Alzheimer's Disease week 7 Flashcards
What is the most common cause of dementia?
Alzheimer’s disease
What are the clinical features of vascular dementia and vascular cognitive impairment? (history, exam)
How do they differ clinically from Alzheimer’s disease (AD)?
Vascular dementia and vascular cognitive impairment
NOTE THIS IS THE SECOND MOST COMMON CAUSE OF DEMENTIA IN THE ELDERLY.
Key features
■ Clinical
- history of vascular risk factors or disease
- sudden onset and/or stepwise cognitive deterioration
- temporal relation of stroke to cognitive impairment
- focal findings on exam suggestive of stroke
- neuroimaging evidence of cerebrovascular disease
■ Neuropathologic
- cerebral infarcts and/or hemorrhages
- large and/or small vessel disease
□ How it differs clinically from AD
■ Temporal course
■ Evidence of cerebrovascular disease
Wht is the second most common cause of neurodegenerative dementia?
Lewy body disease (second to AD)
What is the clinical presentation of Lewy body disease?
What is the neuropathology of Lewy body disease?
How does it differ clinically from AD?
■ Clinical
- slowly progressive cognitive deterioration, with notable fluctuations
- early in disease: memory preserved, but visuospatial abilities affected
- new onset of well-formed visual hallucinations
- parkinsonism (more rigidity or bradykinesia, rather than tremor) and falls
- sensitivity to neuroleptics
■ Neuropathologic
• Lewy bodies in neocortex
□ How it differs clinically from AD
■ Fluctuations
■ Early presentation: different cognitive profile, hallucinations, parkinsonism
T or F: Most often combinations of different pathologies leads to dementia.
True. “Mixed” dementia
What is the macroscopic pathology seen in AD?
□ Generalized cortical atrophy (medial temporal lobes and association cortices)
■ Small gyri
■ Enlarged sulci
□ Ventriculomegaly-hydrocephalus ex vacuo
□ Co-occurrence: atherosclerosis, infarction, hemorrhage
Explain the 2 key microscopic pathologic findings of AD.
Pathology: microscopic
□ 2 key findings:
■ Neuritic (senile) plaques: extracellular accumulation of proteins (including amyloid) and other components
■ Neurofibrillary tangles: intracellular accumulation of hyperphosphorylated tau
The gene for amyloid precursor protein (APP) is located on what chromosome? What is the significance of this?
What 3 proteases cleave APP? What protein is formed with cleavage of APP by these proteases?
What is the normal process of cleavage of APP?
Amyloid beta (Aβ) peptides
□ Derived from amyloid precursor protein (APP)
□ APP gene is located in chromosome 21-Individuals with Downs syndrome are at increased risk of developing AD
□ 3 proteases (secretase α, or β and γ) are involved in cleavage of APP, leading to several Aβ peptides of various lengths (amino acids long)
□ Balance between the various forms of Aβ
Generation of Aβ depends on cleavage of APP
□ If normal cleavage occurs with α secretase first, then Aβ cannot be produced, as this cleavage site is located between the cleavage sites for β and γ secretases
□ If abnormal cleavage occurs with both β and γ secretases first, then generation of Aβ
What is the main component of intracellular neurofibrillary tangles (NFT)?
What is the function of this component?
Neurofibrillary tangles (NFT)
□ Main component of NFT is phosporylated tau (pτ).
□ Tau is a normal cytoskeletal component that helps bind and form microtubules.
□ Tau is critical for normal functioning of the axonal transport system of the neuron (e.g., protein and other nutrient trafficking to and from the cell body).
How does tau become hyperphosphorylated? What is the result of hyperphosphorylation of tau?
□ In AD: abnormal tau metabolism: overactive kinases or underactive phosphatases→ excess phosphorylation of tau (or impaired dephosphorylation of tau) → hyperphosphorylated tau → sticky tau with impaired binding to microtubules → unbound pτ polymerizes into insoluble paired helical filaments (PHF) → NFT
□ Tau accumulates in neuron (cell body, axon, dendrites), plaques, neuropil thread (formed from axonal and dendritic PHF)
What is the pattern of accumulation of NFT vs amyloid plaques?
Selective vulnerability
□ The accumulation of tangles appears to follow a pattern of accumulation (entorhinal, association cortices of the temporal, and other lobes, and then of the primary motor cortices). Primary motor cortices affected if person lives long enough
□ This is not the case for amyloid
What NT deficit occurs earlier and is more profound than changes seen in other NT systems in Alzheimer’s disease?
Where is this NT produced? Where is it released?
Selective vulnerability
□ Loss of neurons in the nucleus basalis of Meynert of the limbic system → loss of cholinergic input to cortex
□ This neurotransmitter deficit occurs earlier and is more profound than changes seen in other neurotransmitter systems
State what neurons are lost in NE and the NT’s they produce.
■ Loss of neurons (area and cell specificity):
- Basal forebrain, including nucleus basalis: >75% neuronal loss (cholinergic system → decreased levels of acetylcholine)
- Entorhinal cortex and neocortex (large pyramidal glutamatergic neurons)
- Hippocampus: CA1 and CA2 (pyramidal glutamatergic neurons)
- Interneurons in neocortex
- Brain stem: locus ceruleus (NE) and raphe (5-HT) (sleep and depression disorders)
What other cellular/synaptic changes occur in AD?
Other changes
■ Loss of receptors: cholinergic (nicotinic), glutamatergic (NMDA), and others
■ Synaptic, dendritic, and other changes
■ Altered levels of enzymes: choline acetyltransferase (ChAT) and acetylcholinesterase (AChE)
In AD, which hypothesis is more accepted as it pertains to the order in which accumulation of amyloid plaques and tangles occurs?
Which is more closely linked to cognitive issues? (plaques or tangles)
□ Amyloid cascade hypothesis: is more accepted that this occurs first and may lead to tangles (see attached, slide 41)
□ Tau hypothesis
□ Other
Accumulation of tangles is more closely linked to cognitive issues
Mutations of what 3 proteins are implicated in autosominal dominant AD?
What do mutations of these proteins result in?
Autosomal dominant AD
□ 3 proteins (PS1, PS2, APP) are transmembrane proteins of unknown function (neural plasticity?)
□ Are presenilins (PS1, PS2) secretases that cleave APP?
□ Mutations of PS1, PS2, APP promote production of longer form of amyloid beta (Aβ42): insoluble and neurotoxic form
What are the mechanisms leadin to cell death in AD?
Mechanisms leading to cell death
□ Oxidative injury
□ Mitochondrial dysfunction
□ Calcium metabolism dysfunction
□ Inflammation
□ Vascular disease (direct and indirect)
□ Cholesterol metabolism dysfunction
□ Apoptosis?
→ cell death and neurotransmitter deficits
