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review histopath > Histo: Neurodegeneration > Flashcards

Histo: Neurodegeneration Flashcards

1
Q

What are prion diseases?

A

Proteinaceous infections only

They are transmissible diseases that have no DNA or RNA

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2
Q

List some examples of prion diseases.

A
  • Creutzfeldt-Jakob disease
  • Gerstmann-Straussler-Sheinker syndrome
  • Kuru
  • Fatal familial insomnia
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3
Q

Describe the histological appearance of brains affected by prion diseases.

A
  • Spongiform change - tissue is full of vacuoles
  • Prion protein deposits
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4
Q

Outline the pathophysiology of prion diseases.

A
  • The normal PrPc protein will unfold and refold into a beta-pleated sheet form (PrPsc) which is more susceptible to aggregation
  • Once a little bit forms (seed), it can propagate
  • The accumulation of insoluble protein in the parenchyma leads to cell death
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5
Q

What are the key features of new variant CJD?

A
  • Sporadic neuropsychiatric disorder
  • Rapidly progessive course
  • Mainly younger patients (<45 years)
  • Associated with BSE
  • Clinical features include cerebellar ataxia and dementia
  • Diagnosed at autopsy
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6
Q

List and describe the main neuropathological features of Alzheimer’s disease.

A
  • Extracellular plaques - extracellular accumulations of amyloid beta
  • Neurofibrilliary tangles - intra-neuronal pathology caused by disruption of the intracellular cytoskeleton
  • Cerebral amyloid angiopathy - deposits of protein in blood vessel walls which impairs normal vascular function
  • Cerebral atrophy - supporting feature
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7
Q

Which part of the brain is often affected by cortical atrophy in Alzheimer’s disease?

A

Inferior horn of the lateral ventricles where the hippocampus is found - this is responsible for loss of short-term memory

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8
Q

Describe how amyloid precursor protein (APP) processing leads to the formation of beta-amyloid plaques.

A
  • Non-amyloidogenic: involves cleavage of the amyloid-beta (A-beta) sequence
  • Amyloidogenic: cleavage occurs at the amino-terminus of A-beta and a second cleavage leads to the production of A-beta

NOTE: the toxicity of A-beta is likely to be intracellular (extracellular plaques are unlikely to cause many issues themselves)

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9
Q

What is tau protein and how does it cause pathology?

A
  • Microtubule-associated protein that is important for maintaining the stability of the cytoskeleton
  • When it becomes hyperphosphorylated it accumulates inside cells and causes cell death
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10
Q

Describe the Braak stages of tau pathology in Alzheimer’s disease.

A
  • Stage 1: tau pathology in the transentorhinal cortex
  • Stage 2: posterior hippocampus
  • Stage 3: immunostaining is visible by eye, affects substantia nigra
  • Stage 4: superior temporal gyrus
  • Stage 5: peristriate cortex
  • Stage 6: striate cortex

NOTE: clinically, symptoms tend to arise in stage 3 or 4

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11
Q

What type of disease is chronic traumatic encephalopathy?

A

Tauopathy

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12
Q

What is responsible for the dark colour of the substantia nigra?

A

Neuromelanin - this is a by-product of dopamine metabolism

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13
Q

On a cellular level, what causes Parkinson’s disease?

A
  • Death of dopaminergic cells of the substantia nigra
  • Cells from the substantia nigra usually project to the basal ganglia (which is important for the initiation of the movement)
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14
Q

Outline the main histological features of Parkinson’s disease.

A
  • Lewy bodies - intracellular accumulations of alpha-synuclein
  • Parkinson’s disease is caused by dysfunction metabolism of alpha-synuclein

NOTE: this was discovered because mutations in the alpha-synuclein gene are associated with rare familial forms of Parkinson’s disease

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15
Q

What is the diagnostic gold standard for Parkinson’s disease?

A

Alpha-synuclein immunostaining

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16
Q

Where is alpha-synuclein pathology in Parkinson’s disease thought to arise from?

A
  • Starts in the brainstem (medulla) and rises up the pons and midbrain
  • Nigral pathology is about stage III. It eventually moves to the basal forebrain and cortices
  • Alpha-synuclein pathology is also seen in peripheral ganglia, in the gut and in the nose
17
Q

What are some non-extrapyramidal symptoms of Parkinson’s disease?

A
  • Sleep disorders
  • Depression
  • Anosmia
18
Q

It is hypothesised that environmental agents may have a part to play in the onset of Parkinson’s disease. Describe two routes by which these agents can enter the brain from the environment.

A
  • Retrograde from the gut to the medulla via the vagus nerve
  • Through the nose
19
Q

What are 4 important differentials to consider in a patient with Parkinsonian symptoms (other than Parkinson’s)?

A
  • Drug-induced Parkinsonism
  • Multiple system atrophy (MSA)
  • Corticobasal degeneration (CBD)
  • Progressive supranuclear palsy (PSP)
20
Q

What is multiple system atrophy (MSA)?

A
  • Alpha-synucleinopathy like PD
  • Accumulates in glial cells rather than neurones
  • Presents similarly to PD
  • It mainly affects the cerebellum so the patients are more likely to present with falls
21
Q

What type of diseases are progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD)?

A

Tauopathies

22
Q

What is Pick’s disease?

A

Characterised by fronto-temporal atrophy which presents with frontal lobe pathology (e.g. dysexecutive syndrome)

23
Q

What are the main histological features of Pick’s disease?

A
  • Marked gliosis and neuronal loss
  • Balloon neurones
  • Tau-positive Pick bodies

NOTE: mutations in tau are associated with a fronto-temporal dementia phenotype often associated with Parkinson’s disease

NOTE: there are 17 autosomal dominant syndromes resulting from mutations in tau

24
Q

Which chromosome encodes tau protein?

A

Chromosome 17q21

25
Q

How many isoforms of tau are there and how are they classified?

A
  • There are 16 exons and alternative splicing can produce 6 isoforms that are either 3R or 4R tau depending on the number of microtubule-binding domains
26
Q

Describe how the types of tau present in Alzheimer’s disease is different from CBD, PSP and Pick’s diease.

A
  • Alzheimer’s - when the tau is put through a Western blot, it will form 3 dense bands. If this is dephosphorylated it will show all 6 isoforms of tau/.
  • CBD and PSP - produces 2 dense bands which, when dephosphorylated, are shown to be made up of only 4R tau (i.e. it is a 4R tauopathy)
  • Pick’s disease - it is a 3R tauopathy
27
Q

Mutations in which genes can cause fronto-temporal dementia?

A
  • Tau
  • Progranulin
28
Q

What is a characteristic feature of frontotemporal dementia associated with progranulin mutations?

A

Atrophy tends to be unilateral

29
Q

Which other protein is thought to be implicated in some types of fronto-temporal dementia?

A

TDP-43 (trafficking protein)

30
Q

What is dementia lacking distinctive histology (DLDH)?

A

Dementia symptoms with no obvious histological changes

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