Neurodegenerative disease Flashcards
What are 3 common features of neurodegenerative disease?
selective vulnerability of specific neurons & systems
misfolded and/or aggregated proteins
sporadic and familial forms
What misfolded protein is associated with alzheimers?
amyloid-B and tau
What misfolded protein is associated with parkinson’s?
a-synuclein
What misfolded protein is associated with frontotemporal lobar degeneration?
tau, ubiquitin, TDP-43
What protein is found in lewy bodies?
a-synuclein
What region is degenerated in parkinson’s?
extrapyramidal system
What region is degenerated in alzheimer’s?
cerebral cortex (higher order association cortices and limbic system)
What region is degenerated in Huntington’s?
extrapyramidal system
What region is degenerated in ALS?
pyramidal system
What neurodegenerative disease has AD inheritance?
huntington’s disease
How might environmental toxins induce neurodegeneration?
reduce mitochondrial funciton; decrease ATP production and increased oxidative stress
How might neuronal metabolism induce neurodegeneration?
is oxidative
How might aging induce neurodegeneration?
affects mitochondrial function
loss of protective enzymes and molecules
progressive hits
Which complex is particularly vulnerable to free radical injury?
complex 1
How does excessive glutamate cause excitoxicity?
persistent activation of NMDA receptors--> excess intracellular calcium--> ATP depletion--> cell death--> more excessive glutamate
What mechansims do cells have to deal with oxyradicals?
ascorbate glutathione superoxide dismutase catalase (these are depeleted with age)
What is the most common form of dementia?
Alzheimer’s disease
What symptoms define alzheimer’s clinically?
impairments in recent memory
decline in cognitive function
results in functional impairment socially or occupationally
WHat are the cognitive domans affected by alzheimers?
memory language abstract thinking & judgement visuospatial or perceptual skills prxis executive function
How do you make a definitive diagnosis of (Dementia of alzheimers type) DAT?
clinical criteria for probably DAT and hisopathologic evidence of DAT
What are the cirteria for probable DAT?
dementia two areas of cognitive impairment progression over time normal sensorium age of onset between 40-90yrs no other disease contributing to the dementia
What are the criteria for possible DAT?
atypical onset/presentation/progression
No systemic or other brain disease capable of producing dementia
gradually progressive decline in a single intellectual function in the absence of any other identifiable cause
What are the clinical findings in stage 1 DAT?
memory-new learning defective, remote recall mildly impaired
poor complex construction/visuospatial skills
poor word generation/anomia
psych features depression/delusions
What are the clinical findings in stage 2 DAT?
memory-recent and remote racall more severely impaired
visuospatial skills-poor constructin and spatial disorientation
acalculia
psych features-delusions
What are the clinical findings in stage 3 DAT?
intellectual functions severely impaired
urinary and fecal incontinence
limb rigidity and flexion posture
What gross features are seen in DAT?
decreased brain weight
atrophy of gyri and widening of sulci
increased size of ventricles (hydrocephalus ex vacuo)
What are diffuse plaques made of?
extracellular accumulation of Abeta protein
What are neuritic plaques made of?
extracellular accumulation of Abeta protein and tau containing neurites
Which type of alzheier’s disease senile plaques are more closely associated with cognitive decline?
neuritic plaque
How commonly is cerebral amyloid angiopathy seen in AD?
almost always, but can occur in absence of AD
What is a neurofibrillary tangle?
intraneuronal accumulation of an abnormally phosphorylated form of tau, a normal MT assoc protein
What is the relationship between NFTs and AD?
unknown
What is the biggest risk factor for AD?
age
What are the key features of early onset AD?
onset <60-65yo
often autosomal dominant mutation, highly penetrant
What are the key features of late onset AD?
onset >60-65
no mendelian pattern of inheritance
What is amyloid precursor protein?
transmenbrane glycoprotein
prescursor to Abeta protein
gene on chromosome 21
What age range to people with trisomy 21 develop AD in?
late 30s
If alpha secretase cleaves within Abeta sequence, what happens?
normal, no Abeta produced
If beta secretase cleaves within Abeta sequence what happens?
Abeta produced
What genes are associated with early onset AD?
presenilin 1
APP
Presenilin 2
What is the only established risk factor for late onset AD?
ApoE gene/apolipoprotien E
presence of E4 modifies genetic risk (leads to increased Abeta deposition)
What types of dementia is cholinergic signaling deficiency present in?
AD
Dementia with lewy bodies
vascular dementia
Which 3 cholinesterase inhibitors are currently in use for dementia?
donepezil
rivastigmine
galantamine
What are some side effects of cholinesterase inhibitors?
GI problems
muscle cramping
abnormal dreams
How does the drug memantine work?
is an NMDA channel blocker, has some efficacy in slowing AD disease prgression
What are some side effects of memantine?
headache
dizziness
