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year 5 - pathology > HISTO: Neurodegeneration > Flashcards

HISTO: Neurodegeneration Flashcards

1
Q

What is the transmissible factor in prion disease? Can it be cleared?

A

There is a transmissible factor but there is no DNA or RNA involved. “Prion” = Proteinaceous Infections Only

The prion protein is transmitted and changes the host protein into the pathological form but cannot be metabolised and accumulates

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2
Q

List 3 examples of prion disease in humans.

A
  • Creutzfeldt-Jakob disease (CJD)
  • Gerstmann-Straussler-Sheinker syndrome
  • Kuru (“to shake” – endemic to Papua New Guinea)
  • Fatal familial insomnia
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3
Q

What is the histology in prion disease?

A

HEE stain - spongiform changes

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4
Q

What is the pathophysiology of prions?

A
  • Normally a n alpha helical format which is loosely folded but …
  • … the normal PrPSc protein can unfold and refold into a beta-pleated sheet
  • This beta pleated sheet is more susceptible to aggregation
  • In some people this can lead to PrPScseed
  • This can propagate and accummulate in the parenchyma of the brain
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5
Q

What is new variant vCJD linked to? What are the clinical features?

A

Linked to BSE (Mad Cow Disease)

  • Clinical features:
    • Patients <45yo
    • Cerebellar ataxia
    • Dementia
    • Longer duration than CJD
    • Diagnosed at autopsy
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6
Q

What is the neuropathologcal components of AD?

A
  1. Extracellular/senile plaques (amyloid-beta)
  2. Neurofibrillary tangles (Tau)
    • Disrupts cytoskeleton of neurones
  3. Cerebral amyloid angiopathy (CAA)
    • Deposits of proteins in the blood vessel walls
    • Impairs vascular function
  4. Neuronal loss (cerebral atrophy)
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7
Q

Where does neuronal loss commonly occur in AD? What is the clinical consequence?

A

Severe atrophy of the hippocampus (inf. horn of lat. ventricles often affected) –> loss of short-term memory

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8
Q

What is shown?

A

Senile plaques

Lump of protein –> halo –> more diffuse protein (we think that this is protein that has been extravasated from cells)

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9
Q

What is shown?

A

Cerebral amyloid angiopathy

  • Deposits of proteins in the blood vessel walls
  • Impairs vascular function
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10
Q

Where does the Abeta sequence sit in the APP?

A

Membrane

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11
Q

APP structure

A
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12
Q

How is A-beta formed?

A
  • Ab is formed by cleavage of APP at a transmembrane site
  • APP can be processed in TWO ways; one is amyloidogenic, the other is non-amyloidogenic:
    • Non-amyloidogenic - Absequence directly cleaved in two
    • Amyloidogenic - Amino terminus of Ab cleaved –> amyloidogenic –> too much Ab –> so Ab thrown out of cell and accumulates –> Ab forms monomers, to oligomers (dimers), to protofibrils and then fibrils (polymers)
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13
Q

Where is A-beta most toxic?

A

Intracellularly

Extracellularly its plaques probably do not cause direct problems

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14
Q

What is shown?

A

Tau

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15
Q

What is the function of Tau normally?

A

Tau protein is a soluble protein present in axons

Tau important for assembly and stability of microtubules

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16
Q

What is the pathophysiology of Tau?

A
  1. Hyperphosphorylated tau is insoluble –> self-aggregates
  2. The self-aggregates form neurofibrillary tangles (neurotoxic)
  3. The tangles result ultimately in microtubule instability and neurotoxic damage to neurones
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17
Q

What is the normal physiology of amyloid?

A
  1. APP cleaved by a-secretase
  2. sAPPa released and the C83 fragment remains
  3. C83 is then digested by g-secretase
  4. Products are then removed
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18
Q

What is the pathophysiology of amyloid/APP in AD?

A
  1. APP cleaved by b-secretase
  2. sAPPb released and the C99 fragment remains
  3. C99 is digested by g-secretase releasing b-amyloid (Ab) protein
  4. Ab protein forms the toxic aggregates
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19
Q

What are CNS macrophages called?

A

Microglial cells

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20
Q

What staging is used for measuring Tau progression?

A

Braak staging - symptoms [S] usually appear at stage 3/4

  1. Stage I = trans-entorhinal region
  2. Stage II = entorhinal region (interfaces neocortex and hippocampus)
  3. Stage III [S] = temporo-occipital gyrus (see the immunostaining by eye)
  4. Stage IV [S] = temporal cortex
  5. Stage V = peri-striatal cortex (cortex around the primary visual cortex)
  6. Stage VI = striatal cortex (occipital lobe)
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21
Q
A
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22
Q

How does Tau presence and spread correlate with symptoms?

A
  • Presence and spread of tau throughout the brain matches up closely with the clinical symptoms seen in the patient
  • Braak staging - uses clinical symptoms, location and amount of Tau
23
Q

Menti: Tau immunostaining in the peristriate but not the striate cortex is consistent with which Braak staging ?

A

V

24
Q

What is PD characterised by the presence of?

A
  • Characterised by the presence of Lewy bodies = cells with a-synuclein (LBD = Lewy Body Dementia)
25
Q

What are Lewy bodies?

A

Intracellular accumulations of alpha-synuclein

26
Q

What symptoms occur as a result of degeneration of cells projecting from the SN to the basal ganglia (caudate and putamen)?

A
  • Basal ganglia are very important in the initiation of movement
  • S/S = bradykinesia, rigidity, pill-rolling tremor
27
Q

What is the diagnosic gold standard in histology in PD?

A

a-synuclein immunostaining

28
Q

Which neurons die in PD? Why does the SN become discoloured?

A

Dopaminergic neurons are lost - usually produce neuromelanin

Their loss causes loss of colour of the substantia niagra

29
Q

What is the proteinopathy in PD?

A

Proteinopathy developed from abhorrent metabolism of a-synuclein – mutations in a-synuclein gene –> PD

30
Q

What is the Braak staging of PD based on?

A
  • Based on the distribution of** **a-synucleinpathology throughout the brain
31
Q

What is the sequence of Lewy body spread (and according to Braak staging of PD)? If niagral pathology is seen what is the stage?

A

Bottom-up spread (Lewy bodies originate in the brainstem) –> from the medulla, up the pons and the midbrain

Nigral pathology is only stage III –> moves into the basal forebrain and the cortices

32
Q

What % of neurons need to be lost for symptoms to occur?

A
  • About 60-70% of nigral neurones need to be lost
33
Q

In PD, apart from the brain, where else is neuropathology seen?

A

Peripheral ganglia of the:

  1. Gut
  2. Nose - anosmia is an early sign of PD

Sleep disorders are also an early sign of PD

34
Q

What % of PD aetiology is genetic?

A

<5%

Rest is thought to be environmental

35
Q

Summarise two environmental aetiology theories for PD.

A

If an environmental agent is implicated, there are two potential access points:

  1. Retrograde from the gut to the medulla via the vagus nerve
  2. Through the nose
36
Q

What are some differentials for PD?

(conditions where Parkinsonism is observed)

A
  • Idiopathic Parkinson’s disease
  • Drug-induced Parkinsonism
  • Progressive supranuclear palsy
  • Corticobasal degeneration
  • Vascular pseudoparkinsonism
  • Alzheimer’s changes
  • Fronto-temporal neurodegenerative disorders
37
Q

Excluding PD which other disorder, often presenting with parkinsonism is associated with alpha synuclein pathology?

A

MSA - multiple system atrophy

38
Q

In contrast to PD, what cells does multiple system atrophy affect?

A

It is also an alpha-synucleinopathy but targetting the gllial cells

39
Q

What symptoms does MSA ususally present with and why?

A

Falls as pathology affects the cerebellum

40
Q

List 3 Tau immunostaining diseases.

A
  1. Progressive supranuclear palsy - PSP
  2. Corticobasal degeneration - CBD
  3. Pick’s disease
41
Q

How does Pick’s disease present?

A

Tend to present with frontal lobe pathology (e.g. dysexecutive syndrome)

42
Q

What is the histology of Pick’s disease?

A
  • Fronto-temporal atrophy
  • Marked gliosis and neuronal loss
  • Balloon neurons
  • Tau-positive Pick bodies
43
Q

What is the inheritance pattern of Tau mutations? How many syndromed result from these? What are these called and why?

A
  1. Autosomal dominant
  2. 17 syndromes
  3. FTDP-17 - fronto-temporal dementia phenotypes 17 - called this as it presents with a fronto-temporal dementia phenotype which is more like that of PD than AD (Alzheimer’s)
44
Q

What types of mutations cause tau pathology as seen in FTDP-17?

A

Missense and splicing mutations

>20 pathogenic mutations have been identified

45
Q

There is a single gene for Tau on 17q21 with 16 exons which can be alternatively spliced. If they are alternatively spliced, how many isoforms of tau form?

A

6 isoforms

46
Q

Tau isoforms - significance of these is that they can be visualised on Western Blot

A

AD is seen in the first column at the bottom alongside differentials for AD

47
Q

What are the two forms of tau? What are the two forms which are the longest and shortest?

A

There are either 3R or 4R forms of tau - depending on the number of microtubule-binding domains that exist in the brain

There are then TWO further subsets with unknown functions:

  • The longest form is 4R/2N
  • The smallest form is 3R/0N
48
Q

What is the significance of the types of tau in the 3 tau immunostaining diseases and AD?

A

CBD/PSP = 4R tauopathy

  • 2 dense bands formed + when dephosphorylated are made up of only the 4R bands

Pick’s disease = 3R-tauopathy

  • 2 dense bands formed + when dephosphorylated are made up of only the 3R bands

AD = all 6 types of Tau (4R and 3R)

  • In AD tau on Western Blot will form 3 dense bands – if this is dephosphorylated, it shows that all 6 types of tau are involved (4R and 3R components)
49
Q

Menti: Which of the following proteins is not associated with forms of frontotemporal dementia?

  • APP
  • Tau
  • TDP
  • FUS
A

APP

50
Q

Are fronto-temporal lobar dementia ubiquinated (FTLD-U) tau positive or negative?

A

NEGATIVE

51
Q

What mutations is FTLD-U associated with?

A

Progranulin mutations - these cause tendency for atrophy to be unilateral

52
Q

Which protein may be defective in FTLD-U? What is its significance in other conditions?

A

TDP-43 (TAR DNA binding protein 43) - this is a trafficking protein

May be the basis for some types of FTLD and is also associated with MND

53
Q

What is Dementia Lacking Distinctive Histology (DLDH) aka?

A

AKA ubiquitin-negative FTLD

54
Q
A

year 5 - pathology (89 decks)

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