab42 peptides were secreted [20], relative to
the Ab40 species, resulting in an 50% increase in the Ab42/Ab40 ratio.
Analysis of plasma Ab from individuals with codon 717 mutations also
showed an approximately twofold increase in Ab42 levels. The in vivo and
in vitro data provided very strong evidence for the hypothesis that increased
levels of Ab42 are produced from the mutated APP, and that this was suffi-
cient to cause early onset AD.
The second FAD mutation identified was also in APP, the ‘‘Swedish’’ or
APPNL, although the mechanism via which it causes AD was established
chronologically earlier than that with the APP717 mutations. Transfection
of APPNL into 293 cells led to a very large increase in the total amount
of Ab secreted into the conditioned medium, accompanied by a large
increase in the b-secretase-cleaved secreted APP, b-sAPP [10]. A twofold
increase in total Ab was found in the plasma of individuals carrying the
APPNL mutation, confirming the cellular results [21]. Thus, increased levels
of total Ab (both Ab40 and Ab42) also cause early onset AD, providing a
very strong basis for the hypothesis that Ab is causative for AD.
Presenilins and AD
Although the APP mutations provided strong evidence for the amyloid-
centric view of AD, such mutations were very infrequent, and the locus on
Chromosome 14 (APP is on Chromosome 21) seemed to account for the
vast majority of FAD cases around the world. The identification of this
gene, PS-1, opened up a new field of investigation for AD researchers.
PS-1 is widely expressed in various tissues and cells and exists in cells as
a noncovalent yet stable complex [22], of a 30 kDa N-terminal fragment
(NTF) and a 15 kda CTF. The NTF and CTF are derived by intracellular
proteolytic cleavage of the intact PS-1 holoprotein [23], and the consequent
stable complex appears to be the functionally relevant form of PS-1. PS-2 is
processed in a similar manner as well. Most cells appear to have a saturable
capacity for forming the stable NTF:CTF complex [24], and transfection of
PS-1 in cell culture usually leads to only a relatively small (about twofold)
increase in the levels of the cleaved forms detected; the PS-1 holoprotein,
under these conditions, appears to be rapidly degraded, and not to be incor-
porated in a functionally relevant complex.
The transfection of Wt PS-1 or PS-2 into cells has no detectable effect

on Ab40 and 42 levels. Transfection of the disease-causing mutant forms
invariably leads, however, to an elevation of Ab42, usually measured as
an increase (50–200%) of the Ab42/Ab42 ratio [25]. All other aspects of APP
metabolism appear to remain virtually unchanged, including the cellular
maturation, turnover, and the extracellular release of a- and b-sAPP. The
disease-causing PS-1 and PS-2 mutants thus selectively increase cleavage
at the Ab42 site, without affecting total levels of Ab (Ab40 + Ab42). Post-
mortem analysis of brains of PS-1 FAD individuals have demonstrated very
high levels of Ab42-positive plaques [17], both of the diffuse, noncompacted
form, as well as the mature neuritic plaques, thus underscoring in vivo the
likely pathogenetic mechanism deduced from the cellular observations.
Knockout of the PS-1 gene in mice leads to severe developmental abnor-
malities and consequential fetal lethality, but primary cortical cultures gen-
erated from premorbid embryonic stages have been used to conclusively
demonstrate that the absence of PS-1 leads to a 80% reduction of both
Ab40 and Ab42 [26], without measurable effects on a- and b-secretory clea-
vages. An elevation of the steady state levels of the a- and b-CTF fragments
is also observed, suggesting that the absence of PS-1 leads to a reduction in
c-secretase cleavage of the CTFs generated by the action of a- and b-secre-
tases. Thus, although the effect of the FAD mutations are restricted to an
increased cleavage of APP at the Ab42 site, PS-1 appeared to have a much
bigger role in c-secretase cleavage of APP-derived CTFs.
A variety of experimental approaches have subsequently established that
this is indeed the case. Mutation of either of two highly conserved aspartic
acid residues in PS-1 and PS-2 leads to a dominant negative phenotype on
Ab production on transfection of such forms into cells [27], accompanied
by the stabilization of APP-derived a- and b-CTFs. Potent inhibitors of
cellular Ab production have been shown to interact directly with PS-1
[28], and the consensus opinion in the field is that the presenilins are essential
biochemical components of c-secretase. The difficulty of demonstrating
increased levels of Ab production on overexpression of the presenilins has
suggested the existence of as yet unidentified cellular factors [24] that may
be necessary for the saturable formation of the high-molecular-weight pre-
senilin complex. Nicastrin has recently been identified as another necessary
component of this complex [29], although its biochemical role remains
unelucidated.
Transgenic models for AD pathology

The APP FAD mutations have also been utilized to obtain transgenic
mice that overexpress in neuronal cells, at high levels, either APPNL
(Tg2576) [30] or the Val fi Phe APP717 (PDAPP) [31]. Both of these lines
of transgenic animals develop, in a age-dependent manner, diffuse and
compact amyloid plaques in the cortex and hippocampus, but not in other
regions spared in AD such as the cerebellum. The pathologic changes
observed in these transgenic mice lines also include microglial activation and
astrogliosis, as well as neuritic changes in the vicinity of plaques that are
remarkably similar to that observed in sporadic AD. Although it has been
difficult to measure frank cell loss in these transgenic lines, other neurofibril-
lary changes highly reminiscent of AD have been shown to occur in the
PDAPP mouse with age [32].
In addition to demonstrating that the APP FAD mutations do result in
the production of amyloid plaques, and ancillary pathologies seen in AD,
these animal models have also proven to be useful in identifying pharma-
cologic agents that modulate the production or clearance of the Ab peptide.
Immunization of the PDAPP transgenic mice with human Ab42 was shown
to result in the clearance of existing plaques by microglial cells by an anti-
body mediated mechanism [33]. Peripheral administration of antibodies
directed to the human Ab was also shown to result in a similar clearance
[34], along with a reduction of the neuritic pathology and glial pathology.
In a separate approach, an inhibitor of c-secretase, identified using cell cul-
ture models, was shown to inhibit the production of Ab in young PDAPP
animals, in a dose- and time-dependent manner [35]. The ability to test
potential drugs and therapeutic approaches directed toward the lowering
of Ab peptide levels and the associated aggregated amyloid deposits has
opened up the way in utilizing these animal models of AD pathology toward
identifying and testing strategies for treating AD.
b-Secretase: initiation of Ab production

Although the overwhelming majority of FAD cases manifest themselves
via PS-1 mutations (increased Ab42), the APPNL FAD family suggested
that b-secretase cleavage of APP is important for Ab generation. Studies
of APP metabolism in cell culture established that b-secretase cleavage pre-
cedes that by c-secretase, and pharmacologic agents that disrupt b-secretase
cleavage of APP selectively inhibit Ab production without inhibitory effect
on a-secretase cleavage. b-secretase cleavage of APP, though observable in
cultured cells, occurs at a much higher level in primary neuronal cultures, as
evidenced by the higher proportion of b-sAPP relative to a-sAPP. This sug-
gested that the enzymatic activity is enriched in the CNS. This indeed turned
out to be the case, and b-secretase was independently identified by (1) bio-
chemical purification from human brain [36], (2) expression cloning in
HEK293 cells [37], and (3) homology based cloning and expression of novel
human aspartic proteases [38]. The unique protein sequence identified by
these different approaches turned out to encode a novel, membrane-bound
aspartic protease, BACE. Knockout of BACE in mice is without any detect-
able developmental consequence, although these mice are totally deficient in
the ability to generate Ab, either from endogenous APP [39] or from concur-
rently expressed human transgenic APP forms [40]. Thus, cleavage of APP
by BACE is absolutely required for the generation of the Ab peptide, and
the lack of biologic redundancy in this process suggests that strategies
directed toward inhibiting the activity of this enzyme in vivo should lead
to salutary effects on the production, and subsequent aggregation, of Ab
peptides.
Summary
The current understanding of the role of amyloid in AD has been estab-
lished by a remarkable congruence of multiple disciplines: neuropathology,
biochemistry, molecular biology, and epidemiologic genetics. Although the
precise etiology of AD still remains poorly understood, the identification of
the key biochemical players in the Ab generation (APP, PS-1 and -2, and
BACE), and the development of transgenic models exhibiting progressive
disease pathology, provide a strong framework on which to build a better
understanding of the molecular events that lead to progressive neurodegen-
eration in AD.
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Med Clin N Am 86 (2002) 641–656
Nonpharmacologic treatment
of behavioral disturbance in dementia
Linda Teri, PhD*, Rebecca G. Logsdon, PhD,
Susan M. McCurry, PhD
Department of Psychosocial and Community Health, University of Washington,
9709 3rd Avenue NE, Suite 507, Seattle, WA 98115, USA
Behavioral disturbances and dementia are inexorably linked. Problems

such as depression, agitation/aggression, wandering, and sleep disturbances
affect most if not all patients at some point in the disease course [1–3].
Highly associated with greater functional impairment in the patient and
increased burden in the caregiver [4–6], such problems critically impede
effective care and are often cited as the most difficult aspect of caregiving
[7]. Consequently, they adversely affect quality of life for the patient as well
as the caregiver.
Despite this, health care providers routinely receive little training in the
direct care management of behavioral problems in dementia. Practical sug-
gestions abound in the literature, however, and although still relatively
sparse, empiric data from clinical trials are accumulating to indicate that
behavioral problems can be effectively managed with nonpharmacologic
treatment. Furthermore, consensus conference documents have concluded
that nonpharmacologic treatment is the most appropriate first step to treat-
ing behavioral disturbances in patients with dementia [8].
This article provides an overview of the treatment of behavioral problems
with nonpharmacologic means as well as guidelines for assessing and treat-
ing the most common behavioral problems seen in dementia, including
depression, agitation/aggression, wandering, and sleep disturbance. We also
discuss the role of the caregiver in nonpharmacologic treatment.
E-mail address: [email protected] (L. Teri).
Preparation of this manuscript was supported in part by grants from the Alzheimer’s
Association (PIO-99-1800) and the National Institutes of Health (AG10483, AG10845,
MH01644).
PII: S 0 0 2 5 - 7 1 2 5 ( 0 2 ) 0 0 0 0 6 - 8
642 L. Teri et al / Med Clin N Am 86 (2002) 641–656
Assessment
The most common method for assessing behavioral disturbance in cogni-
tively impaired older adults is a detailed clinical interview with the patient
and an informant familiar with the patient’s day-to-day functioning, such
as the patient’s family or caregiver. In the interview, the patient and infor-
mant are typically asked about the occurrence, frequency, and severity of
typical problems, including wandering, anxiety, depression, agitation, ag-
gression, sleep disturbances, paranoia, suspiciousness, and verbal or physical
threats or abuse. To ensure that the full spectrum of problems is assessed in
an efficient and thorough manner, a standardized inquiry list is a valuable
tool. Such a list may be administered by a trained staff person (eg, a medical
assistant) or provided to an informant to complete while the patient is being
examined. This process is similar to the preliminary health screening forms
used in many clinics. By asking the caregiver about the presence or absence
of a variety of potential problems, the clinician can then focus on the ones
that are of concern. In addition, the caregiver is given an opportunity to
express concerns on paper and, later, to discuss these concerns privately
with the clinician.
A variety of mood and behavior assessment measures with good psycho-
metric properties have been developed. Table 1 shows a representative sam-
pling of instruments that have been used to measure depression, agitation,
or general psychiatric disturbance in clinical controlled trials with dementia
subjects. Some measures are based on paper-and-pencil informant report,
whereas others require structured interviews with trained clinicians or direct
behavioral observation. The instruments also vary in the data format they
yield. Some (eg, the Cornell Scale for Depression in Dementia [15]) provide
information on the severity of symptoms; others (eg, the Revised Memory
and Behavior Problem Checklist [3]) rate behaviors on the frequency of their
occurrence and provide information about caregiver reactions to symptoms
when they do occur. For some measures (eg, the Neuropsychiatric Inventory
[29]), summary subscale information is computed from a combination of fre-
quency and severity ratings for individual behavioral symptoms. There are
also a number of self-report instruments that have been shown to be valid
when completed by surrogate informants, such as dementia caregivers [24].
As can be seen from Table 1, there is no single instrument that has gained
universal use in clinical trials with dementia patients. The selection of appro-
priate measures varies according to the outcomes targeted by each study,
and behaviors are often included as part of a comprehensive assessment with
other cognitive, functional, and psychosocial measures. Both researchers
and health care providers interested in using screening instruments should
consider a number of factors, including the length of the measure, its
reported sensitivity to change, and specific behaviors of concern for their
clinical population. Providers caring for populations that include non-
English-speaking individuals from multicultural backgrounds or persons
L. Teri et al / Med Clin N Am 86 (2002) 641–656 643
Table 1
Common mood and dementia screening instruments for dementia
Informant Reliability/ Used in clinical
report Interviewer validity controlled
Title questionnaire administered data trials
Agitation
Agitated behavior X X [10] X [11]
in dementia scale
(ABID) [9]
Cohen-Mansfield X X [10,13] X [14]
agitation inventory
(CMAI) [12]
Depression
Cornell scale for X X [16,17] X [18,19]
depression in dementia
(CSDD) [15]
Dementia mood X X [17,21] X [22]
assessment scale
(DMAS) [20]
Geriatric depression X X [24] X [19]
scale (GDS) [23]
Hamilton depression X X [24] X [19,26]
rating scale (HDRS) [25]
General behavioral disturbance
Behavioral pathology X X [16] X [14,18]
in Alzheimer’s disease
(BEHAVE-AD) [27]
CERAD behavior rating X X [10,17] X [26]
scale for dementia
(CERAD-BRSD) [28]
Neuropsychiatric X X [17] X [30]
inventory (NPI) [29]
Revised memory X X [10] X [19,26]
and behavior problem
checklist (RMBPC) [3]
CERAD: Consortium to Establish a Registry for Alzheimer’s Disease.
with limited education or reading skills particularly need to evaluate the

validity of a given instrument for their situation. Readers interested in a
comprehensive review of behavioral screening instruments used in dementia
care and research are referred elsewhere [17,31–35].
Once specific problems are identified, a thorough assessment of their pos-
sible causes is essential. The same behavioral disturbance may be triggered by
a variety of different causes. In assessing behavioral disturbances, the clinician
must consider possible medical triggers, cognitive- or dementia-related trig-
gers, environmental triggers, and caregiver issues. Common causes of behav-
ioral disturbance may include medical illness, injury, medication side effects,
environmental changes, and interpersonal conflicts. For example, restless-
ness may be triggered by an acute medical condition, such as a urinary tract
infection, or by a change in medication. Restlessness may also result from

changes in brain functioning caused by dementia, or it may be related to envi-
ronmental triggers, such as lack of appropriate activity, too much noise or stim-
ulation, or conflicts with people with whom the patient comes into contact.
Treatment
Nonpharmacologic treatments are often recommended as the most ap-
propriate initial strategy for managing behavioral disturbances in persons
with dementia [7,36,37]. The risk of adverse side effects or interactions with
other medications is nonexistent, and the increased involvement of care-
givers often has a secondary benefit of providing overburdened caregivers
with an opportunity to receive support, information, and skills. Further-
more, environmental factors (eg, confusing or noisy surroundings) or inter-
personal factors (eg, arguing with the patient) are frequently the primary
triggers of behavior problems. Attention to these factors through nonphar-
macologic approaches (caregiver education, support, and training in beha-
vioral strategies for management) can be quite effective in alleviating or
preventing behavioral problems in patients with dementia.
Providing education, support, and advice to help families better under-
stand and cope with the disease process has a long clinical history and often
represents the core of any treatment whether it is nonpharmacologic or
pharmacologic. Practitioners often advise families to use strategies to adapt
the environment and modify their own behaviors so as to better care for
patients. The amount and popularity of this kind of information have grown
exponentially in recent years as is evident in the proliferation of books,
training materials, informational handouts, videotapes and worldwide web
technology. For example, The 36 Hour Day [38], long considered a staple
of information to families, is in its second printing with over one-half mil-
lion copies sold worldwide. A videotape training program entitled ‘‘Manag-
ing and Understanding Behavior Problems in Alzheimer’s Disease and
Related Disorders’’ [39] has been used in Alzheimer Association support
groups worldwide. It is also part of standard training in numerous long-term
care facilities; has been translated into Japanese, Korean, and Italian; and
has been used in three controlled trials thus far.
Published reports of nonpharmacologic treatment span two decades. The
earliest reports showed that caregivers were able to learn specific techniques
and successfully reduce problematic behaviors [40–43]. Later, case-con-
trolled and randomized controlled trials investigated the effectiveness of
nonpharmacologic treatment in reducing behavioral problems or delaying
institutionalization in patients with dementia. Three investigations included
behavior training as part of a larger psychoeducational and social support
program and examined general behavioral outcomes and delayed patient
institutionalization [44–46]. One provided a focus on behavioral training
to reduce patient depression [19], and another compared nonpharmacologic
with pharmacologic approaches to reduce patient agitation [11,47]. Although

certainly not conclusive, results thus far suggest that nonpharmacologic
interventions can significantly reduce general patient behavioral problems
[46,47], decrease patient depression [19], delay institutionalization [45], and
increase caregiver satisfaction [48]. (For more detailed reviews of nonpharma-
cologic treatments, the reader is referred to articles by Bourgeois et al [49] and
Teri et al [50].)
The Seattle Protocol

A comprehensive behavioral training program
for reducing behavioral problems in patients with dementia
As mentioned earlier, a videotape training program entitled ‘‘Managing
and Understanding Behavior Problems in Alzheimer’s Disease and Related
Disorders’’ [39] teaches clinicians and caregivers to use a systematic beha-
vioral approach to behavioral problems. The program consists of a series
of 10 videotapes and a written trainer’s guide designed to provide back-
ground information about dementia and related disorders, teach caregivers
skills to modify behavior problems that interfere with proper care, and iden-
tify and address the special needs of caregivers. Didactic information along
with vignettes of specific problems and solutions guides caregivers through a
systematic approach called the ‘‘A-B-C’s of Behavior Change.’’ In this
approach, caregivers learn that ‘‘A’’ is the antecedent or triggering event
that precedes the problem behavior, ‘‘B’’ is the behavior of concern, and
‘‘C’’ is the consequence of that behavior. Once the chain of behavior occur-
rence and response is understood, caregivers are provided with methods to
change either the antecedents or the consequences so as to change the prob-
lem behavior. (For more information on this program, the reader is referred
to the article by Teri [51].)
Once the caregiver understands and can identify the A-B-C’s of a problem,
a step-by-step problem-solving strategy is implemented involving six steps:
Identify the problem. This is defining the ‘‘B’’ of the A-B-C’s. The care-
giver needs to articulate exactly what the problem is in a specific and
informative manner. For example, ‘‘arguing all the time’’ may seem
clear to the caregiver, and the health provider may even think he or she
understand what that means, but ‘‘arguing’’ can take many forms.
What is the nature of the arguments? Do they really occur ‘‘all the
time,’’ or are they more common at certain times of the day or with cer-
tain people? What specifically is said? The more clearly a caregiver can
define a problem, the more likely it is that he or she can carry out an
effective course of action.
Gather information about the circumstances surrounding the problem.
This is defining the ‘‘A’’ and ‘‘C’’ of the A-B-C’s. Identify what happens
immediately before the problem occurs and what happens immediately
after the problem begins. Many problems have more than one antecedent
and consequence, and the more caregivers understand how the A-B-C’s fit
together, the more likely it is that they can successfully intervene.
Set realistic goals and make plans to achieve those goals. For a plan to
work, it must be creative but realistic and tailored to the individual pa-
tient and caregiver. For example, whereas a caregiver may ‘‘want the
patient to be happy,’’ this goal is too broad and unstructured. Goals
of ‘‘increasing pleasant activity’’ and ‘‘not discussing upsetting topics’’
are more realistic and more achievable. Start with small achievable
goals, and proceed step by step.
Encourage rewards for the patient and the caregiver for small successes.
Changing behavior is hard work for everyone involved. It is important
for caregivers to reward themselves and their patients for their accom-
plishments no matter how small.
Continually evaluate and modify plans. It is important that caregivers be
consistent in carrying out plans but flexible in trying new approaches.
Strategies need to change as caregivers discover some that do and do
not work.
One goal of the A-B-C approach is to help teach caregivers to develop
strategies on their own so that once treatment is concluded, they can effec-
tively deal with new problems that may develop over the course of the dis-
ease. In addition, specific suggestions can be helpful. In the Seattle Protocol,
these suggestions are again framed in an A-B-C approach. We now provide
some suggestions for management of several of the most common and trou-
bling behavior problems, including depression, agitation/aggression, wan-
dering, and sleep disturbances. For additional suggestions (although not
framed within an A-B-C approach), the reader is referred to the books by
Robinson et al [52], self-help books (eg, The 36 Hour Day [38] and Alzhei-
mer’s Disease: A Guide for Families [53]), and materials available from the
Alzheimer’s Association (www.alz.org; 1-800-272-3900).
Depression
Depressive symptoms occur in 30% to 70% of individuals diagnosed with
Alzheimer’s disease, the most common form of dementia in older adults [54–
56]. Unhappiness, withdrawal, inactivity, fatigue, expressions of guilt and
worthlessness, tearfulness, and loss of interest can all signify depression.
Patients with dementia gradually lose the ability to engage in enjoyable hob-
bies or activities, and because of their cognitive impairment, they may be
unable to identify replacement activities. Consequently, they may spend
much of their time in activities that are not gratifying or meaningful, or they
may disengage from activity altogether.
Methods for modifying antecedents and altering consequences to depres-
sive behaviors include:
• Increase and encourage enjoyable activities. Identifying activities that

the person has enjoyed in the past and modifying them to be appropri-
ate for the patient’s current level of functioning is a good way to begin.
The Pleasant Events Schedule-AD [57,58], a 53-item inventory, was de-
signed to help caregivers identify simple everyday pleasant activities that
might be incorporated in the daily care of patients with dementia. Items
include being outside, listening to music, having meals with family or
friends, helping around the house, exercising, and going for a ride in
the car.
• Redirect and refocus. Patients with depression and dementia are often
incapable of ridding themselves of depressing thoughts. They need assis-
tance in distracting themselves and thinking nondepressing thoughts.
Memory books [59] with pictures of happier times, reminiscing of plea-
sant experiences, or having cheerful conversations can be quite helpful.
• Increase social activities. Initiating pleasant social activities that keep
the patient alert and involved can significantly improve a depressed
mood. Plan outings with someone whose company the patient enjoys,
particularly if the patient complains of feeling isolated or lonely. If
the patient has had to stop driving, arrange transportation to activities
the patient enjoys but is no longer able to attend without assistance.
• Eliminate sources of conflict and frustration. Patients with depression
often are asked to engage in activities they can no longer do. By ensur-
ing that patients are not continually challenged and frustrated, sources
of conflict and frustration can be alleviated (and sometimes eliminated),
resulting in a more contented patient.
• Depressed patients often have depressed caregivers [60]. If the patient
lives with a caregiver, evaluate and discuss the caregiver’s own affective
state. Improving caregiver mood is likely to have a positive outcome on
patient behavioral problems.
Agitation
Agitated behaviors, such as irritability, restlessness, physical and verbal
aggression, resisting needed assistance, pacing, and wandering, affect be-
tween 70% and 90% of patients with dementia at some point during the
course of the disease [3,61]. As with depression, agitation may have a variety
of causes, including physiologic, environmental, and interpersonal triggers.
Furthermore, these causes often interact. For example, patients may have
decreased tolerance for stimulation or decreased inhibition of inappropriate
behaviors as a result of neurologic changes. They may experience agitation
or catastrophic reactions in response to environmental triggers, such as
overstimulation or activities they do not understand (eg, being bathed by
a caregiver they do not know or remember). The key to nonpharmacologic
intervention for episodes of agitation or aggression is to identify and avoid
their triggers, thus reducing their frequency or impact.
Methods for modifying antecedents and altering consequences to agitated

or disruptive behaviors include:
• Intervene early. Recognition of problems and early intervention can
help to prevent agitation and catastrophic reactions.
• Stay calm. Remain calm yourself as you strive to calm the patient. Use a
reassuring and gentle voice. Use touch judiciously and gently. (Some pa-
tients do not find touch reassuring; they may lash out.) Avoid arguing
or trying to reason while the person is agitated. Arguing almost always
causes the agitation to escalate.
• Prevent aggression. Approach an agitated person slowly from the front.
Tell the person what you are going to do, and try not to startle him or
her. Stand or sit at eye level rather than standing over the person.
• Redirect and refocus. Distract the patient with questions about the prob-
lem, and gradually turn his or her attention to something unrelated
and pleasant. Change activities, go to another room, or leave the situa
tion.
• Get help immediately if there is imminent danger.
Wandering
Cognitively impaired individuals who wander pose a danger to themselves
and are of considerable concern to their care providers and family [62,63].
Most research on wandering has focused on nursing home– or dementia
clinic–based samples. In these samples, wandering occurs in up to 65% of
patients at some point in the disease process and is related to severity of cog-
nitive impairment [63–65], rate of cognitive decline [66], and decreased length
of survival [67,68]. In an investigation of disruptive wandering behavior in a
population-based sample of 193 individuals with Alzheimer’s disease, 24% of
subjects had wandered at least once, and 12% had wandered within the past
week. Wandering occurred in subjects at all levels of cognitive impairment,
but greater frequency of wandering was associated with significantly more
impairment in cognition, day-to-day functioning, and behavior. Caregiver
distress increased significantly with increased frequency of wandering [69].
There have been no published randomized controlled trials of interven-
tions for wandering in dementia [70]. Research on strategies for preventing
dangerous wandering has been conducted primarily in long-term care
settings, and promising approaches include environmental modification
[71,72], activity programming [73], electronic alarm systems [74], and rein-
forcement of nonwandering behaviors [75].
Methods for modifying antecedents and altering consequences of wan-
dering include:
• Environmental modification. Visual cues and labels can be used to direct
wanderers in a particular direction or away from potential dangers. For
example, clear and unambiguous labels on bathrooms and bedrooms may
direct residents to appropriate areas, whereas visual barriers, such as floor

grids or stop signs, discourage wanderers from crossing into areas that are
off limits. Removing objects or cues from the environment that suggest
leaving, including coats or hats, and disguising exits by blending them
in with surrounding walls may help to prevent individuals from banging
on doors or repeatedly attempting to leave. Interesting displays or seating
areas help by inviting individuals to stop pacing and enjoy them.
• Provide activities. Many individuals with dementia seem to wander be-
cause of boredom or loneliness. Programs that engage individuals in
meaningful activities, exercise, and social interaction may decrease wan-
dering and other problem behaviors.
• Install electronic alarm systems. Electronic alarms are in wide use in de-
mentia residential care programs and range from a key code box and
alarm that sounds when doors are opened to special radio transmitters
that track the movements of individuals who wear them. These alarms
do not prevent wandering but alert care providers so that dangerous
consequences of wandering can be prevented.
• Have a safety plan. Keep a current photograph for reference in case the
person should get lost. Have the person wear an identification bracelet
with contact information and clearly marked with the statement ‘‘mem-
ory impaired.’’ Secure it so that it cannot be easily removed or slipped
off. Clothing labels with this information may also be sewn into the per-
son’s clothing. The Alzheimer’s Association’s ‘‘Safe Return’’ program is
a resource for educational materials and identification labels for wan-
derers and their caregivers.
Sleep disturbances
Wandering at night, bedtime agitation, disturbed sleep, and night-day
reversal are common problems for persons with dementia [76]. When pre-
sent, such problems are quite stressful for family members. Caregivers who
are awakened frequently during the night to reassure or assist the dementia
patient eventually become exhausted. This exhaustion, and its associated
impact on physical and emotional health, is one of the most common rea-
sons why caregivers are forced to institutionalize their loved ones [77,78].
There is general agreement that hypnotic treatments for sleep problems
should be used sparingly in the elderly so as to minimize falls, impaired
memory, drug-related sleep disorders, or aggravation of a preexisting sleep
apnea syndrome [79,80]. Cognitive-behavioral and psychoeducational strat-
egies are readily available and known to be effective in normal older adults
[81,82], but they have not been systematically studied in persons with
dementia. There is evidence that environmental and behavioral factors, such
as time spent in bed during the day, environmental noise and light, and
nighttime incontinence care practices, are associated with sleep disturbances
in institutionalized older adults [83–86]. One recent study in 29 nursing
home residents found that a combination of light physical exercise and other
behavioral strategies (eg, keeping patients out of bed in the late afternoon
and evening or providing quiet nighttime incontinence care) produced sig-
nificant improvements in measures of percentage of total sleep and duration
of sleep episodes [87]. There is also a growing amount of literature suggest-
ing that timed bright light exposure may be helpful in reducing the sleep dis-
turbances found in Alzheimer’s disease patients [88,89].
Methods for modifying antecedents and altering consequences associated
with sleep disturbances in persons with dementia include:
• Strive for consistent bedtime and rising times. Regular sleep time habits
and routines help to reinforce time cues for demented individuals and
may also promote circadian rhythmicity by maximizing cues to the
brain’s time-keeping system [90]. Although there have been no clinical
trials demonstrating the value of consistent sleep habits in dementia pa-
tients, sleep regularity is considered an important aspect of the treat-
ment and prevention of sleep disturbances in all older adults [80].
• Limit daytime napping. In the later stages of disease, many persons with
dementia spend a significant proportion of their daytime hours asleep
[91,92]. Reductions in daytime napping, particularly in combination
with an increase in physical activity, can increase the likelihood that
the dementia patient has longer and more consolidated nighttime sleep.
• Restrict use of alcohol and caffeinated beverages (including chocolate
products). When consumed close to bedtime, these can disrupt sleep
and exacerbate the preexisting tendency of dementia patients to awaken
more often and spend less time in deep (slow wave) sleep [93,94]. A light
bedtime snack comprising foods that promote sleep, such as milk, bana-
nas, or cheese, may reduce patient awakenings that are caused by night-
time hunger.
• Eliminate or reduce environmental nuisance factors that may interrupt
sleep. Reductions in light levels and nighttime noise have been shown to
be critical for the alleviation of sleep disturbances for nursing home res-
idents [83]. In community home settings, potential environmental
causes of disturbed patient sleep that should also be evaluated include
the impact of household pets, live-in adult children or grandchildren,
caregiver snoring, and outside traffic noise.
• Be aware that changes in daily routine, such as family get-togethers or
holidays, may produce a worsening in nighttime sleep. Try to plan
ahead, and build in some quiet ‘‘catch-up’’ time after any out-of-the-
ordinary planned activity.
Role of the caregiver

Practically speaking, teaching caregivers strategies to use with the patient
on a daily basis is the focus of most nonpharmacologic treatments. Care-
givers may include family members, unpaid caregivers, or paid caregivers

who have a role in the patient’s day-to-day care. In planning management
strategies, it is important to have a good understanding of the resources,
skills, and energy of these individuals. A variety of factors have an impact
on the caregiver’s ability to carry out recommended changes, and these fac-
tors must be addressed for successful nonpharmacologic treatment. For
example, the degree of stress and burden the caregiver is currently experienc-
ing influences the caregiver’s willingness and ability to carry out a behavior
change plan. Many caregivers are employed or have other family responsi-
bilities in addition to caring for their relative with dementia. Some caregivers
have physical or mental health problems of their own that interfere with
their ability to follow through with treatment. The past and present relation-
ship between patient and caregiver influences the manner in which the
patient and caregiver interact and, potentially, the occurrence and treatment
of behavioral problems. Health care providers must spend time talking with
the caregiver about their own concerns and well-being and address these
problems when they are identified.
Treatment must be tailored to meet the needs of both the patient and the
caregiver to be most effective. Because dementia is a progressively worsening
condition, flexibility and creativity are needed to modify and adapt strate-
gies as problems evolve. Finally, it is important to respect the dignity of the
patient and the caregiver when developing treatment plans.
Conclusion
Most if not all patients with dementia experience behavioral problems.
Some forms of dementia seem particularly prone to behavioral disturbances.
For example, individuals who have dementia with Lewy bodies may present
with psychotic symptoms early in the course of dementia [95,96]. Persons
with either frontotemporal or subcortical dementia often exhibit prominent
impairment in executive functioning (eg, problem solving, judgment, plan-
ning) that affects patient care and safety; mood and personality changes are
also common [97,98]. Whatever the cause, behavioral problems are preva-
lent, pervasive, and disruptive. They adversely affect patient and caregiver
alike, often leading to patient institutionalization and caregiver burnout.
It is important for health care providers to assess the occurrence and
impact of these behaviors so as to best care for their patients with dementia.
Measurement tools can augment the clinical interview to help the practi-
tioner obtain a thorough assessment of behavioral problems. Once identi-
fied, these problems may be amenable to nonpharmacologic treatments
designed to prevent or alleviate such problems. Although such strategies
have been subjected to few rigorous controlled clinical trials, extensive clin-
ical experience exists indicating their utility, and results thus far support the
use of these strategies in patients with dementia. Caregivers, whether they
are family members, long-term care staff, or health care professionals, are
critical to the assessment and treatment of behavioral problems. Oftentimes,
they are the sole providers of care for patients with dementia and must learn
how to manage the variety of problems that are experienced, including
depression, agitation, wandering, and sleep disturbance.
We have provided an overview of the literature in this area as well as
detailing one method using the A-B-C approach to patient care. We have
also provided specific suggestions as to how to begin a treatment plan
for common problems, such as depression, agitation/aggression, wandering,
and sleep disturbance. As more and more patients become elderly and more
and more elderly persons become demented, health care providers must
become familiar with nonpharmacologic treatment of behavioral problems
in dementia. Furthermore, they must be able to impart this knowledge to
those caregivers providing essential daily care of patients with dementia.
Acknowledgements
The authors thank Elizabeth ‘‘Buzzy’’ Mounce for her help in prepara-
tion of this article.
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Med Clin N Am 86 (2002) 657–674
Pharmacologic treatments of dementia

Lauren T. Bonner, MD*, Elaine R. Peskind, MD
Department of Psychiatry and Behavioral Sciences, University of Washington
School of Medicine, and Veterans Affairs Puget Sound Health Care System,
Mental Illness Research, Education, and Clinical Center, 116 MIRECC,
1660 South Columbian Way, Seattle, WA 98108, USA
Alzheimer’s disease (AD) and other forms of dementia are estimated to

affect millions worldwide. Because estimates of the incidence and prevalence
of dementia are criteria dependent, the true number of people affected by
dementia in the United States is unknown. Is it estimated that AD, the most
common cause of dementia, accounts for nearly 70% of dementias [1]. There is
still debate about the second and third most common forms of dementia.
Recent neuropathologic studies have demonstrated that dementia with Lewy
bodies (DLB) may be the second most common cause of dementia, accounting
for 15% to 25% of dementia cases [2]. Other sources consider vascular/multi-
infarct dementia (VaD) to be the second most common cause of dementia [3].
Because AD and other forms of dementia are diseases of the aged, preva-
lence rates should increase as our population continues to age. AD is esti-
mated to affect 4 million Americans [4]. Currently, approximately 5% of
Americans aged 65 years and older suffer from AD, with an estimated
30% to 50% of Americans aged 85 years and older suffering from the dis-
order [1]. By the year 2050, the number of Americans suffering from AD
is estimated to rise to 14 million [4].
AD is characterized by a gradual insidious onset of memory loss, global
cognitive deterioration, and functional deterioration. Short-term memory is
affected early in the course of the illness, reflecting early involvement of the
hippocampus and medial temporal lobes. Visuospatial deficits and executive
dysfunction also appear early in the illness. Gradually, as the disease process
advances, all cognitive functions are impaired. The duration of the illness
is 5 to 10 years, with pneumonia or sepsis as the usual cause of death. The
E-mail address: [email protected] (L.T. Bonner).
This work was supported by the Department of Veterans Affairs and NIA AG05136 and
AG18644.
PII: S 0 0 2 5 - 7 1 2 5 ( 0 2 ) 0 0 0 0 7 - X
658 L.T. Bonner, E.R. Peskind / Med Clin N Am 86 (2002) 657–674
typical findings on neuropathologic examination include hippocampal and

neocortical neuritic plaques, neurofibrillary tangles, and neuronal loss.
Although there is no cure for AD, two pharmacologic treatment options
can provide symptomatic improvement in cognitive and functional dete-
rioration: cholinesterase inhibitors and vitamin E. Cholinesterase inhibitors,
which exert their effects by increasing the availability of intrasynaptic acetyl-
choline, have been demonstrated to be more effective than placebo in the
treatment of the cognitive deficits of AD [5–16]. The antioxidant vitamin E
(a-tocopherol) slows functional deterioration in AD [17]. In this article, we
review data supporting the use of cholinesterase inhibitors and vitamin E
in the treatment of AD and related dementias and present recommendations
for incorporating their use into clinical practice. Unless otherwise specified,
when specific effect sizes are described, the efficacy data presented were
derived from analysis of observed cases.
Minimizing excess disability

Before consideration of pharmacologic management of the cognitive
impairments of dementia, sources of excess disability and comorbidity should
be eliminated or reduced, with special emphasis on the use of nonpharmaco-
logic approaches to treatment. Comorbid medical and psychiatric condi-
tions, such as depression, should be identified and optimally treated. Avoid
polypharmacy; that is, use the fewest number and lowest effective doses of
medications for comorbid medical and behavioral conditions. In addition,
certain classes of drugs should be avoided if possible, particularly those with
anticholinergic or sedating side effects. The list of drugs that may contribute
to cognitive impairment is large. Common offenders include oxybutynin used
for treatment of urinary incontinence, the anticholinergic tricyclic antide-
pressants amitriptyline and imipramine, and the benzodiazepine antianxiety
and hypnotic drugs. Alcohol puts endangered neurons at even greater risk; in
the patient with a dementing disorder, alcohol use should be minimized.
Optimizing vision, hearing, and nutrition helps to maximize function and
promote general health. Caregiver support is a crucial component of manag-
ing the dementia patient. AD is often described as causing more suffering in
caregivers than in the AD patients themselves, and depression in AD care-
givers is common. The clinician should inquire about the presence of depres-
sive symptoms in the AD caregiver and provide treatment or appropriate
referral. Periodic respite for the caregiver is often beneficial.
Caregivers need to be provided with education, encouragement, and prac-
tical advice. This includes instructing caregivers in providing an appropriate
environment for the demented patient and in the fundamentals of behavior
management techniques. Provision of appropriate referrals for needed
services is important as well. Caregivers should be encouraged to utilize the
resources of their local Alzheimer’s Association chapter.
L.T. Bonner, E.R. Peskind / Med Clin N Am 86 (2002) 657–674 659
Cholinergic systems and memory:

cholinergic hypothesis of Alzheimer’s disease
There have been clear demonstrations of presynaptic cholinergic deficits
in AD [18–21]. In AD, there is well-documented loss of neurons in the
nucleus basalis of Meynert [21,22], the basal forebrain nucleus that is the site
of origin of the cholinergic neurons that project widely to many brain
regions, use acetylcholine as their neurotransmitter, and are involved in
memory and other cognitive functions. In addition to loss of cholinergic
neurons, there is a marked decrease in the activity of choline acetyltransfer-
ase, the synthetic enzyme for acetylcholine, in target areas in the cortex and
other brain regions as well as overall reductions in other markers of choli-
nergic activity [18–20,22–26]. These findings provide a scientific rationale for
the consideration of cholinergic strategies as a treatment for AD.
Several strategies have been attempted to increase cholinergic transmis-
sion in the brain. These strategies are analogous to the dopaminergic
enhancement strategies that have proven successful in ameliorating the
motor disturbances of Parkinson’s disease. These include choline and phos-
phatidylcholine precursor loading [27–31], muscarinic and nicotinic choliner-
gic receptor agonists [32], and cholinesterase inhibitors [5–16,33]. The only
drugs that have demonstrated efficacy and safety in large-scale, placebo-
controlled, randomized trials in AD are the cholinesterase inhibitors. By inhib-
iting the degradative metabolism of acetylcholine released by presynaptic
cholinergic neurons, cholinesterase inhibitors increase the amount of synap-
tic acetylcholine available for neurotransmission.
Cholinesterase inhibitor use in Alzheimer’s disease

Cholinesterase inhibitors for which data from large-scale placebo-con-
trolled clinical trials support efficacy in the treatment of AD include the US
Food and Drug Administration (FDA)–approved drugs tacrine, donepezil,
rivastigmine, and galantamine (Table 1). Multicenter trials were conducted
in patients with mild to moderate disease, defined as having a Mini-Mental
State Examination (MMSE) [34] score between 10 and 24. The criteria used
to diagnose AD included the Diagnostic and Statistical Manual III–Revised
[35] and Diagnostic and Statistical Manual IV [36] of the American Psychia-
tric Association and the National Institute of Neurologic and Communicative
Disorders and Stroke–Alzheimer Disease and Related Disorders Association
criteria [37]. The efficacy measures used in these trials were generally uniform
and included the Alzheimer’s Disease Assessment Scale–Cognitive Subscale
(ADAS-Cog) [38] as a primary efficacy measure. The ADAS-Cog, scored
from 0 to 70, with higher scores reflecting increased severity of cognitive
impairment, generally declines approximately 6 to 10 points per year in the
mild to moderate stages of AD, with 8 points as the average decline over
1 year. Drug-placebo differences of approximately 3 to 4 points on the
Table 1
Cholinesterase inhibitor titration schedule
Titration period/maximum
Cholinesterase Starting dose increase per titration
inhibitor dose period Maximum dose
Donepezil 5 mg qhs 4–6 weeks/5 mg 10 mg qhs
Rivastigmine 1.5 mg bid 4–6 weeks/1.5 mg bid 6 mg bid (total of 12 mg)
Galantamine 4 mg bid 4–6 weeks/4 mg bid 12 mg bid (total of 24 mg)
Abbreviations: qhs, at bedtime; bid, twice daily.
ADAS-Cog over 6 months have been accepted as indicating drug efficacy.

This difference represents approximately 6 months of cognitive and functional
ability. Various measures of quality of life, activities of daily living, and non-
cognitive behavioral disturbances supported drug efficacy in various trials. It
is becoming increasingly clear that, on average, cholinesterase inhibitors sta-
bilize cognitive function and activities of living for at least 1 year in the AD
patient with mild to moderate cognitive impairment [11,39–42].
The most frequent adverse events experienced by subjects in cholinester-
ase inhibitor trials reflect effects of increased cholinergic activity on the gas-
trointestinal system. Nausea is the most common adverse effect, followed by
vomiting and diarrhea. These effects are dose dependent. Weight loss has
also been demonstrated with some cholinesterase inhibitors.
The only absolute contraindication to use of cholinesterase inhibitors is
severe hypersensitivity to the specific drug or its derivatives. Caution is ad-
vised with use in patients who have a previous history of allergy or adverse
reactions to prior cholinesterase inhibitors, severe liver disease, preexisting
bradycardia, peptic ulcer disease, current alcoholism, asthma, or chronic
obstructive pulmonary disease.
Tacrine
Tacrine, the ‘‘first generation’’ cholinesterase inhibitor, was shown to
have modest efficacy in improving cognition in several large-scale placebo-
controlled trials in AD [7,8,10]. After 6 months of treatment, the drug-
placebo differences on the ADAS-Cog obtained from intent-to-treat analysis
(ITT) were approximately four points, interpreted as delay of cognitive
decline by approximately 6 months [7,8,10].
A retrospective analysis of the tacrine trial data suggests that tacrine
doses of greater than 80 mg/d may delay time to nursing home placement
and provides evidence for long-term cost-effective use of tacrine [42]. In this
study, 102 patients on low-dose or no tacrine (80 mg or less/d) were com-
pared with 198 patients on high-dose tacrine (>80 mg/d). Patients were fol-
lowed for approximately 800 days. At the end of this period, 45% of patients
in the low-dose or no-tacrine group had undergone nursing home placement
as compared to approximately 21% of patients in the higher dose tacrine
group. These findings suggest that benefits of cholinesterase inhibitors on

stabilization of cognition, function, and behavior translate into caregivers
being able to provide care at home longer.
During the tacrine trials, a high incidence of reversible hepatotoxicity and
gastrointestinal adverse effects resulted in poor study completion rates [7,
8,10]. In clinical practice, tacrine-induced reversible hepatotoxicity occurs
in up to 50% of patients [43]. Because transaminase levels may reach up
to 10 times the normal level, the FDA requires monitoring of transaminases
during dose titration and maintenance therapy, recommending measuring
alanine aminotransferase levels weekly for the first 18 weeks, with monitor-
ing every 3 months after a stable dose is reached. Weekly monitoring should
be resumed for an additional 6 weeks if the dosage is adjusted up. Tacrine
has been demonstrated to have clinically significant drug-drug interactions
with cimetidine and theophylline [44].
Because of the availability of other cholinesterase inhibitors that are not
hepatotoxic, lack significant drug-drug interactions, and have more conve-
nient dosing regimens, the use of tacrine is limited to patients with an initial
good response to this agent.
Donepezil
The piperidine derivative donepezil is a noncompetitive reversible acetyl-
cholinesterase inhibitor with specificity for the brain [45]. Donepezil has
been demonstrated to be modestly effective in stabilizing the cognitive func-
tion of AD patients in three large, randomized, placebo-controlled trials
[5,12,13]. These trials all used ITT analyses.
Donepezil is metabolized in the liver; its half-life is approximately 70
hours. Donepezil has no significant effect on the metabolism of other drugs,
including cimetidine, theophylline, warfarin, furosemide, and digoxin; done-
pezil metabolism is inhibited by ketoconazole and quinidine [44,46].
Donepezil at doses of 5 and 10 mg was compared with placebo in a
30-week treatment trial [13]. Four hundred seventy-three patients with
AD were randomly assigned to three treatment groups: placebo or 5 or 10
mg of donepezil. Significant and equivalent drug-versus-placebo group dif-
ferences were found for both the 5- and 10-mg donepezil groups on the
ADAS-Cog. The mean difference between active treatment and placebo
groups was approximately three points. There was no difference between the
5- and 10-mg doses. Donepezil was well tolerated, with no significant differ-
ence in occurrence of adverse events between the 5-mg and placebo groups.
An international study of 818 patients with the same study design demon-
strated similar results [5]. There were significant drug-versus-placebo differ-
ences on the ADAS-Cog. The mean drug-versus-placebo differences for the
5- and 10-mg donepezil groups were 1.5 and 2.9 points, respectively. A trial
in 468 patients consisting of a 12-week treatment phase followed by a
3-week washout phase compared 5 and 10 mg of donepezil with placebo and
demonstrated similar results [12]. In this trial, both treatment groups

demonstrated improvement in ADAS-Cog scores when compared with pla-
cebo, with mean drug-versus-placebo differences of 2.5 points for the 5-mg
group and 3.1 points for the 10-mg treatment group, reflecting a difference
equivalent to appropriately 6 months of cognitive deterioration.
Because of its safety and ease of administration, donepezil is considered a
‘‘second-generation’’ cholinesterase inhibitor with several clear advantages
compared with tacrine. Donepezil is not hepatotoxic, and liver transaminase
monitoring is not necessary [5,12,13]. Donepezil is administered in a single
bedtime dose; the recommended starting dose of donepezil is 5 mg at night,
with or without food. If the drug is well tolerated, the dose may be increased
to 10 mg after 4 to 6 weeks. Gastrointestinal side effects and occasional sleep
disturbance are the most common adverse effects.
Rivastigmine
Like donepezil and tacrine, rivastigmine is a noncompetitive reversible
inhibitor of acetylcholinesterase [47,48]. ‘‘Pseudoirreversible’’ enzyme inhibi-
tion has also been used to describe its mechanism of action, because the dura-
tion of inhibition of acetylcholinesterase induced by rivastigmine is longer
than its half-life [49,50]. Rivastigmine has relatively more inhibitory activity
for butyrylcholinesterase than acetylcholinesterase compared with other cho-
linesterase inhibitors [51]. The clinical relevance of this differential property
remains unclear. Compared with other cholinesterase inhibitors, rivastigmine
may have increased selectivity for the hippocampus and neocortex, which are
the areas of the brain preferentially affected by AD [47,51,52].
Rivastigmine is metabolized by the cholinesterases in brain, liver, and
intestine and is renally excreted [50,51]. Rivastigmine has been shown to
have no effect on the metabolism of other drugs, including warfarin, diaze-
pam, fluoxetine, and digoxin [50,51]. It has not been shown to affect hepatic
enzymes or other laboratory parameters [6,14,50,51].
Clinical trials indicate that rivastigmine is modestly effective in the treat-
ment of the cognitive impairments of mild to moderate AD [6,14]. Rivastig-
mine was compared with placebo in a 26-week international treatment trial
[14]. Seven hundred twenty-five patients with mild to moderate AD were ran-
domly assigned to three treatment groups of 1 to 4 mg of rivastigmine, 6 to 12
mg of rivastigmine, or placebo. Dose increases occurred weekly, with a max-
imum dose increase of 1.5 mg/d allowed during the 12-week dose escalation
phase. During weeks 8 through 12, no dose changes were permitted. There was
a 13-week maintenance phase during which the dose could be adjusted with the
goal of administering the highest tolerated dose. Mean drug-versus-placebo
differences on the ADAS-Cog were 0.17 for low-dose rivastigmine and 2.58 for
high-dose rivastigmine. Only the high dose differed significantly from placebo.
In the United States, a 26-week, double-blind, placebo-controlled trial of
699 patients compared low-dose rivastigmine (1–4 mg), high-dose rivastigmine
(6–12 mg), and placebo [6]. Patients in the 6- to 12-mg rivastigmine group
demonstrated significantly better cognitive function than patients treated with
placebo. The mean drug-versus-placebo difference in the ADAS-Cog between
the 6- to 12-mg group and the placebo group was 4.94 points. In addition,
patients receiving high-dose rivastigmine demonstrated better preservation
of functional ability as measured by the Progressive Deterioration Scale [53]
when compared with the placebo group.
There was an additional 6-month extension phase of the US trial in which
all patients who completed the double-blind phase were eligible for treatment
with a flexible maintenance dose of rivastigmine, ranging from a minimum of 1
mg administered twice daily to 6 mg administered twice daily [41]. Initially, all
patients were treated with open-label rivastigmine at a rate of 1 mg adminis-
tered twice daily for the first week, with maximum allowed dose increases of
1 mg administered twice daily per week for a maximum allowed total dose
of 6 mg administered twice daily. Decreases in dose were allowed per patient
tolerability, with a minimum required dose of 1 mg administered twice daily.
The change in ADAS-Cog score at week 52 was compared in four groups: the
three original treatment groups given placebo, 1 to 4 mg of rivastigmine, or 6
to 12 mg of rivastigmine, and a fourth group consisting of a theoretic 52-week
placebo group based on a modeling procedure of the projected decline if pla-
cebo had been continued for the full 52 weeks. Mean treatment differences on
the ADAS-Cog at week 52 for the original placebo group were 1.4 points ver-
sus the original 6- to 12-mg/d rivastigmine group, 0.3 points versus the original
1- to 4-mg/d rivastigmine group, and 4.3 points versus the theoretic 52-week
placebo group. The theoretic 52-week placebo group versus the original 6- to
12-mg/d rivastigmine group mean difference in ADAS-Cog scores was 5.7
points. These data suggest that rivastigmine may modify the course of AD and
are consistent with data for other cholinesterase inhibitors [11,39,40,42].
The recommended starting dose of rivastigmine is 1.5 mg administered
twice daily given with breakfast and dinner. Administration of rivastigmine
at mealtime helps to minimize nausea. Although the rivastigmine package
insert recommends titration increases at 2-week intervals, gastrointestinal
adverse effects may be minimized by using a slower 4- to 6-week titration
schedule. The dose should be increased to 3 mg administered twice daily,
then to 4.5 mg administered twice daily, and finally to 6 mg administered
twice daily at 4- to 6-week intervals as tolerated. As with all cholinesterase
inhibitors, the dose should be titrated slowly upward to the maximum toler-
ated dose. If rivastigmine therapy is interrupted for more than a few days, it
is recommended that treatment be restarted at 1.5 mg administered twice
daily (the lowest starting dose) and then titrated up again every 4 to 6 weeks
to the highest tolerated dose. Nausea, the most common side effect, can be
minimized by adequate hydration. If necessary, an antiemetic may be used.
As with other cholinesterase inhibitors, the incidence of gastrointestinal side
effects is dose dependent. Rivastigmine is the only cholinesterase inhibitor
with which weight loss is a clinically meaningful problem.
Galantamine
Galantamine hydrobromide, a derivative of the snowdrop plant, is the
most recently approved cholinesterase inhibitor. Unlike tacrine, donepezil,
and rivastigmine, it is a competitive and reversible acetylcholinesterase inhib-
itor. It has little effect on butyrylcholinesterase, being more selective for acet-
ylcholinesterase [54].
Galantamine is unique among cholinesterase inhibitors in having a poten-
tial second mechanism of action as an allosteric modulator at the nicotinic
cholinergic receptor [55,56]; this effect is separate from cholinesterase inhibi-
tion [55]. In vitro, galantamine acts as an ‘‘allosterically potentiating ligand,’’
increasing the likelihood of acetylcholine-induced channel opening and de-
creasing the rate of receptor desensitization [55]. This additional mechanism
of action is a possible explanation for the finding that the amount of cholines-
terase inhibition induced by galantamine and other cholinesterase inhibitors
does not correlate well with their clinical ‘‘potency’’ [55]. The clinical relevance
of this property is unknown, however.
Galantamine is metabolized by the liver [44,57] and has no effects on the
metabolism of other drugs. It is renally excreted. The half-life of galanta-
mine is 7.5 hours. Absorption is not affected by food.
The results of three published large-scale placebo-controlled trials indi-
cate that galantamine is modestly effective in the treatment of the cognitive
impairments of mild to moderate AD [11,15,16]. These trials also demon-
strate that galantamine preserves the activities of daily living. All trials
demonstrated that doses of 16, 24, and 32 mg were significantly statistically
superior to placebo.
Galantamine at doses of 8, 16, and 24 mg administered in divided doses
twice daily was compared with placebo in a 21-week treatment trial in 978
patients with AD [15]. Doses were started at 8 mg/d (4 mg twice-daily dosing)
and were increased by 8 mg/d every 4 weeks. Significant drug-versus-placebo
group differences were found for both the 16- and 24-mg galantamine groups
on the ADAS-Cog. The mean differences between the 16- and 24-mg–versus-
placebo groups were 3.3 and 3.6 points, respectively, on the ADAS-Cog,
which is equivalent to approximately 6 months of cognitive function. There
was not a statistically significant difference between the 16-mg versus 24-mg
dose groups. Both doses were well tolerated. The number of discontinua-
tions secondary to adverse events in the placebo and active treatment groups
was similar (7% in the placebo group and 6%–10% in the active treatment
groups) and increased in a dose-dependent fashion. In addition, galanta-
mine had similar beneficial effects on global function and behavior.
Galantamine at doses of 24 and 32 mg was compared with placebo in two
26-week treatment trials—one in the United States and the other interna-
tional [11,16]. Both studies demonstrated that galantamine significantly
improved cognitive function relative to placebo. Mean differences between
the 24- and 32- mg–versus-placebo groups on the ADAS-Cog were 3.9 and
3.8 points in the US trial and 3.1 and 4.1 points in the international trial,
a difference equivalent to approximately 6 months of cognitive function.
There was no statistically significant difference between the 24-mg versus
32-mg groups.
In the US trial, there was an additional 6-month extension phase during
which all patients who completed the double-blind phase were eligible for
open-label treatment with 24 mg of galantamine [11]. Patients taking
24 mg of galantamine for 12 months demonstrated preservation in activities
of daily living compared to patients who received placebo for six months
followed by 24 mg open-label galantamine for six months. Activities of daily
living were evaluated by using the Disability Assessment for Dementia [58].
Those patients who were randomized to placebo in the 26-week parallel-
group design who then went on to open-label active galantamine in the
6-month extension formed, in effect, a delayed-start design group. Interest-
ingly, this group of patients’ cognitive function then stabilized but never
reached the level of the patients who had received 12 months of continuous
active drug. Thus, at the 12-month time point, there remained a statisti-
cally significant difference in the ADAS-Cog scores between patients on
12-month continuous galantamine versus 6 months of placebo followed
by 6 months of galantamine (2 points on the ADAS-Cog). These data and
similar data from other cholinesterase inhibitor studies suggest these agents
may have disease-modifying effects that may slow disease progression in AD.
All trials demonstrated that galantamine had no effect on liver transami-
nases or other laboratory parameters. As with other cholinesterase inhibi-
tors, gastrointestinal adverse events were the most common side effects
and increased with increasing dose. Mild weight loss was also common.
The recommended starting dose of galantamine is 4 mg administered twice
daily given with breakfast and dinner. Administration of galantamine at
mealtime helps to minimize nausea associated with its use. The dose is
increased by 4 mg administered twice daily every 4 to 6 weeks as the patient
tolerates it. If galantamine therapy is interrupted for more than a few days, it
is recommended that treatment be restarted at 4 mg administered twice daily,
with the patient then titrated up every 4 to 6 weeks to the highest tolerated
dose. Nausea, the most common adverse event, usually resolves within a
week and can be further minimized by adequate hydration. If necessary, an
antiemetic may be used.
Cholinesterase inhibitor use in moderate to severe Alzheimer’s disease

A small international trial [9] evaluated the use of donepezil in patients
with moderate to severe AD. In this 24-week trial, 290 AD patients with
MMSE scores between 5 and 18 were randomly assigned to two treatment
groups: 5 to 10 mg of donepezil or placebo. The primary efficacy measure
was the Clinician’s Interview-Based Impression of Change with caregiver
input [59], a seven-point scale ranging from markedly improved to markedly
worse based on a semistructured interview performed with the patient and

caregiver. Various secondary efficacy measures of cognition, global func-
tioning, and behavior were also obtained.
Last observation carried forward analysis revealed significant differences
between the donepezil and placebo groups. Sixty-three percent of donepezil-
treated patients received Clinician’s Interview-Based Impression of Change
with caregiver input ratings of improved or no change in comparison to 42%
of placebo patients. There were significant drug-versus-placebo differences
in all secondary efficacy measures as well. This study suggests that donepezil
may stabilize or improve cognition and functional status in patients with
moderate to severe AD. Larger studies are needed to confirm these results.
Summary
In summary, the cholinesterase inhibitors have provided the first known
effective treatments for the cognitive deficits of AD. Symptomatic efficacy is
modest and may include positive effects on memory, language, praxis, and
problematic noncognitive behaviors, such as pacing, delusions, and unco-
operativeness. It should be noted, however, that only approximately one
third of patients have clinically meaningful improvement in cognitive func-
tion. It is much more common for patients to have stabilization of their cog-
nitive, behavioral, and functional status. This is the message that should be
conveyed to patients and their families: the goal of treatment is stabilization.
Currently available data suggest that this period of stabilization at or near
baseline function lasts at least a year [11,29,39–42].
Vitamin E and antioxidants in Alzheimer’s disease

Vitamin E
Vitamin E (a-tocopherol) administration is a second pharmacologic
approach to slowing progression in AD. Vitamin E has been demonstrated
to protect cell membranes from oxidative damage and, in animal models, to
reduce hippocampal neurodegeneration [60,61]. The production of neuro-
toxic free radicals during oxidative metabolism has been suggested as a
potential mechanism of neurodegeneration in AD [62]. This neurobiologic
consideration, plus the demonstration that the monamine oxidase inhibitor
selegiline seems to slow disease progression in Parkinson’s disease, another
late-life neurodegenerative disorder, has stimulated investigation of drugs
with antioxidant activity as therapeutic agents for AD.
Several small placebo-controlled trials and a much larger Alzheimer’s
Disease Cooperative Study clinical trial [17] provide evidence for the efficacy
of antioxidant strategies in slowing disease progression in AD. The Alz-
heimer’s Disease Cooperative Study consisted of a four-arm parallel-group
study in which 341 patients with moderate-stage AD were randomized to
receive one of three active treatments or placebo for a 2-year period. The
active treatments consisted of vitamin E at a dose of 1000 IU administered
twice a day, selegiline (1-deprenyl) at a dose of 10 mg (given as 5 mg twice a
day), or a combination of vitamin E and selegiline. Primary outcome mea-
sures were indices of functional decline: progression from moderate to
severe dementia; loss of two of three basic activities of daily living, ie, feed-
ing, grooming, and toileting; nursing home placement; or death.
Vitamin E and selegiline both delayed progression to the outcome end-
points. The average delay for vitamin E was approximately 230 days com-
pared with placebo. Because of its low cost and relative safety, vitamin E
is now recommended in addition to a cholinesterase inhibitor for slowing
progression in AD. Vitamin E is started at a dosage of 400 IU/d and is
increased by 400 IU as tolerated each week until the maximum dose of
2000 IU in divided doses administered twice daily is reached. Because vita-
min E inhibits platelet adhesion [63,64] and may alter vitamin K–dependent
coagulation factors [65,66], its use is contraindicated in patients with vita-
min K deficiency, and cautious use is recommended in patients receiving
anticoagulant therapy.
Ginkgo biloba
Ginkgo biloba is a traditional Chinese herbal medicine with reputed
mood-elevating, cognitive-enhancing, and behavior-altering properties. Its
theoretic properties include anti-inflammatory and antioxidant effects
[67,68]. Although its safety profile has not been fully characterized, ginkgo
biloba is a modest anticoagulant [68].
EGB 761, a standardized extract of the Ginkgo biloba tree, was evaluated in
a 52-week, double-blind, randomized, placebo-controlled trial to assess effi-
cacy and safety in patients with AD and VaD [69]. Primary outcome measures
included the ADAS-Cog and the Clinical Global Impression of Change. In
addition, the nonvalidated Geriatric Evaluation by Relative Rating Instru-
ment (GERRI) [70], a caregiver-rated measure of patient functioning, was
used as an outcome measure. The GERRI is a 49-item inventory that includes
a range of scores from 1 to 5 in which an increasing score indicates poorer
patient functioning. An ITT analysis was used to compare data.
When compared with placebo, EGB 761 at a dose of 40 mg three times
a day demonstrated a small but statistically significant difference in the
ADAS-Cog with a drug-versus-placebo difference of 1.4 points. There was
also a statistically significant drug-versus-placebo group difference in the
GERRI of 0.14 points. There was no difference demonstrated in the Clinical
Global Impression of Change. The number of adverse events was similar in
the placebo and active treatment groups. There was a high attrition rate dur-
ing the 52-week trial; only 137 of the 309 subjects included in the ITT anal-
ysis completed the trial. The effects of EGB 761 on agitation and mood were
assessed but not reported.
The results of this study must be interpreted with caution. There are a
number of methodologic flaws that render interpretation of the data some-
what difficult. Until the results of this study are replicated and the safety
profile of ginkgo biloba is further clarified with regard to potential for caus-
ing significant bleeding events, the use of ginkgo biloba in AD is not sup-
ported by the available data. In addition, the manufacture of ginkgo
biloba and other herbal supplements is unregulated and lacks FDA-
mandated standards for potency and purity.
Treatment of dementia with Lewy bodies

DLB is characterized by a cluster of signs and symptoms distinct from
AD, including dementia, hallucinations, early-stage parkinsonian motor
features, and fluctuating cognitive deficits [2,71,72]. Neuropathologically,
cortical neurons of DLB patients exhibit Lewy bodies—spherical intracyto-
plasmic inclusions [2]. Patients with DLB demonstrate a number of neuro-
anatomic and neurochemical deficits, including a decreased numbers of
neurons in the substantia nigra and abnormalities of the dopaminergic, cho-
linergic, serotonergic, and noradrenergic neurotransmitter systems [2,73].
DLB patients demonstrate more severe deficits of choline acetyltransferase
activity and more functional and upregulated postsynaptic muscarinic
receptors when compared with AD patients [72–74].
Because the cholinergic deficit in DLB is thought to be greater than in
AD, patients with DLB have been hypothesized to have a better response
to cholinesterase inhibitors than patients with AD [2,73]. Although there are
no FDA-approved treatments for DLB, case reports and open-label studies
as well as one recent double-blind placebo-controlled clinical trial have sug-
gested efficacy of cholinesterase inhibitors in the treatment of DLB [75–77].
McKeith and colleagues [76] reported a 23-week European study of 3 mg
(1.5 mg twice a day) to 12 mg (6 mg twice a day) of rivastigmine versus
placebo in 120 patients diagnosed with mild to moderately severe probable
DLB. DLB was defined by consensus guideline criteria. Mild to moderate
disease was defined by an MMSE score of greater than 9. A 20-week titra-
tion and treatment phase was followed by a 3-week washout phase. The
maximum length of the titration period was 8 weeks.
The Neuropsychiatric Inventory (NPI) [78] and a ‘‘computerized cognitive
assessment system speed score’’ (a sum of scores reflecting various param-
eters, including picture recognition reaction times, spatial memory, and word
recognition) were the primary efficacy measures [76]. MMSE scores and other
global index measures were used as well as the NPI-4, a subscale cluster of the
four items on the NPI identified as a DLB cluster: apathy, depression, delu-
sions, and hallucinations.
Fifty-six percent of patients reached the maximum daily dose of 12 mg, and
92% reached doses of 6 to 12 mg. Differences between the rivastigmine and
placebo groups on the NPI-4 and computerized cognitive assessment system
speed score were statistically significant. Sixty-three percent of patients in the

rivastigmine group demonstrated at least a 30% reduction from baseline in
NPI score as compared to 30% in the placebo group. The rivastigmine and pla-
cebo groups did not differ with respect to MMSE scores or global function.
After the 3-week study medication washout period, differences between the
placebo- and rivastigmine-treated groups on the NPI were no longer significant.
In summary, cholinesterase inhibitors may also be effective in the treatment
of DLB. One small placebo-controlled trial demonstrated that rivastigmine
was effective in the treatment of behavioral deficits of DLB [76]. Large-scale
placebo-controlled trials are necessary to confirm these results, however.
Treatment of vascular dementia

There are currently no FDA-approved treatments for VaD. Because the
cause of VaD is a consequence of cerebrovascular disease, treatment of VaD
has focused on controlling the risk factors for cerebrovascular disease [79,80].
Prompt identification and treatment of hypertension, the major risk factor
for stroke, are critical in the prevention of stroke and VaD [79,80]. In addi-
tion, management and modification of lifestyle factors are crucial, including
the elimination of cigarette smoking, weight reduction, nutritional education,
and treatment of hypercholesterolemia and hypertriglyceridemia [79,80].
Summary
The management of dementia patients encompasses pharmacologic,
behavioral, and psychosocial intervention strategies. Before pharmacologic
intervention is instituted, it is important that sources of excess disability and
comorbidity be eliminated or reduced. Identification of comorbid medical
and psychiatric conditions, such as depression and delirium, should be iden-
tified and appropriately treated. Providing caregivers with education, sup-
port, and practical advice is a critical component of the management of
the demented patient.
The current standard of care for pharmacologic management of the cog-
nitive and functional disabilities of AD consists of the combination of a cho-
linesterase inhibitor and high-dose vitamin E. This standard is based on the
results of large-scale, double-blind, placebo-controlled trials.
Cholinesterase inhibitors are the only FDA-approved pharmacologic
treatments for AD. Cholinesterase inhibitors have been shown to be effec-
tive in the treatment of the cognitive, behavioral, and functional deficits
of AD. Large-scale placebo-controlled trials of tacrine, donepezil, rivastig-
mine, and galantamine have demonstrated moderate benefits in patients
with mild to moderate AD. Donepezil, rivastigmine, and galantamine are
the first-line choices in the treatment of AD because of their lack of hepato-
toxicity, ease of administration, few significant drug-drug interactions, and
mild to moderate side effects.
There are few contraindications to the use of cholinesterase inhibitors.

Known hypersensitivity to a specific drug or its derivatives is the only true
contraindication. Cautious administration of cholinesterase inhibitors is
advised in patients who have a previous history of allergy or adverse
reactions to prior cholinesterase inhibitors, severe liver disease, preexisting
bradycardia, peptic ulcer disease, current alcoholism, asthma, or chronic
obstructive pulmonary disease.
Nausea, vomiting, diarrhea, and anorexia are the most common side ef-
fects of cholinesterase inhibitors. These gastrointestinal side effects can be
minimized by gradual dose increases, administration with food, adequate
hydration, and judicious use of an antiemetic.
Vitamin E has been demonstrated to slow the progression of AD in sev-
eral small and one large placebo-controlled trials. Because of its low cost
and safety, it is recommended in addition to a cholinesterase inhibitor for
the treatment of AD.
There are no FDA-approved treatments for DLB and VaD. One small
placebo-controlled trial demonstrated that rivastigmine may be effective in
the treatment of DLB. More large-scale placebo-controlled trials are needed
to confirm the results of this study. Treatment of VaD focuses on the con-
trol, identification, and management of cerebrovascular disease and vascular
risk factors. Although there are no peer-reviewed reports on the efficacy of
cholinesterase inhibitors for VaD or mixed AD/VaD, early reports suggest
that these agents may also be effective for mixed AD/VaD. The indications
for the use of cholinesterase inhibitor drugs are eventually likely to broaden
to include DLB, mixed AD/VaD, and AD in its more advanced stages.
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Med Clin N Am 86 (2002) xi–xiii

them to be distinguished from other dementing illnesses. Correctly diagnos-

E-mail address: [email protected]

The diagnosis and diﬀerential diagnosis

Dementia is a clinical syndrome characterized by acquired impairment in

Clinical evaluation of patients with memory complaints

provide useful information for distinguishing these two common dementia

History of behavioral disturbances

History of functional impairment

medication, and performing household tasks. More detailed discussions of

Mental status examination

provides valuable qualitative information in multiple cognitive domains;

cognitive function tests given in English. Individuals relatively ﬂuent in

Diagnostic evaluation of dementia

Presently, these techniques are expensive and time-consuming. Neither sin-

Diﬀerential diagnosis of memory and cognitive impairment

Cognitive changes with normal aging

performance demonstrate declines in memory with age. Speciﬁcally, it has

Mild cognitive impairment

Identifying less common causes of dementia

Lewy bodies. Fluctuations in performance, often over a period of minutes,

slow. Language disturbances may be an early feature, with anomia progres-

Dementias associated with parkinsonism

is poorly responsive to levodopa and is associated with cerebellar dysfunction,

Dementia related to chronic subdural hematoma

Dementias associated with infectious disease

General paresis refers to the dementia associated with parenchymatous

Dementia associated with metabolic disturbance

Normal pressure hydrocephalus

diagnostic certainty beyond a good history, examination, and structural brain

Vascular dementia revisited:

Vascular dementia (VaD) is an etiologic category that includes clinical

* E-mail address: [email protected] (G.C. Román).

recognized. Concurrently, Tomlinson, Blessed, and Roth demonstrated that

cortical-subcortical circuits that underlie executive functions, motivation,

Vascular and circulatory lesions

denomination of ‘‘mixed’’ dementia. Hénon et al [44] found a 16% preva-

Risk factors for vascular dementia

Clinical forms of vascular dementia

Acute-onset vascular dementia

Poststroke multi-infarct dementia

Dementia caused by a single cortical-subcortical infarction

Dementia from capsular genu infarction

Subacute (subcortical) vascular dementia

Lacunar state (état lacunaire)

Senile dementia of the Binswanger type

poor retrieval and intact recognition. Apathy, depression, and behavioral

Cerebral autosomal dominant arteriopathy

Cerebral amyloid angiopathy

Diagnosis of vascular dementia

Demonstration of the presence of vascular lesions by brain MRI or CT

pathologically resembling mesial temporal lobe sclerosis [100]. By deﬁnition,

Separating Alzheimer’s disease from vascular dementia

Treatment and prevention

Other risk factors

disease and disturbances of the microcirculation. Blood glucose control

Drug treatments for vascular dementia

Calcium channel blockers

Neuroprotective (Nootropic) agents

randomized 1219 subjects with mild to moderate VaD selected according to