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Alzhiemers short

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Alzhiemers

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Alzhiemers short

  1. 1. TREATMENT OF ALZHEIMER’S DISEASE
  2. 2. HISTORY • Dr.Alois Alzheimer-German psychiatrist & neuropathologist • Identified Alzhiemer’s disease in a patient at the Frankfurt Asylum named Auguste Deter.
  3. 3. Dr.Alois Alzheimer Auguste Deter
  4. 4. CLINICAL OVERVIEW • Progressive loss of memoryloss of short term memory that precedes loss of long term memory • Disordered cognitive functions • Vegetative state • Death asso. with complications of immobility eg:pneumonia or pulmonary embolism
  5. 5. Genetics Early onset • Autosomal dominant • Mutations in – APP –Amyloid beta precursor protien – PSEN1 –presenilin 1 – PSEN2-presenilin 2 • Aβ is generated by sequential cleavage of APP by 2 enzymes,β secretase & γ secretase • Presenilins form the catalytic core of γ secretase Late onset • Sporadic • APOE-encodes lipid carrier protien- Apolipoprotien E
  6. 6. PATHOPHYSIOLOGY • Amyloid plaqueextracellular deposition of β amyloid protien in cortex, hippocampus, amygdala & sub cortical nuclei • Intraneuronal neurofibrillary tangles Tau protiens
  7. 7. PATHOPHYSIOLOGY • Aβ & tau induce neuronal dysfunction by – Direct impairment of synaptic transmission & plasticity – Excitotoxicity – Oxidative stress – neuroinflammation
  8. 8. NEUROCHEMISTRY • Deficiency of Acetylcholine • Due to atrophy & degeneration of subcortical cholinergic neurons • particularly in Nucleus basalis of Meynert in the forebrain that projects to frontal cortex & hippocampus
  9. 9. CHOLINERGIC NEURONS Ach ↓
  10. 10. NEUROCHEMISTRY • Excitotoxicity due to enhanced glutamate transmission via NMDA receptors
  11. 11. TREATMENT –Treatment of cognitive symptoms –Treatment of behavioral symptoms
  12. 12. Treatment of cognitive symptoms
  13. 13. TREATMENT • Augmentation of cholinergic transmission – Mainstay • Reversible choline esterase inhibitors that can cross BBB • First line of treatment 1. Tacrine-first drug approved,but rarely used now due to hepatotoxicity 2. Donepezil 3. Rivastigmine 4. Galantamine-can stimulate nicotinic receptors,can be used in later stage
  14. 14. TREATMENT • Peripheral cholinergic side effects- Diarrhoea,nausea,vomiting &↑ urination • Memantine- – Noncompetitive antagonist of NMDA receptor – Better tolerated & less toxic
  15. 15. TREATMENT • Peripheral cholinergic side effects- Diarrhoea,nausea,vomiting &↑ urination • Memantine- – Noncompetitive antagonist of NMDA receptor – Better tolerated & less toxic • Vit E +Antioxidants-vit C,vitA,Zn,Se,bioflavanoids,-↓ progression
  16. 16. TREATMENT • Augmentation of cholinergic transmission – Mainstay • Reversible choline esterase inhibitors that can cross BBB • First line of treatment 1. Tacrine-first drug approved,but rarely used now due to hepatotoxicity 2. Donepezil 3. Rivastigmine 4. Galantamine-can stimulate nicotinic receptors,can be used in later stage
  17. 17. TREATMENT • Antiamyloid monoclonal antibody- bapineuzumab & solanizumab-failed in phase III clinical trial • Vaccination against human beta amyloid- under study
  18. 18. TREATMENT M1 agonist 1. Xanomeline – – Improves cognition and reduces psychotic symptoms – Failed during Phase II clinical test due to side-effects - nausea and diarrhea. 2. Talsaclidine – Enhances non-amyloidogenic processing of APP and decreases CSF Aβ level in AD patients – Discontinued due to side-effects - sweating and salivation
  19. 19. TREATMENT Gingko biloba- • Plant extract • Positive effects on neurons • Have antioxidant and anti-inflammatory properties.
  20. 20. TREATMENTTarget/Approach Candidate Name Trial Phase Gamma Secretase Modulator/NSAID R-flurbiprofen Phase III (completed) Gamma Secretase Inhibitor Semagacestat Phase III (completed) Antibody to amyloid beta Bapineuzumab Phase III (completed) Natural Antibodies to amyloid beta IVIg Phase II (completed)
  21. 21. TREATMENT Treatment of behavioral impairment • Antidepressants – SSRIs • Atypical antipsychotics – Risperidone, Olanzapine, Quetiapine  For agitation and psychosis. • Mood stabilizers –Lithium
  22. 22. THANKYOU

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