32 Neurodegenerative diseases Flashcards
List genetic determinants of AD
Genetic Determinants of Alzheimers Disease:
Dominant Mutations of:
- ? mutation = early onset // some cause hereditary vascular amyloidosis
- ? = 14q24.3 = 70% early onset FAD // Many have myoclonus // may have spastic paraparesis
- ? - 1q31-q42 = early or late onset
- Mutation of ? may prevent development of AD in Icelanders
Which mutations Lead to increase in Ratio of A-beta42 vs A-beta40? Whats the difference between these two compounds?
Genetic Determinants of Alzheimers Disease:
Dominant Mutations of:
- APP mutation = early onset // some cause hereditary vascular amyloidosis
- Presenilin1 (PSEN1) = 14q24.3 = 70% early onset FAD // Many have myoclonus // may have spastic paraparesis
- Presenilin2 (PSEN2) - 1q31-q42 = early or late onset
- Mutation of Beta-APP may prevent development of AD in Icelanders
Which mutations Lead to increase in Ratio of A-beta42 vs A-beta40? PSEN1/2
Whats the difference between these two compounds? 42 more likely to aggregate
Genetic determination of Alzehimers
Trisomy 21:
-Chromosome 21 is the site of ? gene
-duplication of ? described in some kindreds of early onset AD
some have severe ?
– greater ? than in sporadic AD
– if have ? have even greater amyloid deposition
– earliest change is ? in neurons & astrocytes
* then ? plaques
* then ? plaques
* then ?
Trisomy 21:
-Chromosome 21 is the site of APP gene
-duplication of APP gene described in some kindreds of early onset AD
some have severe CAA
– greater amyloid deposition than in sporadic AD
– if have APOE ε4 have even greater amyloid deposition
– earliest change is Aβ in neurons & astrocytes
* then diffuse plaques
* then neuritic plaques
* then NFTs
Cerebral amyloid angiopathy (CAA) is a condition in which proteins called amyloid build up on the walls of the arteries in the brain
The APOE gene provides instructions for making a protein called apolipoprotein E. This protein combines with fats (lipids) in the body to form molecules called lipoproteins.
Neurofibrillary tangles (NFTs) are a characteristic neuropathological lesion of Alzheimer’s disease (AD)
Genetic Determination
? - chr 19q13.2
– Caucasian and Japanese carriers of ? have 10-30 x the risk of developing AD by 75 yo
– affects both ? and ? forms
– apoE may be involved in transport or processing
of ?
– APOE є 2 is ?
є 4 allele of apolipoprotein E - chr 19q13.2
– Caucasian and Japanese carriers of 2 є 4 alleles have 10-30 x the risk of developing AD by 75 yo
– affects both sporadic and familial forms
– apoE may be involved in transport or processing
of APP
– APOE є 2 is protective
Describe basic macro- and microscopic features of Alzheimers
Gross External:
- Atrophy of ?
- ?symmetry?
- Sparing of ?
- Sparing of ?
- Quite variable in extent
Describe basic macro- and microscopic features of Alzheimers
Gross External:
- Atrophy of fronto-temporo-parietal atrophy
- symmetrical
- Sparing of occipital cortex
- Sparing of primary motor & sensory cortices
- Quite variable in extent
Describe basic macro- and microscopic features of Alzheimers
Gross
on Section:
- Proportionate loss of volume of ?
- ? - especially temporal horn
- Atrophy of ? and ?
Pallor of ? and ?
3 usually well preserved
Gross
on Section:
- Proportionate loss of volume of centrum ovale
- ventriculomegaly - especially temporal horn
- Atrophy of hippoocampi and amygdalae
Pallor of loci cerulei and substantiae nigrae in 1/4-1/3
Basal ganglia, thalamus, and hypothalamus usually well preserved
Describe basic macro- and microscopic features of Alzheimers
Micro: Histopathology
- Neurofibrillary tangles (NFTs) - TAU
- Neuropil threads
- Senile plaques and amyloid deposits
- Cerebral amyloid angiopathy
- Hirano bodies
- Granulovacuolar degeneration
- Perisomatic granules
- Tangle associated neuritic clusters
- Synaptic dysfunction/loss
- Spongiform change
Describe laboratory methods used in diagnosis of Alzheimers
Biomarkers of Neurodegenerative disease:
Abeta deposition:
- Seen through ?
- Reduced ?
Generic Neurodegeneration:
- atrophy seen on ?
- Elevated ? - total and phosphorylated
- Hypometabolism on ?
Biomarkers of Neurodegenerative disease:
Abeta deposition:
- Seen through Amyloid PET scanning
- Reduced CSF A-beta-42
Generic Neurodegeneration:
- atrophy seen on MRI
- Elevated CSF Tau - total and phosphorylated
- Hypometabolism on FDG-PET
Describe the amyloid hypothesis
The amyloid cascade hypothesis postulates that the neurodegeneration in AD caused by abnormal accumulation of amyloid beta (Aβ) plaques in various areas of the brain.
What is Mild Cognitive Impairment?
Pre-clinical phase of neurodegenerative disease
- MCI is an intermediate stage between the expected cognitive decline of normal aging and the more serious decline of dementia
Neurotransmitters associated with Neurodegenerative disease:
Cholinergic:
- Located in ?
- Role: ?
Serotonergic:
- Location: ?
- Role: ?
Noradrenergic:
- Location: ?
Dopaminergic:
- Location: ?
Neurotransmitters associated with Neurodegenerative disease:
Cholinergic:
- Located in Basal Nucleus of Meynert
- Role: Memory formation/consolidation
Serotonergic:
- Location: Dorsal Raphe Nucleus
- Role: Memory impairment
Noradrenergic:
- Location: Locus Coeruleus
Dopaminergic:
- Location: Substantia Nigra and Ventral Tegmental Area
What are Neurofibrillary Tangles? How are they observed?
Shape dependent on neuron:
- Flame shaped in ?
- Globose in ? or ?
Ghost Tangles ~ extracellular
- Especially ? cortex
- Lack the ? sequence of Tau
Silver Stains:
- ?
- ?
- ?
- ?
IHC:
- ?, ?
- Shows ?
Neurofibrillary tangles (NFTs) are a characteristic neuropathological lesion of Alzheimer’s disease (AD) seen upon H&E
Shape dependent on neuron:
- Flame shaped in pyramidal cells
- Globose in Basal nucleus of Meynert or LC
Ghost Tangles ~ extracellular
- Especially entorhinal cortex
- Lack the C-terminal sequence of Tau
Silver Stains:
- Bielschowsky
- Gallyas
- Bodian
- Sevier-munger
IHC:
- Tau, ubiquitin
- Shows pretangles
NFT - EM
- seen as ?
- Atomic force microscopy = ?
Progression by EM:
- ? aggregates of PHFs and other filaments, some in relation to ?
- Then densely compacted masses of PHFs in ? and ?
NFT - EM
- seen as Paired helical filaments (PHFs)
- Atomic force microscopy = twisted ribbons
Progression by EM:
- Perinuclear aggregates of PHFs and other filaments, some in relation to nuclear pores
- Then densely compacted masses of PHFs in soma and apical dendrites
PHFs = paired helical filaments
Neurofibrillary tangles (NFTs) - TAU
NFT distribution
Affected neurons:
- Large ? neurons, primarily ?
Distribution
- Most severe: ? cortex, ?
NFT distribution
Affected neurons:
- Large pyramidal neurons, primarily glutamatergic
Distribution
- Most severe:
- enterohinal cortex (Layers II and IV),
- CA1 - Layers II, III, V
Neurofibrillary tangles (NFTs) - TAU
Neuropil threads:
- Small threadlike ? processes
- In laminae ? and ?
- Dendrites - ? labeling
- Contain ?
Accompany NFTs and Neurotic Sensory Processes
- Numbers proportional to ?
- Therefore correlate with ?
Hyperphosphorylated Tau also in ? ; may co-localize with ?
Neuropil threads:
- Small threadlike tortuous tau (+) processes
- In laminae II and III
- Dendrites - MAP-2 labeling
- Contain paired helical filaments
Accompany NFTs and Neurotic Sensory Processes
- Numbers proportional to NFT load
- Therefore correlate with with severity of dementia
Hyperphosphorylated Tau also in synaptic terminals ; may co-localize with Abeta
Progression of Tau lesions
- evidence to suggest that tau is propagated via ? connections
– disconnection prevents ?
– injections in mice lead to ? at
injection site and in areas connected to that site - basis of ? staging
- evidence to suggest that tau is propagated via anatomical connections
– disconnection prevents tau accumulation
– injections in mice lead to tau accumulation at
injection site and in areas connected to that site - basis of Braak & Braak NFT staging
Normal Amyloid Pathway
- ? – APP
-
? protein
– 3 common isoforms – ? – alternative splicing - ? predominant form in neurons
- located on chr. ?
- normal cleavage by ? leads to secreted N-terminal ? fragment sAPPα
– implicated in ?, ?, ?, ? - also ? fragment CFTα – this is then cleaved . . .
- receptor mediated transport across ?
- can also be degraded by a variety of enzymes
– ? and especially ?
- amyloid precursor protein – APP
-
transmembrane protein
– 3 common isoforms – 695, 791, 770aa – alternative splicing - first (695) predominant form in neurons
- located on chr. 21.q21
- normal cleavage by α-secretase leads to secreted N-terminal APP fragment sAPPα
– implicated in neuroprotection, synaptic plasticity, synaptogenesis, neurite outgrowth - also C-terminal fragment CFTα – this is then cleaved . . .
- receptor mediated transport across BBB
- can also be degraded by a variety of enzymes
– insulin degrading enzyme and especially neprilysin
Amyloidogenesis
- Non-amyloidogenic pathway (?):
– Both ? and ? ? activity
– ? acts in the middle of the Abeta sequence thus precluding Abeta production - Amyloidogenic pathway (?):
– Sequential action of ? and ? secretase – ? and ? amino acid residues
- Non-amyloidogenic pathway (alpha-secretase):
– Both alpha and gamma secretase activity
– Alpha secretase acts in the middle of the Abeta sequence thus precluding Abeta production - Amyloidogenic pathway (beta-secretase):
– Sequential action of beta and gamma secretase – Abeta42 and 40 amino acid residues
Abnormal Amyloid Pathway - Amyloidogenic
- βsecretase
– an ?
– ? cleaving enzyme – hence: BACE
– highly expressed in neurons – only ?
– cleaves ? and yields ? & ? - γ secretase activity
– protein complex: presenilin, ?, APH-1 & PEN-2
– ? is the catalytic subunit
– cleaves ? to yield Aβ and the APP intracellular domain
– most Aβ are ? & ? - in AD more ? – this is the more amyloidogenic
- βsecretase
– an aspartyl protease
– β site APP cleaving enzyme – hence: BACE
– highly expressed in neurons – only BACE1
– cleaves APP and yields sAPPβ & CFTβ - γ secretase activity
– protein complex: presenilin, nicastrin, APH-1 & PEN-2
– presenilin is the catalytic subunit
– cleaves CFTβ to yield Aβ and the APP intracellular domain
– most Aβ are Aβ40 & Aβ42 - in AD more Aβ42 – this is the more amyloidogenic
Senile Plaques
- focal deposits = senile plaques – layers ? & ? (neuritic)
– dense ? deposits – some seen on ? - 20-50 microns
- core of ? plaque – primarily ?
- surrounded by ?
- then diffuse ? zone of ?
– some associated with neuritic ?
– some immunolabel but do not stain with Congo-red
* said to contain mainly ?
- focal deposits = senile plaques – layers II & III (neuritic)
– dense spherical deposits – some seen on H&E - 20-50 microns
- core of neuritic plaque – primarily Aβ42
- surrounded by clear halo
- then diffuse peripheral zone of immunoreactivity
– some associated with neuritic corona
– some immunolabel but do not stain with Congo-red
* said to contain mainly Aβ40
Senile Plaques
* focal deposits
- associated with:
* activated microglia: ? responsible for conversion of ? deposit into amyloid; more likely trying to ? Aβ
- astrocytes: deposits surrounded by ?, apparently appears late in evolution of plaque
- neurites
– in corona, contain ?, ?, ?, degenerating ?
– probably ? - ? origin-in transgenic mice cortico-cortical
– synaptic ? present - ? aberrant axonal connections
– Type1– ?,degenerating(Thal)
– Type 2 – ? - may be numerous ? (+) sprouting processes around the core
- many abnormalities of nearby ?
- focal deposits
- associated with:
- activated microglia: ? responsible for conversion of diffuse Aβ deposit into amyloid; more likely trying to phagocytose Aβ
- astrocytes: deposits surrounded by astrocytic processes, apparently appears late in evolution of plaque
- neurites
– in corona, contain PHF, lipofuscin, dense bodies, degenerating mitochondria
– probably axonal - ? origin-in transgenic mice cortico-cortical
– synaptic vesicle present - ? aberrant axonal connections
– Type1–tau(+),degenerating(Thal)
– Type 2 – AβPP (+) - may be numerous choline acetyltransferase (+) sprouting processes around the core
- many abnormalities of nearby dendrites
Diffuse Deposits:
– poorly immunoreactive, therefore amount depends on sensitivity of Ab ~ enriched in Aβ42
– 50-100’s of microns, blurry boundaries
– as subpial band in isocortex
- predominant form early stages
– lake-like - presubiculum
– fleecy – internal layers entorhinal cortex
– diffuse in striatum and molecular layer of cerebellum
– have been found in large numbers in intellectually normal
* perhaps explains retention of Pittsburgh compound B in their brains
– recent evidence suggests that these persons are more likely to progress to AD
– only some label with ApoE
– often w/ CAA
* amount of subpial deposit correlates with degree of CAA
Diffuse Deposits:
– poorly ?, therefore amount depends on sensitivity of Ab ~ enriched in ?
– 50-100’s of microns, blurry boundaries
– as subpial band in ?
- predominant form early stages
– lake-like - ?
– fleecy – internal layers ?
– diffuse in ? and molecular layer of ?
– have been found in large numbers in intellectually normal
* perhaps explains retention of ? in their brains
– recent evidence suggests that these persons are more likely to progress to ?
– only some label with ?
– often w/ ?
* amount of subpial deposit correlates with degree of ?
Other Plaques
- cotton wool
– round homogeneous on ?
– contain ?
– sparse ? components
– in familial AD due to del exon 9 of ? - inflammatory
– strong ?/? component – also in ? mutations
- cotton wool
– round homogeneous on H&E
– contain Aβ42
– sparse glial components
– in familial AD due to del exon 9 of PSEN1 - inflammatory
– strong astrocytic/microglial component – also in PSEN mutations
Diagnostic Criteria
AD neuropathologic change should be ranked along three parameters (?, ?, ?) to obtain an “ABC score”
AD neuropathologic change should be ranked along three parameters (Amyloid, Braak, CERAD) to obtain an “ABC score”
Diagnostic Criteria
AD neuropathologic change should be ranked along three parameters (Amyloid, Braak, CERAD) to obtain an “ABC score”
A. ? score:
A0: no ? or ? plaques
A1: Thal phase 1 or 2
- 1: exclusively in ?
- 2: additionally in ?
A2: Thal phase 3
- Extending to ?
A3: Thal phase 4 or 5
- 4: involving ?
- 5: Present in ?
A. Abeta plaque score:
A0: no Aβ or amyloid plaques
A1: Thal phase 1 or 2
- 1: exclusively in neocortex
- 2: additionally in allocortex
A2: Thal phase 3
- Extending to diencephalic nuclei // striatum // cholinergic nuclei of basal forebrain
A3: Thal phase 4 or 5
- 4: involving brainstem
- 5: Present in cerebellum
B. NFT stage (modified from Braak for silver-based histochemistry [20] or phospho-tau immunohistochemistry [19])
B0: no NFTs
B1: Braak stage I or II
B2: Braak stage III or IV B3: Braak stage Vor VI
C. Neuritic plaque score (modified from CERAD [21]) C0: no neuritic plaques
C1: CERAD score sparse
C2: CERAD score moderate
C3: CERAD score frequent
Diagnostic Criteria
AD neuropathologic change should be ranked along three parameters (Amyloid, Braak, CERAD) to obtain an “ABC score”
B. ? stage
B0: ?
B1: ?
B2: ?
B3: ?
B. NFT stage
B0: no NFTs
B1: Braak stage I or II
B2: Braak stage III or IV
B3: Braak stage Vor VI
A. Abeta plaque score:
A0: no Aβ or amyloid plaques
A1: Thal phase 1 or 2
A2: Thal phase 3
A3: Thal phase 4 or 5
C. Neuritic plaque score (modified from CERAD [21]) C0: no neuritic plaques
C1: CERAD score sparse
C2: CERAD score moderate
C3: CERAD score frequent
Diagnostic Criteria
AD neuropathologic change should be ranked along three parameters (Amyloid, Braak, CERAD) to obtain an “ABC score”
C. ? score
C0: no ?
C1: CERAD score ?
C2: CERAD score ?
C3: CERAD score ??
C. Neuritic plaque score
C0: no neuritic plaques
C1: CERAD score sparse
C2: CERAD score moderate
C3: CERAD score frequent
A. Abeta plaque score:
A0: no Aβ or amyloid plaques
A1: Thal phase 1 or 2
A2: Thal phase 3
A3: Thal phase 4 or 5
B. NFT stage
B0: no NFTs
B1: Braak stage I or II
B2: Braak stage III or IV
B3: Braak stage Vor VI
