Lec 58 Alzheimer's Flashcards
What are clinical features of alzheimers?
- slow onset memory loss + other cog impairment without loss of consciousness
- progressive disorientation
- loss of learned motor skills and language
- behavior and personality changes
- impaired performance of activities of daily living [ADLs]
- focal neurological deficits not seen early
- median survival 5-10 yrs
- eventually become mute and bedridden
What is pathology of alzheiemers?
- intracellular neurofibriallary tangles with hyperphosphorylated tau deposits
- extracellular plaques with AB amyloid core
- cerebral atrophy, hydrocephalus ex vacuo
What are risk factors for alzheimers?
- aging
- bio facotrs: DM, HT, obesity, abnormal immune/inflammatory response, genetics
- environmental: cognitive inactivity, traumatic injury, drugs
What are neuropathic findings in alzheimers?
gross:
- cerebral cortical atrophy primarily in frontotemporal association cortex
- dilation symmetrically of lateral ventricles
- hippocampal atrophy
microscopic:
- extracellular deposits of amyloid AB = senile plaque
- intracellular neurofibrillary tangles of hyperphosphorylated tau
- loss hippocampal + cerebrocortical neurons [esp. ACh]
Do number of plaques correlate to cognitive decline? what about tangles?
more tangles = more cognitive decline
plaques not correlated
What is structure of senile plaques? how synthesized?
- extracellular B amyloid core
- amyolid-B [AB] synthesized by cleaving amyloid precursor protein [APP]
- surrounded by abnormally formed neurites
What is structure of neurofibrillary tangles?
intracellular
hyperphosphorylated tau protein = insoluble cytoskeletal dementia
What are braak and braak stages of AD neurofibrillary tangles?
1/2 neurofibrillary tangles in temporal lobe transentorhinal cortex
3/4 increasing limbic lobe involvement
5/6 widespread involvement neocortex
What 3 proteins associated with familiarl alzheimers early onset? their chr location?
early onset:
- chr 21 = amyloid precursor protein [APP]
- chr 14 = presenilin-1 [PSEN1]
- chr 1 = presenilin-2 [PSEN2]
What protein involved with alzheimers last onset?
chr19 = ApoE4
controls brain amyloid accumulation
1/2 of alzheimers pts have mut there
Why do down syndrome pts develop alzheimers?
APP [amyloid precursor protein] is on ch 21
What variant is protective against alzheimer?
ApoE2 on Chr 19
What is the amyloid hypothesis?
deposition of AB peptides in cortex [esp Ab42] starts pathogenic cascade which ultimately leads to synaptic dysfunction, neurodegeneration
has been challenged in recent years
What are biomarkers for AD in person with cognitive deficit?
- measure AB amyloid by florbetapir-PET imaging [clarifies etiology of known dementia but does not rule out other dementias besides AD, still could be lewy body, etc]
- ratio CSF AB amyloid/CSF tau protein level [predict progression from mild cognitive impairment to AD]
- functional and structural imaging
What is cholinergic approach to AD? possible treatment?
memory and cognitive disturbance thought to result from reduced ACh transmission
- pts with AD have decreasd ACh synthesis/projections
treat: donepezil, rivastigmine, galantamine = cholinesterase inhibitors = for mild to moderate AD symptomatic treatment OR memantine = NMDA receptor antagonist for moderate to severe
