Histopathology - Neurodegeneration Flashcards
Dementia
Memory impairment and
aphasia or
agnosia or
apraxia or
disturbance in executive functioning
Pathological protein of the following diseases causing dementia
AD LBD Corticobasal degeneration FTD linked to Chr 17 Pick's disease MSA (multiple system atrophy) PSP (progressive supranuclear palsy)
AD
tau, b amyloid
LBD
a synuclein
ubiquitin
Corticobasal degeneration
tau
FTD linked to Chr 17
tau
Pick’s disease
tau
Multiple system atrophy
Lewy bodies/ a synuclein
targets glial cells
PSP (progressive supranuclear palsy)
tau
Prion disease histology
Spongiform change
Prion protein deposits
(in prion disease there is no RNA or DNA involved)
AD mx
anticholinesterases
glutamate antagonists
nAChR agonists
Neuropathology of AD
Senile plaques of ab amyloid
Neurofibrillary tangles of tau protein
cerebral amyloid angiopathy
neuronal loss
Amyloidogenic vs non amyloidogenic processing of APP
Non amyloidogenic – ab sequence in APP is directly cleaved in 2 by a secretase
Amyloidogenic - amino terminus of Ab is cleaved - therefore Ab is intact
Normal physiology of APP cleavage
- APP cleaved by α-secretase
- sAPPα released and the C83 fragment remains
- C83 is then digested by γ-secretase
- Products are then removed
APP cleavage leading to Ab
- APP cleaved by β-secretase
- sAPPβ released and the C99 fragment remains
- C99 is digested by γ-secretase releasing β-amyloid (Aβ) protein
- Αβ protein forms the toxic aggregates
When does Tau start causing probelms?
When it becomes hyperphosphorylated –> accumulates inside the cell and can cause cell death
Tau progression Braak staging
Stages 1- 6
When do we start seeing sx
o Tau progression (Braak staging) / symptoms [S] appear at stage 3 or 4:
Stage I = trans-entorhinal region (temporal lobe)
Stage II = entorhinal region (interfaces neocortex and hippocampus) (temporal lobe)
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, visual association areas)
Stage VI = striatal cortex (occipital lobe, in the primary visual cortex)
PD histology
Loss of DA neurones in SN
Lewy bodies in affected neurones
Lewy bodies = intracellular accumulations of a synuclein
PD = proteinopathy developed from abhorrent metabolism of a synuclein = mutations in a synuclein gene
Diagnostic gold standard of PD
Immunostaining for alpha synuclein
Amyloid plaques
Neurofibrillary tangles
Lewy bodies
https://th.bing.com/th/id/R.1e759e1c3f0d67ba6637454ccbf961f4?rik=oeoN592Q4OLQLw&pid=ImgRaw&r=0
Lewy bodies
https://th.bing.com/th/id/OIP.hoJeUVXGGwc2eSPcOHobZAHaFC?pid=ImgDet&rs=1
Braak staging in PD
Based on the distribution of a synuclein pathology throughout the brain
Bottom-up spread
brainstem –> medulla –> pons –> midbrain –> basal forebrain –> cortices
Braak 1+2 - autonomic + olfactory disturbances*
Braak 3+4 - sleep and motor disturbances**
Braak 5+6 - emotional and cognitive disturbances
**Sleep disorders are considered to be a prodrome of PD
*anosmia is a common sign of PD TRAP Tremor Rigidity Amnesia Postural instability
pathology also seen in peripheral ganglia, nose, gut
Parkinson plus syndromes buzzwords
- Lewy Body dementia
- Progressive supranuclear palsy
- Corticobasal syndrome
- Multiple system atrophy
- Vascular parkinsonism
• Lewy Body dementia – fluctuating cognition, visual hallucinations and early dementia
• Progressive supranuclear palsy tauopathy limited vertical gaze (downgaze more specific) early falls axial rigidity and akinesia dysarthia dysphagia
• Corticobasal syndrome tauopathy unilateral parkinsonism dystonia/myoclonus apraxia ± “alien limbs” phenomenon progressive non-fluent aphasia
• Multiple system atrophy
synucleinopathy (Lewy bodies/ a synulein)
Cerebellar predominant or parkinsonism predominant
early autonomic dysfunction (previously Shy-Drager syndrome)
patients tend to present with falls
• Vascular parkinsonism
multi-infarct presentation
gait instability and lower body parkinsonism
less likely associated with tremor
