gc08-3 - Dementia Treatment and Prevention Maria T Caserta...

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1 Dementia Treatment and Prevention Maria T. Caserta, MD, PhD Director of Geriatric Psychiatry Dept. of Psychiatry and Behavioral Medicine USF Dementia • Dementia is a major public health concern – Prevalence – Chronicity – Caregiver burden – Financial costs There are no cures for the neurodegenerative dementias.
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2 Alzheimer brain - microscopic The hallmarks of Alzheimer's pathology are amyloid plaques and neurofibrillary tangles, both of which are visualized here with thioflavin-S labeling. Neurofibrillary tangles are seen here as "flame- shaped" structures, and often fill the neuronal cell body which they occupy. Amyloid plaques are seen as diffuse and round fibrous structures. From the Basic Human Brain Research Laboratory at Northwestern University’s Alzheimer’s disease Center: http://www.brain.nwu.edu/galle ry/P&Tpicture.htm
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3 Course of Aging, MCI and AD AAMI / ARCD MCI Clinical AD Time (Years) Cognitive Decline “Brain ”AD Brain Aging Mild Moderate Moderately Severe Severe (Ferris, 4/03) Brain Aging Possible Treatment Outcomes Function Time Treatment Disease arrest Slowed progression Symptomatic benefit No benefit
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4 Dementia • Clinicians prescribe various pharmacotherapies to alleviate symptoms and delay disease. • Currently 5 drugs have FDA approval for treating and managing dementias. Therapeutic approaches based on pathogenic mechanism • Cholinergic deficiency • 1st generation: • 2nd generation: • Cholinesterase inhibitors: • Tacrine • Donepezil • Galantamine • Rivastigmine
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5 Correlation of cognitive function with cholinergic dysfunction Comparison of 11 C-nicotine uptake as assessed by PET and the MMSE 1 1 Reprinted with permission from Nordberg A. Biological markers and the cholinergic hypothesis in Alzheimer's disease. Acta Neurol Scand Suppl . 1992;139:54-8. PMID: 1414270 http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?uid=1414270&form=6&db=m&Dopt=b (S)(-)- 11 C-nicotine uptake nCi/cm 3 /dose bw -1 Normal cholinergic function* *Adapted with permission from Adem A. Putative mechanisms of action of tacrine in Alzheimer's disease. Acta Neurol Scand Suppl. 1992;139:69-74. PMID: 1384265 http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?uid=1384265&form=6&db=m&Dopt=b Acetyl CoA + Choline Ach Ach ChAT Presynaptic neuron Choline Choline + Acetate Acetylcholinesterase Cholinergic receptor Postsynaptic neuron Synaptic cleft
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6 Therapeutic Approaches • Glutamate neurotoxicity • Memantine partially blocks the N-methyl-D aspartic acid (NMDA) receptor and prevents excess stimulation of the glutamate system. • Excessive activation of the NMDA receptor by glutamate increases the vulnerability of CNS neurons leading to degeneration. Acetylcholinesterase inhibitors (AChEIs) are the best developed therapy and are used for mild to moderate disease.
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gc08-3 - Dementia Treatment and Prevention Maria T Caserta...

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