Neurobiology of Dementia

Majid Barekatain, M.D.,Associate Professor of Psychiatry

NeuropsychiatristIsfahan University of Medical Sciences

27-28 Ordibehesht 1392April 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: 198-205

Coronal Image of the Brain of an Older Adult with Normal Cognition

Dement Geriatric Cogn Disord 2001; 12: 198-205

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 40-42

A Beta domain

Amyloid Precursor Protein

1

40-42

1

770

17

Cell

mem

bran

e

Gamma Secretase

Proteolytic Cleavages of APP to Produce A Peptide

Selkoe DJ et al. JAMA. 2000;283:1615-1617.

-amyloid precursor protein

-secretase

A peptide

-secretase

Extracellular space

TM Cytoplasm

COOHNH2

Proteolysis of the APP

1. APP + alpha secretase + gamma secretase = P3 (soluble) 17

40-42

2. APP + beta secretase + gamma secretase = AB (insoluble) 1

40-42

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

•Who can suggest the next case!?

Dementia Due to Head Trauma