Alzheimer's Disease Flashcards
what are the anti-alzheimer drugs?
Donepezil
Galantamine
Memantine
Rivastigmine
Valproic Acid ??
Pioglitazone??
Rasagiline??
what is alzheimer’s disease?
a neurodegenerative disorder of the elderly
1/12 of population 65-75 yrs of age
1/3 of population >85 yrs of age
Accounts for 60 -80% of all dementias
On average, the life expectancy following diagnosis is approximately seven years.Fewer than three percent of individuals live more than fourteen years after diagnosis. Adapted from Wikipedia
what are the symptoms (4 A’s and one D of AD)?
what about dementia?
4 A’s and one D of AD:
Anterograde amnesia
Aphasia – “speechlessness”
Apraxia – unable to perform
tasks
Agnosia – inability to recognize
common objects
Disturbance in executive
function
dementia:
short term memory loss
impaired memory retrieval
impaired ability to generate ideas and to manipulate concepts mentally
impaired judgment and evaluation
labile and inappropriate emotions
motor functions are generally intact until late stages of the disease
what is the neuropathology of AD?
Neurodegeneration is prominent in many brain areas at autopsy
Diffuse cortical atrophy
high density of plaques and tangles in the frontal and temporal cortices
loss of cholinergic neurons in the nucleus basalis of Meynert that project to the frontal cortex
loss of locus coeruleus neurons may even precede nBM loss
neurodegeneration starts many years before appearance of symptoms
development of a pre-symptomatic diagnosis is crucial
summary of confusing slide with APP processing
Alpha-secretase (alpha cleavage) negates the creation of amyloid beta. While beta-secretase (beta cleavage) promotes the creation of amyloid beta.
Gamma secretase is there to liberate the amyloid beta.
Beta cleavage promotes amyloid beta. Alpha cleavage negates it, you don’t want amyloid beta.
what is a good summary about alzheimers?
4 A's and one D of AD:
Anterograde amnesia
Aphasia – “speechlessness”
Apraxia – unable to perform tasks
Agnosia – inability to recognize
common objects
Disturbance in executive function
motor functions are generally intact until late stages of the disease.
neuropathology -
Diffuse cortical atrophy
Loss of LC and nBM neurons
High density of plaques and tangles
Disrupted APP processing
how is alzheimers disease treated?
Acetylcholine replacement therapy (?)
based on early reports of ACh deficiency in AD and remarkable success of dopamine replacement in PD, this seemed reasonable
However, 25 years later, only limited success with acetylcholinesterase (ACh-E) inhibitors such as donepezil, galantamine and rivastigmine
Acetycholine breakdown products aren’t toxic. So there is no increase in the speed of progression.
look at the comparison slide of donepezil (Aricept), Galantamine (Reminyl), and Rivastigmine (Exelon) (slide 12)
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what does memantine (Memox) do?
Memantine (Memox)
Non-competitive low affinity antagonist at NMDARs
At therapeutic doses only partial blockade (low potency)
In contrast to psychotoxic agents such as phencyclidine (PCP) or ketamine which block all channels
Non-competitive antagonist at the nAChRs (Aβ stimulates this to increase Glu release)
Memantine is recommended to manage moderate-severe AD in patients intolerant or contraindicated for AChE inhibitors
No apparent benefit in mild AD (?)
what is nitromemantine?
Nitromemantine
(new with improved effects
– in testing phase)
Nitroglycerin added to memantine to enhance targeting/binding to extrasynaptic NMDA receptors
Nitrosylates the extrasynaptic chronically active NMDA receptor causing desensitization
what is anti Beta-amyloid?
Anti- ß-amyloid
vaccines don’t work
valproic acid reduces/prevents formation of ß-amyloid deposits in trans-genic mouse models of Alzheimer’s Disease
Qing et al. Valproic acid inhibits Abeta production, neuritic plaque formation, and behavioral deficits in Alzheimer’s disease mouse models. J Exp Med.2008 Nov 24;205(12):2781-9
clinical trials in people are being planned (in progress)
Pioglitazone shown to stimulate amyloid clearance and reversal of cognitive deficits in mouse models of AD
Mandrekar-Colucci et al. Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer’s Disease. J Neurosci. (2012) 32(30):10117-128
what does anti-oxidant therapy have to do with things?
Anti-oxidant therapy
in vitro, antioxidants block the neurotoxicity of ß-amyloid
so far, only 1 clinical trial has been published
2000 IU vitamin E daily slowed progression of dementia in probable AD patients
gingko biloba and vitamin E listed in Toronto Notes (2012) as other (not proven) treatment possibilities
similar neurotoxic mechanisms seem to be at work in what?
similar neurotoxic mechanisms seem to be at work in head trauma, stroke, Parkinson disease, Alzheimer disease and other neurodegenerative conditions
what are existing anti-oxidant interventions? and what about vitamine E, C, and ethanol?
existing anti-oxidant interventions include:
vitamin E -tocopherol (synthetic or natural)
vitamin C ascorbic acid (not megadose)
blueberries wild or domestic
strawberries local or imported
ethanol your choice (2 to 3 drinks per day)
BUT !!!
In a meta-analysis of vitamin E trials, Miller et al., (2005, Annals of Internal Medicine), found increased mortality in people with chronic diseases taking doses above 400 i.u. per day, i.e., high dose may be harmful rather than helpful.
Vitamin C above 4 or 5 grams daily increases free radical formation by converting ferric to ferrous which catalyzes the ‘hydrogen peroxide to hydroxyl radical’ reaction.
At concentrations above 180 mg% or so, ethanol starts being metabolized by CYP mixed function oxidase enzymes which increases free radical formation.
