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Histopathology > Neurodegeneration > Flashcards

Neurodegeneration Flashcards

1
Q

Define Prion diseases. How is it acquired?

A

A series of diseases with common molecular pathology

Transmissible factor

No DNA or RNA involved

Prion (pr*_oteinaceous _*i*_nfectious _*only)

Also called spongiform encephalopathy

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2
Q

What are the types of Prion diseases?

A

Humans

  • Creutzfeldt-Jakob disease - most common
  • Gerstmann-Straüssler-Sheinker syndrome
  • Kuru
  • Fatal familial insomnia
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3
Q
A

H&E stain

Spongiform change

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4
Q
A

Prion protein deposits

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5
Q

Describe the development of the prion protein.

A
  • The normal PrPSc protein can unfold and refold into a beta-pleated sheet form which is much more susceptible to aggregation
  • Once a little bit of this forms, it can propagate
  • This leads to a lot of insoluble protein accumulating in the parenchyma of the brain
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6
Q

What is the new Variant CJD (vCJD)? Who gets affected? What is it associated with?

A

Bovine spongiform encephalopathy - BSE

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7
Q

What is the neuropathology of AD?

A
  • Extracellular/senile plaques- amyloid beta
    • Neurofibrillary tangles (tau)
      • Disrupts cytoskeleton of neurones
    • Cerebral amyloid angiopathy (CAA)
      • Deposits of proteins in the blood vessel walls
      • Impairs vascular function
    • Neuronal loss (cerebral atrophy)
      • Shrinkage of brain
      • Hippocampus (inf. horn of lat. ventricles often affected) → loss of short-term memory
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8
Q
A

Right: large ventricles and cerebral atrophy - AD

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9
Q
A

Senile plaques in the brain

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10
Q
A

Cerebral amyloid angiopathy

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11
Q

What is the APP structure?

A
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12
Q

What is APP processing? Which pathway is more common?

A

Non-amyloidogenic pathway

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13
Q

What do amyloid plaques do?

A
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14
Q
A

Tau immunostaining - deposition

  • This is a microtubule-associated protein (used for maintaining stability of the cytoskeleton)
  • When it becomes hyperphosphorylated it starts causing problems
    • Accumulates inside the cell and eventually it will cause cell death
    • Presence and spread of tau throughout the brain is quite stereotypical and matches up quite closely with the clinical symptoms seen in the patient  Braak staging (clinical symptoms, location and amount of Tau)
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15
Q

How do we stage Alzheimer’s disease

A
  • Tau progression (Braak staging) / symptoms [S] appear at stage 3 or 4:
    • Stage I = trans-entorhinal region
    • Stage II = entorhinal region (interfaces neocortex and hippocampus)
    • Stage III [S] = temporo-occipital gyrus (see the immunostaining by eye)
    • Stage IV [S] = temporal cortex
    • Stage V = peri-striatal cortex (cortex around the primary visual cortex)
    • Stage VI = striatal cortex (occipital lobe)
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16
Q
A

Mid brain - lost almost all pigment in substantia nigra

17
Q

What is the progression of Parkinson’s?

A
  • Characterised by the presence of Lewy bodies = cells with a-synuclein (LBD = Lewy Body Dementia)
  • Dopaminergic cells produce neuromelanin → colours the substantia nigra (SN)
  • Parkinson’s disease = death of dopaminergic cells of SN → coloration of SN lost
  • Cells from the SN project to the basal ganglia (caudate and putamen)
    • Basal ganglia are very important in the initiation of movement
    • S/S = bradykinesia, rigidity, pill-rolling tremor
18
Q
A

Smooth hyaline inclusions - Lewy body

19
Q

What is the diagnostic gold standard for Parkisons?

A
  • Lewy bodies are intracellular accumulations of a-synuclein
  • Parkinson’s disease = a proteinopathy developed from abhorrent metabolism of a-synuclein – mutations in a-synucleingene → PD
  • a-synuclein immunostaining = diagnostic gold standard
20
Q

Describe the staging of Parkisnons.

A
  • Braak PD stages:
    • Based on the distribution of a-synuclein pathology throughout the brain
    • Bottom-up spread (originate in the brainstem) → from the medulla, up the pons and the midbrain (so nigral pathology is only stage III) → moves into the basal forebrain and the cortices
21
Q

What is the significance of peripheral ganglia?

A
  • NOTE: pathology is also seen in peripheral ganglia, in the gut and in the nose (i.e. anosmia is an early sign of PD)
    • Sleep disorders are considered to be a prodrome for Parkinson’s disease

There may be an environmental factor

22
Q

What are the causes of Parkinsonism?

A
  • Idiopathic Parkinson’s disease•Drug-induced Parkinsonism
  • Multiple system atrophy - may present as a cerebellar or Parkinsonism type problem
  • Progressive supranuclear palsy
  • Corticobasal degeneration
  • Vascular pseudoparkinsonism
  • Alzheimer’s changes
  • Fronto-temporal neurodegenerative disorders
  • 20 other disorders
23
Q

What is the pathology of multiple system atrophy?

A
  • a-synucleinopathy → however, it targets glial cells
  • It tends to affect the cerebellum and the patients are more likely to present with falls
24
Q

What are the tau immunostaining diseases?

A
  • Progressive Supranuclear Palsy / PSP
  • Corticobasal Degeneration / CBD
  • Pick’s disease
25
Q
A

MSA

26
Q
A

Corticobasal degeneration

27
Q
A

Progressive supranuclear palsy

28
Q

What is Pick’s disease?

A

Fronto-temporal atrophy

Marked gliosis and neuronal loss

Balloon neurons

Tau positive Pick bodies

29
Q
A

Tau positive pick bodies in the hippocampus

30
Q

Describe the tau structure ?

A

Single gene on 17q21

16 exons

Alternative splicing gives rise to 6 isoformsv3R or 4R-tau (microtubule-binding domains)

Two further inserts with unknown functionvShortest form (3R/0N) foetal

31
Q

Describe the different isoforms of tau?

A
32
Q

What is the significance of the types of tau?

A
  • AD = all 6 types of Tau (4R and 3R)
    • When Alzheimer’s disease tau is put through a Western blot it will form 3 dense bands – if this is dephosphorylated, it shows that all 6 types of tau are involved (4R and 3R components)
  • CBD/PSP = 4R tauopathy
    • CBD and PSP → 2 dense bands → when dephosphorylated are made up of only the 4R bands
  • Pick’s disease = 3R-tauopathy
33
Q

Describe front-temporal lobar dementias. What are the genetic bases? What mutations is it associated with? What is it also associated with?

A
  • There are many forms of fronto-temporal dementia with different genetic bases:
    • FTLD-tau (Pick’s disease, PSP, CBD)
    • Tau-negative FTLDs (i.e. FTLD-U (ubiquitinated) from mutations in progranulin)
  • Fronto-temporal dementia associated with progranulin mutations → tendency for the atrophy to be unilateral
  • Problems with TDP-43 (trafficking protein) thought to be the basis for some types of FTLD (associated with MND)
    • TDP-43 = TAR DNA Binding Protein 43
  • Other associations:
    • FUS pathology
    • C9ORF72 mutations

Histopathology (14 decks)

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