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Neurobiology of Dementia

Neurobiology of Dementia. Majid Barekatain , M.D., Associate Professor of Psychiatry Neuropsychiatrist Isfahan University of Medical Sciences 27-28 Ordibehesht 1392 April 16-17, 2013. Dementing Illnesses: Proteinopathies. DAT: beta amyloid => posterior cortex (parietal / temporal)

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Neurobiology of Dementia

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  1. Neurobiology of Dementia MajidBarekatain, M.D., Associate Professor of Psychiatry Neuropsychiatrist Isfahan University of Medical Sciences 27-28 Ordibehesht 1392 April 16-17, 2013

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

  3. Neuritic Plaques

  4. Neurofibrillary Tangles

  5. 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

  6. DAT: Distribution of Neuritic Plaques

  7. DAT: Distribution of NFT

  8. Coronal Image of the Brain of an Older Adult with Normal Cognition Dement Geriatric Cogn Disord 2001; 12: 198-205

  9. Brain MRI Images of Older adults with a) Alzheimer’s Disease b) Normal Cognition and c) DLB Dement Geriatric Cogn Disord 2001; 12: 198-205

  10. Flurodeoxyglucose (FDG) PETnormal DAT

  11. Metabolism of the Amyloid Precursor Protein 1 Amyloid Precursor Protein Beta Secretase Cleavage Site Alpha Secretase Cleavage Site 17 1 17 Cell membrane A Beta domain 40-42 Gamma Secretase Gamma Secretase Cleavage Site 40-42 770

  12. -amyloid precursor protein Extracellular space TM Cytoplasm A peptide COOH NH2 -secretase -secretase Proteolytic Cleavages of APPto Produce A Peptide Selkoe DJ et al. JAMA. 2000;283:1615-1617.

  13. Proteolysis of the APP APP + alpha secretase + gamma secretase = P3 (soluble)1740-42 APP + beta secretase + gamma secretase = AB (insoluble) 1 40-42

  14. 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

  15. DLB

  16. Differential Diagnosis

  17. 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.

  18. Vascular Dementia

  19. Who can suggest the next case!?

  20. Dementia Due to Head Trauma

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