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Originally published in: Volume 4, Number 4
Volume 4, Number 5
Volume 4, Number 6, May 2001
JuneJuly 2001
August 2001, Pages 11
13,14,15
13,14,15
may2001_dementia
Dementia: Biological and
Clinical Advances--Part I
Cognitive Assessment and Neuroimaging of Dementia
Bob Chaudhuri, MD
Department of Psychiatry,
University of Toronto,
Toronto, ON.
Contributions from:
Morris Freedman, MD, FRCPC
Director, Behavioural Neurology
and Senior Scientist,
Rotman Research Institute,
Baycrest Centre for Geriatric Care,
Professor of Medicine (Neurology),
University of Toronto,
Toronto, ON.
Larry Leach, PhD, CPsych
Psychologist, Department of Psychology,
Baycrest Centre for Geriatric Care,
Adjunct Professor,
University of Toronto,
Toronto, ON.
Wendy Meschino, MD, CCFP, FRCPC,
FCCMG
Clinical Geneticist,
North York General Hospital,
Toronto, ON.
On Sunday, March 18th, a series of speakers discussed cognitive
assessment and neuroimaging in dementia. The speakers included Dr.
Morris Freedman, Dr. Larry Leach, Dr. Robert van Reekum, Dr. Sandra
E. Black and Dr. Wendy Meschino.
The focus of Dr. Freedman's workshop was the Bedside Assessment of
Cognitive Function. He demonstrated cognitive screening tools in
dementia and selective supplementary testing from the Behavioural
Neurology Assessment that was developed at Baycrest and that is
currently being prepared for publication.
Dr. Freedman showed how clock drawing is an easy to administer and
sensitive measure of cognitive function. However, not all time
settings are equally good for demonstrating deficits. A preferred
time to ask the patient to draw is "10 after 11." He gave striking
examples in which the clock-drawing test was more sensitive than the
Folstein Mini-Mental Status Exam (MMSE). He pointed out that, in
conjunction with the clock drawing, mental status testing in the
office setting can be effective in defining and tracking the
patient's cognitive function.
There are a variety of common clinical problems that are
associated with making a diagnosis of dementia.
The first problem is how best to test the patient's memory. Memory
is almost always impaired in Alzheimer disease, although poor memory
does not necessarily mean AD; intact memory suggests a diagnosis
other than AD.
Generally, a patient has a history of memory loss and he or she,
and/or the family, is concerned about the possibility of
dementia.
The second problem is how best to test the patient's attention.
The MMSE uses serial 7s and spelling the word 'world' backwards as
tests; however, using months backwards or, in severe cases, having
the patient use serial 1s subtraction from one hundred is useful.
A third problem is how to assess language. Dr. Freedman stated
that listening to the pattern of spontaneous speech (fluent vs.
nonfluent), and testing comprehension, naming and repetition are very
useful. Fluent speech suggests a temporal-parietal lesion, and
non-fluent points to a frontal lesion. AD produces fluent speech
until the later stages.
Auditory comprehension testing involves the assessment of single
words, phrases and whole body commands. He suggested that the
clinicians also test repetition of single words and phrases, and test
naming by showing the patient common objects to name (e.g. pencil and
watch). In Alzheimer disease, naming is impaired and repetition is
normal in the early stages.
Dr. Freedman outlined testing for ideomotor apraxia, which is the
inability to pretend to carry out a motor activity to command (e.g.
comb your hair) when the activity is one that can be performed easily
in spontaneous situations. To determine if a patient has apraxia,
give a verbal command. If the patient fails to respond correctly to
the command ask him or her to imitate the action. Finally, ask the
patient to use the real object if imitation is impaired.
Visuospatial function is commonly impaired early in the course of
AD. Clock drawing is a sensitive test of visuospatial function.
Supplementary testing includes drawing to command and copy, such as a
house, a flower and a cube.
Dr. Freedman summarized by stating that there are a number of
tests of memory. These include asking patients the year, month, day,
place, name of the Prime Minister and Premier and immediate and 5
minute 3 word recall words such as cat, apple, table. Attention can
be tested through serial 7s and 3s subtraction and by reciting the
months backwards. Naming can be tested by asking patients to name
objects. Asking the patient to draw a clock, with the time set to 10
after 11, is an effective method to test visuospatial function.
Testing similarities and proverb interpretation assesses the ability
to manipulate acquired knowledge. It should be noted that the tests
of similarities and proverbs may be somewhat confounded by cultural
biases. Copying patterns of multiple loops or alternating sequences
can be used to assess frontal lobe function. Perseveration on these
tasks, and deficits on world list generation of animal names or words
beginning with the letter F, are often seen following frontal brain
damage.
This workshop reviewed the basic aspects of the mental status exam
that make up screening assessment in an office setting. Dr. Freedman
concluded that testing cognitive function is very important for the
differential diagnosis of dementia.
Dr. Larry Leach presented the next workshop on Neuropsychological
Assessment in Dementia. The learning objectives of this lecture were:
to determine whether an individual met the basic criteria for
dementia; to evaluate the effectiveness of cognitive testing in
identifying dementia; and to establish a battery of tests that
describes the cognitive profile of a patient with dementia.
The DSM-IV modified definition of dementia was discussed and
compared to the definitions provided by Cummings and Benson (1983)
and by Strub and Black (1981).1,2
The test battery domains were discussed in terms of memory,
abstract reasoning, perceptual functioning, constructional ability,
language, praxis, mood, global intelligence and cognitive
functioning.
Common referral questions include: a) "Is impairment present?"
b)"What is the pattern of impairment?" c)"What is the etiology?" d)
"Is it mood related?" d) "And has there been a change?"
Dr. Leach also discussed diagnostic issues involving the effects
of age, education, gender and culture.
The Prevalence of dementia was discussed and found to have an
incidence of 2.4% in the population aged 5 to 74, 11.1 % in the
population aged 75 to 84, and 34.5% in the population over age
85.
Dr. Leach reached several conclusions regarding the use of the
MMSE as a diagnostic tool, including that:
a) It was poor for diagnosing dementia when prevalence is less
than .60%;
b) It was adequate for ruling out moderate to severe cognitive
impairment when prevalence is below .35%, except for those patients
who are over the age of 80 and had a lower educational status.
Cut-off scores need to be adjusted according to age and
education.
The following criteria for diagnosing 1) Frontal-Temporal
Dementia, 2) Lewy-body disease, 3) Vascular Dementia, and 4)
Alzheimer Dementia, were discussed. Special tests for dementia were
discussed.
Cognitive and neuropsychological tests provide insights into the
nature and severity of brain dysfunction as well as brain regions
that are dysfunctional in dementia. The pattern of impairment
reflects brain regions affected more so than the cause of
dysfunction. Therefore, there are practical limitations to diagnosing
cause based solely or primarily on the results of mental status
examination or neuropsychological assessment. Despite this
limitation, the pattern of deficits due to dementia are clearly
distinguishable for those cognitive disruptions associated with
depression.
Dr. Robert van Reekum followed Dr. Leach with a presentation on
the importance of neuropsychiatric evaluation in dementia. He
emphasized that changes in mood and behaviour are common in these
patients and can cause suffering, impact on disability and handicap,
influence diagnosis and have prognostic implications. Perhaps most
importantly, these changes in mood and behaviour are treatable. He
divided factors that should be assessed into premorbid factors, which
included a past history of medical, psychiatric, personal,
neurodevelopmental and social factors, and responses to previous
treatments, and current factors. The current factors include medical
status, arousal antecedents/precipitants/patterns, and cognitive and
neurologic status.
A variety of different behaviours are common in patients with
dementia. Because the actual dementia may mimic or mask psychiatric
disorders, the evaluation of psychiatric illness in this population
must take into account the direct effects of CNS disease. Some of the
behavioural symptoms of dementia, such as psychosis, may warrant
pharmacological intervention. Anxiety, agression, disinhibition and
apathy may also warrant treatment.
Finally, Dr. van Reekum stressed the need for structure, reliable
and valid Behavioural inventories to improve the consistency of
behaviour quantification in these patients. He reviewed one such
inventory, the Neuropsychiatric Inventory (NPI).
Dr. Sandra Black presented the pros and cons of the currently
available techniques for neuroimaging in dementia. The objectives of
this workshop were:
a) To review currently available structural and functional imaging
techniques;
b) To review principles for the interpretation of brain-behavior
relationships in dementia;
c) To illustrate the above in case examples of patients with
dementia.
|
Currently available techniques for neuroimaging in
dementia include magnetic resonance imaging (MRI), positron
emission tomography (PET) and CT scan. The relative merits
of these techniques were discussed.
|
CT scanning in dementia has the following strengths: it has
excellent spatial resolution; it is relatively cheap and widely
available, it rules out major pathologies; and, if applied correctly,
medial temp width can be measured. However, it also presents the
following weaknesses: there is less contrast; there is a problem of
bone artifact; it is less sensitive to pathology; and the patient is
exposed to radiation.
Magnetic resonance imaging (MRI) gives excellent spatial
resolution, no bone artifact and better contrast with high
sensitivity, and is low risk. However, it has a higher cost than does
CT scanning and is less readily available and takes longer to image
(but this is changing), and there are associated contraindications
(pacemaker, aneurysm and claustrophobia).
Positron Emission Tomography (PET) has the strength of being
versatile: injected radiolabel can measure regional cerebral blood
flow, metabolism or receptors; direct quantification is possible;
there is fair resolution; and it can measure brain activation using
subtraction. On the downside, it has a high costs associated with it
(cyclotron and special team); it is a scarce resource and not widely
available; and there is a risk associated with exposure to
radiation.
Single Photon Emission Computed Tomography is relatively cheap and
widely available, and the injected radio label measures regional
brain perfusion; but it only offers relative quantification, gives
poor spatial resolution and again has a risk of radiation
exposure.
All of these techniques are useful in different ways for the
diagnosis of dementia. Examination of blood flow, oxygen utilization,
cerebral atrophy and brain function can be demonstrated using these
techniques.
The final lecturer was Dr. Wendy Meschino who discussed the use of
Genetic Testing for Dementia in Clinical practice. The objectives of
the presentation were how to approach a family history of dementia,
risk assessment of hereditary dementia, what tests are available,
determining when testing is helpful and providing information on how
to get testing done. Alzheimer disease risk factors were identified
as: increasing age, a positive family history of AD, Down Syndrome,
cognitive impairment, head injury, low education level, and aluminum
exposure (controversial). Exposure to exogenous estrogen for women
and the presence of arthritis may be protective.
The family history of dementia work-up includes:
a) Taking a detailed three-generation pedigree, noting specific
symptoms, such as the age of onset and the number of unaffected
relatives;
b) Obtaining medical records, including autopsy, to determine
whether the patient suffers from AD or some other condition.
Less than 5% of AD is inherited as an autosomal dominant trait.
These cases are usually early in onset. Hereditary factors combined
with environmental factors (complex inheritance) play a role in a
further 15-25% of mostly late-onset cases. The remaining 75% are
sporadic, late-onset and indistinguishable in phenotype from
hereditary forms.
Dr. Meschino reviewed a list of genes that are now known to cause
hereditary dementias. For early-onset AD these include Presenilin 1,
APP and Presenilin 2. Presenilin 1, a gene on chromosome 14, accounts
for the majority of early-onset cases. The average age of onset is in
the 40's. Some cases of frontotemporal dementia (FTD) are associated
with mutations in the tau gene. Notch3 mutations have been found in
patients with CADASIL (cerebral autosomal dominant arteriopathy with
subcortical infarcts and leukoencephalopathy).
There are also a number of genes that are believed to predispose a
patient to late-onset AD. These risk modifier genes are: the e4
allele of the APOE gene on Chromosome 19 (e4 has the effect of
decreasing the age of onset), and A2M-2 on Chromosome 12 (in some
studies associated with an increased risk of developing AD). These
are examples of genes which affect susceptibility to disease, but do
not directly cause it. Genetic testing for APOE is not recommended
for asymptomatic individuals because the test cannot determine
whether an individual will or will not develop AD in the future.
Prior to genetic testing, patients should be provided with genetic
counselling, especially when undergoing pre-symptomatic testing.
Important information to cover in the session includes outlining the
differences between hereditary and sporadic AD, late-onset and
early-onset AD, and the risk of developing AD in the general
population compared to the risk for that individual.
There are a number of important ethical issues that need to be
considered when discussing predictive testing. The patient must be
able to make an informed choice; that is, there should be no patient
coercion. The clinician should outline the various reasons for
knowing or not knowing the diagnosis, the effects it may have on the
family and the potential that they will be subject to discrimination.
In general, requests for prenatal diagnosis for adult-onset diseases
are infrequent, and testing in childhood is strongly discouraged.
One of the following criteria should be met before Alzheimer
testing is considered:
a) An individual affected with AD, with onset at less than 60
years;
b) A first-degree, unaffected relative of an affected individual,
in a family with 2 or more early-onset cases (all affected are
deceased);
c) 2 or more living affected family members with onset greater
than 60 years (DNA samples needed from both relatives).
As part of this presentation a video clip was shown from a recent
CBC Nature of Things episode called Amanda's Choice, in which a young
woman from northern Ontario underwent genetic testing for early-onset
Alzheimer disease. There was an extensive family history of the
disease in her mother's family with onset of the disease in the
mid-30's. She was shown receiving her genetic test results from the
presenter as well as genetic counselling. The film explored the
emotional impact of living at risk for this devastating disease and
the effects on her family.
In summary, these workshops were highly educational and practical. From the
neuropsychiatric assessments, MRI and PET diagnostic tests for different dementias,
to the ethics and practicality of genetic testing, these workshops appealed
to the novice and expert alike.
Dementia:
Biological and Clinical Advances--Part II
Dementia:
Biological and Clinical Advances--Part III
References
- Cummings JL, Benson DF. Dementia: A Clinical Approach 1983.
Butterworths & Company, Canada.
- Strub RL, Black, FW. The Mental Status Examination in
Neurology 1981. Philadelphia: FA Davis.
june2001_rotman
Dementia: Biological and
Clinical Advances--Part II
|
Christine Oyugi, BSc
Managing Editor,
Geriatrics & Aging.
Edited by:
Karl Farcnik, BSc, MD,
FRCPC
Psychiatrist, Division of Geriatric
Psychiatry, University Toronto,
Part-time staff,
Toronto Western Hospital, Toronto, ON.
|
Contributions from:
Serge Gauthier, MD,
FRCPC
Director, McGill Centre for Studies in Aging,
Professor of Medicine (Neurology),
McGill University, Montreal, QC.
Dr. Katarina
Rogaeva
Research Associate, Centre for
Research in Neurodegenerative diseases,
University of Toronto, Toronto, ON.
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Introduction
With Canada's aging population, dementia has become a growing
problem. Eight percent of Canadians who are over the age of 65 suffer
from dementia, of these approximately 60% are believed to have
Alzheimer disease. Dementia is an age-related disease, with the
prevalence increasing from 2.4% of those from 65-74 years of age, to
34.5% of those 85 and older. There are sixty thousand new cases of
dementia diagnosed each year, and the costs of providing health care
for these patients continue to escalate. It is with these alarming
statistics in mind that clinicians gathered to hear the latest
developments in the biology of dementias presented during the 11th
annual Rotman conference. Various dementias were discussed at the
conference including Frontotemporal lobar dementia (FTLD). FTLD is
the third most common form of cortical dementia following Alzheimer
disease (AD) and Dementia with Lewy Bodies. It is often mistaken for
AD, yet it presents strikingly different clinical and
histopathological features and therefore, must be managed distinctly.
This article will serve as a summary of some of the key points
presented during the first day of this conference on Monday, March
19th.
In her opening remarks, Dr. Rogaeva, a Research Associate at the
Centre for Research in Neurodegenerative diseases at the University
of Toronto, gave a brief overview of the genetic variability and
pathobiology of Alzheimer Disease. AD is a neurological disorder that
is characterized by a slow degenerative process affecting cognitive
function. At a histopathological level, AD patients are characterized
by the deposition of senile plaques within the brain, as well as
within the walls of cerebral blood vessels. It is believed that
through some unknown mechanism, these senile plaques exert a toxic
effect on surrounding neurons, resulting in the neuronal degeneration
found in AD patients. Other pathology that is seen includes reactive
microglia, swollen neurons and intracellular neurofibrillary
tangles.
The primary constituent of these senile plaques is the amyloid
b peptide (Ab).
Two proteases, b-secretase and g-secretase
cleave this peptide from a larger precursor protein, b-amyloid
precursor protein (b-APP). Essentially,
b-secretase cleaves APP to produce an
APPsb soluble fragment.
The pathogenesis of AD has been linked to both genetic and
environmental factors (See Figure 1).
A number of genes have been identified as influencing the
development of AD including APO E, the presenilin genes and
b-APP gene. (See Figure 2).
Of these, presenilin 1 (PS1) mutations are said to account for
majority of the early-onset familial AD cases. In a study that
screened AD patients for PS1 mutations, 11% of the cases had
mutations in regions coded by PS1 and, of these, 21 were novel
mutations. The study also found that the AD patients who had a
positive PS1 test were significantly younger (46 ±11yrs) than
were the patients who tested negative for PS1 (60±11yrs).
According to Dr. Rogaeva, screening for presenilin mutations is
likely to be successful and cost-efficient if it is targeted to the
right groups.
The deposition of Ab in the brains of AD patients is linked to the
pathology that is characteristic of the disease. In his talk, Dr.
Younkin, Director of Research and Professor of Pharmacology at the
Mayo clinic in Jacksonville, explained the role of Ab aggregation in
the pathogenesis of AD with a focus on whether it is an essential
early event in the disease process. One clue to the role of Ab can be
garnered from patients with Down Syndrome or trisomy of chromosome
21. These patients invariably develop AD pathology by age 40 and have
been found to have high Ab levels in their plasma. Interestingly,
this increase in plasma levels of Ab is seen prior to the onset of
symptoms. Studies have shown that all mutations that are linked to AD
increase the extracellular concentrations of Ab; this phenomenon
occurs prior to the development of the disease and fosters
Ab aggregation. Aggregated Ab has been
shown to be directly toxic to neurons in culture; for this reason
inhibition of b or g-secretase,
thereby reducing Ab concentrations, has
emerged as a therapeutic target for AD. Clinical trials are currently
underway to assess the efficacy of immunization with b-secretase.
Plasma and cerebrospinal fluid (CSF) levels of Ab
have been shown to increase with age (over age 65 years). A study
comparing patients with typical late-onset AD to age-matched controls
found that Ab was increased in AD
patients. Some of these patients had levels similar to those found in
patients with trisomy 21 or familial AD. What is interesting with
late onset AD is that, as the disease progresses, there is a decline
in the levels of Ab in the plasma and CSF. The reason for this
decline is not well understood, although microglial clearance has
been implicated.
Although plasma levels of Ab are not
adequate for making a diagnosis of AD, they may be useful as a
biomarker for the disease. According to Dr Younkin, in the future,
therapies could be targeted to patients with elevated Ab
in the same way that patients are treated for elevated cholesterol
levels to prevent cardiovascular disease. The study of Ab
is only one of many approaches to the study of AD. Other approaches
could play important roles in the disease progression and could also
be key targets for therapeutic intervention.
Dr. Wilhelmsen, Associate Professor of Neurology at the University
of Carlifornia, gave a brief overview on the pathobiology of
taupathies. His talk was based on clinical evidence gained from a
family with members that suffered from a variety of neurodegenerative
diseases. Some of the symptoms observed included: behavioural
disinhibition, dementia--which differed from that seen in AD in that
there was a relative preservation of language and praxis--and
Parkinson's disease, without the typical tremor and non-responsive to
L-DOPA. Most members of the family with the disease eventually
developed amyotrophy--which is the loss of motor neurons resulting in
the development of brisk reflexes, but reduced motor power in the
limbs. However, by the time that most patients were dying they were
all akinetic, in a fetal position and bed-ridden, making it difficult
to recognize that they had typical signs of motor neuron disease.
Personality changes were observed in family members including
aggressiveness, depression, alcoholism, hyper- and hypo-sexuality,
childishness, craving for sweets and hyper-religiosity.
Interestingly, they did not respond very well to neuroleptics. The
age of onset of symptoms ranged from 25-56 years.
At the time of autopsy, microvascular changes were observed in the
anterior temporal cortex of the frontal lobes, between layers II and
III. Other pathology includes, rare ballooned neurons, swollen
vacuolated anterior horn cells, loss of pigmented cells in the
substantia nigra and gliosis in the hippocampus.
Linkage analysis was performed and a link was found to chromosome
17. This analysis was done on several families all of whom had
suffered from a variety of disorders including progressive
Parkinsonism and dementia with palido-ponto-nigral degeneration
(PPD), frontotemporal dementia and primary progressive aphasia (PPA).
Several of these families had mutations in the tau gene, which has
been implicated in the formation of neurofibrillary tangles in AD.
Tau protein deposits have been linked to a variety of
neurodegenerative diseases, many of which are frontotemporal
dementias or movement disorders, collectively referred to as
tauopathies--Pick's disease, progressive supranuclear palsy, and
corticobasal degeneration.
What is the function of tau? The tau gene is large and has a
complex pattern of alternative spicing. The protein has domains that
have been shown to affect the assembly of microtubules. Disruption of
this alternative splicing is enough to cause a dysfunction of the tau
protein and resulting neurodegeneration. It appears that the
regulation of splicing of the gene is important for maintenance of
normal brain function. Future research is needed to elucidate whether
it is the aggregation of the protein that ultimately results in
disease.
Many doctors have never seen a case of progressive supranuclear
palsy (PSP). The disease is often misdiagnosed as Parkinson's disease
until the patient fails to respond to normal therapy for PD. The
prevalence of the disease is less than that for PD. The pathology of
PSP is marked by the precipitation of tau protein throughout the
midbrain. Although PSP is primarily a sporadic disease, studies show
that a precipitating mutation may be required for the disease to
occur.
Aggregates of tau protein are seen in many neurodegenerative
disorders suggesting that this process may be a common pathway in the
pathology of these diseases. Although the importance of the tau gene
is known, more research is needed into the interaction of tau with
other genes, as well as the regulation and metabolism of tau. Future
efforts to develop animal models of tau-mediated neurodegeneration
should provide further insights into the onset and progression of
tauopathies, as well as Alzheimer disease. This could lead to the
discovery of effective therapies for these disorders
The next speaker was Dr. David Westaway who began his review of
the latest research in prion diseases. Prion diseases, or
transmissible spongiform encephalopathies, are fatal
neurodegenerative disorders. These neurodegenerative diseases include
scrapie in sheep, mad cow disease in cattle, and Creutzfeldt-Jakob
disease (CJD) in humans. Prion diseases may present as genetic,
infectious or sporadic disorders, all of which involve the
post-translational modification of the prion protein (PrPC) into the
disease-causing PrPSc. CJD generally presents as progressive dementia
where as the other forms of prion disease typically manifest as
ataxia-like disease.
More than 20 mutations of the PrPC gene are now known to cause the
inherited human prion diseases, and significant genetic linkage has
been established for five of these mutations. However, why or how
these mutations cause the protein to change and result in disease is
not really understood.
The function of PrPC is still unknown, although there is some
evidence that it is involved in the binding of Cu(II) ions. Recent
studies suggest that PrPC may function in signal transduction through
a pathway involving Fyn tyrosine kinase. Fyn is associated with
acetylcholine receptors in muscle cells. It is highly expressed in
the limbic system and may have a role in myelination. It was hoped
that deletion of the mouse Prnp gene would alter the phenotype such
that conclusions could be made with respect to the function of PrPC.
Studies in mice show that injection with PrPSc results in death
within 150 days. However, Prnp0/0 knockout mice are resistant to
prion infection. This provides evidence that cellular PrP is
necessary for disease pathogenesis.
Dr. Sandra Black then gave an overview of the use of neuroimaging
biomarkers for AD. An ideal test for AD should: reflect the
pathophysiology of the disease, allow for pathologic evaluation,
allow for early detection, differentiate AD from other dementias, be
non-invasive, be affordable, have a sensitivity greater than 80% for
detecting AD and a specificity of greater than 80% for distinguishing
other dementias. The desired sensitivity and specificity of a
biomarker depends on its purpose.
Dr. Black suggested that current clinical techniques can be termed
the "bronze standard" for diagnosis. This is based on the combined
use of history, and physical and cognitive examination, as well as
blood test and neuroimaging to exclude secondary causes. The "gold
standard" is based on tissue pathology. Biochemical markers for AD
include apolipoprotein E (ApoE) genotyping, and several potential CSF
markers including: beta-amyloid, possibly reflecting amyloid
deposition and formation of senile plaques; PHFtau protein as a
marker for the phosphorylation state of tau, and formation of
neurofibrillary tangles; (total) tau protein, a normal axonal
protein, used as a marker for ongoing neuronal and axonal
degeneration, and the CSF/serum albumin ratio, as a marker for
blood-brain barrier damage, used to exclude patients who also have
cerebrovascular pathology.
Functional imaging techniques such as PET and SPECT also serve as
important diagnostic tools. Recently, functional studies have shown
abnormalities in the posterior cingulate and medial temporal regions
of patients who show memory impairment and later develop AD. This
finding is potentially useful in detecting pre-clinical AD, but it is
difficult to apply to individual cases.
With the emerging therapeutic compounds for the treatment of AD,
an important role of imaging is in monitoring whether treatment is
actually slowing down the progression of atrophy. Several techniques
have been proposed to monitor the progression of the atrophy, but
currently, none can be performed reliably. It is likely that both
quantitative neuroimaging and biochemical profiles (urine and serum)
together with clinical neurobehavioural assessments will be needed in
order to achieve the required sensitivity for diagnosing and
monitoring AD. Dr. Black stressed the urgent need for sensitive and
specific tests.
Dr.Serge Gauthier gave the final talk of the day on currently
available and future therapies for AD and related conditions. In his
opening remarks, Dr. Gauthier stressed that it is important for
clinicians to be knowledgeable of the fact that AD is not just one
condition, but entails a mild stage AD, moderate AD and severe AD.
Different treatments are effective at different stages in the
disease.
In typical cases, AD progresses through relatively predictable
stages, as described in the Global Deterioration Scale of Reisberg
et al., (Reisberg B, Ferris SH, Deleon MJ, Crook T. The global
deterioration scale for assessment of primary degenerative dementia.
Am J Psychiatry 1994;44:2203-6). The estimated time from diagnosis to
death is usually 5-8 years. In typical AD, most patients initially
present with a change of mood, which improves over time. They then
experience a linear cognitive and functional decline including a loss
of autonomy for instrumental and self-care activities of daily
living. Most patients have some degree of neuropsychiatric change,
including hallucinations, misidentifications (Capgras syndrome),
delusions and paranoid ideation, aggression or apathy, wandering and
sexual disinhibition. The appearance of early-onset motor or gait
disturbances, including asymmetrical grasp responses is atypical and
suggests conditions other than AD. Dr. Gauthier described milestone
steps in the progression of AD. These are important as they may act
as future therapeutic targets (Table 1).
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TABLE 1
Milestones in Progression of
AD
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a) Diagnosable dementia
b) Loss of IADL (Instrumental Activities of Daily
Living)
c) Emergence of neuropsychiatric symptoms
d) Nursing home placement
e) Loss of basic ADL
f) Death
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Different stages of AD present different issues in management of the
disease. In the early stages of AD the management issues include
making an accurate diagnosis, patient and caregiver education,
advance power of attorney, advance directives and whether the patient
should continue driving. In the moderate stages, the physician should
carefully monitor the patient's autonomy. At this stage it is very
important to monitor the health and well-being of the caregiver.
Management issues in the final, severe stages of AD include cessation
of cholinesterase inhibitors and end-of-life decision making.
Taken together the speakers presented a great deal of useful information on
the pathobiology of a variety of neurodegenerative diseases. Understanding the
genetic and biochemical basis of these diseases may allow for treatments tailored
to various disease stages, as well as providing useful biomarkers to enable
detection of those patients who are most at risk.
Dementia:
Biological and Clinical Advances--Part I
Dementia:
Biological and Clinical Advances--Part III
aug_2001_rotman
Dementia: Biological and
Clinical Advances--Part III
Christine Oyugi, BSc
Managing Editor,
Geriatrics & Aging.
Edited by:
Karl Farcnik, BSc, MD, FRCPC
Psychiatrist, Division of
Geriatric Psychiatry,
University Toronto,
Part-time staff,
Toronto Western Hospital, Toronto, ON.
Contributions from:
Morris Freedman, MD, FRCPC
Director, Behavioural Neurology
Program, Baycrest Centre for Geriatric Care and Staff Scientist,
Rotman Research Institute, Toronto, ON.
Helena C. Chui, MD
Professor of Neurology,
University of Southern California
Los Angeles, Ranchos Los Amigos
National Rehabilitation Center, Downey, CA, USA.
Ian McKeith, MD, FRCPsych
Professor of Old Age Psychiatry,
Institute for Health of the Elderly
University of Newcastle Upon Tyne, UK.
- What are the clinical features of Frontotemporal and Lewy Body
Dementias?
- What is the relationship between dementia and vascular
disease?
- How would you differentiate among the different
dementias?
- Does determining the distinction between Mild Cognitive
Impairment and dementia have any clinical relevance or is it
merely an academic exercise?
These are a few of the topics that were addressed by speakers
during the last day of the 11th Annual Rotman Conference. This
article summarizes the points presented during the last day of this
conference on Tuesday, March 20th.
Dr. Morris Freedman, Director of the Behavioural Neurology Program
at Baycrest Centre for Geriatric Care and a Staff Scientist at the
Rotman Research Institute in Toronto, provided an extensive clinical
review of frontotemporal dementia (FTD). The features of FTD are
important for the differential diagnosis of this disease from
Alzheimer disease (AD). Patients with FTD have marked personality and
emotional changes that include loss of social awareness, and
antisocial or disinhibited behaviour (e.g. use of rude speech,
neglect of personal hygiene and grooming); they may also become
easily distracted. These patients typically have poor insight and may
not recognize that they have any behavioural problems. Other features
include overeating, excessive smoking, oral exploration of objects
and stereotypical behaviour such as wandering.
Language is a key factor in distinguishing FTD from AD. FTD
patients have early preservation of language, in contrast to the
situation in AD patients where language is primarily affected early
in the course of the disease. As AD patients become more impaired,
they develop fluent aphasia with comprehension problems. FTD patients
experience a reduction in speech capacity, which may eventually lead
to mutism, but their comprehension is relatively preserved. Memory
loss in FTD is variable and not as severe as that with AD.
The pathophysiology of FTD involves the anterior temporal and
frontal lobes. There are two forms of neuropathology--a microvacuolar
form and a gliotic form. The microvacuolar form involves the general
loss of neurons, microvacuolar degeneration (a spongiform-type of
change), a mild astrocytic gliosis and primarily involves laminae
I-III. There are no Pick cells or bodies that are seen in Pick's
disease, but clinically one cannot differentiate between Pick's
disease and FTD. The gliotic form of FTD represents the pathology of
Pick's disease and involves all the cortical layers. There is intense
astrocytic gliosis and Pick bodies may be present. There has been
some debate as to whether the microvacuolar form and the Pick-type
pathology represent the same or different disorders.
FTD has an earlier age of onset than does AD; the average age of
onset is between 50-60 years of age. The disease duration averages
8-10 years. Although the precise cause of FTD remains unknown, there
is a genetic predisposition to the disease in some patients. Fifty
percent of patients with FTD have a positive family history and up to
18% have an abnormality on chromosome 17 (autosomal dominant).
There is also a relationship between FTD and motor neuron disease;
some patients with FTD also develop motor neuron disease, symptoms of
which can appear before or after the onset of FTD. If a diagnosis of
FTD is made, it is important for physicians to be aware of the
co-occurrence of motor neuron disease.
FTD patients have normal EEG results in the early phases of the
disease--in fact an abnormal early EEG argues against a diagnosis of
FTD. SPECT analysis shows deficits in frontal and temporal perfusion;
however, this is not a diagnostic feature, as AD patients can have
the same feature. Neuropsychological assessments show a marked
deficit on frontal tests, with an absence of severe amnesia and
perceptual 'parietal' deficits (e.g. copy to command is still
good).
FTD is one of three prototypical clinical syndromes comprising the
broader entity of frontotemporal lobar degeneration: Frontotemporal
dementia (FTD), Primary Progressive Aphasia (PPA) and semantic
dementia (SD). The difference among the three conditions is based on
the location of the pathology--FTD is frontotemporal, SD involves
lesions in the temporal lobes bilaterally, and PPA involves left
frontotemporal pathology. SD, more so than either FTD or PPA, is
easily confused with AD--similar to patients with AD, these patients
have fluent speech and comprehension deficits. But unlike those with
AD, these patients lose the meaning of words and objects with
relatively good preservation of memory. PPA is less likely to be
confused with AD because patients' speech becomes non-fluent.
Although patients show serotonergic deficits, there are currently
no drugs available for the treatment of FTLD. SSRI's may improve some
of the behavioural problems. As patients do not have cholinergic
deficits, cholinesterase inhibitors will not help and may actually
aggravate symptoms.
Dr. Ian McKeith, Professor of Psychiatry from the Institute of
Health in the Elderly in Newcastle, England, updated the conference
attendees on the current understanding of Lewy Body Dementia. Lewy
body dementia (DLB) accounts for 15-20% of all dementias in old age,
but has only been widely recognized since the mid-1990s. The clinical
phenotype of Lewy Body Dementia (DLB) is related to the site,
severity and amount of Lewy body pathology. DLB is characterized by
the presence of Lewy bodies in the brainstem (substantia nigra and
locus coeruleus), and in the subcortical (nucleus basalis of Meynert)
and cortical regions of the brain. Neuronal loss and gliosis are also
present in those areas. In some cases, there is an overlap between
DLB, AD and Parkinson's disease (PD). As is the case in patients with
both AD and PD, DLB patients have b-amyloid plaques and
neurofibrillary tangles in their brains, although not in sufficient
numbers to make a diagnosis of AD. The core clinical features of DLB
include fluctuating cognitive impairment (seen in 80% of patients),
persistent visual hallucinations (70% of patients) and Parkinsonism
(75% of patients). These features are used to distinguish between DLB
patients and AD patients (See Table 1). Other features which are
supportive of DLB but lack specificity are: transient lack of
consciousness (40%), falls and syncope (50%), systematized delusion
(70%), neuroleptic sensitivity (50%), depression (50%) and REM sleep
disorder (no estimates available). DLB is commonly mis-diagnosed as
AD, as patients are equally impaired on both the MMSE and the
Cambridge Cognitive Examination (CAMCOG). However, DLB patients
perform worse on tests of attention (e.g. reaction time),
visuospatial performance (e.g. clock drawing) and visual perception
(e.g. fragmented letters). A Consensus guideline for the clinical and
pathological diagnosis of dementia with Lewy bodies was developed in
1996. Several studies have been performed to validate these criteria
and have found that the Consensus criteria for DLB performed as well
in prospective studies as did those for AD and vascular dementia
(VaD), with a high diagnostic sensitivity. Fluctuation is an
important diagnostic indicator, reliable measures of which need to be
further developed. Although specificity of the clinical diagnostic
criteria is generally high, 17-78% of cases may be missed. This may
be attributed to clinicians being unaware of the criteria or
unfamiliar with the diagnosis. The potential contribution of
neuroimaging to the differential diagnosis of DLB from other
dementias remains uncertain, although relative preservation of the
hippocampus and temporal lobe is found in DLB when compared with
AD.
|
TABLE 1
Core Clinical Feature of DLB vs.
AD
|
|
Clinical Feature
|
DLB
|
AD
|
|
Fluctuating Cognitive Impairment
|
80%
|
60%
|
|
Persistent Visual Hallucinations
|
70%
|
15%
|
|
Parkinsonism (bradykinesia, rigidity, gait)
|
75%
|
20%
|
Currently, there is no treatment that stops the progression of DLB.
Much of the focus on treatment has been the management of the
neuropsychiatric symptoms of the disease and the associated movement
disorders. Unfortunately, 50% of patients show sensitivity to older
neuroleptics including haloperidol and phenothiazines, and these
patients are more likely to die than are those not treated with these
drugs. However, newer antipsychotics such as olanzapine and
quetiapine may be relatively safer for the management of DLB. Recent
studies have shown a benefit of acetylcholinesterase inhibitors with
respect to the treatment of behavioural, as well as cognitive,
aspects of this disease, and it is possible that these drugs could
become the treatment of choice in the future.
Dr. Helena Chui, a Professor from the University of Southern
California, gave a talk on cognitive impairment due to subcortical
ischemic vascular disease.
Ischemic vascular disease (IVD) is a common cause of dementia in
the Western world. Similar to the situation with AD, the incidence of
VaD increases with age. However, the exact incidence and prevalence
of VaD is difficult to discern. The major problem remains the
disagreements with regards to diagnostic criteria and their
implementation. In particular, there is uncertainty regarding the
following:
- The classification of patients who show both vascular and
degenerative features (mixed-dementia);
- The difficulty choosing among several different clinical
criteria (e.g., the Hachinski Ischemic Score);
- The use of imaging findings in defining VaD;
- The minimal level of disease severity required for a patient
to be included in epidemiologic studies.
The problem in diagnosing vascular dementia lies in the causal
relationship. It is not very difficult to diagnose dementia and, with
the recent advancements in structural imaging, it is also not very
difficult to diagnose vascular disease. The conundrum is--what is the
relationship between the two and how do we know that the vascular
lesion seen in imaging is causing the dementia syndrome? According to
Dr. Chui, the term Vascular Dementia is too broad. VaD is not a
disease, but only one possible phenotypic expression of vascular
brain injury. For this reason, her talk focused on subcortical
ischemic vascular dementia (SIVD). There are many types of
cerebrovascular disease, leading to variable clinical and symptomatic
expressions (Figure 2). There are a number of guidelines available on
the effective treatment of risk factors that lead to these conditions
and this should be the focus of SIVD management. The frequency of
SIVD seems to vary depending on the ethnic group; it is more common
in persons of Japanese or African American descent.
The small vessels affected in SIVD are within the brain parenchyma
and are small penetrating arterioles approximately 100 to 600 mm in
diameter. The predominant risk factors for SIVD are diabetes
mellitus, hypertension, amyloid angiopathy (a subset of AD), cerebral
autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy (CADASIL). SIVD is a term that can be used for
either the disease or the dementia syndrome. According to Dr. Chui,
SIVD represents a more homogeneous clinical and pathological entity,
which may be a more useful target for treatment, especially if the
target is the cerebrovascular disease and cerebrovascular brain
injury rather than its symptomatic expression.
There are two proposed underlying pathophysiologic mechanisms of
how SIVD leads to ischemic brain injury--Occlusion and Hypoperfusion.
Occlusion leads to small lacunar complete infarcts, cystic necrosis,
and loss of all tissue elements (neurons, axons, glia, astrocytes).
It leads to a more homogeneous phenotype including subcortical
dementia, affective disorder such as depression, extrapyramidal signs
and pure motor and sensory deficits. Hypoperfusion results from
widespread narrowing of small penetrating arterioles, leading to
incomplete infarction where there is a selective loss of tissue
elements. For instance, in the white matter there will first be a
loss of oligodendrocytes with demyelination, astrogliosis and, later,
a loss of axons. Hypoperfusive ischemic brain injury has been
postulated to be the cause of Binswanger syndrome, which is
characterized by a combination of deep white matter changes, as well
as a slowly progressive subcortical dementia, gait disturbance and
urinary incontinence.
Our current understanding of how cognitive impairment relates to
SIVD hinges on the lacunar hypothesis. This hypothesis states that
the likelihood of dementia is related to the number, size and
location of lacunar infarcts within parallel frontal subcortical
loops (Prefrontal Cortex-caudate-globus pallidus-thalamus-PFC).
However, recent imaging studies showed that the best correlate
between dementia and SIVD was atrophy and not the volume or the
number of lacunar infarcts. Clinical evaluation of SIVD should
include tests of working memory, recognition memory and executive
function.
The treatment of SIVD can be divided into three components. The
first is primary prevention, where one tries to prevent infarction or
vascular cognitive impairment by managing vascular risk factors such
as hypertension and diabetes. For secondary prevention, where there
is evidence of vascular brain injury--infarction, incomplete
infarction or vascular cognitive impairment--the goal is to prevent
the recurrence or the progression of disease. There is evidence that,
even at this stage, one should continue to manage hypertension but
also administer other treatments. Tertiary treatment refers to
symptomatic treatment of memory and cognitive impairment.
Acetylcholinesterase inhibitors are currently being studied for this
purpose; currently, none have been approved for this purpose.
Dr. Chertkow, Associate Professor of Neurology and Neuropsychiatry
at McGill University, presented a talk on high and low technological
approaches to the early diagnosis of AD. According to Dr. Chertkow,
the goal in trying to delineate an early mild cognitively impaired
group is to identify which individuals will or will not deteriorate
over finite periods of time (5-10yrs). One of the difficulties in
studying individuals with Mild Cognitive Impairment (MCI) is the lack
of accepted diagnostic criteria. A diagnosis of MCI can be made if
patients meet the following criteria: (a) complain of defective
memory; (b) normal activities of daily living; (c) normal general
cognitive function; (d) abnormal memory function for age; and (e)
absence of dementia. However, there are varying inclusion criteria
that may overlap with the aforementioned.
Some researchers contend that patients with MCI may be an
in-between group (i.e. individuals who are between normal aging and
mild AD) (See Dr. Petersen's talk). The issue is to prognosticate and
to define those who are going to progress from this state and those
who will not. Prognosis in MCI varies depending on how you
characterize your group, but severity of symptoms often predicts
progression to AD. Researchers are trying to identify biological and
cognitive markers that will assist the general physician in
delineating MCI individuals who will progress to AD in a finite time
period. The characteristic of a good marker is that it should be
precise and simple, should be inexpensive, should be reliable and
non-invasive and should have the ability to be validated in
pathological cases. Recently, Chertkow and colleagues completed a
study on mild memory loss in the elderly. The study looked at 90
individuals who passed the above criteria for MCI and followed them
for 3-5 years. Over the course of the study, 51 patients deteriorated
to dementia (50 of them meeting the criteria for probable AD) and 39
did not deteriorate. Initially, about 15-17% of the MCI individuals
progressed to AD each year; however, even after 10 years,
approximately 15% of the individuals did not have dementia and did
not appear to be progressive. Therefore, there is a subgroup of MCI
patients who do not progress to AD.
There were some interesting differences between those individuals
that progressed to AD and those that did not. The progressing group
had an older age of onset of their symptoms and performed slightly
worse on the MMSE at the time of presentation. The researchers
further assessed a number of clinical variables--history, risk
factors for AD, physical examination--in order to identify predictors
for progression of MCI to AD. The only variables useful as predictors
were age, the presence of vascular disease, the number of years the
individual smoked, the symptom duration and the MMSE score at initial
presentation. It was suspected that some of these factors may have
been explained by the same variable and a logistic regression
analysis was necessary to find out which factors contribute to the
prediction. When this was done, the only significant variables
remaining were age at onset of memory problems and the MMSE. This
predicted progression in about 67% of the MCI group. In addition,
retrospectively, individuals who had lack of orientation to time in
the MMSE also progressed to AD.
Hippocampal atrophy (MRI volumetrics) may also be useful as a
predictor for progression. MCI patients have hippocampal volume that
is intermediary between normal individuals and AD patients (who have
significant shrinkage). SPECT scanning and APOE genotype did not
appear be useful in predicting progression. The researchers set up an
algorithm that was a combination of low-tech and high-tech
measures--an approach that can be used by physicians in the future.
The algorithm allows a physician to establish a score and stratifies
the progression of AD in MCI individuals. In the study, individuals
that scored zero on the algorithm never progressed to AD and those
who scored 4 or more developed AD.
Dr. Petersen, Director of the Mayo Alzheimer's Disease Research
Center, gave an update of recent clinical trials on MCI. A definitive
diagnosis of AD can only be made after death through the use of
neuropathological methods. For the past 15 years, there have been
good criteria for probable AD and correspondence between probable AD
and definite AD is about 80-90%, if the usual guidelines for
diagnosis are used. Research on MCI suggests that there is a
transitional point between normal aging and probable AD. The problem
for a physician is how to care for a person who presents at this
stage and what to tell the family.
The MCI group of patients is an important group to study because
they may give us insight into normal aging. From a practical point of
view, these individuals may need to be told that they have a
cognitive profile that puts them at a greater risk of developing AD,
although, as previously mentioned, some patients may not progress to
AD. Physicians have to be very careful not to over-diagnose patients
with MCI. Do people who fulfil the criteria actually progress to AD
at an accelerated rate and, ultimately, can something be done to
impede the development of AD in these individuals using
cholinesterase inhibitors or secretase inhibitors? Dr. Petersen and
colleagues obtained data from the longitudinal study on aging in
Rochester, Minnesota. It should be noted that the subjects (largely
Caucasian, middle income) were not necessarily representative of the
general population. The cognitive function of these subjects has been
followed for approximately 20 years. Usually, early in the disease,
the patients are not anosagnosic but are actually aware of their
memory impairment. MCI patients that meet this criteria progress to
probable AD at a rate of 12% per year compared to controls that
progress at a rate of about 1-2% per year. According to Dr Petersen,
after 10 years, 80% of these patients progress to AD. There are
qualitative features that help predict who is more likely to progress
to AD and who is not. The inability of persons to benefit from cues,
and hippocampal atrophy, were positive predictors of progression.
Currently, clinical trials are underway to test the use of all the
second-generation cholinesterase inhibitors in MCI (Table 2) as well
as vitamin E, and COX-2 inhibitors. MCI individuals, if well
characterized, present a sample population that will progress to AD
at a known rate and are an important target group for preventive
therapy. Finding a control for this study group is
difficult--age-appropriate controls could be contaminated, as they
may include subjects who themselves have MCI.
|
TABLE 2
Clinical Trials in
MCI
|
|
Sponsor
|
Duration of Study
|
Endpoint
|
Drugs being tested
|
|
Alzheimer's Disease Cooperative Study (ADCS)
|
3 years
|
Clinical probable AD
|
Vitamin E
Donepezil
|
|
Merck Frosst
|
2-3 years
|
Clinical probable AD
|
Rofecoxib
|
|
Novartis
|
2 years
|
Clinical probable AD
|
Rivastigimine
|
|
Janssen-Ortho
|
2 years
|
Clinical probable AD
|
Galantamine
|
|
Pfizer
|
6 months
|
Symptomatic improvement
|
Donepezil
|
Most individuals with MCI will go on to develop AD. In the future,
we may also determine predictive phases of other dementias, where a
patient can present with slight impairment in multiple domains, or a
slight impairment in a single, non-memory domain. These could be used
as predictors of the development and progression of several
conditions including Frontotemporal dementia, Lewy body dementia, or
even primary progressive aphasia.
At least for the relationship between MCI and AD, we now have available criteria
that can allow for clinical trials to determine the efficacy of intervention
at this stage, possibly preventing the inevitable progression toward AD.
Dementia:
Biological and Clinical Advances--Part I
Dementia:
Biological and Clinical Advances--Part II
Further Readings
- Barber R, Ballard C, McKeith IG, Gholkar A, O'Brien JT,
Volumetric study of dementia with Lewy bodies--A comparison with
AD and vascular dementia Neurology 2000;54:1304-1309.
- Chui H. Dementia due to subcortical ischemic vascular disease.
Clin Cornerstone 2001;3(4):40-51.
- Jack CR Jr, Petersen RC, Xu Y, et al. Rates of hippocampal
atrophy correlate with change in clinical status in aging and AD.
Neurology. 2000 Aug 22;55(4):484-89.
- Longstreth WT Jr, Manolio TA, Arnold A, Burke GL, Bryan N,
Jungreis CA, et al. Clinical correlates of white matter findings
on cranial magnetic resonance imaging of 3301 elderly people. The
Cardiovascular Health Study. Stroke 1996 Aug;27(8):1274-82.
- McKeith IG, Ballard CG, Perry RH, Ince PG, O'Brien JT, et al.
Prospective validation of consensus criteria for the diagnosis of
dementia with Lewy bodies. Neurology. 2000 Mar
14;54(5):1050-8.
- Petersen RC, Stevens JC, Ganguli M, Tangalos EG, Cummings JL,
DeKosky ST. Practice parameter: early detection of dementia: mild
cognitive impairment (an evidence-based review). Report of the
Quality Standards Subcommittee of the American Academy of
Neurology.Neurology. 2001 May 8;56(9):1133-42.
- Petersen RC. Aging, mild cognitive impairment, and Alzheimer's
disease. Neurol Clin. 2000 Nov;18(4):789-806. Review.
- Petersen RC, Smith GE, Waring SC, Ivnik RJ, Kokmen E, Tangelos
EG. Aging, memory, and mild cognitive impairment. Int
Psychogeriatr 1997;9 Suppl 1:65-9.
- Rocca WA, Kokmen E. Frequency and distribution of vascular
dementia.Alzheimer Dis Assoc Disord 1999 Oct-Dec;13 Suppl
3:S9-14.
- Shah S, Tangalos EG, Petersen RC. Mild cognitive impairment.
When is it a precursor to Alzheimer's disease? Geriatrics. 2000
Sep;55(9):62, 65-8. Review.
Originally published in: Volume 4, Number 4
Volume 4, Number 5
Volume 4, Number 6, May 2001
JuneJuly 2001
August 2001, Pages 11
13,14,15
13,14,15
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