Neuropathology Of Neurodegeneration Flashcards
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.
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
What does disease of the parietal lobe lead to?
Visuospatial impairment
Impaired integration of sensory inputs
Agnosia
Apraxia
e.g. neglect, Gerstmann
What does disease of the occipital lobe lead to?
Visual impairment
(e.g. posterior cortical atrophy)
What does disease of the temporal lobe lead to?
Lateral: receptive dysphasia (Wernicke’s), automatisms
Medial: disorders of memory, hallucinations
What does disease of the frontal lobe lead to?
Impairments in judgement, abstract reasoning, inhibition, planning
What is the unifying pathology of neurodegenerative diseases?
Accumulation of filamentous proteins (amyloid)
Which disorders show extra cellular protein aggregates?
Prion diseases - PrP
Alzheimer’s - amyloid beta
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
Which disorders show intranuclear protein aggregates?
Huntington’s - Huntingtin
SCA - Ataxin
DRPLA - atrophin-1
How many repeats might you see in a Ray doublet or triplet band?
3 or 4
What is the age of onset of Alzheimer’s?
40-90
What is the average time from Alzheimer’s onset to death?
9-12 years
What are the genes associated with familial AD?
Chromosome 21 - APP
Chromosome 19 - APOE E4
Chromosome 14 - PSEN1
Chromosome 1 - PSEN2
What would you see histologically in an Alzheimer’s brain
Extracellular neurotic plaques (AB)
Intracellular neurofibrillary tangles (tau)
What is Braak staging associated with?
Tau pathology
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
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
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
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
