Neurodegenerative disease
April 2008
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Pt. 4
Major categories of neurologic disease
527
30
31
32
33
34
35
36
37
38
39
40
41
42
43
Disturbances of cerebrospinal fluid and its circulation
529
Intracranial neoplasms and paraneoplastic disorders
546
Infections of the nervous system (bacterial, fungal, spirochetal, parasitic) and sarcoidosis
Viral infections of the nervous system, chronic meningitis, and prion diseases
631
Cerebrovascular diseases
660
Craniocerebral trauma
747
Multiple sclerosis and allied demyelinative diseases
771
The inherited metabolic diseases of the nervous system
797
Developmental diseases of the nervous system 850
Degenerative diseases of the nervous system
895
The acquired metabolic disorders of the nervous system
959
Diseases of the nervous system due to nutritional deficiency-983
Alcohol and alcoholism
1004
Disorders of the nervous system due to drugs, toxins, and other chemical agents-1016
592
Characteristics of
neurodegenerative disease
• Insidious in onset
• Progressive course
• Selective death/dysfunction of neurons
Characteristics of
neurodegenerative disease
•
•
•
•
Insidious in onset
Progressive course
Selective death/dysfunction of neurons
Etiology unclear
Examples of neurodegenerative
disease:
•
•
•
•
Alzheimer’s disease
Parkinson’s disease
Frontotemporal dementia
Amyotrophic lateral sclerosis (Lou Gehrig’s
disease)
• Spinocerebellar ataxia
• Huntington’s disease
Neurodegenerative disease is
common
Neurodegenerative disease
prevalence:
• Alzheimer’s disease:
– 1-2% age 65-75; 50% over age 85
• Parkinson’s disease
– 13/100,00; 0.5-1% age 60-69; 1-3% over age 80
• Frontotemporal dementia
– 1 per 10,000?
• ALS
– 1-2 per 100,000 per year
• Spinocerebellar ataxias
– 0.3-3 per 100,000
• Huntington’s disease
– 1 in 10,000
Organization of presentation:
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Clinical presentation and diagnosis
Pathology
Genetic risk factors
Environmental risk factors
Pathogenesis (stories we tell)
Treatments available (ie, the need for better
treatments)
Alzheimer’s presentation
• Starts with memory loss--repetitive stories,
repetitive questions, forgotten events,
progressing to the point that ADLs are
affected.
• By the time of diagnosis, a second
“cognitive domain” is affected (language,
spatial function, executive dysfunction)
Alzheimer’s course:
• Progressive loss of cognitive abilities and ADLs,
leading ultimately to a vegetative state, and finally
death (infection, malnutrition, MI, CVA)
• Average time from dx to death = 8-10 years
• Rate of progression is variable
• Behavior changes (psychosis, depression, apathy,
agitation) are especially variable
• “If you’ve met one patient with
Alzheimer’s……you’ve met one patient with
Alzheimer’s”
Alzheimer’s pathology
•
•
•
•
Amyloid plaques
Neurofibrillary tangles
Neuronal death and brain atrophy
Cholinergic projection system withers
Senile plaques
• Extracellular deposits
• Plaques described as “diffuse”, “neuritic”, or
“cored”
• These may represent different ages of plaque
• Neuritic plaques are one of the pathologic criteria
for diagnosis of Alzheimer’s disease
• Composed chiefly of beta amyloid
Beta amyloid
• Beta amyloid is a 39-43 amino acid peptide
• Derived from 700 amino acid amyloid
precursor protein (APP)
• APP may be processed to “amyloidogenic”
or “non-amyloidogenic” pathways
-Amyloid Plaques
SIGMA-ALDRICH
Neurofibrillary tangles
• Intracellular inclusion
• Chief component is hyper-phosphorylated
tau
• Tau is a normal intracellular protein which
stabilizes microtubules
Alzheimer’s pathology
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•
•
•
Amyloid plaques
Neurofibrillary tangles
Neuronal death and brain atrophy
Cholinergic projection system withers
Alzheimer’s disease: genetic risk
factors (autosomal dominant)
• Amyloid precursor protein
• Presenilin-1
• Presenilin-2
Alzheimer’s disease: genetic risk
factors (sporadic)
• Apolipoprotein E
– Alleles: E2, E3, E4
– E4 is present in 15% of population
– E4 is present in 45-50% of Alzheimer’s
Alzheimer’s disease:
environmental risk factors
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•
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Low educational attainment
Head injury
Depression
Vascular risk factors (HTN, DM,
hypercholesterolemia)
Alzheimer’s disease: stories re
pathogenesis
• Braak staging (“tau hypothesis”?)
• Amyloid hypothesis
• Cholinergic hypothesis
Braak staging
• Based on the
predictable spread of
tangle pathology
– First entorhinal cortex
– Then entorhinal cortex
+ hippocampus
– Then entorhinal cortex
+ hippocampus +
association cortex
Braak staging of AD
Braak 1-2 Braak 3-4
Tangle
histology
Braak 5-6
Atrophy
on MRI*
Entorhinal Entorhinal + Entorhinal +
cortex
hippocampus hippocampus
+ cortex
Same as
Same as
Same as
above
above
above
Clinical
status
Healthy
aging
Isolated
AD-type
memory loss dementia
(“MCI”)
*(Kaye et al 1997, Silbert et al 2003)
Amyloid hypothesis of AD
• Holds that neurotoxicity of beta amyloid
drives the neurodegenerative process
• But:
– beta amyloid is produced under physiologic
conditions--how could it be toxic?
Merlini and Bellotti, NEJM 349:583-596, 2003
Merlini and Bellotti, NEJM 349:583-596, 2003
Evaluating the amyloid
hypothesis-pros and cons
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•
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•
Clinicopathologic correlation
Genetics of AD
Cell culture studies
Animal studies
Pathologic correlates of dementia
severity (Terry, 1991)
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•
•
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Amyloid plaques:
Neurofibrillary tangles:
Neuronal loss:
Synaptic density:
poor
better
same as tangles
best
• So…..clin-path studies do not support the
amyloid hypothesis
Evaluating the amyloid
hypothesis-pros and cons
• Genetics of AD------------------pro
– Autosomal dominant AD associated with
mutations in amyloid precursor protein (APP)
– Trisomy 21 also associated with overexpression of APP and AD
– “presenilin” initially identified in autosomal
dominant AD, since shown to be a component
of gamma secretase-- enzyme which processes
APP to beta amyloid
Evaluating the amyloid
hypothesis-pros and cons
•
•
•
•
Clinicopathologic correlation--con
Genetics of AD------------------pro
Cell culture studies--------------pro
Animal studies-------------------+/-
Cholinergic hypothesis of AD
• Based in part on clin-path observation of
correlation between cholinergic markers and
dementia severity
Other putative mechanisms:
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Inflammation
Oxidative damage
Ubiquitin-proteasome dysfunction
Mitochondrial dysfunction
Metal dyshomeostasis (copper, iron)
Excitotoxicity
Axonal transport dysfunction
Treatments available for AD
• Clinical trials of multiple cholinergic agents have
shown enough efficacy to be FDA-approved, but
none is dramatically effective
• Anti-amyloid therapies are in Phase 3 trials
• Anti-tau therapies are in earlier trials
• Gene therapy with NGF is also under way
targeting the cholinergic system
Parkinson’s disease-clinical
• Cardinal signs:
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–
–
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Tremor
Rigidity
bradykinesia
Gait impairment
Parkinson’s-clinical
• Traditionally considered purely a disorder
of movement
• Now appreciated to include autonomic
nervous system dysfunction (before motor
impairment) and cognitive dysfunction
(after motor impairment)
Parkinson’s disease pathology
Parkinson’s pathology:
Lewy bodies
• Intraneuronal inclusions comprised of alpha
synuclein and other proteins
• Initially thought to be confined to substantia nigra
and other projection systems that deteriorate in PD
• Subsequently identified throughout the nervous
system, from brainstem to cortex
• Incidental Lewy bodies seen in as many as 7-10%
of asymptomatic individuals over age 60
Parkinson’s genetic risk factors
• “familial cases are on record, but the
evidence is rather unsubstantial…” Adams
and Victor 1985
• “Though there is no evidence to indicate a
hereditary factor, a familial evidence is
claimed by some.” Merritt’s Textbook of
Neurology, 1984
Parkinson’s genetic risk factors
But..despite the number of genes implicated in rare sub-types of PD,
Most cases of “garden-variety” PD are not explained by genes (as in AD)
Parkinson’s:
environmental risk factors
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Age
Male gender
Rural living
Smoking is protective
Parkinson’s pathogenesis: Braak
staging suggests a progressive
“synuclein-opathy”:
• Lewy bodies spread caudal-->rostral
• Stage 1-2: Lewy bodies in medulla and olfactory bulb (asymptomatic)
• Stage 3-4: Lewy bodies in substantia nigra, locus coeruleus,
cholinergic basal forebrain (parkinson’s symptoms appear when >80%
of nigral neurons gone))
• Stage 5-6: Lewy bodies in forebrain (dementia)
Parkinson’s pathogenesis:
other models:
• MPTP model
– Gives rise to selective neuronal death and
parkinsonism, but no Lewy bodies
• Rotenone model (Greenamyre)
– Chronic intravenous infusion of mitochondrial
complex I inhibitor in rats
– Produces selective neuronal death,
parkinsonism, and Lewy bodies
Parkinson’s treatments:
• Dopaminergic therapy has dramatic
symptomatic effects
• Surgical therapies--both ablative and deep
brain stimulator therapies have symptomatic
effects
• Gene therapy with trophic factors is under
investigation
• No proven neuroprotectant therapy to date
Frontotemporal dementia-clinical
• Presents as personality change and
disinhibition, in the absence of significant
memory loss
• Also may present as a primary disorder of
language
• Progresses to a more generalized dementia
over time
Frontotemporal dementiapathology
• Clinical syndrome with a variety of
underlying pathologies (Pick’s disease,
“DLDH”, others)
• Many have neurofibrillary tangles
Frontotemporal dementiagenetics
• Most cases of FTD are sporadic
• A mutation in the tau protein is a cause of FTD in
a minority of cases (FTDP=17).
• Tau is a normal intracellular protein which
stabilizes microtubules.
FTD-treatment
• Nothing available
Amyotrophic lateral sclerosisclinical
• Also known as “motor neuron disease” or “Lou
Gehrig’s disease”
• Presents as slowly progressive weakness and
muscle wasting.
• Death within 2-5 years in most patients due to
respiratory failure
• Concomitant FTD in a sub-population of patients
(subclinical neuropsych changes may be more
common)
ALS-pathology
ALS-genetics
• About 10% of cases are familial
• About 2-3% are caused by mutations in
Cu/Zn SOD
ALS-treatment
• Riluzole, a glutamate antagonist, prolongs
survival by a few months
• Treatment trials with trophic factors have
failed
• No other symptomatic or neuroprotectant
therapy
• No SOD-directed therapy
Spinocerebellar ataxia-clinical
• Slowly progressive gait disorder, slurred
speech, and clumsiness
• Age of onset widely variable--from early
childhood to late life
• Patients look like they are intoxicated with
alcohol
Spinocerebellar ataxia-pathology
Spinocerebellar ataxia-genetics
(autosomal dominant)
How and why does a polyglutamine repeat in several different
proteins--give rise to a single phenotype? (there are other phenotypes
associated with other polyglutamine repeats)
Neurodegeneration-summary
signs
region
histology protein
AD
dementia HC, ctx
Plq, NFT AB, tau
PD
motor
Lewy b.
alphasyn
FTD
dementia ctx
NFT
tau
ALS
weakness Motor n. MN loss SOD
SCA
ataxia
HD
S. nigra
Cb, SC
Cerebel’r many
atrophy
Chorea, Caudate, inclusion Huntingdementia ctx
tin
Unanswered questions
• How does the identification of the deranged
protein in each disease explain the selective
vulnerability of neurons?
• Are the mutated proteins themselves
neurotoxic? Or what?
• What can we learn from transgenic mouse
models? (examples: APP, tau mutants)
Questions?