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weight of adult brain
- 3 pounds
- medium cauliflower
how many neurons and synapses in brain?
- 100 billion neurons
- 100 trillion synapses
what does AD manifest as?
what are two major stages of AD
- symptomatic (prodromal: between initial symptoms and fall out)
- --->dementia of the Alzheimer type
what does the prevalence of plaques suggest?
there is a preclinical stage of AD
what happens in preclinical AD with plaques in neocortex (what type mostly), tangles in entorhinal cortex& hippo, cell loss, CDR?
- many plaques (diffuse greater)
- many tangles
- little to none cell loss
- CDR 0
what happens in very mild AD with plaques in neocortex (what type mostly), tangles in entorhinal/hippocampus, cell loss, CDR?
- many plaques
- many tangles
- substantial cell loss (30%-60%)
- very mind dementia or MCI CDR 0.5
what is the point of preclinical
to treat early pathological processes (lower amyloid) to prevent subsequent neurodegeneration and cognitive decline and dementia
what is the issue with late treatment
what is the result of early treatment
halt or delay cognitive decline
what does preclinical treatment do?
prevents cognitive decline
what are the roles of CSF biomarkers in clinical setting?
- prognostic (predict cognitive decline)
- theragnostic (detect biochemical effects of treatment)
biomarkers of AD in CSF
- decrease in AB42
- increase in tau or phosphorylated tau
what kind of imaging agents can be used to detect biomarkers of AD?
AV-45 and PIB
what is mean cortical binding potential
average from the pre-frontal cortex, gyrus rectus, lateral temporal cortex and precuneus areas (have high PiB uptake in those with symptomatic AD)
what does CDR mean?
clinical dementia rating
what is a marker of cortical amyloid and what is not
- low CSF ab42 is a marker
- low plasma levels of ab40 and ab42
how does brain volume and CSF ab42 levels compare in normal and mild AD patients?
- lower csf ab42 is associated with smaller brain volume (or volumetric reduction over 1 year, also not restricted to parts where AD affects) in normal older individuals
- no pattern in those with mild AD
how does CSF tau and brain volume compare in individuals with mild AD and normal individuals
- higher CSF tau associated with smaller volume in individuals with mild AD
- no pattern in normal patients
to what extent does CSF biomarkers reflect underlying AD pathology?
very much so even if individuals are cognitively normal
what is CDR-SB score?
- summing each of six domains (memory, orientation, judgment& problem solving, community, hobbies, personal care)
- ranges from 0 to 18 (bad)
does csf ab42 predict the future cognitive decline in individuals?
yes it predicts the rate of decline in individuals with mild dementia
what does abnormal CSF ab42 and tau(s) predict?
- increase rate of cognitive decline (CDR-SB) in individuals with mild AD (CDR 0.5)
- CSF tau/AB 42 predicts progression from normal to MCI or AD dementia
how long doe preclinical stage span?
10-15 years prior to dementia onset
what does it mean to shift from cure to prevention
start early intervene in cognitively normal individuals to prevent neurodegeneration and symptomatic AD
info gathered over long period of time
what are some acetylcholinesterase inhibitors
- cholinesterase inhibitors (aricept, cognex)
what is the role of acetylcholine
improves cognition, mood, and behavior and so promotes better daily function
memantine is what type of drug?
- NMDA receptor antagonist
- quell overactivity by glutamate, (overactivity=cell death)
- does not interfere with buildup of cell lesions that drive disease progression
what are some current therapies
- abeta immunotherapies (monoclonal antibodies)
- gamma secretase inhibitors and modulators (GSM)
- regulators of APP metabolism and abeta aggregation
why is interesting about y-secretase inhibitor LY 450139
enters and exits brain rapidly (within 12 hours) and reduces production (not clearance) of CNS AB
what are tau focused therapies?
- hyper-phosphorylation (GSK 3-beta inhibitors)
- aggregation inhibitors
what are neuroprotective agents
trying to boost natural brain chemicals that enhance health of neurons
what does the prevalence of plaques compared to DAT suggest?
there is a preclinical stage
what are clinicopathologic features?
plaques, tangles, cell loss, clinical diagnosis and pathological diagnosis
where does early treatment start vs preclinical?
- mildly impaired stage
- cognitively normal
why does a CDR of 1-2 suggest?
mild or moderate DAT
mean cortical PIB binding (binding potential)
mean of 4 areas with high PIB uptake in those with symptomatic AD
what does CSF tau/AB42 predict?
progression from MCI to AD dementia over 5 years
what is CDR-SB
clinical dementia rating-sum of boxes
what does abnormal CNS ab42 and tau predict?
increased rate of cognitive decline in mild AD
what are cholinesterase inhibitors?
what do inhibitors of enzymes that produce amyloid beta do?
modify action of enzymes that cut a large protein (APP) in a way that releases ab peptides
vaccines or antibodies that clear beta amyloid
vaccines induce body to produce antibodies that bind to amyloid and clear them from the brain
block production of toxic form of tau or impede its aggregation into tangles
boost natural brain chemicals that enhance the health of neurons
decrease ab production
- b and y secretase inhibitors
- a secretase enhancers
decrease ab aggregation
- decrease metal ion mediated fibrilization
- reduction of ab monomers
- decrease b-pleated sheet formation
increase ab degradation
- neprilysin (degrades ab)
- IDE activation
increase ab clearance
- active vaccination (activate body's production of antibodies)
- passive immunization with monoclonal antibody against ab epitope
- passive immunization with antibody against specific conformational forms of ab (such as oligomers, protofibrils)
decrease in tau and NFT
- prevent tau hyperphos
- decrease tau aggregation
- stabilize microtubules
- active and passive immunization against tau
neuroprotection or neuroregeneration
- anti-apoptotic agents
- antioxidant to preserve metabolic/mitochondrial function
- decrease inflammatory damage
- nerve growth factor enhancement
- stem cell based neuron replacement
what are some strategies for prevention
- vitamine E and C
- heart smart diet