Neurobiology of Dementia Majid Barekatain, M.D., Associate Professor of Psychiatry Neuropsychiatrist Isfahan University of Medical Sciences Ordibehesht 1392 April 16-17, 2013

Dementing Illnesses: Proteinopathies DAT: beta amyloid => posterior cortex (parietal / temporal) FTD: tau => anterior cortex (frontal / temporal) DLB: alpha synuclein => limbic system / midbrain / brain stem / cortex

Neuritic Plaques

Neurofibrillary Tangles

Evidence for Beta Amyloid as the Putative Toxic Agent in DAT The clinical phenotype of AD corresponds to impairment in brain regions with the highest plaque burdens The degree of intellectual impairment in AD directly correlates with AB plaque burden Beta amyloid deposition is associated with inflammatory changes in the cerebral cortex including cell death Most cases of familial AD are caused by mutations in genes regulating expression of presenilin DAT occurs uniformly in patients with Down’s syndrome (trisomy 21) at an early age

DAT: Distribution of Neuritic Plaques

DAT: Distribution of NFT

Dement Geriatric Cogn Disord 2001; 12: Coronal Image of the Brain of an Older Adult with Normal Cognition

Dement Geriatric Cogn Disord 2001; 12: Brain MRI Images of Older adults with a) Alzheimer’s Disease b) Normal Cognition and c) DLB

Flurodeoxyglucose (FDG) PET normal DAT

Metabolism of the Amyloid Precursor Protein Beta Secretase Cleavage Site Alpha Secretase Cleavage Site 17 Gamma Secretase Cleavage Site A Beta domain Amyloid Precursor Protein Cell membrane Gamma Secretase

Proteolytic Cleavages of APP to Produce A  Peptide Selkoe DJ et al. JAMA. 2000;283:  -amyloid precursor protein  -secretase A  peptide  -secretase Extracellular space TMCytoplasm COOH NH 2

Proteolysis of the APP 1.APP + alpha secretase + gamma secretase = P3 (soluble) APP + beta secretase + gamma secretase = AB (insoluble)

Dementia of Lewy Body Dementia with Lewy bodies overlaps clinically with Alzheimer’s disease and Parkinson’s Disease. DLB often has a rapid or acute onset, with especially rapid decline in the first few months. DLB tends to progress more quickly than Alzheimer’s disease. fluctuating cognition with great variations in attention and alertness from day to day and hour to hour, recurrent visual hallucinations (observed in 75% of people with DLB), and motor features of Parkinson's. Suggestive symptoms are REM-sleep behavior disorder. hypersensitivity to neuroleptic and antiemetic medications

DLB

Differential Diagnosis

Vascular Dementia Dementia caused by problems in supply of blood to the brain, typically by a series of minor stroke. Was previously referred to as "multi-infarct dementia” Vascular dementia is the second most common form of dementia after Alzheimer’s Disease (AD) in older adults. Presents with cognitive impairment, acutely or subacutely, after an acute cerebrovascular event. After the onset a stepwise progression is typical.

Vascular Dementia

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