M. Alzheimer

Etiopatogenesis patological proteins u neuritic plaques u  amyloid u amyloid precursor protein (APP)  sekretase  sekretase  amyloid  APP plaques transduction

Etiopatogenesis patological proteins  Neurofibrillar tangles u tau protein u in CNS – stabilization of microtubullar network u AD - abnormal fosforylation - shortened of tau protein  Is not able to make connection with mikrotubulles  Interactions with other proteins  hellical fibers  degeneration of neurons  apoptosis

Etiopatogenesis brain atrophy

Etiopatogenesis ACh deficit

Etiopatogenesis inflammation activated microglial cells Alzheimer - reactive astrocytes, microglia

Etiopatogenesis genetic factors

New criteria for AD diagnosis A.Impairment of episodic memory B.Atrophy of medial temporal structures on MRI C.Abnormal cerebrospinal fluid markers D.Specific metabolic pattern evidenced with molecular neuroimaging methods E.Familial genetic mutations Dubois a kol., 2007

Memory  Epizodic memory – significantly impaired episodic memory - for recalling informations from memory, it needs personal experience

Clinical criteria AD Failure of short episodic memory and its recolling (hippocampal atrophy, do not save information,  no benefit of helping to patient) Failure of visuospatial orientation Failure of executive functions ( such as planning, working memory, attention, problem solving, verbal reasoning, inhibition, mental flexibility, multi- tasking, initiation and monitoring of actions)

Clinical criteria AD Deterioration of fatic, gnostic functions and praxia Apathy, agresivity, anxiety, depression

B. Atrophy of medial temporal structures on MRI  Common in AD – 71 – 96%  Frequent in MCI – 59 – 78%  Less frequent in normal ageing – 29%  Sensitivity and specificity more than 85% Dubois a kol., 2007

Medial temporal structures on MRI

MRI - hippocampus

Alzheimer diseaseNormal MRI

C. Abnormal cerebrospinal fluid biomarkers  Amyloid  42 - A  42 -   Total tau protein – t-tau -   Phospho-tau protein – p-tau - 

D. Specific metabolic pattern evidenced with molecular neuroimaging methods (PET)  With 18F-FDG PET (F – fluoro-2- deoxyglucosis) – visualisation of hypometabolism in temporoparietal region  With PiB PET (PiB-Pittsburg compound) – substance binding to amyloid and is visible by PET

18F-FDG PET

D. Specific metabolic pattern evidenced with molecular neuroimaging methods Rabinovici a kol., 2009

D. Specific metabolic pattern evidenced with molecular neuroimaging methods (SPECT)  99mTc-HMPAO SPECT (measure blood flow)  in AD. Woman, age 56, dg.: AD, MMSE Transversal brain section – rCBF reduction in parietal cortex of both hemispheres and in F and T cortex in left hemisphere. Kupka a kol.

E. Familial genetic mutations  Tri autosomal dominant mutations cause AD  Chromosome 21 – amyloid precursor protein  Chromosome 14 – presinilin 1  Chromsome 1 – presenilin 2

Diagnosis  Laboratory tests  Blood count, sugar, Na, K, urea, TSH, cholesterol (total, LDL, HDL), B12,  others

Therapy  Increasing of cholinergic activity  Acetylcholine inhibitors  DONEPEZIL (ARICEPT)  RIVASTIGMIN (EXELON)  GALANTAMIN (REMINYL)

Therapy  Modulators of glutamatergic transmission  Memantin – blocer of NMDA receptor channels

Therapy  Behaviour problems  Agressivity  Insomnia  Depression

Lewy body dementia  Memory loss  Parkinson syndrome  Visual halucinations  Worsening after neuroleptics

Frontotemporal lobar degeneration 3rd most often neurodegenerative dementia Starting before age of 65 (35-75) Shorter time of survival Faster progression of cognitive and functional deficit

Frontotemporal lobar degeneration - FTLD 3 types Frontotemporal dementia Primary progressive (non-fluent) aphasia Semantic dementia

Frontotemporal lobar degeneration - FTLD Early behavioral -dysexecutive syndrom and fatic and/or gnostic functions 20-40% - positive family history Dysexecutive syndrome – dysfunction in executive functions – like planning, abstract thinking, flexibilty, behaviour control

Frontotemporal lobar degeneration - FTLD MRI Atrophy of frontal lobes and anterior part of temporal lobes, amygdala, sometimes with assymetry Symmetry – in frontal dementia Asymetric FT atrophy mainly in left hemisphere– primary progressive aphasia Bilateral symmetric aphasia T neokortex – semantic dementia

Frontal dementia

Primary progressive aphasia

Semantic dementia

Vascular dementia  Dementia - loss of cognitive functions - memory problems  Cerebrovascular disease

Classification of VaD 1.Multiinfarct dementia (K,S) 2.Demencia after stroke in strategic localisation 3.Small vessel disease (K,S) 4.Hypoperfusion (surgery in older age  risc 4- times) 5.Dementia after brain haemorrhage 6.Other mechanisms

Risk factors of dementia TIA Stroke Arterial hypertension Diabetes mellitus Atrial fibrillation Hyperlipidemia

VaD vs AD

Vascular dementia Sudden onset of cognitive decline, fluctuations ! Small vessel disease – slow onset, slow progression Gait problems and falls Incontinentia in early stages

Dg VaD - CT

Dg. VaD - MRI

Dg. VaD MRI

Dg. VaD – Ultrasound and AG

Therapy VaD AChE Inhibitors and memantin ? Stroke prevention ASA, clopidogrel, dipyridamol + ASA Anticoagulant th – AF Therapy of risk factors