I can’t remember where I put my things I must be getting AL-ZHEIMER’s DISEASE

2. I can’t remember where I put my things I must be getting AL-ZHEIMER’s DISEASE Felwa al-Qazlan

3. What do former president reagan and actor michael J. fox have in common ?

4. AL-ZHEIMER’s DISEASE It Charactarized by memory impairment and other cognitive deficits with preservation of a normal level of consciousness late features : Apraxia Short attention span Disorientation language loss (eventually) Depression Anosognosia * In AD BOTH short and long term memory are affected

5. the cases of AD are dividing into 4 main clinical groups • :which are • 1- sporadic late onset (most common) • 2-familial late onset (uncommon) • 3- familial early onset (rare) • 4- associated with Down’s syndrome

6. ETIOLOGY : • -It’s the most common age related neurodegenerative • Disease • 4th leading cause of death and the most common cause of • Dementia that cause problem with memory among elderly . • - • Most cases are sporadic (no known • Cause) but 5-10% are familial (rare)! • * The incidence is progressively increased • with Advanced age ) • familial cases present at 30-40 years old • -Females are affected twice more than males (?) • -Down syndrom has been increased the risk of developing AD (?)

7. EARLY AD : Genetic defect (mutation) in APP (ch 21) or component of gamasecretase (presinliin 1(ch14) presinillin 2 (ch1) , late AD : apoE4(ch19), SORL1 Ch12 mutation which encodes for alpha-2 macroglobulin Pathogenesis of AD Familial forms Affect the neurons and neuronal function rate of accumlation of AB peptide Hyperphosphorlation of microtubule binding protein (tau) Small aggregation Large agg. (plaques) they elicit inflammatory response leading to further injury 1- neurotransmitter alteration 2- neurons and synaptic end toxicity Redisribution of tau from axon to dentrites and cell body Aggregation into tangles Neuronaldeath

8. APP and presenilin mutation AB40,AB42 formation PHYSIOLOGICAL PATHWAY processing of APP S APP AB40 AB42 Groth factor function Aggregation phosphatase tau –p -----------tau <------------ kinases Amyloid plaques NUERONAL DEATH Neurofibrillary tangles Paired helical filaments

9. processing of APP

11. HOW DOES AD PAITENT BRAIN’S APPEAR GROSSLY ? AND EXPLAIN THE MICROSCOPIC FEATURES OF AD!

12. Morphology : GROSSLY : brain is reduced in weight ,cortical atrophy with narrowing of gyri and widening of sulci , white matter loss is accompanied by dilatation of the ventricular system ( compensatory hydrocephalus) MICROSCOPIC ; the cytopathological hallmarks of AD are: 1- intracellular neurofibrillary tangles (hyperphosphrlated form of TAU protein that normally binds to microtubules )_ 2- extracellular (senile ) amyloid plaques ( core of beta amyloid peptides surrounding by altered nerve fibers &reactive glial cells ( in hypocampus ) 3- amyloidangiopathy 4- granulovacular degeneration : Multiple, small intraneuronalcytoplasmic vacuoles. Some contain dark granules Known as hirano bodies

15. TTT of Alzheimer’s disease There is NO CURE for AD but currently drugs are aimed to either improving the cognition and cholenergic transmission within CNS or preventing excitotoxic actions resulting from over stimulation of NMDA-glutamate receptors in selected brail areas . the pharmacological intervention is only palliative and has short term benefit .

16. ACHEIs (donepezil , tacrine , velnacrineِِِِِِِِِِA- • Rivastigmine , glantamine ) 1- DONEPEZIL ; it has no effect on the course of disease but it can improve cognitive function 2- TACRINE ; long acting (6-8hrs) MOA : all of them are non-competitive inhibitors of ACHE in CNS . Except glantamine ;its competitve Galantamine may also be acting as an allosteric modulator of the nicotinic receptor in the CNS Tacrine also inhibit MAO -> decrease release of GABA(inhibitory NT in CNS) +increase norepinephrine, serotonin and dopamine from nerve endings

17. NMDA- receptor antagonist ( MEMANTINE) • It neuroprotective and can slow the rate of memory loss , used in moderate and severe cognitive loss . • It is more effective than ACEIs . • MOA : block NMDA receptor associated ion channel (ca+, Na+) • At theraputic dose : partial blockage of channel . It allows limited ca+ flow throuhunbloked channel to preserve other vital processes that depend on ca+.

18. What are the NEW TRENDs IN TTT of AD ?

19. 1-vit.E or other antioxidants - protect neuron from • free radical damage • (American journal of nursing 2003, KARGER medical and scientific bublisher 2006) • . • 2-ca+ channel blockers. -protect neurons from ca+ ion • induced injury • (CMAJ canadian medical association 2003) • 3-Cholestrol lowering drugs  lower brain concentration of • Pubmed 2003, medscape))APOE4 • 4-Anti-inflammatory drugs  for B amyloid aggregate that induce inflammatoty response • (International weekly journal of science 2010) • 5-drugs used in DM as DM has a risk for developing • AD later on • NEW YORK ACADEMY OF SCIENCE 2012) • . • 6-Reverseneurodegeneration with new magnesium (compound prohealth 2013 )

20. Alzheimer’s disease ; it’s the most common cause of dementi * Etiology ; most of cases are sporadic , few are familial * Pathogenesis ; deposition of amyloid beta due to genetic defect in precursor protein * Gross and microscopic features : hallmark of AD ? * TTT of AD : no cure for AD but recently drus aimed to eitherimprovingthe cognition and cholenergic transmission within CNS or preventing excitotoxic actions from over stimulation of NMDA-glutamate receptors

21. ..REFRENCES ..

22. What one memory would you save ! #onememory