Neurol Clin N Am 20 (2002) 779–808
Inherited dementias
Peter Hedera, MDa, R. Scott Turner, MD, PhDb,*
a
Department of Neurology, Vanderbilt University, Nashville, Tennesse
Cognitive Disorders Section, Department of Neurology, University of Michigan
Health System, and Veterans Affairs Medical Center Geriatric Research
Education and Clinical Center, Ann Arbor, Michigan
b
Familial Alzheimer’s disease and related amyloid angiopathies
Although age-related progressive cognitive decline has been known since
antiquity, a case report by Alois Alzheimer described the neuropathology
associated with a ‘‘peculiar’’ dementing syndrome [1]. Dr. Alzheimer
reported the 5-year clinical course of a 51-year old woman with progressive
dementia and autopsy findings of neuronal loss, neurofibrillary tangles,
and miliary amyloid plaques found by light microscopic examination of
Bielshowsky silver-stained brain sections. Thus, he was the first to suggest a
link, perhaps causal, between this dementing disease and the abnormal proteinaceous aggregates in brain. Or were they merely ‘‘tombstone’’ epiphenomena? The debate continues.
Alzheimer’s disease (AD) now affects approximately 2–3% of individuals
at age 65, with an approximate doubling of incidence for every 5 years of age
afterward. The prevalence of AD in one study approaches 50% of those over
age 85 [24]. Although AD is the most common etiology of progressive
dementia in the elderly in the U.S., it is not inevitable with aging, and ‘‘escapees’’ warrant further epidemiologic and genetic study. In 1990, there were
an estimated 4 million people in the U.S. with AD. Because of an expanding
population and increasing life expectancy the number of affected individuals
is projected to increase to 14 million in the U.S. in 2050. The Diagnostic and
Statistical Manual, 4th edition (DSM-IV), or the National Institute of Neurologic, Communicative Disorders and Stroke-AD and Related Disorders
Association (NINCDS-ADRDA) criteria are used for the clinical diagnosis
This work was supported by the Department of Veterans Affairs Geriatrics Research
Education and Clinical Center and Grant No. P50 AG08671 from the National Institutes of
Health.
* Corresponding author. VAMC GRECC, 2215 Fuller Road, Ann Arbor, MI 48105.
E-mail address: raymondt@umich.edu (R. Scott Turner).
0733-8619/02/$ - see front matter 2002, Elsevier Science (USA). All rights reserved.
PII: S 0 7 3 3 - 8 6 1 9 ( 0 1 ) 0 0 0 2 0 - 2
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of AD [20,64]. These criteria are similar and require a gradually progressive
dementia severe enough to impair social or occupational functioning with
other etiologies excluded [54]. By definition, dementia requires a decline in
memory and at least one other cognitive domain—visuospatial skills, language and calculation, praxis, gnosis, or frontal and executive function. A
diagnosis of definite AD requires light microscopic examination of brain tissue sections (by autopsy, or rarely by brain biopsy). Thus, only possible and
probable AD are routinely diagnosed in the clinic. Possible AD is diagnosed
when uncertainty arises from an additional secondary etiology of dementia
or the dementia has an atypical onset, course, or presentation. Diagnostic
accuracies, compared to autopsy, for possible and probable AD by
NINCDS-ADRDA criteria are approximately 50–60% and 80–90%, respectively, in specialized centers.
The Khachaturian pathologic criteria for AD require that the density of
amyloid plaques and neurofibrillary tangles in brain sections exceed a given
threshold that increases with age [52]. In contrast, the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) criteria focus exclusively
on the density of amyloid plaques (the sine qua non pathologic marker of
AD), in brain sections compared to given (published) high-power microscopic fields. In part because neurofibrillary tangles are not specific to
AD, they were not considered essential to the diagnosis [68]. The recent
‘‘Reagan criteria’’ for AD, however, require both amyloid plaques and neurofibrillary tangles in multiple brain regions, and declare all such pathology
abnormal [98]. These criteria incorporate the CERAD plaque density scale
as well as Braak and Braak [5] staging of the density and distribution of
pathologic abnormalities found in AD brain [5,68]. Despite numerous other
profound neuropathologic changes in brain (neuronal and synaptic loss,
gliosis, inflammation, cholinergic deficits, microvascular amyloid angiopathy, oxidative damage, mitochondrial dysfunction, etc) the mainstay of
pathologic diagnosis remains silver staining of brain sections and light
microscopic examination of the density and distribution of amyloid plaques
and neurofibrillary tangles—in other words, methods used by Dr. Alzheimer
in 1907. As documented by Braak and Braak [5], the neuropathology of AD
is not random but affects entorhinal cortex and hippocampus followed by
other limbic structures and neocortex [5]. This is consistent with the initial
primarily amnestic clinical presentation of patients with AD followed my
several years of progressive and gradual decline in multiple cognitive
domains. As is true for all neurodegenerative diseases, the etiology of the
selective vulnerability of different brain regions to AD pathologies remains
obscure.
The major risk factor for AD is aging. Even subjects with Down’s syndrome and individuals with genetic polymorphisms or mutations that
increase risk of AD require a degree of aging before signs and symptoms
commence. It remains unknown, however, what specific factors associated
with aging increase risk of AD. Having a first-degree relative with AD
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increases one’s risk of developing AD approximately 2- to 4-fold, and this
risk grows higher with increasing numbers of affected first-degree relatives.
These familial risks clearly implicate genetic factors in AD pathogenesis.
However, several environmental factors also increase the risk of developing
AD. For example, a low level of education or severe head trauma with loss
of consciousness both increase risk. Conversely, advanced education may be
protective. For unclear reasons, female gender also increases risk of AD and
this is hypothesized to be due to a lack of post-menopausal estrogen
[96,103]. Recently, a resurgence of studies in risk factors for stroke, such
as hypertension, diabetes mellitus, smoking, hypercholesterolemia, and possibly hyperhomocysteinemia, suggest that they may also increase risk of
AD. Whether these factors act directly on AD pathogenic mechanisms, or
indirectly by vascular compromise, or both, remains unclear [56].
Down’s syndrome (trisomy 21), including translocation Down’s (21q), is
clearly linked to AD [25]. The high prevalence of progressive dementia in
subjects with Down’s syndrome led to autopsy observations of typical AD
pathology, including neurofibrillary tangles and amyloid plaques, in aging
brain. However, the onset of dementia occurs in the third to fifth decade
of life and neuropathology is found even earlier [87]. The mechanism may
be a gene dosage effect since amyloid precursor protein (APP) is encoded
on chromosome 21q. Cells of Down’s syndrome patients express about
1.5 times the normal amount of APP, and thus secrete higher levels of Ab
peptides derived from APP by the proteolytic enzymes termed b-secretase
and c-secretase. Ab peptides, including Ab40 and Ab42, are intrinsically
insoluble and are the major component of amyloid plaques in AD brain.
Like many other human diseases, the identification and analysis of probands and pedigrees with rare genetic forms of a common sporadic disease
proved instructive with regards to disease causation and potential treatment
strategies. Thus, much has been learned about the possible cause of AD by
the study of rare patients with early-onset familial AD (OMIM # 104311)
[87]. Other than a pedigree analysis showing an early-onset (presenile)
highly-penetrant autosomal dominant pattern of inheritance, these genetic
forms of AD are similar, both clinically and pathologically, to the overwhelming majority (>95%) of patients with sporadic (senile) AD. Thus, proposed pathogenic mechanisms of familial AD may be extrapolated to
sporadic AD.
The first gene mutations linked to familial AD were missense mutations
in the APP gene on chromosome 21. Not coincidentally, missense mutations
in APP cluster near the two proteolytic cleavage sites that release Ab from
APP (Fig. 1). The location of these APP mutations immediately suggested a
pathologic mechanism favoring amyloidogenic (producing Ab) over nonamyloidogenic APP catabolism (a toxic gain of function). For example, a
double missense mutation in APP (K670N/M671L, in the 770 isoform numbering system) near the b-secretase cleavage site increases both Ab40 and
Ab42 generation. In contrast, any one of several single missense mutations
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Fig. 1. Amyloid precursor protein (APP) processing. APP is a transmembrane protein that may
be cleaved either by a- and c-secretases to release p3 and a large amino-terminal ectodomain
(the nonamyloidogenic pathway) or by b- and c-secretases to release 4 kD Ab peptides
including Ab40 and Ab42 and a large amino-terminal ectodomain (the amyloidogenic
pathway). Ab is the major component of amyloid plaques in AD brain. Missense mutations
causing familial AD are clustered adjacent to b - or c-secretase cleavage sites and alter APP
processing to favor Ab42 generation. Mutations linked to amyloid angiopathy and dementia
cluster near the a-secretase cleavage site.
in APP near the c-secretase site (T714I, V715M, I716V, V717I, G, F, or L,
and L723P) increases only Ab42 secretion. In vitro studies reveal that Ab42
is even more spontaneously amyloidogenic than Ab40, again suggesting a
disease mechanism. The identification of these APP mutations led to the
notion that amyloid deposition in brain parenchyma causes AD—the amyloid hypothesis of AD (Fig. 2)—and allowed the generation of transgenic
mice that develop AD-like pathologies. In fact, these transgenic mice exhibit
age-dependent behavioral decline in learning and memory and progressive
amyloid deposition in brain [29,45]. However, they do not develop neurofibrillary tangles, neuronal loss, or loss of synaptic cholinergic markers,
making them at best a partial AD-like model of human disease [30].
Pathogenic mutations within the Ab sequence generally result in a different phenotype than AD, and present clinically with a combination of
progressive dementia and lobar hemorrhagic or microvascular ischemic
strokes. The pattern of inheritance is autosomal dominant. Pathologically,
they are characterized by massive amyloid accumulation within blood vessel
walls in addition to parenchymal amyloid deposition as seen in AD. Pathogenic missense mutations are known within the Ab sequence at positions
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Fig. 2. The amyloid cascade hypothesis of Alzheimer’s disease (AD). Ab, derived from APP,
forms insoluble neuritic plaques (NP) in brain, leading to neuronal morbidity and mortality,
and neurofibrillary tangles (NFT). A ghost tangle remains when a neuron containing a NFT
dies. In this model, genetic risk factors for AD (Down’s syndrome, mutations in APP,
presenilin-1 (PS-1), or presenilin-2 (PS-2), and the apolipoprotein E4 (ApoE4) polymorphism)
are located proximally, implying their causal role in AD pathogenesis. The mechanisms
whereby age, female gender, and head trauma increase risk are obscure. In parallel with these
pathologic events in brain, cognitively normal elderly individuals become progressively
amnestic and demented for several years until death. Current drug treatments for AD such
as acetylcholinesterase inhibitors and perhaps antioxidants (vitamin E) act on putative distal
targets, allowing only modest, symptomatic, and temporary clinical benefit. Novel potentially
disease-modifying treatments in clinical trials may prevent or treat AD by targeting more
proximate causal events. These approaches include developing b- or c-secretase inhibitors to
retard Ab generation, metal chelation to prevent Ab/amyloid deposition, and immunization
to promote Ab/amyloid clearance.
692, 693, and 694 near the a-secretase cleavage site (Fig. 1). Because these
mutations are intrinsic to Ab, they may also alter its propensity to form
insoluble amyloid fibrils and shorter protofibrils. The APP A692G (Flemish)
mutation promotes Ab production but retards its fibrillogenesis; this mutation leads to a combination of microvascular amyloidopathy and AD pathology, and presents with dementia and cerebral hemorrhages. The APP
E693Q (Dutch) and APP D694N (Iowa) mutations promote amyloid fibril
formation from Ab and also present clinically with dementia and lobar hemorrhages; the APP E693K (Italian) mutation presents similarly, possibly by
a similar mechanism. Finally, the APP E693G (Arctic) mutation retards
Ab40 and Ab42 production but enhances protofibril formation and presents
clinically as AD, suggesting that protofibril formation from Ab may be
the unifying event in AD pathogenesis [39]. Like all amyloidopathies, the
b-pleated sheet conformation of Ab in amyloid plaques and blood vessels
results in their fluorescence with thioflavin-S staining as well as apple-green
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birefringence in Congo red-stained sections visualized with polarized light.
A cautionary note: hereditary cerebral congophilic angiopathies with
dementia are not limited to mutations in the Ab sequence of APP, but
include other amyloidogenic proteins such as cystatin C and transthyretin.
Most familial AD does not have an APP mutation, implicating other
affected genes. By study of these pedigrees, mutations were identified in presenilin-1 (for ‘‘presenile’’, or onset less than 60–65 years of age) on chromosome 14 or the homologous gene presenilin-2 on chromosome 1 (see
www.alzforum.org for a complete list of familial AD mutations). In fact,
of the rare early-onset familial forms of AD, the most commonly found
mutation is of presenilin-1. The identification of these mutants provided a
test for the amyloid hypothesis of AD. Would they alter APP metabolism
and Ab generation? Again, studies of cells in culture, samples (skin fibroblasts, serum, etc.) taken from affected patients, and transgenic mice reveal
that all presenilin mutations increase Ab42 generation from APP (a toxic
gain of function) [86]. Double transgenic mice expressing both human
mutant APP and human mutant presenilin-1 exhibit markedly accelerated
amyloid deposition in brain compared to transgenic mice carrying only
human mutant APP. Thus, in common to all known familial AD mutations
is an increased production of Ab42 from APP. However, presenilin mutations may have other detrimental effects promoting AD, for example, by
increasing neuronal apoptosis.
Another major advance in the genetics of AD was the surprising discovery of the link between Apolipoprotein E (ApoE) polymorphisms on chromosome 19 and sporadic late-onset AD [94]. ApoE is synthesized in the liver
and plays a role in lipid and cholesterol transport in lipoprotein particles in
blood. In the brain ApoE is secreted by glia, with receptors on neurons. The
function of ApoE in the brain is unclear, but it may be involved in central
lipid and cholesterol metabolism. Three ApoE polymorphisms—2, 3, and
4—result in six possible genotypes. These polymorphisms differ by only one
or two amino acid residues at positions 112 and 158 (out of 299). The gene
frequency in the population is 3 > 4 > 2. Having either one or two apoE4
alleles increases the risk of developing late-onset AD and lowers the average
age of onset with a gene dosage effect. In other words, the hierarchy of individual risk is ApoE4/4 > ApoE4/x > ApoEx/x. The ApoE2 allele is slightly
protective, and ApoE3 is intermediate in risk. Genetic risks may be additive,
for example in ApoE4-positive individuals with APP mutations, but the
ApoE allele has no impact on the most aggressive earliest-onset form of
AD found in individuals with presenilin-1 mutations.
The mechanisms whereby ApoE polymorphisms affect AD risk are
unknown. ApoE does not influence APP metabolism; rather, in vivo and
in vitro evidence suggests that ApoE4 promotes the formation of insoluble
fibrillar amyloid from soluble Ab peptides. For example, double transgenic
mice have been developed expressing mutant human APP and either human
ApoE3 or ApoE4; similar to humans, mice expressing human ApoE4 develop
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a greater amyloid burden in brain. Murine ApoE knockout lines expressing
human mutant APP develop no amyloid plaques, again suggesting a role
for ApoE in amyloidogenesis. However, additional mechanisms whereby
ApoE4 increases risk of AD have not been excluded.
Other than ApoE, genetic linkages to the sporadic late-onset form of AD
remain controversial. For example, an increased risk of developing lateonset AD is also reported with polymorphisms in the a2-macroglobulin
(a2-M) and low-density lipoprotein-related receptor protein (LRP) genes–
both on chromosome 12. Perhaps not coincidentally, a2-M and ApoE, both
ligands for Ab and the LRP, may all play a role in Ab clearance or deposition in brain. A locus on chromosome 10 may also increase the risk of
sporadic late-onset AD. New genetic linkages for increased risk of AD will
no doubt be found in the future and this effort will be aided by bioinformatics—analysis of massive databases of human genome sequences, with single
nucleotide polymorphisms (SNPs) and haplotypes, of large populations
(such as the Icelandic study). This information will shed further light on the
pathogenesis of AD, and every genetic linkage identified will be a test of
the amyloid hypothesis.
In favor of the amyloid hypothesis of AD is the evidence that Down’s syndrome, APP and presenilin mutations, and the ApoE4 polymorphism either
promote Ab generation, especially Ab42, or its deposition in brain as amyloid. In fact, immunohistochemical stains reveal that early Ab deposits in
aging brain are primarily Ab42. These pre-amyloid deposits (diffuse plaques)
may evolve into mature neuritic plaques, and thus have been likened to fatty
streaks that develop into atherosclerotic plaques in blood vessels. These diffuse plaques, unlike neuritic plaques, are thought to be benign because they
are not surrounded by dystrophic neurites (swollen and deformed axonal and
dendritic neuronal processes) and reactive gliosis (microglial and astrocytic)
and are not associated with clinical dementia [87].
Evidence against the amyloid hypothesis of AD is the poor correlation of
neuritic plaque burden, compared to neurofibrillary tangle density or synaptic loss, to clinical dementia, and weak evidence for linkage to other putative
downstream pathologies, such as apoptosis, oxidative injury, inflammation,
and mitochondrial dysfunction. For example, Ab peptides and fibrils are
thought to be neurotoxic, but in vivo evidence is only suggestive, and mechanisms, perhaps involving elevated intracellular Ca2þ levels, are unclear.
Also, there is poor linkage of amyloid plaques to the other major hallmark
neuropathology of AD—neurofibrillary tangles that are composed primarily of phosphorylated tau. Two recent studies, however, including one with
human mutant tau and APP double transgenic mice, support the notion that
Ab pathology precedes and accelerates tau pathology [37,60]. Amyloid may
be necessary but not sufficient to cause AD; neurofibrillary tangle formation, neuronal and synaptic loss, and other pathologies, albeit downstream of amyloid deposition, may be equally important to induce clinical
dementia.
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Presenilin-1 testing is commercially available (see www.athenadiagnostics.
com) and may be diagnostic for AD in the rare patient with early-onset dementia (usually age 30–55) and a pedigree showing an autosomal-dominant
pattern of inheritance. Because more than 60 different mutations in presenilin-1 are known (almost all single missense mutations) the entire presenilin-1
gene is sequenced, and this sometimes uncovers novel mutations. As is true
in general for genetic markers of adult-onset diseases, presenilin-1 testing
should not be obtained in minors, and with consenting symptomatic adults
(or their legal guardian) testing must be obtained only if genetic counseling
is available. Prenatal screening and testing of asymptomatic individuals in
affected pedigrees raise ethical concerns. ApoE genotyping is commercially
available but its application should be limited to research studies since this
information adds little to the predictive value of clinical diagnosis, adds
cost, and requires follow-up genetic counseling for the patient and family
members [99]. Individuals with ApoE4 may not necessarily develop AD with
age and many patients with AD do not carry the ApoE4 allele. Due to their
rarity, genetic testing for APP and presenilin-2 mutations are not commercially available.
In the late 1970s, a profound cholinergic deficit was discovered in
human AD cerebral cortex. The source of this deficit is loss of cholinergic
neurons in the basal forebrain (nucleus basalis of Meynert) that project to
the hippocampus and neocortex and play a role in learning and memory
[17]. These observations led to the hypothesis that supplementation of central cholinergic systems may be an effective treatment strategy for AD. In
fact, the only drugs with proven efficacy in the treatment of cognitive deficits in patients with AD are acetylcholinesterase inhibitors [23,63]. The
first of these medications approved by the U.S. Food and Drug Administration was tacrine (Cognex, approved 1993) [53]. However, this drug is
limited by its Q.I.D. dosing and titration, side effects (especially nausea,
vomiting, diarrhea, and hepatotoxicity), and requirement for serum alanine
aminotransferase monitoring. Thus, newer acetylcholinesterase inhibitors
without hepatotoxicity—donepezil (Aricept, Pfizer, NY approved 1996),
rivastigmine (Exelon, Novartis, Basel, Switzerland approved 2000), and
galantamine (Reminyl, Jaussen, Titusville, NJ approved 2001)—have
eclipsed tacrine (Cognex, Pfizer, NY) [82]. There are few direct comparison
trials of these drugs, but efficacy in improving or maintaining outcome
measures over time appears comparable. Other central cholinergic supplementation strategies (cholinergic precursors, muscarinic cholinergic receptor agonists, etc) failed to prove efficacy. Other medications have
questionable efficacy for the treatment of AD. Clinical trials of Ginkgo biloba
extract in patients with mixed dementias are inconclusive. The antioxidants a-tocopherol (vitamin E) and selegiline (Deprenyl) delay functional
decline and death in AD patients [84]. No cognitive benefits were found,
but these were secondary endpoint measures in this study. There was no
additive effect of the two compounds, but either was superior to placebo.
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Despite flaws in this study, vitamin E (1000 IU B.I.D.) is routinely recommended to patients with AD.
Although epidemiologic and pilot data are promising, treatment trials with
estrogens have mostly shown no beneficial cognitive effect in postmenopausal women with AD. Likewise, despite a considerable inflammatory
response to amyloid in brain and promising pilot studies of older nonsteroidal anti-inflammatory inhibitors (NSAIDs), drugs inhibiting cyclooxygenase-2 specifically (COX-2 inhibitors) have also proven disappointing in
AD patients. Prednisone treatment is also without cognitive benefit in AD
patients. Since retrospective epidemiologic studies appear promising, ‘‘statins’’ that lower serum cholesterol levels are being explored for potential
benefit in prevention or treatment of AD. A phase II trial of atorvastatin
(Lipitor) is in progress. Some clinical trials are focusing on more proximate
events with the hypothesis that treatment of AD patients may be ‘‘too little,
too late’’. Thus, some trials are enrolling individuals with minimal cognitive
impairment (MCI), a pre-dementia syndrome with high risk of conversion
to dementia [73]. For example, treatment with estrogen in post-menopausal
women, donepezil (Aricept), or vitamin E, is being studied in patients with
MCI for potential efficacy in delaying or preventing the onset of dementia
and AD. The exact neuropsychometric boundaries between normal aging,
MCI, and dementia, however, are controversial.
To date, all treatments for AD are thought to be symptomatic only with
no beneficial effect on underlying progressive disease processes. In support
of this notion, cessation of donepezil (Aricept) results in acute loss of clinical
benefits [82]. Construction of the amyloid cascade hypothesis and recent
identification of the b- and c-secretases responsible for the release of Ab
from APP have sparked an intense search for inhibitors of these protease
enzymes as potential treatments for AD. For example, c-secretase inhibitors
are now being studied in Phase II clinical trials. There is strong evidence to
suggest that presenilins either are c-secretases or an important component of
the c-secretase complex [87]. Unfortunately, these proteases are not specific
to APP and have other important normal functions. For example, c-secretase cleaves both APP and Notch, a protein essential to normal mammalian
development and adult processes such as hematopoesis. Underscoring its
importance in normal development, homozygous presenilin-1 knockout
mice are lethal in utero (and resemble Notch knock-out mice). A c-secretase
inhibitor may therefore have dose-limiting toxic side effects. Another promising approach is inhibition of b-secretase, since mice with this gene (BACE-1)
knocked out are viable and appear normal. Inhibitors of b-secretase are in
the preclinical phases of investigation.
Because of gliosis and humoral inflammatory responses to amyloid in AD
brain tissue, it was hypothesized that immunization of human APP transgenic mice with Ab may exacerbate disease. In contrast, immunized mice
develop little or no amyloid deposition, indicating a novel therapeutic strategy [85]. The mechanism of action remains unclear but immunization may
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promote Ab and amyloid clearance by anti-Ab immunoglobulin (IgG) complexes and phagocytic cells (microglia) in brain; peripheral immune-mediated
Ab clearance (a ‘‘sink’’) has not been excluded. Immunization not
only prevents but also removes established amyloid plaques in human APP
transgenic mouse brain. In support of the amyloid hypothesis, immunization
prevents both plaque deposition in transgenic mouse brain and behavioral
decline in learning and memory tasks. A Phase II clinical trial of Ab42 vaccination in AD patients with mild to moderate dementia was halted due to
encephalitic complications.
An alternate strategy with orally administered Clioquinol, (Novartis,
Basel, Switzerland) a metal chelator, also prevents age-dependent amyloid
plaque deposition in transgenic APP mouse brain [13]. Ab peptides bind
selectively to Cu2þ and Zn2þ and thus, chelators of these ions solubilize
Ab amyloid deposits in AD brain. A phase II clinical trial of Clioquinol
(with vitamin B12) is in preparation. Finally, gene therapy for AD faces
enormous barriers, such as access to the central nervous system, limited
duration and extent of gene expression, and detrimental host responses to
the vector or gene product. Nevertheless, a phase I clinical trial of nerve
growth factor (NGF)-expressing fibroblasts injected into the brain of AD
patients is underway. NGF promotes survival of neurons, including cholinergic neurons in the basal forebrain.
AD research has become a model of how biochemical pathology and
molecular genetics have quickly brought us to the threshold of safe and
effective disease-modifying therapies. After decades of anosagnosia writ large
and therapeutic nihilism, the clinical identification of rare patients and pedigrees with familial AD allowed the development of transgenic animal models of disease to test hypotheses and potential therapies. The challenge
remains, however, to return to the clinic with new treatments for familial
and sporadic AD based on our recent advances in understanding of this devastating neurodegenerative disorder.
Frontotemporal dementias and related tauopathies
Dr. Arnold Pick reported several patients with aphasia and dementia
who had circumscribed brain atrophy on autopsy [74]. Postmortem analysis
of these patients performed by Dr. Alzheimer showed that plaques similar
to those seen in his now famous case of a ‘‘peculiar’’ dementing syndrome
were absent in Dr. Pick’s cases [1,2]. Moreover, Alzheimer was the first to
demonstrate the presence of argyrophilic inclusions and swollen achromatic
neurons in this condition that became known as Pick’s disease. Progressive dementia with early personality changes, disinhibition, limited speech
output leading to aphasia, and with pathologic changes consisting of focal
fronto-temporal atrophy, argyrophilic intraneuronal inclusions (also known
as Pick’s bodies) and achromatic neurons (Pick’s cells) has become a
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prototype of fronto-temporal dementia of Pick’s type. However, it soon
became apparent that the majority of patients with similar clinical features
and brain atrophy limited to the frontal and temporal lobes did not have the
pathologic hallmarks of Pick’s disease; histologic examination demonstrated
gliosis and spongiosis in the fronto-temporal cortex. One of us (RST) reported
the pathologic findings of three cases of progressive non-fluent aphasia to be
this more frequent pathology termed ‘‘dementia lacking distinctive histopathology’’—neuronal loss and gliosis without neurofibrillary tangles, Lewy
bodies, or Pick bodies [102]. There is considerable confusion in the literature
regarding the nosology of this type of dementia. The Lund and Manchester
research groups proposed clinical and pathologic criteria for this type of
dementing disorder; they also suggested the term frontotemporal dementia
(FTD) [97]. Even though FTD is a clinically and pathologically a heterogeneous group of dementing disorders, it is the preferred nomenclature at
present (OMIM #600274).
Many patients with FTD have affected first-degree relatives and a few
large pedigrees with an autosomal dominant mode of inheritance have been
identified. Several terms describing this condition have been used and linkage to chromosome 17q was first established in a pedigree with a dementing
disorder designated as disinhibition-dementia-parkinsonism-amyotrophy
complex [107]. Additional families have been mapped to 17q21.1-q21.3 suggesting genetic homogeneity of this condition [26]. The gene coding for
microtubule associated protein tau (MAPT) is located within the region
of chromosome 17q that was shared by all definitely linked families with
FTD. Neuropathologic examination demonstrated the presence of taupositive intraneuronal inclusions in several familial cases and thus MAPT
gene was a leading candidate as a cause of FTD. Identification of mutations
in this gene has confirmed the link between tau and FTD [47,76]. For a complete list of tau mutations and polymorphisms linked to neurodegenerative
disease, see www.alzforum.org.
The exact prevalence of FTD has not been established but it is probably
the third most common type of dementia after AD and dementia with Lewy
bodies. FTD may account for up to 20% of all neurodegenerative dementia
cases [69]. However, many patients are probably misdiagnosed. The fraction
of patients with FTD diagnosed as probable AD varied from 9% in the Consortium to Establish Registry for Alzheimer’s Disease (CERAD) autopsy
data to 15% in another series of demented patients [31,55]. A clinical survey
using the Lund-Manchester diagnostic criteria estimated the frequency of
FTD in patients with onset of dementia before the age of 65 years at 12%
[83]. The prevalence of FTD increases with age similar to AD and Stevens
et al, estimated the prevalence of FTD at 1.2:1,000,000 in the third decade,
3.4:1,000,000 in the fourth decade, 10.7:1,000,000 in the fifth and
28:1,000,000 in the sixth decade [93].
Similar to other neurodegenerative dementias, FTD has an insidious
onset and progressive course. Personality changes with early loss of social
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and personal awareness, disinhibition with socially inappropriate behavior,
easy distractibility with impersistence, and perserverative or utilization
behavior are typical heralding features of FTD [69,97]. Spontaneous speech
becomes limited with frequent sterotypical speech and repetition of certain
phrases; echolalia is also common. Patients with prominent signs of disinhibition may have increased verbosity but stereotypy of speech is typically
present. Early behavioral symptoms may also include alcoholism, depression, or schizoaffective disorder and thus create difficulties in diagnosis early
in the disease course. Personality changes and psychiatric symptoms may
precede frank dementia by many years. Initially, short-term memory is
spared together with visuospatial skills in contrast to AD; deficits in attention, problem solving skills, planning and other executive functions can be
detected during neuropsychological evaluation [69,97]. However, the difference between AD and FTD in advanced stages of dementia are less prominent and both conditions can be difficult to distinguish. The presence of
frontal cortical atrophy on brain MRI and frontal lobe hypoperfusion
detected by SPECT or PET also support the diagnosis of FTD [69].
Two distinctive neurobehavioral syndromes have been described in
patients with focal brain atrophy. An isolated deficit in expressive language
with relatively preserved perception was designated as primary progressive
aphasia (PPA) while severe naming and word comprehension with fluent
and grammatically correct language was designated as semantic dementia
(SD) [67,89,102]. Occasionally, patients from the same family may exhibit
different behavioral phenotypes further supporting the notion that FTD,
PPA and SD are related and reflect the differences in anatomical distribution
of focal brain atrophy [69].
Frontal dementia can be associated with motor abnormalities, especially
in familial cases. The concurrence of extrapyramidal syndrome with bradykinesia, rigidity, and postural instability with dementia is the most common;
tremor is typically absent and hypokinetic-rigid syndrome is not levodopa
responsive. Lower motor neuron dysfunction with amyotrophy can be also
seen in some patients. Some families linked to chromosome 17q were originally classified based on the most conspicuous clinical signs as pallido-ponto-nigral degeneration or disinhibition-dementia-parkinsonism-amyotrophy
complex [106,107].
The majority of patients with FTD have a ‘‘presenile’’ (ie, less than 65
years) onset between 50 and 60 years [93,106]. Early age of onset is also part
of the proposed diagnostic criteria [69,97]. However, patients with the onset
of FTD in the seventh decade have also been reported and ‘‘senile’’ (ie, more
than 65 years) onset of frontal type dementia does not exclude the diagnosis
of FTD [14,58]. The clinical picture of familial and sporadic cases of FTD is
almost identical. Even though some studies suggest that familial cases of
FTD have onset of disease ten years earlier than sporadic FTD cases
(60.9 10.6 years and 72.3 8.5 years, respectively) [106], this was not confirmed in other case series of FTD [93].
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Genetic studies of patients with FTD identified several pedigrees with a
clear autosomal dominant mode of inheritance. Wilhelmsen et al [107], were
the first to identify linkage to a group of markers on chromosome 17q in a
pedigree that they classified as disinhibition-dementia-parkinsonism-amyotrophy complex [107]. Several other pedigrees were subsequently linked to
the same region. A consensus conference held in Ann Arbor, MI in 1996
identified 15 pedigrees linked to 17q21.1-q21.3 [26]. The association of an
extrapyramidal syndrome with FTD was also emphasized and all families
with proven linkage to chromosome 17q were designated as frontotemporal
dementia and parkinsonism [26]. Analysis of clinical features of affected subjects from these families revealed that they are very similar to diagnostic criteria proposed by the Lund and Manchester research groups, further
supporting the link between FTD and frontotemporal dementia and parkinsonism. There is evidence for genetic heterogeneity of FTD as a second locus
on chromosome 3p11.1-q11.2 was identified in some families with autosomal dominant frontal lobe dementia [8]. The proportion of affected subjects
with a positive family history of FTD is between 40% to 60% [38,93]. It is
also intriguing that most patients who meet the neuropathologic criteria for
Pick’s disease in the strictest sense (with Pick bodies and Pick cells) are
sporadic cases.
Mutations in the MAPT gene in some families linked to the FTD locus on
chromosome 17q21 were identified in 1998 [47,76]. Missence and splice site
mutations in this gene cosegregated with the disease thus confirming the role
of tau in FTD [47,76,92]. However, there are also several FTD families with
definitive linkage to 17q21 and without detected mutations in the MAPT
gene; it is likely that mutations in intronic sequences or in regulatory regions
of the gene disrupt the expression of tau and its biochemical properties
[47,76].
Tau belongs to the microtubule associated protein (MAP) family and it
contains several microtubule binding domains [10]. It is primarily found
in neurons where it plays a role in microtubule assembly and stability, and
may also participate in axonal extension and maintenance. The gene coding
for tau has 16 exons. Tau expression is highly regulated by alternative splicing of exons 2, 3 and 10, resulting in the presence of six different isoforms,
ranging from 352 to 441 amino acids, in adult human brain [10]. Each of
these isoforms is likely to have different functions as their expression varies
in different stages of development. Depending on whether exon 10 is
excluded or included, tau has either 3 (3R tau) or 4 (4R tau) microtubule
binding repeats [10]. In adult human brain the amount of 3Rtau/4Rtau is
approximately equal.
The identification of different types of mutation in the MAPT gene provided an important insight into the variability of pathologic changes seen in
kindreds with chromosome 17-linked FTD. Several mutations affecting the
exon 10 5¢ splice site have been identified [47,92]. The majority of splice site
mutations lead to disruption of normal regulation of tau expression and
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preferable incorporation of exon 10. This results in higher proportion of 4R
tau and the functional consequence of this mutation; 4R tau binds microtubules with a higher affinity than the 3R isoform [32]. Families with this type
of mutations have prominent tau pathology with mostly 4R isoforms. Missence mutations outside exon 10 alter the biochemical properties of tau,
resulting in decreased microtubule binding capacity or decreased rates of
tau-stimulated microtubule polymerization [41]. Tau-positive inclusions in
families with this type of mutation contain both 3R tau and 4R tau isoforms. The neuropathologic classification based on the presence and ration
of various isoforms of tau has been proposed [65].
Prominent tau pathology is not limited to FTD and can be seen in other
neurodegenerative dementias, frequently referred to as tauopathies (see
Display Box) [57]; the MPPT gene is a leading candidate gene for these disorders. Progressive supranuclear palsy (PSP), characterized by supranuclear
gaze paralysis, hypokinetic-rigid syndrome with prominent postural instability and dementia is considered a sporadic disorder, though familial occurrence has been also reported [111]. Patients with PSP have a significant
homozygous overrepresentation of a polymorphic dinucleotide repeat in
intron 9 in the MAPT gene, called the A0 allele compared to control subjects [16]. No mutations in the MAPT gene have been found in PSP and this
suggests that A0 is a low-penetrance PSP-susceptibility allele. Hyperphosphorylated tau in the neurofibrillary tangles in PSP contains only isoforms
with exon 10, i.e., tau with 4 microtubule binding repeats [88]. Similarly,
overrepresentation of 4R tau in tau-positive neuronal inclusions is associated with corticobasal degeneration (CBD) [65]. CBD is a sporadic disorder;
aphasia, apraxia, and alien hand phenomenon combined with an asymmetric extrapyramidal syndrome are key diagnostic features of CBD [80].
Box 1. Neurodegenerative conditions with prominent
tau abnormalities [58]
Frontotemporal dementia (including Pick’s disease)
Alzheimer disease
Corticobasal degeneration
Gerstmann-Sträussler-Scheinker disease
Progressive supranuclear palsy
Amyotrophic lateral sclerosis-Parkinsonism-Dementia
complex of Guam
Postencephalitic parkinsonism
Dementia pugilistica
Niemann-Pick disease type C
Subacute sclerosis panencephalitis
Trisomy 21 (Down syndrome)
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Recently, a linkage disequilibrium between polymorphism CA3662 in the
MAPT gene and the risk for amyotrophic lateral sclerosis-parkinsonismdementia complex of Guam has been found [77]. However, linkage analysis
of one large Chamorro pedigree excluded the FTD locus on chromosome
17q suggesting that CA3662 is a modifying factor for a yet unidentified gene
causing amyotrophic lateral sclerosis-parkinsonism-dementia complex of
Guam.
Familial prion diseases
Prion disorders are a group of diseases causing a progressive neurodegenerative process with severe dementia. Prions can affect both humans and
many animal species. Prion disorders can be classified as sporadic, acquired
and genetic (inherited) [15]. Familial Creutzfeldt-Jakob disease (CJD)
(OMIM #1234000), Gerstmann-Sträussler-Scheinker disease (GSS) (OMIM
#137440) and familial fatal insomnia (FFI) (OMIM #600072) are examples
of genetic prion disorders that are reviewed here.
Prion disorders are also known as transmissible spongiform encephalopathies because the brain extracts from affected humans or animals are infectious (see below). Infection by slow or atypical viruses has been proposed.
However, a rather extensive search failed to identify the presence of nucleic
acid associated with this infection. The term prion was coined by Dr.
Stanley Prusiner who suggested that prions are a novel class of infectious
particles lacking either RNA or DNA [78]. The ‘‘protein infectious agent’’
or prion theory has now gained considerable support. The elucidation of
pathogenesis of inherited prion disorders was one of the crucial pieces in the
prion puzzle. Prions disorders have a unique position among other inherited
neurologic disorders because they are caused both by different germline
mutations and by infection, as they are transmissible by inoculation.
The incidence of CJD has been relatively constant during the last few decades at approximately 1:1,000,000 [48]. Inherited prion disorders, especially
familial CJD account for only 10–15% of all prion cases [15]. Several isolated population groups have been known to have a particularly high incidence of CJD: Chile, the Orava and Lucenec regions in Slovakia, and
Libyan-Tunisian Jews are a few examples of regions and ethnic groups with
an increased incidence of CJD [34]. This was attributed to various environmental factors, such as consumption of lightly cooked sheep brains and eyes
by Israeli Jews born in Libya and Tunisia, who have an annual incidence of
CJD between 2.3 and 3.5 per million [43]. However, detection of a germline
mutation in the prion protein gene (PRNP) (see below) confirmed that the
familial occurrence of CJD accounts for the increased frequency in these
ethnic groups.
CJD is best characterized as a rapidly progressive dementia with myoclonus [48]. Even though this description is principally true for both sporadic
and familial patients, familial CJD cases may differ in some clinical aspects
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that can create diagnostic difficulties. The age of disease onset in sporadic
CJD is between 45 and 75 years, with the peak in the sixth decade in the majority of patients. The course of CJD is brutally fast and more than 80% of
patients without a family history die within one year of onset. In general,
patients with inherited forms of CJD tend to have an earlier age of onset
and longer course. Moreover, there is a correlation between genotype (ie,
type of mutation in the PRNP gene) and phenotype (see below).
The first symptoms of CJD are quite non-specific and almost one third of
the patients complain of fatigue and insomnia [6,48]. Memory complaints
are prominent in another third of patients with a rapid progression to
dementia. The most challenging diagnostic dilemmas arise in patients with
less typical presentation, such as early focal neurologic symptoms and signs,
including visual loss, aphasia, or ataxia. For instance ataxia is a heralding
symptom in almost 15% patients. Ataxia was especially prominent in kuru,
another form of prion disease seen in the Fore tribes of Papua New Guinea.
Kuru also played an important role in our understanding of prion biology
after the discovery that the disease was transmitted by consuming brains
of affected persons during cannibalistic rituals [28].
CJD is rapidly progressive and patients become profoundly demented.
Startle myoclonus is present in more than 80% of all patients, even though
it may become less prominent in later stages of the disease. However, myoclonus is less common in familial cases and only approximately one half of
inherited forms of CJD have prominent myoclonus. Pyramidal, extrapyramidal and cerebellar symptoms are also typical; lower motor neuron signs,
visual disturbance or cortical blindness and choreoathetosis are less common and again, may cause diagnostic problems and delay the correct diagnosis. Akinetic mutism can be seen in terminal stages. The differences
between clinical presentation were the basis for a clinical classification recognizing six main subtypes; however, there is no evidence that these subtypes have a different pathogenesis [108].
CJD can be relatively easily recognized in patients with rapidly progressive dementia and startle myoclonus. The diagnosis can be further
supported by periodic discharges on electroencephalogram (EEG). Generalized, bisynchronous 1–2 cycle/sec discharges superimposed on slower
background can be seen in the majority of patients. Repeat EEG recordings
can increase the diagnostic yield if previous studies were negative. EEG
discharges can be absent in some mutations in the PRNP gene (see below).
Analysis of the 14-3-3 protein from the cerebrospinal fluid (CSF) is another
useful diagnostic test [46]. This protein is found normally but is elevated in
patients with CJD. However, elevation of the 14-3-3 protein in the CSF is
not specific for prion disorders. Other conditions including encephalitis and
acute ischemic stroke are associated with higher CSF level of 14-3-3. However, if only patients with progressive dementia and normal cell count in the
CSF are selected, the sensitivity and specificity for the diagnosis of CJD is
more than 95% [46]. This is true only for sporadic cases as many patients
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with familial CJD have normal levels of the 14-3-3 protein. Tissue examination remains the gold standard for the diagnosis of CJD. Brain biopsy is
sometimes necessary to establish the diagnosis in patients with an atypical
clinical course [9].
CJD is also referred to as a spongiform encephalopathy because of prominent spongiform vacuolization of the gray matter, accompanied by gliosis
and neuronal loss. Accumulation of insoluble prion protein (PrPSc indicating the scrapie isoform of the protein, also called PrPCJD) (see also below) in
plaques is present in approximately 15% patients with sporadic CJD [9].
Immunostaining with antibodies against PrPSc reveals a widespread reactivity in synapses and around the vacuoles. PrPSc is derived from the cellular
isoform PrPC (indicating the cellular isoform of the protein) that is encoded
by the PRNP gene mapped to chromosome 20p12 [81]. The whole coding
region consists of two exons and only the second exon is translated into a
253 amino acid protein. The gene also contains an unstable region of five
variant tandem octapeptide coding repeats between codons 51 and 91 [15].
The first mutation in the PRNP gene was a 144 bp insertion in the open
reading frame of the gene detected in a family with a typical CJD; however,
the identical mutation was also detected in an unrelated family with a lateonset dementia and without any pathologic hallmarks of a spongiform encephalopathy [71]. This example indicates that the clinical phenotype of
human prion disorders can be variable resulting in their underdiagnosis. The
most common mutation, accounting for more than 70% of all familial cases
is the glu200-to-lys mutation (E200K). This mutation is present in Libyan
Jews and Slovaks with familial CJD [34,43]. A haplotype analysis confirmed
that this mutation originated independently in these ethnic groups. The clinical picture of familial CJD due to E200K mutations resembles the course of
sporadic cases and the average age of onset is 55 8 years; myoclonus and
typical EEG changes are also common. The penetrance of this mutation is
not complete (ie, not every individual who inherited the mutation will develop the disease) and is estimated around 60% to 80%; it also increases
with the age [34,43].
Another common mutation in familial CJD is asp178-to-asn (D178N);
this mutation is always associated with homozygosity for valine on codon
129 (see below) [35]. In general, these patients have an earlier age of onset
(46 7 years) and a prolonged disease duration. EEG changes are absent
in the vast majority of patients with this mutation [7]. More than 10 repeats
in the region of the gene with octapeptide repeats is also associated with
CJD [33]. These patients can manifest the disease as early in their twenties
and the longest known disease duration in this type of mutation was 13
years.
Individuals with sporadic CJD have no detectable mutations in the
PRNP gene. However, certain polymorphic changes are more commonly associated with CJD, especially due to iatrogenic infection and the recently reported ‘‘new variant’’ of CJD (nvCJD) associated with the outbreak of bovine
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spongiform encephalopathy (mad cow disease) in the United Kingdom
[15]. The most relevant polymorphism is on codon 129 where either methionine or valine is present. Data from the Caucasian population show that
half of individuals are heterozygous (51%) at residue 129; homozygosity for
methionine is found in 38% and for valine in 11% [72]. Patients who developed CJD after iatrogenic transmission (human growth hormone, corneal
transplants, dural grafts) are typically homozygotes for valine [15]. Homozygosity for methionine is found in the majority of sporadic cases of CJD.
Moreover, all reported patients with nvCJD were homozygous for methionine [15,109]. Patients with nvCJD were atypically young with the mean age
of onset 29 years. Emotional lability and dysesthesias are heralding symptoms followed by ataxia; dementia is a later finding in nvCJD [109]. Postmortem analysis demonstrated prominent amyloid plaques in the cortex
and cerebellum. Similar histological findings were reported in kuru, a prion
disease transmitted by cannibalism. Polymorphism on codon 129 also modifies the course of familial CJD. Individuals who inherited a PRNP mutation
and are heterozygotes on codon 129 have later onset of disease that those who
are homozygous either for valine or methionine [15].
GSS is a rare familial disorder with an autosomal mode of inheritance.
Only a handful of families are known and the estimated prevalence is 2–5
per 100 million. GSS typically presents with progressive ataxia between the
third and fourth decades, followed by the development of spasticity with
hyporeflexia, extrapyramidal and lower motor neuron symptoms; dementia
is usually a later sign [18]. The clinical presentation may vary even among
the affected members from the same family. Pathologic hallmark of GSS are
multicentric amyloid plaques that are positive for PrP protein. These plaques are most commonly found in the cerebellum but the cerebral cortex
is involved as well. The extent of spongiform vacuolization varies and may
be absent.
GSS can be divided into three types and the discovery of various mutations in the PRNP gene supports this clinical classification [42]. The ataxic
form of GSS closely resembles patients originally reported by Gerstmann,
Sträussler and Scheinker. Analysis of a large pedigree with GSS showed
linkage to chromosome 20 and subsequently, the pro-to-leu mutation on
codon 102 was found in affected individuals [22]. This mutation was also
found in other unrelated families with the same phenotype. Another type
of GSS is a variant with neurofibrillary tangles (NFT). Postmortem examination of patients from an Indiana kindred with autosomal dominant progressive dementia and extrapyramidal symptoms revealed prominent NFTs
and amyloid plaques. NFTs were undistinguishable from those seen in AD;
however, plaques did not contain b amyloid protein but were positive for
PrP protein. These patients had the phe198-to-ser mutation in the PRNP
gene [42]. The third subtype of GSS is telencephalic presenting with progressive dementia; mutation ala117-to-val cosegregated with the disease in these
patients [44].
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FFI is another dominantly inherited prion disease where disruption of the
sleep/wake cycle leads to progressive insomnia. Ataxia and autonomic dysfunction are also common. Insomnia progresses into a dream-like condition
and later into coma. Pathologic changes are mostly limited to the anterior
ventral and medial dorsal nuclei of the thalamus. It was surprising that patients with FFI had the D178N mutation because the same mutation is associated with familial CJD [66]. However, patients with FFI were homozygous
for methionine on residue 129 while patients whose phenotype was consistent with CJD had valine on the same residue on both alleles in the PRNP
gene [36]. A sporadic form of FFI without D178N mutation has been also
reported.
Transmission of kuru via brain homogenate after intracerebral inoculation to chimpanzees prompted a search for viral particles as a cause of
spongiform encephalopathies [28]. Subsequent research failed to identify a
virus and it was proposed that spongiform encephalopathies are transmitted
by a protein infectious agent or prion [78]. This theory gained wide acceptance after isolation of a protease-resistant scrapie (prion disorder affecting
sheep) peptide that was linked to infectivity. The sequence of PrPSc was
identical to a wild type protein encoded by the PRNP gene that was later
mapped to chromosome 20 [81]. PrPSc is protease resistant, insoluble and
contains b pleated sheet, while PrPC is protease sensitive, soluble, and contains only a helix. Analysis of PrPC and PrPSc did not reveal any changes in
the amino sequence or known covalent posttranslational modifications [79].
Current evidence suggests that scrapie prion protein is an abnormal isoform of host-produced PrPC protein. PrPSc is derived by conformational
change during conversion of PrPC protein and this conversion does not
require synthesis of new protein [79]. Germline mutations in the PRNP gene
most likely result in synthesis of PrPC protein that is unstable and transforms into PrPSc. This also explains the fact that familial CJD and GSS can
be transmitted by brain extracts. PrPSc in sporadic or iatrogenic cases probably functions as a template that promotes conversion of PrPC into
PrPSc [79].
The normal function of PrPC remains unknown. Mouse knock-out lines
that do not express PrPC have a relatively unremarkable phenotype [11].
PrPC is expressed in synapses and studies with hippocampal slices showed
abnormalities in inhibitory synaptic transmission. However, these mice are
resistant to scrapie after intracerebral inoculation and this has further supported the hypothesis that PrPSc is derived from PrPC [12].
British and Danish familial dementia
Worster-Drought et al, reported a single family in which affected members present in the fifth decade with a spastic gait disorder followed by cerebellar ataxia [110]. Cognitive decline was heralded by apathy and memory
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decline, followed by a progressive dementia. The mode of transmission was
consistent with an autosomal dominant mode. Histologic examination
showed a conspicuous congophilic angiopathy. Two additional families that
shared a common ancestry with the original family were reported in 1990
[75]. Postmortem examination showed a widespread congophilic angiopathy
and non-neuritic amyloid plaques in the cerebellum, hippocampus and
amygdala. Neurofibrillary tangles were present in hippocampal neurons.
The classification of the disorder was uncertain and it was suggested that
this was a novel type cerebral amyloid angiopathy of a British type. This disorder was later designated as familial British dementia (FBD) (OMIM
#176500) [75].
Analysis of amyloid material from the plaques from one typically affected
patient with FBD identified previously unknown protein subunit [104]. This
peptide was derived from a novel precursor protein designated as integral
membrane protein 2B (ITM2B), which has a single transmembranespanning domain. The BRI gene coding this protein is mapped to chromosome 13q14. Sequencing of the BRI gene in affected individuals with FBD
detected a single base substitution in the stop codon resulting in open reading frame that is 33 nucleotides longer. Release of the 34-carboxy-terminal
peptide from the abnormal ITM2B protein results in generation of insoluble
amyloid peptide that was present in the vessels and non-neuritic amyloid
plaques in the brains of FBD subjects [104].
BRI gene was also analyzed in patients with previously reported Danish
type of dementia (OMIM # 117300) [95]. Heralding symptom in this kindred was the development of cataracts and deafness; ataxia and dementia
with psychotic features were observed in the fourth decade. These patients
had a 10-bp duplication one residue before the stop codon of the BRI gene,
again resulting in a production of longer precursor protein with the amyloid
subunit produced from the last 34 C-terminal amino acids [105].
Cerebral autosomal dominant arteriopathy with subcortical infarcts
and leukoencephalopathy (CADASIL)
Several families with recurrent strokes leading to multi-infarct dementia
have been reported before 1993. The disorder was transmitted in an autosomal dominant mode. Patients, who typically did not have traditional risk
factors for stroke, experienced stepwise deterioration with multiple subcortical strokes causing progressive dementia in the majority of cases. White matter degeneration with cystic changes, resembling Binswanger disease, which
was associated with nonamyloid angiopathy were pathologic hallmarks.
The disorder was described using several terms, including hereditary multiinfarct dementia and subcortical arteriosclerotic encephalopathy [61,90,
91]. In 1993 Tournier-Lasserve et al., studied a large pedigree with subcortical strokes and dementia, and proposed the term Cerebral Autosomal
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Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy,
also designated as CADASIL (OMIM # 125310) [101]. They also demonstrated a tight linkage to the group of markers on chromosome 19q12.
Subsequent research by the same group led to the discovery of mutations
in the NOTCH-3 gene as a cause of CADASIL [49]. CADASIL are the first
example of genetically determined multi-infarct dementia.
No epidemiologic data about CADASIL are available at present and this
entity has been considered a rare cause of dementia. More that 150 families
of different ethnic backgrounds have been reported [18]; however, it is quite
likely that this condition is often unrecognized and thus more common than
previously thought.
Cerebral ischemia is the most common manifestation of the disease, and
transient ischemic attacks (TIA) or strokes are seen in more than 80% of
all patients [21,112]. The typical age of stroke onset is in the fourth decade
but patients in their twenties can suffer from strokes. Only a small fraction
of patients have hypertension and no stroke risk factors can be identified in
the majority of affected individuals. Strokes can result in various degrees of
neurologic deficit and also cause dementia. Most strokes are classic lacunar
strokes localized in the subcortical white matter or basal ganglia.
Cognitive decline is the second most common presentation of CADASIL
[19,21,112]. Typically, cognitive deficit occurs in a step-wise fashion, reflecting new ischemic events. However, many patients may present with a progressive deterioration of cognitive function without any obvious strokes
or TIAs, resembling a neurodegenerative dementing process [40]. The prevalence of dementia in CADASIL is estimated between 30% to 50% in symptomatic patients, even though more patients have signs of mild cognitive
deficit without meeting formal criteria for dementia [19,21,112]. The risk
for dementia increases with age and the majority of patients meet DSMIV criteria for dementia in the fifth and sixth decades [20]. Cognitive complaints are the initial symptom in approximately 5% of cases. The pattern
of dementia seen in patients affected by CADASIL falls into the category
of subcortical dementia with deficits in attention, episodic memory and disturbance of visuospatial skills; aphasia and apraxia are typically absent.
However, cognitive deficit is quite variable even within CADASIL families.
Many patients may exhibit prominent frontal lobe signs with disinhibition,
apathy and perseverations. Moreover, frequency of depression is also higher
in these patients and up to 20% of all patients have severe depression. Mood
disorder must be distinguished from irreversible cognitive decline. Dementia
is commonly associated with a gait disorder, urinary incontinence and signs
of pseudobulbar palsy [19].
Analysis of larger cohorts of CADASIL patients revealed additional clinical features seen in these patients. Migraines with aura (classic migraine)
are particularly common and have been reported in almost half of all
patients [21,112]. Most common neurologic symptoms associated with headaches are visual and sensory disturbances but hemiplegic attacks are also
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quite common. Moreover, headaches are the first symptom in 40% of all
patients. Thus, migraines and TIAs are the most common presenting symptom of this entity. There is a considerable intra- and interfamilial variability
in frequency of migraines and several pedigrees without migraines have been
reported. The frequency of migraines may increase prior to first ischemic
events in some patients. Epilepsy, especially with the onset of seizures in
thirties is also common and typically is the sequel of strokes. CADASIL
is a progressive disorder with shortened life span in affected individuals. The
average age at death varied between 57 to 61 years with the range from 28 to
76 years. Stroke and its complications were the most common cause of death
followed by pneumonia [18].
Diagnosis of CADASIL still requires a high index of suspicion and it is
very likely that this condition is largely underdiagnosed. Clinical presentation of CADASIL is non-specific and pleiotropic. The diagnosis can be established relatively easy in individuals from large kindreds with a positive family
and individual history of strokes, headaches and dementia. However, the
hereditary nature is often overlooked because many patients are not symptomatic before reaching age 50, and some family members can be misdiagnosed. This diagnosis should be considered in patients younger than 50
years without significant cerebrovascular disease risk factors who suffer from
strokes and have a history of migraines or subcortical dementia. Increased
signal changes in the subcortical white matter (leukoaraiosis) and in the
brainstem can be seen on T-2 weighted MR images, together with evidence
of lacunar strokes in basal ganglia and centrum semiovale; cortical strokes
are typically absent [100] (Fig. 3). The presence of signal changes in the
external capsule has been suggested as a highly specific finding in CADASIL
patients [70]. Signal hyperintensities can be detected even in presymptomatic
CADASIL patients who inherited the mutation or affected individuals who
have only history of migraines without TIAs or strokes [112]. MRI abnormalities are nevertheless nonspecific and the diagnosis cannot be solely based on
neuroimaging criteria. Multiple sclerosis, systemic lupus erythematosus,
mitochondrial encephalopathy with lactic acidosis, and Binswanger disease
among others, must be distinguished from CADASIL.
A definitive diagnosis of CADASIL should be supported by the presence
of a mutation in the disease-causing gene or by a pathologic diagnosis demonstrating typical vascular changes. CADASIL is an arteriopathy with
thickening of the media and lumen reduction of small and medium size penetrating arteries leading to multiple strokes [4]. Similar pathologic changes
are present in the leptomeningeal vessels. The vascular thickening is caused
by accumulation of eosinophilic material that is strongly periodic acid
Schiff-positive and negative after staining for amyloid [4]. Electron microscopy is also characteristic because of the presence of granular osmiophilic
granules located between degenerated smooth muscle cells or within the
thickened basal lamina (Fig. 4) [4,100]. Even though clinical symptoms in
CADASIL are limited to the central nervous system, similar vascular
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Fig. 3. FLAIR MR imaging of the brain of a patients with CADASIL demonstrating subcortical strokes and leukoencephalopathy.
Fig. 4. Electron microscopy from a skin biopsy of a CADASIL patient demonstrating osmiophilic granules.
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changes are present in small vessels in multiple organs, including the skin.
Evaluation of the vessels for pathologic hallmarks of CADASIL from skin
biopsies has been suggested as a diagnostic test thus eliminating the need
for more invasive procedures, including brain biopsy [62]. Analysis of skin
biopsy, including electron microscopy confirmed that this test is both sensitive and specific for the diagnosis of CADASIL, even in early stages of the
disease; however, the rate of false negative skin biopsies remains to be determined [62].
A linkage study performed on two unrelated families from northern
France identified tight linkage to a group of microsatellite markers on
chromosome 19q13.1 [101]. Subsequent genetic analysis of 13 additional
kindreds with clinical and radiologic features of CADASIL confirmed
linkage to this region and suggested that this familial stroke syndrome is
genetically homogeneous. Joutel et al., identified a gene with a strong
homology to a mouse Notch-3 gene and 90% of patients affected with
CADASIL had mutation segregating with the disease [49]. Human Notch-3
contains 33 exons encoding for 2,321 amino acids. Notch genes are glycosylated transmembrane proteins and human Notch-3 gene contains 34 epidermal growth factor (EGF) domains in the extracellular part of the
protein. Each of these EGF domains contains six highly conserved cysteine
residues. Detected mutations are always missense mutations causing a gain
or loss of a cysteine and thus resulting in an odd number of cysteine residues
[49,50]; the only exception is one splice-site mutation that has the same consequence on the number of cysteine residues. Moreover, mutations are not
distributed randomly and approximately 65% of all mutations are clustered
within exons 3 and 4 encoding for first five EGF domains [50]. This facilitates screening for mutations. A genetic test for Notch-3 is available as a
clinical test, even though some laboratories screen only exons 3 and 4. There
is no compelling evidence that CADASIL is genetically heterogenous and
the same phenotype can be caused by mutations in others genes. Japanese
patients with strokes and subcortical dementia have been reported but this
condition is inherited in an autosomal recessive mode; moreover, these
patients also had prominent low back pain without any evidence of lumbar
disk herniations [27].
How the mutation in the Notch-3 gene causes adult onset strokes and secondary dementia remains unknown. The Notch-3 gene belongs to the group
of highly conserved Notch-LIN-12 genes that play an important role in
intracellular signaling during development [3]. Notch-3 is highly expressed
during gastrulation and in the developing central nervous system; however,
postnatal expression appears to be limited to vascular smooth muscle cells
[51]. The product of mutated Notch-3 gene contains unpaired cysteines and
it is likely that they undergo abnormal protein conformation or abnormal
cross-linking with other proteins. Two possible explanations how mutations
in the Notch-3 gene may lead to the pathology seen in CADASIL are a
Notch signaling defect or protein accumulation [51]. Analysis of brain
P. Hedera, R.S. Turner / Neurol Clin N Am 20 (2002) 779–808
803
tissues obtained from patients with CADASIL revealed accumulation of
a Notch-3 cleavage product, which includes an extracellular domain where
all EGF domains are present at the cytoplasmatic membranes of vascular
smooth muscle cells [51]. Surprisingly, the osmiophilic granules do not contain Notch-3 cleavage products. Thus, it is apparent that the smooth muscle
cells in the vessels are affected by the mutations in the Notch-3 gene; however, it remains to be elucidated how this leads to vascular thrombosis.
Therapy of patients with CADASIL is also controversial. Several authors
have suggested antiplatelet agents based on the clinical experience with other
types of strokes; however, there is no evidence based on controlled clinical
trials to support this treatment. Increased incidence of microbleeds has been
demonstrated in patients with CADASIL and it is plausible that antiplatelet
agents or anticoagulation may increase the risk for bleeding [59]. Migraines
are also common in CADASIL and triptans should be avoided because of
possible vasoconstriction and increased risk of migrainous strokes.
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