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Alzheimer disease

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Alzheimer disease

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Alzheimer disease

  1. 1. ALZHEIMER’S DISEASE BY Dr VISHESH ROHATGI
  2. 2. OVERVIEW • What is Alzheimer Disease? • Causes of AD • History • AD and brain (Pathophysiology) • Hypothesis • Management
  3. 3. Although the risk of developing AD increases with age – in most people with AD, symptoms first appear after age 60 (5% incidence) AD is not a part of normal aging. Alzheimer’s disease is an irreversible, progressive brain disease that slowly destroys memory and disorders cognitive function. What is AD?
  4. 4. HISTORY
  5. 5. History of Alzheimer’s Disease • In November 1906, at a German psychiatrists meeting, Alois Alzheimer presented the pathological findings on a brain of a 56 y.o. woman who died after a progressive dementia
  6. 6. The Case Auguste Deter • This 51 y.o. woman was admitted to Frankfort hospital in 1901 for progressive dementia. • She was under the care of Dr. Alzheimer until her death in 1906. He did an autopsy, examined her brain & described the typical abnormalities of what would be called later Alzheimer’s Disease.
  7. 7. History, Continued • This case did not prompt any reaction untill Kraepelin, in 1910, referred to it as “Alzheimer’s Disease” (presenile dementia) in the 8th edition of his psychiatry book
  8. 8. History Continued • 1962: Corselis: presenile & senile dementias have the same pathological abnormalities • 1983:Coyle et al: Acetylcholine deficit in the cortex • 1995: The first gene abnormalities in familial Alzheimer disease are identified (Presenilin 1 & 2)
  9. 9. CAUSES OF AD
  10. 10. AD AND BRAIN (PATHOPHYSIOLOGY)
  11. 11. Plaques and Tangles: The Hallmarks of AD The brains of people with AD have an abundance of two abnormal structures: An actual AD plaque An actual AD tangle • beta-amyloid plaques, which are dense deposits of protein and cellular material that accumulate outside and around nerve cells • neurofibrillary tangles, which are twisted fibers that build up inside the nerve cell Volicer L. Clin Geriatr Med. 2001;17:377-391.
  12. 12. HYPOTHESIS
  13. 13. b a g g APP Protein: (1) b-secretase cuts APP protein, giving: (2) g-secretase cuts this residue, giving: or Ab40 Fragment Soluble Ab42 Fragment Unsoluble, aggregates into plaques 1. BETA AMYLOID HYPOTHESIS
  14. 14. Amyloid precursor protein (APP) is membrane protein that sits in the membrane and extends outward. It is though to be important for neuronal growth, survival, and repair. From: www.niapublications.org/pubs/unraveling/01.htm
  15. 15. Enzymes cut the APP into fragments, the most important of which for AD is called b-amyloid (beta-amyloid) or Ab. From: www.niapublications.org/pubs/unraveling/01.htm
  16. 16. Beta-amyloid is “sticky” so the fragments cling together along with other material outside of the cell, forming the plaques seen in the AD brain. From: www.niapublications.org/pubs/unraveling/01.htm
  17. 17. Neurofibrillary Tangles Neurons have an internal support structure partly made up of microtubules. A protein called tau helps stabilize microtubules. In AD, tau changes, causing microtubules to collapse, and tau proteins clump together to form neurofibrillary tangles. 2. TAU HYPOTHESIS
  18. 18. • Presenilin 1 (PS1) and presenilin 2 (PS2) are highly homologous 43-50 kD proteins with eight transmembrane domains • Presenilin’s are crucial components of the enzymes that work to cleave APP at gamma secretase site (catalytic core), and mutations in presenilins cause the production of A-beta42 and A-beta43 peptides (insoluble forms of A-beta) Shen & Kelleher (2007), PNAS, 104:403-408. 3. PRESENILIN HYPOTHESIS
  19. 19. 4. APOLIPOPROTEIN E AND OTHER GENES HYPOTHESIS From Sleegers et al. (2010) Trends in Genetics, 26, 84-94, p. 87
  20. 20. • It has been hypothesized that brains of patients with AD may have lower levels of plasmin • The higher production of amyloid peptide together with less efficient degradation would to A-beta accumulation and aggregation 5. PLASMIN HYPOTHESIS
  21. 21. • Calcium modulates many neural processes, including synaptic plasticity and apoptosis • Increased intracellular calcium elicits the characteristic lesions of this disorder, including the accumulation of amyloid-beta, the hyperphosphorylation of TAU and neuronal death 6. CALCIUM HYPOTHESIS LaFerla, F.M. (2002) Calcium dyshomeostasis and intracellular signalling in alzheimer’s disease. Nature Reviews Neuroscience 3, 862-872
  22. 22. 7. FREE RADICAL HYPOTHESIS • Oxidative damage from free radical molecules can injure neurons. • A study shows that an elevated level of homocysteine is associated with increased risk of AD.
  23. 23. •Marked decrease in choline acetyltransferase and loss of cholinergic neurons in brain • Involves nucleus basalis in forebrain , frontal cortex and hippocampus •There is also noradrenergic and serotonergic depletion due to degeneration of brainstem nuclei such as the locus coeruleus and dorsal raphe. 8. NEUROTRANSMITTER HYPOTHESIS
  24. 24. http://www.ambion.com/tools/pathway/pathway.php?pathway=Alzheimer's%20Disease%20Pathway
  25. 25. MANAGEMENT
  26. 26. How is Alzheimer’s Disease managed at present? • Ideally, management should involve an interdisciplinary approach for assessment, treatment & education • The roles of nutritionists, caregivers, nurses, social workers and patients associations can be vital for the long term care • Pharmacological treatment – Cholinesterase inhibitors – Memantine
  27. 27. The 3 targets for Pharmacotherapy • Cognitive decline: memory, language, orientation, concentration, etc. • Behavioral abnormalities: delusions, aggressiveness, anxiety, depression, psychosis etc.. • Activities of Daily Living: dressing, bathing, feeding, use of household appliances, etc.
  28. 28. CHOLINESTERASE INHIBITORS RIVASTIGMINE GALANTAMINE DONEPEZIL
  29. 29. Galantamine
  30. 30. Rivastigmine patch: a new approach to dementia therapy
  31. 31. Smooth and continuous drug delivery over 24 hours Graphic representation (not „real‟ data) Increased side effects Poor activity “Optimal therapeutic window” Druglevelintheblood Peak Oral Dose Trough Patch Time
  32. 32. Other cholinesterase inhibitors
  33. 33. Dimebon (latrepirdine) -Phase III -Cholinesterase inhibitor and also a NMDA-antagonist
  34. 34. Ladostigil - Combined neuroprotective effects with monoamine oxidase (MAO) -A and -B and cholinesterase inhibitory activities in a single molecule, - Phase II clinical trial
  35. 35. Nicotine • Nicotine is a cholinergic agonist that acts both postsynaptically and pre-synaptically to release acetylcholine • Nicotine evoked improvement in learning and memory is mediated through neuropeptide Y
  36. 36. http://www.drugdevelopment-technology.com/projects/phenserine/phenserine4.html
  37. 37. MEMANTINE
  38. 38. Memantine
  39. 39. Winblad et al Int J Geriatr Psychiatry 2007
  40. 40. SEARCH FOR NEW TREATMENTS
  41. 41. • TREATMENT BASED ON AMYLOID PATHOLOGY • TREATMENT BASED ON TAU PATHOLOGY • TREATMENT BASED ON OTHER MECHANISMS
  42. 42. Vassar, R., and Bennet, B.D. (1998) Beta-secretase cleavage of alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286, 5440-5464
  43. 43. Aβ-degrading enzymes (neprilysin) Imatinib • A tyrosine kinase inhibitor, was shown to elevate NEP protein, mRNA levels, and activity in human neuroglioma cells Valproic acid • Up-regulating NEP expression and activity in human neuroblastoma SH- SY5Y cell lines. Estrogen Green tea Hong-Qi et al. Translational Neurodegeneration 2012, 1:21
  44. 44. M1 muscarinic agonist • Activation of M1 mAChRs – Enhanced secretion of sAPPα, (via α-secretase activation), – Decreased Aβ (via γ-secretase inhibition), – Inhibits Aβ- and/or oxidative stress-induced cell death. Talsaclidine • Phase II • In a double-blind, placebo-controlled, and randomized clinical study in AD patients, treatment with talsaclidine decreased CSF Aβ about 20% as compared with the baseline
  45. 45. Statins • Phase II • Cholesterol-rich diet increased β-secretase processing of APP while cholesterol lowering resulted in decreased Aβ production
  46. 46. Metals
  47. 47. Clioquinol Phase II
  48. 48. Apolipoprotein E (ApoE) promotes Aβ clearance Bexarotene Phase II Hong-Qi et al. Translational Neurodegeneration 2012, 1:21
  49. 49. Solanezumab Phase III
  50. 50. Melatonin - Phase III - This neurohormone prevents neuronal death caused by exposure to the amyloid beta protein. - It inhibits the aggregation of the amyloid beta protein into neurotoxic microaggregates. - Prevent the hyperphosphorylation of the tau protein in rats. Hong-Qi et al. Translational Neurodegeneration 2012, 1:21
  51. 51. • TREATMENT BASED ON AMYLOID PATHOLOGY • TREATMENT BASED ON TAU PATHOLOGY • TREATMENT BASED ON OTHER MECHANISMS
  52. 52. Prevention of phosphorylation of tau • Cyclin-dependent kinase-5 (CDK5) is a kinase suggested to phosphorylate tau in AD. • Glycogen synthase kinase (GSK)-3β has also been suggested as a drug target to inhibit tangle formation. Lithium and Propentofylline (PPF) • Phase II • It reduced the active form of GSK-3β and prevented the hyperphosphorylation of tau. Hong-Qi et al. Translational Neurodegeneration 2012, 1:21
  53. 53. Davunetide • Neuroprotective • Phase 2 Dementia: update for practitioner. Columbia university
  54. 54. Prevention of the aggregation of tau • Methylene blue – phase II • Methylthioninium chloride • Phenothiazines, • Anthraquinones • Polyphenols • Thiacarbocyanine dyes • N-phenylamines, • Thiazolyl-hydrazides, rhodanines,
  55. 55. • TREATMENT BASED ON AMYLOID PATHOLOGY • TREATMENT BASED ON TAU PATHOLOGY • TREATMENT BASED ON OTHER MECHANISMS • Monoamine Oxidase Inhibitors • Resveratrol • DHA • Caprylidene • Cell transplantation and Gene therapy
  56. 56. Monoamine oxidase inhibitors Neurobiology of aging, 2000
  57. 57. Resveratrol • Phase III • Red wine bioactive compounds • Inhibition of Aβ aggregation, by scavenging oxidants and exerting antiinflammatory activities Hong-Qi et al. Translational Neurodegeneration 2012, 1:21
  58. 58. Caprylidene • Medium chain triglyceride produced by processing coconut oil or palm oil • FDA Approved March 2009
  59. 59. DHA Phase III MECHANISMS: DHA is a major component of neuron membranes and has multiple functions, including modulation of presenilin.
  60. 60. Cell transplantation and gene therapy • Transplantation of cholinergic-rich tissue or peripheral cholinergic neurons ameliorates abnormal behavior and cognitive function • GENE THERAPY – NGF administration in a phase I trial – Aβ-degrading enzymes Hong-Qi et al. Translational Neurodegeneration 2012, 1:21
  61. 61. Famous Alzheimer’s patients: Ronald Reagan, Charlton Heston, Rita Hayworth, George Fernandes

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