Neurodegenerative diseases - Columbia University127 patients / 100 000 population aged 80 y &...
Transcript of Neurodegenerative diseases - Columbia University127 patients / 100 000 population aged 80 y &...
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NeurodegenerativeNeurodegenerative diseasesdiseases
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Alzheimer disease
Dementing disorders Frontotemporal dementiaPick disease
Chromosome 17-linked dementias
Movement disorders Parkinson disease (PD)(30% develop dementia)
Dementia with Lewy bodies
Movement disorders &dementia
bodiesDiffuse Lewy body disease (DLBD)
Alzheimer disease Lewy body variant
Huntington disease (HD)(ADLBV)
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Usual aging vs. morbidity
Neuronal lossmorbidity
D
A is
Neurofibrillary changesNeuritic
gi
seachangesNeuritic
plaquesng
as
Hirano body
g esHirano body
Granulovacuolar degenerations
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Usual aging v.s Alzheimer disease (AD)NeuropathologyNeuropathology
89 year-old, AD74 year-old, Control
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Hirano body10 - 30 µmadjacent or
withincytoplasm pyramidalneurons of
hippocampus
Granulovacuolar degeneration
hippocampus
g
Vacuole: 3 - 5 µm Found in µGranule: 1 - 2 µmCytoplasmicespecially seen in
70 percentof brains ofneurologically
pyramidal neuronsof hippocampus
normalindividuals
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Neuritic (senile) plaques (Bielschowsky - 640 X)(Bielschowsky - 640 X)
Neuritic plaque180 µm diameter
replaces about 100 neurons& 106 synapses
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Amyloid
Congo red stain
β− pleated sheet conformation, insoluble
Congo red stain
Under polarized light
Salmon pink Apple greenbirefringent
Fluorescent with Thioflavine stain
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Neurofibrillary tangles of Alzheimer
Alzheimer A. Über eigenartige Krankheitsfälle des späteren Alters. Zeitschrift für die gesamte Neurologie und Psychiatrie (Berlin) g g y ( )
1911;4:356-85. (“Fortgeschrittene Erkrankung”)
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Usual aging vs. morbiditymorbidity
Neuronal loss DNeuronal lossLewy A i
sNeurofibrillary changesNeuritic
bodygi
seachangesNeuritic
plaques Pick bodyng
as
Granulovacuolar degenerationHirano body
g esGranulovacuolar degenerationbody s
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Alzheimer disease (AD)
- Irreversible neurodegenerative diseaseIrreversible neurodegenerative disease- Causes memory loss - Decreases ability to thinkDecreases ability to think- Insidious onset- Continuous slow decline in cognitionContinuous, slow decline in cognition- Currently, no cure- Definite diagnosis: NeuropathologicDefinite diagnosis: Neuropathologic examination
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Alzheimer disease in the USAlzheimer disease in the USMost common cause of dementia
90 percent are sporadic; 10 percent are familial
Prevalence rate over the age of 60 years (y)1900-5500 patients per 100,000 population
> 50 percent of n rsing home residents> 50 percent of nursing home residents
Annual incidence rateincreases exponentially with advancing age
2.4 patients / 100,000 population aged between 40 & 60 y127 patients / 100 000 population aged 80 y & over127 patients / 100,000 population aged 80 y & over
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Alzheimer disease (AD) in the USIn 2000, there were
4.5 million persons with AD (*)
By 2050 -> 13.2 million AD patients (*)
Estimated cost of AD$100 billion / year (1993)
4th or 5th leading cause of death
n AD patients will continue to increase unless discoveriescontribute prevention of the disease (*)
(*) Archives of Neurology, 2003. 60:1119-1122Neurology, 2005(Suppl 3). 65:S31-S32)
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Control Alzheimer disease (AD)
Single photon emission computerized tomography (SPECT)In AD: Parietal hypoperfusionyp p
From: The Neuropathology of Dementia, M. Esiri & J. MorrisCambridge University Press. 1997
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Alzheimer disease (AD) : NeuropathologyCerebral atrophy
Atrophy = Widening of sulci + Narrowing of gyri
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Permanent loss of predominantly glutamatergic,pyramidal neurons of neocortexpyramidal neurons of neocortex
Basal nucleus of Meynert (cholinergic system)
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CA1CA1
CA4CA4
St. gr.
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Neurofibrillary tangles
A: Early stageB: Intermediate stagestageC: End stage (ghost)A HE B & C Sil
AA: HE, B & C: Silver
B C
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Neurofibrillary tangles: ultrastructure
Paired helical filaments8 12 h li ll d8 - 12 nm, helically wound
InsolubleReact with silver stains
Hyperphosphorylated Tau? Ab l ki? Abnormal kinase or phosphatase activities
Tau: normal neuronalproteins, bind to microtubules
regulate their assembly
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Neuritic (senile) plaques (Bielschowsky)
640 X
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Precuneus
Cuneus
Calcarine
β−amyloid
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β-amyloid
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Substantia nigra pars reticulata (SNr), ( ),
& compacta (SNc)
CoeruleusCoeruleusNorepinephrine
Paradoxical sleepCortical activation
D l XDorsal n. X
LHE
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Pick disease
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Pick body
Cytoplasmic, round, argyrophilic, tau positive, ubiquitin positive,tau positive, ubiquitin positive,
10 - 15 µm acrossα−synuclein negativey g
Pick bodies usually involveneocortical p ramidal ne ronsneocortical, pyramidal neuronshippocampal, pyramidal neuronsstratum granulosum of dentate gyrusstratum granulosum of dentate gyrusamygdalastriatumstriatumbrainstem
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Pick body
Bielschowsky Tau
3633/5
3633/18Tau positive
Ubiquitin positiveq pα-synuclein negative
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Ballooned neurons
Pick disease
Ballooned neurons
Primary progressive aphasia
2424
Corticobasal degeneration
Chromosome 17-linked dementia
Corticobasal degeneration
Alzheimer diseaseAlzheimer diseaseProgressive supranuclear palsy
Creutzfeldt-Jakob disease
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Parkinson disease
And
Dementia with Lewy bodiesDementia with Lewy bodies
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Alzheimer disease
Dementing disorders Frontotemporal dementiaPick disease
Chromosome 17-linked dementias
Movement disorders Parkinson disease (PD)(30% develop dementia)
Dementia with Lewy bodies
Movement disorders &dementia
bodiesDiffuse Lewy body disease (DLBD)
Alzheimer disease Lewy body variant
Huntington disease (HD)(ADLBV)
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Parkinson disease
1919: Trétiakoff, C.
50,000 Americans / year -> diagnosed with PD
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Parkinson disease (PD)
BradykinesiaRigidityRigidity
Resting tremorPostural instabilityy
Neuronal lossCytoplasmic inclusion: Lewy body
Pars compacta of substantia nigrap gNucleus coeruleus
Substantia innominataHypothalamus
Dorsal nucleus of vagus
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Braak HK, et al. (2003). Staging of brain pathology related toSporadic Parkinson’s disease. Neurobiology of Aging 24:197-211
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Neuronal lossCytoplasmic inclusion: LewyCytoplasmic inclusion: Lewy
bodyDorsal nucleus of vagusNucleus coeruleus ParkinsonNucleus coeruleus
Pars compacta of substantia nigraHypothalamus
Substantia innominata > Mesolimbic
disease
Substantia innominata -> Mesolimbic cortex
If, in addition, neurons with Lewy body in
cerebral neocortex (-> dementia)
Diffuse Lewybody disease
cerebral neocortex ( dementia)
If, in addition, neuritic plaques or neurofibrillary tangles
AlzheimerDisease
L b dneuritic plaques or neurofibrillary tangles or both in cerebral cortex
(as seen in Alzheimer disease)
Lewy bodyvariant
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Lewy body
Cytoplasmic inclusion, round, 8 - 30 µm
Brainstem type, discreteyp ,Cortical type, ill-defined
Found in% f5% of asymptomatic, elderly subjects
100% of patients with Parkinson disease or with Lewy body dementia
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Parkinson diseaseParkinson disease
ControlControl
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2120
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Head caudate
Putamen
nucleus
Compacta
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MPTPMPTP
MAO BPh NCH3 Ph NCH
MPTP MPP+
1-Methyl-4-Phenyl-1 2 1 Methyl 41-Methyl-4-Phenyl-1, 2, 3, 6-
Tetrahydropyridine
1-Methyl-4-Phenylpyridinium
ionion
Not toxic Toxic
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VIDEOVIDEO
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Dementia with Lewy body (LB)Diffuse LB disease
Lewy bodies & Lewy neuritesNeocortex, hypothalamus, substantia innominata, , yp , ,
substantia nigra (compacta), coeruleus, dorsal nucleus of vagus
Nucleus coeruleusSubstantia nigra
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Huntington disease
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Huntington disease
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CAGCAG repeats
??
M t
Normal allele Abnormal allele
Huntington diseaseMay or may not
develop the disease
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Control, 34 y.o.
Huntington disease, 48 y.o.
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Huntington diseaseBetween early and late stagesBetween early and late stages
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Ordered and topographic distribution
Coronal plane
Sagittal planeSagittal plane
Dorso-ventral direction Caudo-rostral direction
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Huntington diseaseLate stageLate stage
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VIDEO
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End-stage (Grade 4/4)
VIDEO
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Control
Dorsal-medial
HD
Ventral
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Excitotoxicityy
ReceptorsNMDA AMPA
Kainate Metabotropic
Normal
HD+HDIT15
HD
PolyQ
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Nuclear inclusions
Mouse R6/2 145 CAG
14 y.o. w 82/12 CAG145 CAG 82/12 CAG
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Huntington diseaseHuntington diseaseLate onset
Relatively early stageRelatively early stageSlow progression
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