Neuropathology Of Neurodegeneration Flashcards by Jessica Tingle

What is a neurodegenerative disease?

Condition which primarily affects the neurones in the human brain and/or spinal cord resulting in a loss of their structure and/or function.

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What is dementia?

The development of multiple cognitive deficits that represent d a decline from previous level of functioning and is severe enough to impair occupational and/or social functioning

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What does disease of the parietal lobe lead to?

Visuospatial impairment
Impaired integration of sensory inputs
Agnosia
Apraxia
e.g. neglect, Gerstmann

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What does disease of the occipital lobe lead to?

Visual impairment
(e.g. posterior cortical atrophy)

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What does disease of the temporal lobe lead to?

Lateral: receptive dysphasia (Wernicke’s), automatisms

Medial: disorders of memory, hallucinations

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What does disease of the frontal lobe lead to?

Impairments in judgement, abstract reasoning, inhibition, planning

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What is the unifying pathology of neurodegenerative diseases?

Accumulation of filamentous proteins (amyloid)

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Which disorders show extra cellular protein aggregates?

Prion diseases - PrP
Alzheimer’s - amyloid beta

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Which disorders show cytoplasmic/neuritic protein aggregates?

Parkinson’s, DLB - alpha synuclein (neurons)
MSA - alpha synuclein (glia)

ALS, FTD (FUS, TDP-43)

AD, ALS, PSP, CBD, GGT, Pick’s - Tau

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Which disorders show intranuclear protein aggregates?

Huntington’s - Huntingtin
SCA - Ataxin
DRPLA - atrophin-1

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How many repeats might you see in a Ray doublet or triplet band?

3 or 4

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What is the age of onset of Alzheimer’s?

40-90

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What is the average time from Alzheimer’s onset to death?

9-12 years

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What are the genes associated with familial AD?

Chromosome 21 - APP
Chromosome 19 - APOE E4
Chromosome 14 - PSEN1
Chromosome 1 - PSEN2

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What would you see histologically in an Alzheimer’s brain

Extracellular neurotic plaques (AB)
Intracellular neurofibrillary tangles (tau)

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What is Braak staging associated with?

Tau pathology

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What are the Braak stages 1 and 2?

Transentorhinal - asymptomatic

1: small density of NFTs in transentorhinal cortex

2: moderate density in transentorhinal cortex and small density in hippocampus CA1

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What are the Braak stages 3 and 4?

Limbic - incipient AD

3: Moderate density throughout CA1, introduction to fusiform gyrus, amygdala

4: Severe involvement in same areas, introduction to cortex

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What are the Braak stages 5 and 6?

Isocortocal - symptomatic

5: tangles throughout the hippocampus, sorted through the isocortex but soaring sensory and motor cortices

6: increased density of tangles, involvement of thalamus, hypothalamus, substantia nigra

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What is the staging for amyloid beta?

Thal 1-5

What is amyloid angiopathy?

Amyloid beta forms in the blood vessel walls, weakening the vessels
Can cause infarcts or haemorrhages

Important co-pathology with AD
Occurs without AD also

What staining can you use for amyloid?

Congo red
Silver
Immunohistochemistry

What are some problems with the amyloid cascade hypothesis?

Disease symptoms correlate better with tau than AB pathology

Drug trials using anti AB treatments haven’t been so effective (aducanumab)

How is it hypothesised that tau proteins accumulate?

Like prion proteins - seeding and propagation model

Recent results using tau contradict this

What are the diagnostic criteria for Parkinsonism?

2 out of 3: Bradykinesia Rigidity Tremor

What are the hallmark features of idiopathic Parkinson’s disease?

Mask like face Forward tilt Reduced arm swing Shuffling gait Trembling

What are the pathological hallmarks of Parkinson’s?

Lewy bodies Absence of neuromelanjn in the substantia nigra

Where are Lewy bodies seen in LBD?

Substantia nigra and cortex

How do Lewy bodies in the cortex differ from those in the substantia nigra?

No halo Harder to detect on HNE stain Requires immunohistochemistry

What other conditions show Parkinsonism?

Progressive supranuclear palsy Corticobasal degeneration Multiple system atrophy Vascular dementia PDC Guam

What drugs can give Parkinsonian symptoms?

Dopamine antagonists (Antipsychotics)

What are the three types of vascular dementia?

Multi infarct dementia Diffuse white matter changes - Binswanger type Strategic infarct

What movement abnormalities are associated with vascular dementia?

Hemiparesis bellismus Parkinsonism

What are the pathological hallmarks of Huntington’s Disease?

Shrinkage of the caudate and putamen Ubiquitinated huntingtin inclusions (intranuclear)

What are the three main syndromes of FTD?

Behavioural variant Progressive non fluent aphasia Semantic variant

What are Pick inclusions composed of?

Tau

What would be seen macroscopically in the FTD brain?

Frontotemporal atrophy Widening of sulci Shrinkage of gyri

What is the most common type of FTD inclusion?

TFP-43

What is the prognosis for ALS/MND?

Less than a year

What are hallmarks of symptoms of ALS/MND?

Atrophy/weakness of muscles Upper motor neuron signs - hyperreflexia Bulbar palsy - problems with tongue and swallowing

What are the genes associated with familial ALS?

C9ORF72 (repeat expansion) TARDP SOD1 FUS

Where are most mutalstiond in TDP43?

Glycine rich region

What is the most common inclusion in ALS?

TFP-43

How did iatrogenic CJD come about?

Growth hormone from pituitary Dural and corneal transplants

How does CJD present?

Ataxia Myoclonus Motor neurone disorders

What is the protein only hypothesis of prion disease?

Prion protein undergoes a conformational change (from alpha helix to beta pleated sheet) which acts as a template for more protein conversion

What changes are seen histologically in prion disease?

Spongiform change in the brain Prion protein deposition

What is the histological hallmark of vCJD?

Florida plaque