I. DEFINITION OF DEMENTIA
II. CLINICAL FEATURES OF DEMENTIA
III. CLINICAL FEATURES OF ALZHEIMER'S DISEASE
(AD)
IV. NEUROPATHOLOGIC FEATURES OF AD
V. PROSPECTS FOR TREATMENT
I. CLINICAL FEATURES
II. NEUROPATHOLOGY
III. NEUROCHEMISTRY
IV. GENETICS
V. EPIDEMIOLOGY
VI. ETIOLOGY AND PATHOGENESIS
VII. THERAPEUTIC STRATEGIES
VOCABULARY TERMS
Terms you should be familiar with:
Dementia
Alzheimer's disease
Multi-infarct dementia
Dementia pugilistica
Pick's disease
Binswanger's disease
Neurofibrillary tangle
Neuritic plaque
Hirano body
Granulovacuolar degeneration
OBJECTIVES: The objectives of these two hours are to recognize the significance
of the aging population, to recognize the significance of dementia, and
to come to an understanding of the most common cause of dementia, namely
Alzheimer's disease.
Dementia is a syndrome featuring deterioration of previously acquired intellectual abilities sufficiently severe to interfere with social or occupational functioning, or both. Impairment of memory, abstract thinking, and judgment is evident in a fully developed case. Dementia does not imply irreversibility.
Alzheimer's disease (AD) was definitively described in 1907 in a 51 year
old woman with a 4 and 1/2 year course of progressive dementia. Clinical
features included memory decline, paranoid delusions, auditory hallucinations,
aphasia, apraxia and agnosia. Examination of the brain following death showed
the presence of masses of silver positive fibers (neurofibrillary tangles
[NFTs]) in many neurons in the cerebral cortex, in addition to a severe
loss of cortical neurons. In 1963, ultrastructural studies of the cerebral
cortical lesions were described. During the 1970s, specific neurotransmitter
deficits were found in AD raising the possibility that some symptoms of
the disease could be treated by pharmacological intervention. More recently,
molecular biological approaches and other new technologies have offered
better insight into pathogenic mechanisms of AD and have set the stage for
potentially understanding this disorder, with the ultimate goal of treatment
or prevention.
Dementing diseases represent one of the major health problems facing
our society. The symptom complex of dementia can be caused by over 70 different
disorders
(1) Many of these disorders are treatable or reversible, and include:
Based on this list, it should be immediately clear that the major goal in
approaching the diagnosis of dementia is to rule out treatable or reversible
causes. Nevertheless, AD remains the most common form of adult onset dementia.
A community based study suggested that approximately 4 million persons in
the U.S. have AD (2), and it represents the fourth leading cause of death
in this country (3).
Criteria for the clinical diagnosis of probable AD have been established
(4) and have been validated by autopsy findings (5).
The primary criteria are:
Supportive criteria include progressive decline in specific functions such
as language, motor skills, and perception; impaired activities of daily
living and altered behavior; family history of a similar disorder; plateaus
in the course of the illness; and associated symptoms of depression, insomnia,
incontinence, delusions, illusions, hallucinations and verbal, emotional,
or physical outbursts. Diagnostic accuracy for AD in most recent series
is approximately 90% (1). The clinical picture of AD can be quite heterogeneous,
and can be divided into three stages (early, middle and late). Patients
generally spend two to three years in each stage of the disease, with each
stage representing a progressive level of disability. The hallmark of AD
is a steadily progressive deterioration of intellectual function, although
the rate of progression is highly variable. Many patients have plateau periods
in which there is an apparent arrest of progression. The mean survival time
of AD patients in the U.S. is eight years and the range of survival is one
to 20 years.
Generalized seizures occur in approximately 10% of patients (6), and myoclonic
jerks are found in an additional 10% of patients (6). Atypical clinical
presentations of AD occur in approximately 10% of patients (7). These include
progressive aphasia, visual agnosia, pure memory loss, right parietal lobe
syndrome of spatial disorientation, and personality changes (paranoid or
bizarre behavior).
There are no definitive diagnostic studies for AD, and this is why the clinical
diagnosis is always given as probable AD. Postmortem examination is required
for confirmation of the diagnosis. Numerous laboratory and radiologic studies
are of value in excluding other dementing illnesses, and include:
The CT scan remains the brain imaging study of choice in the evaluation
of dementia. Changes of cortical atrophy and ventriculomegaly are not specific
for the diagnosis of AD, but are supportive findings. There is no compelling
reason to use MRI at the present time. If the dementia has been present
for less than six months, an examination of cerebral spinal fluid is recommended
to rule out entities that cause chronic meningeal irritation. The EEG adds
little to the evaluation of dementia except in situations in which seizures
are suspected. The mainstay of diagnosis remains a careful history and examination,
augmented by neuropsychological evaluation.
Neuropsychological assessment is important in confirming the presence of
a dementing process, defining the kinds of impaired cognitive function,
separating psychiatric illnesses from dementia, and following changes in
cognition. In our clinic, we do routine neuropsychological evaluations every
six months, and we have found that this information is extremely useful
for prognosticating about the disease. It should be emphasized that neuropsychological
testing does not give a definitive diagnosis. A simple, convenient screening
battery consists of the Folstein Mini-Mental State Exam, the Blessed Dementia
Rating Scale, and the Alzheimer's Disease Assessment Scale.
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Grossly, the AD brain shows variable degrees of cerebral cortical
atrophy, more in younger than in older patients. The atrophy is usually
generalized but is most prominent in the frontal and temporal lobes. It
should be emphasized that some individuals with clinical and histological
features of AD show minimal atrophy. The centrum semiovale white matter
is diminished in size, and the lateral ventricles are variably enlarged.
The major microscopic alterations in AD are neuritic or senile plaque (SP)
formation, NFT formation, selective neuron loss and shrinkage, altered neuritic
processes and synapse loss. Specific diagnostic criteria for quantitation
of SP and NFT in various age groups have been established (8).
SP are complex structures composed of dystrophic neuritic processes, extracellular
amyloid, astrocytes with their processes, and microglia (9). SPs are present
in abundance in the association areas of the frontal, temporal and parietal
lobes, amygdala, hippocampus, and piriform cortex. A direct correlation
of SP density, severity of dementia, and decline in cholinergic markers
has been reported (9). Some AD patients have abundant SP formation and decreased
cholinergic markers and somatostatin, but few neocortical NFTs (10). These
findings suggest that the SP is the most important and consistent microscopic
lesion in AD.
SPs contain amyloid, the subject of recent intense research in AD (11,12).
The extracellular amyloid fibrils present in SPs are composed of a 42-43
amino acid peptide known as ß amyloid protein (ßAP). ßAP
is a fragment of a larger, membrane spanning glycoprotein, amyloid precursor
protein (APP). The gene coding for APP maps to the long arm of chromosome
21 (13,14). One fragment of the complex APP molecule has been shown to be
toxic to cultured neurons (15), whereas another has been found to prolong
survival of cultured neurons (16). ßAP, similar to that in SPs, is
present in blood vessel walls in the brain and leptomeninges in almost all
AD patients (12).
NFTs are neuronal cytoplasmic collections of tangled, silver positive filaments.
They are present in the neocortex, hippocampus, amygdala, substantia nigra,
locus ceruleus, dorsal raphe, and other brain stem nuclei in AD. In the
cortex, they are most frequently seen in the 3rd and 5th layers. In the
hippocampus, they are present in greatest number in CA1 and the subiculum.
Perhaps the most important microscopic feature of AD is selective neuron
loss (17). In the neocortex, the greatest loss has been found in pyramidal
neurons of the frontal and temporal lobes. A consistent neuron loss is also
found in the CA1 area and subiculum of the hippocampus, and the basolateral
amygdala. Neuronal loss is a feature of the cholinergic nucleus basalis
of Meynert (18) and septal nuclei in AD. Loss of neurons from the noradrenergic
locus ceruleus in AD is present in the central region projecting to the
temporal and parietal cortex, but not in the region projecting to the basal
ganglia, cerebellum, or spinal cord (19). Neuron loss from the serotonergic
dorsal raphe nucleus, superior central nucleus and dorsal tegmental nucleus
also has been reported (19).
The most consistent neurotransmitter alteration found in the AD brain
is a loss of the cholinergic markers choline acetyltransferase and acetylcholinesterase
(20). Brain biopsy studies have shown that choline acetyltransferase is
diminished early in the disease, and that high affinity choline uptake and
acetylcholine synthesis are reduced in AD (21). The loss of neurons in the
cholinergic nucleus basalis of Meynert, a correlation between the loss of
choline acetyltransferase and decline in mental status scores (22), and
scopolamine-induced memory loss in normal individuals have led to the cholinergic
hypothesis in AD (20) that has served as the basis for therapeutic trials.
It is now apparent that AD is a multineurotransmitter deficiency disease.
Biopsy and post mortem studies have shown a presynaptic noradrenergic deficit
in AD neocortex (21). Other neurotransmitters prominently depleted in AD
include serotonin, somatostatin, corticotropin-releasing factor, and glutamate.
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Genetic linkage studies, using recombinant DNA techniques, have shown
that the proximal region of chromosome 21 contains a locus for susceptibility
of familial early-onset AD in some pedigrees (23,24). This fact is of considerable
interest because the gene coding APP is also on chromosome 21. However,
two other groups of investigators, using autopsy-documented kindreds, have
not shown evidence for linkage between chromosome 21 and familial AD (25,26).
More recent linkage studies have suggested the existence of a locus on chromosome
19 in late-onset familial AD (27), and an additional locus for early-onset
AD on chromosome 14. Thus it seems most likely that familial AD is a heterogeneous
disorder.
Three recent studies have reported a missence mutation in the APP gene that
is associated with the disease in families with hereditary AD (28-30). All
of the mutations are located at codon 717 although the single amino acid
substitution is different in each family. In one family all patients with
the mutation developed early onset AD, while those without the mutation
did not develop the disease.
An additional feature of the genetics of AD is the link with Down syndrome
(DS) (31). Most individuals with DS have an extra copy of chromosome 21.
DS patients who live into their 40s (or longer) develop SPs and NFTs and
have a decline in brain cholinergic markers similar to that in AD. This
suggests that DS and AD may have common etiologic or pathogenic mechanisms.
Of added interest, studies have shown an increase in DS in families with
AD.
Of considerable interest is the fact that several recent reports have documented
an association between the apolipoprotein E, type e4 allele, on chromosome
19, and both late-onset familial and sporadic AD (32).
Age is a strong risk factor for AD. A community based study has shown
that the overall prevalence of AD in the U.S. is 3% for persons 65-74 years
old, 19% for those 75-84 years old, and 47% for those over age 86 (2). Demographic
trends indicate that there will be a sizable increase in the number of people
over age 65 during the next few decades. In addition, the over-85 age group
is the most rapidly growing segment of the U.S. population. It has been
suggested that there could be 14 million individuals with AD by the year
2040.
Other significant risk factors for AD have been identified (33,34). A family
history of dementia or AD is a significant risk factor for AD, especially
in cases with onset before age 70. Several studies have shown a significantly
greater occurrence of concussive head trauma in AD patients.
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The etiology and pathogenesis of AD are not known. Any hypothesis about the etiology and pathogenesis of AD must consider many factors, including genetics, risk factors, environmental variables, variable clinical course, neuropathologic features, multiple neurotransmitter deficits, relationship to DS, and the normal aging process. Hypotheses that have been advocated by various research groups include:
Most likely, this complex disorder has multiple causes. It is highly probable
that there are genetic etiologies, one or several primary environmental
etiologies, and other instances with a strong interplay between genetic
and environmental factors. A rational basis for therapy or prevention will
not be available until the etiologies and pathogenesis of the disorder are
determined.
Therapeutic strategies for AD can be divided into symptomatic, biologic, and "etiologic specific". Using this classification, one can approach the treatment of AD using the following schema:
Following an introduction to the biology of AD (clinical features, neuropathology,
neurochemistry, genetics, epidemiology, and etiology and pathogenesis),
therapy will be discussed in the context of the above classification with
emphasis on symptomatic and biologic therapy.
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[ Introduction and Objectives | Basic Reactions of the CNS | Vascular Disease | Trauma to the CNS | Alcohol and the CNS | Infections of the CNS | Tumors of the CNS | Diseases of the Myelin Sheath | Spinal Cord Disease | Muscle Disease | Congenital Anomalies of the CNS | Neuropathology of AIDS | Degenerative Diseases of the CNS | Dementia and Related Issues | Unconventional Transmissible Agent (Prion) Diseases ]
Questions?
Comments? Send a message to the CATS guru: jkessler@salus.uvm.edu
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