6/3- Neuropathology of Dementia Flashcards
Key feature (anatomical) of dementia?
Cortical degeneration
Causes of cortical degeneration?
- Alzheimer’s dz
- Pick’s dz (frontotemporal dementia)
- Lewy body dementia
These are the 3 MCCs of neurodegenerative dementia (each have varied initial symptoms)
What does this show?
Cortical atrophy
(Left side shows caudate atrophy and hydrocephalus ex vacuo of Alzheimer’s dz?)
(Right side shows frontotemporal degeneration/Pick’s disease; selective in frontal and temporal regions)
2 categories of dz within Alzheimer’s?
Classical
Variant
2 categories of disease within Non-Alzheimer’s neurodegenerative diseases with dementia?
Tauopathies (PSP):
- FTD complex/Pick’s dz
Synucleinopathies (PD, LBD):
- Lewy Body Complex
What is seen microbiologically in Alzheimer’s dz?
- Beta-amyloid (extracellular) + Tau (intracellular)
What is seen microbiologically in Pick’s dz/FTLD?
- Tauopathy (pure)
seen microbiologically in Lewy Body Dementia (LBD)?
- Alpha synuclein
Where does atrophy start in Alzheimer’s?
Starts in amygdala, hippocampus, and temporal lobe
Neuronal changes in Alzheimer’s?
- Loss of cortical cholinergic innervation
(Central) cholinesterase inhibitors now in clinical use in mild-moderate cases
Characteristics of Alzheimer’s dz (symptoms)?
- MEMORY DISTURBANCES
- Starts with short-term memory
- Onset may be subtle
- Early onset cases are typically genetic
What anatomical features are seen grossly with Alzheimer’s?
Cortical atrophy and hydrocephalus ex vacuo
Histological features of Alzheimer’s dz?
- Neuritic plaques- EXTRAcellular
- Neurofibrillary trangles- INTRAcellular
- Amyloid deposition in mature neuritic plaques and in the walls of cortical and leptomeningeal blood vessels
- Many people believe that the plaques (beta-amyloid) are the initiating event and the tangles (hyperphosphorylated tau) are 2ndary
- AD therefore is a beta-amyloidopathy
What is this?
Plaques and tangle seen in Alzheimer’s dz
- Silver stain binding proteins rich in B-sheets and fibrillogenesis Seen center left is a plaque (extracellular)
- Black structures are axons adjacent to deposition of B-amyloid; stuff like tau begins to accumulate within the processes
- Most of the plaque is comprised of B-amyloid with neuroprocesses with accumulations of tau
Seen center right is a process with accumulation of tau (tangle?)
CERAD plaque estimation in Alzheimer’s dz (picture)
Few, moderate, or many
What is this?
Neurofibrillary tangles in Alzheimer’s dz (deposition of tau)
- When tau is deposited in this way, it becomes hyperphosphorylated
Plaque staging or counting has a ____ (good/poor) correlation with dementia. Tangle staging has a ___ (good/poor) correlation with dementia.
Plaque staging or counting has a poor correlation with dementia (HOW MANY PLAQUES)
Tangle staging has a good correlation with dementia (WHERE ARE THE TANGLES)
Progression of Alzheimer dz (main steps)?
- Pre-symptomatic
- Mild cognitive impairment (MCI)
- Alzheimer’s dz
Progression of Alzheimer’s: Pre-symptomatic?
The pt has no cognitive impairment.
There is growing evidence that EC beta-amyloid is accumulating and tangles are beginning to form, esp in the hippocampus and adjacent temporal cortex
Progression of Alzheimer’s: Mild cognitive impairment (MCI)?
The pt has mild deterioration of memory and cognitive function that worries the patient but which does not interfere with daily living
Progression of Alzheimer’s: Alzheimer’s dz?
These individuals are frankly demented on clinical examination, neuropsychological evaluation and there is impairment of activities of daily living
T/F: Alzheimer’s plaques can grow overnight
True
Study with mice has shown that they can grow significantly overnight
Timeline of plaque development/growth in Alzheimer’s?
Plaques form in a day; macrophages/microglia react within a couple days; neurotic processes form within days
- Day 1: microplaque
- Day 2: distended neurites, amyloid-B-oligomer, astroglia and microglia first appear
- Day 3: dystrophic neurites
- Day 7: mature plaque
How many people with MCI will go on to develop Alzheimer’s?
Roughly 1/2
What is this?
Amyloid angiopathy in Alzheimer’s dz
- Beta amyloid in vascular walls (typically cleared in blood, but if excessive accumulation in EC space, can build up in vessel wall -> fragility and IC hemorrhaging)
What is Pick’s disease? Key clinical features?
Frontotemporal dementia
- Uncommon severe dementing dz Symptoms
- FRONTAL DISINHIBITION
- (rare cases of new artistic/musical abilities)
Micro anatomical features of Pick’s disease?
Micro:
- Neuronal loss and gliosis
- Ballooned neurons
- NO plaques, tangles, or granulovacuolar
- Faintly basophilic intraneuronal cytoplasmic inclusions (Pick bodies) immunoreactive for tau
Pick’s is a pure TAUOPATHY
Gross anatomical features of Pick’s disease?
Gross:
- Marked temporal and frontal atrophy
- “Knife edge” gyri
- Sparing of post 2/3 of superior temporal gyrus, parietal lobes, and precentral (motor) gyrus
What is this?
Cortical atrophy seen in Pick’s disease (Frontotemporal Atrophy
) - so thin gyri that they look like “knife edge”
What is this?
Pick bodies in Pick’s dz
What is this?
Tau inclusions: Globose tangles in PSP
- Silver stain
What is this?
Tau inclusions: Pick bodies in Pick’s dz
- Silver stain; Pick bodies are the larger blots while nuclei are smaller
What is this?
Neuronal loss, gliosis, rarefaction in Pick’s dz
- Rarefied = not many neurons; a lot of open space
- Notice: no plaques (unlike AD)
What is seen micro in Lewy Body Dz?
- Subtle eosinophilic cytoplasmic inclusions in cortical neurons (Lewy bodies)
- Difficult to identify on H&E; immunopositive with alpha-synuclein
What is the most common cause of dementia? 2nd most common cause?
1st: Alzheimer’s disease
2nd: Lewy Body disease
Clincical features of Lewy Body disease?
- Fluctuating cognitive features (starkly different from day to day!)
- Visual hallucinations (often well-formed, cartoon-like; pt is aware that they are hallucinating)
- Extrapyramidal features may occur (e.g. some features of Parkinsonism)
What is this?
UL: Parkinson’s disease (loss of SN)
UR: Lewy bodies in pigmented neurons with central core and halo
LL: Lewy body
LR: Cortical Lewy Bodies
(PD and LBD are synucleinopathies)
What is this?
Cortical Lewy Bodies
- a-synuclein
(Parkinson’s dz and Lewy body dementia are synucleinopathies)
Pharmacological approaches?
Central cholinesterase drugs
- Donepezil
- Rivastigmine
- Galanthamine
Glutaminergic neurotransmission modulators (use any place there’ degeneration and a lot of glutamate buildup)
- Riluzole (for ALS)
- Memantine (for Alzheimer’s)
Parkinsonism Sx (in LBD) may be treatable with DA, but cost may exceed therapeutic benefit
