מחלת אלצהיימר טיפול במעכבי כולין אסטרז ובממנטין במחלת אלצהיימר 1. CP Ferri, M Prince, Brayne et al. Alzheimer's Disease International. Global prevalence of dementia: a Delphi consensus study. Lancet, 2005;366:2112–2117 2. World Health Report 2003—Shaping the futureWHO, Geneva (2003) 3. Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82(4),239–259. 4. Morris R, Mucke L. Alzheimer's disease: A needle from the haystack. Nature.200616;440(7082):284-5 5. Small SA, Duff K. Linking Abeta and tau in late-onset Alzheimer's disease: a dual pathway hypothesis. Neuron. 2008;60(4):534-42. 6. Meraz-Ríos MA, Lira-De León KI, Campos-Peña V, et al. Tau oligomers and aggregation in Alzheimer's disease. J Neurochem. 2010;112(6):135367. 7. Takashima A. Amyloid-beta, tau, and dementia. J Alzheimers Dis. 2009;17(4):729-36. 8. Corder EH, Saunders AM, Strittmatter WJ,et al.Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993;261(5123):921-3 9. Gatz M, Reynolds CA, Fratiglioni L, et al. Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry. 2006;63(2):168-74 10. Hardy J, Myers A, Wavrant-De Vrieze F. Problems and solutions in the genetic analysis of late-onset Alzheimer's disease. Neurodegener Dis. 2004;1(4-5):213-7. 11. Jonsson T, Atwal JK, Steinberg S et al. A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. Nature. 2012;488(7409):96-9. 12. Mesulam MM, Hersh LB, Mash DC, et al. Differential cholinergic innervation within functional subdivisions of the human cerebral cortex: a choline acetyltransferase study. J. Comp. Neurol.1992;318(3),316–328. 1 13. Carnes KM, Fuller TA, Price JL. Sources of presumptive glutamatergic/aspartatergic afferents to the magnocellular basal forebrain in the rat. J Comp Neurol. 1990;302(4):824-52. 14. Zilles K, Werner L, Qü M, Schleicher A, Gross G. Quantitative autoradiography of 11 different transmitter binding sites in the basal forebrain region of the rat-evidence of heterogeneity in distribution patterns. Neuroscience. 1991;42(2):473-81. 15. Francis PT, Palmer AM, Snape M, Wilcock GK. The cholinergic hypothesis of Alzheimer’s disease: a review of progress. J. Neurol. Neurosurg. Psychiatr. 1999;66(2):137–147 16. Bowen DM, Benton JS, Spillane JA, et al. Choline acetyltransferase activity and histopathology of frontal neocortex from biopsies of demented patients. J. Neurol. Sci.1982;57(2–3),191–202. 17. Davis KL, Mohs RC, Marin D et al. Cholinergic markers in elderly patients with early signs of Alzheimer disease. JAMA. 1999; 281(15),1401–1406. 18. Neary D, Snowden JS, Mann DM et al. Alzheimer’s disease: a correlative study. J. Neurol. Neurosurg. Psychiatr.1986;49(3),229–237. 19. Wilkinson DG, Francis PT, Schwam E, Payne-Parrish J. Cholinesterase inhibitors used in the treatment of Alzheimer’s disease: the relationship between pharmacological effects and clinical efficacy. Drugs Aging. 2004;21(7),453–478. 20. Birks J. Cholinesterase inhibitors for Alzheimer's disease. Cochrane Database Syst Rev. 2006 21. Kuhl DE, Minoshima S, Frey KA, et al. Limited donepezil inhibition of acetylcholinesterase measured with positron emission tomography in living Alzheimer cerebral cortex. Ann Neurol. 2000;48(3):391-5. 22. Farlow MR, Lilly ML; ENA713 B352 Study Group. Rivastigmine: an openlabel, observational study of safety and effectiveness in treating patients with Alzheimer’s disease for up to 5 years. BMC Geriatr. 2005;5:3. 2 23. Tariot PN, Farlow MR, Grossberg GT, et al . Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA. 2004;291:317-324. 24. Doody RS, Geldmacher DS, Gordon B, et al.; Donepezil Study Group. Open-label, multicenter, phase 3 extension study of the safety and efficacy of donepezil in patients with Alzheimer disease. Arch Neurol. 2001;58(3):427-433. 25. Rogers SL, Doody RS, Pratt RD, et al. Long-term efficacy and safety of donepezil in the treatment of Alzheimer’s disease: final analysis of a US multicentre open-label study. Eur Neuropsychopharmacol. 2000;10(3):195-203. 26. Grossberg G, Irwin P, Satlin A et al. Rivastigmine in Alzheimer disease: efficacy over two years. Am J Geriatr Psychiatry. 2004;12(4):420-431. 27. Lyketsos CG, Reichman WE, Kershaw P, et al. Long-term outcomes of galantamine treatment in patients with Alzheimer disease. Am J Geriatr Psychiatry. 2004;12(5):473-482. 28. Raskind MA, Peskind ER, Truyen L, et al. The cognitive benefits of galantamine are sustained for at least 36 months: a long-term extension trial. Arch Neurol. 2004;61(2): 252-256. 29. Khang P, Weintraub N, Espinoza RT. The use, benefits, and costs of cholinesterase inhibitors for Alzheimer’s dementia in long-term care: are the data relevant and available? J Am Med Dir Assoc. 2004;5(4):249-255. 30. da Costa Dias FL, da Silva RM, de Moraes EN, Caramelli P. Cholinesterase Inhibitors Modulate Autonomic Function in Patients with Alzheimer's Disease and Mixed Dementia. Curr Alzheimer Res. 2013 31. Farlow MR, Salloway S, Tariot PN, et al. Effectiveness and tolerability of high-dose (23 mg/d) versus standard-dose (10 mg/d) donepezil in moderate to severe Alzheimer's disease: A 24-week, randomized, doubleblind study. Clin Ther. 2010;32(7):1234-51. 32. Cummings J, Froelich L, Black SE, et al. Randomized, double-blind, parallel-group, 48-week study for efficacy and safety of a higher-dose rivastigmine patch (15 vs. 10 cm²) in Alzheimer's disease. Dement Geriatr Cogn Disord. 2012;33(5):341-53. 3 33. Fonnum F. Glutamate: a neurotransmitter in mammalian brain. J. Neurochem.1984;42(1),1–11. 34. Auerbach JM, Segal M. A novel cholinergic induction of long-term potentiation in rat hippocampus. J. Neurophysiol.1994;72(4),2034–2040. 35. Greenamyre JT, Maragos WF, Albin RL et al. Glutamate transmission and toxicity in Alzheimer’s disease. Prog. Neuropsychopharmacol. Biol. Psychiatry.1998;12(4),421–430. 36. Snyder EM, Nong Y, Almeida CG et al. Regulation of NMDA receptor trafficking by amyloid-b. Nat. Neurosci.2005;8(8),1051–1058. 37. Danysz W, Parsons CG. Alzheimer’s disease, β-amyloid, glutamate, NMDA receptors and memantine – searching for the connections. Br. J. Pharmacol.2012;167(2),324–352. 38. Procter AW, Palmer AM, Francis PT et al. Evidence of glutamatergic denervation and possible abnormal metabolism in Alzheimer’s disease. J. Neurochem.1998;50(3),790–802. 39. Francis PT. Altered glutamate neurotransmission and behaviour in dementia: evidence from studies of memantine. Curr. Mol. Pharmacol. 2009;2(1),77–82. 40. Reisberg B, Doody R, Stöffler A et al. Memantine Study Group. Memantine in moderate-to-severe Alzheimer’s disease. N. Engl. J. Med.2003;348(14),1333–1341. 41. Tariot PN, Farlow MR, Grossberg GT et al. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA. 2004;291(3),317–324. 42. Winblad B, Jones RW, Wirth Y, Stöffler A, Möbius HJ. Memantine in moderate to severe Alzheimer’s disease: a meta-analysis of randomised clinical trials. Dement. Geriatr. Cogn. Disord.2007;24(1),20–27. 4 43. Gauthier S, Loft H, Cummings J. Improvement in behavioural symptoms in patients with moderate to severe Alzheimer’s disease by memantine: a pooled data analysis. Int. J. Geriatr. Psychiatry.2008;23(5),537–545). 44. Gauthier S, Wirth Y, Möbius HJ. Effects of memantine on behavioural symptoms in Alzheimer’s disease patients: an analysis of the Neuropsychiatric Inventory (NPI) data of two randomised, controlled studies. Int. J. Geriatr. Psychiatry.2005;20(5),459–464. 45. Cummings JL, Schneider E, Tariot PN, Graham SM; Memantine MEMMD-02 Study Group. Behavioral effects of memantine in Alzheimer disease patients receiving donepezil treatment. Neurology.2006;67(1),57– 63. 46. Choi SH, Park KW, Na DL, et al; Expect Study Group. Tolerability and efficacy of memantine add-on therapy to rivastigmine transdermal patches in mild to moderate Alzheimer's disease: a multicenter, randomized, openlabel, parallel-group study. Curr Med Res Opin. 2011;27(7):1375-83. 47. Nyakas C, Granic I, Halmy LG, et al. The basal forebrain cholinergic system in aging and dementia. Rescuing cholinergic neurons from neurotoxic amyloid-β42 with memantine. Behav. Brain Res.2011;221(2),594–603. 48. Gauthier S, Loft H, Cummings J. Improvement in behavioural symptoms in patients with moderate to severe Alzheimer’s disease by memantine: a pooled data analysis. Int J Geriatr Psychiatry. 2008;23:537-545. 49. Vidal JS, Lacombe JM, Dartigues JF, et al. Evaluation of the impact of memantine treatment initiation on psychotropics use: a study from the French national health care database. Neuroepidemiology. 2008;31:193200 50. Wilkinson D, Andersen HF. Analysis of the effect of memantine in reducing the worsening of clinical symptoms in patients with moderate to severe Alzheimer’s disease. Dement Geriatr Cogn Disord. 2007;24(2):138145. 5 51. Francis PT, Parsons CG, Jones RW. Rationale for combining glutamatergic and cholinergic approaches in the symptomatic treatment of Alzheimer's disease. Expert Rev Neurother. 2012;12(11):1351-65. 52. Lopes JP, Tarozzo G, Reggiani A, et al. Galantamine potentiates the neuroprotective effect of memantine against NMDA-induced excitotoxicity. Brain Behav. 2013;3(2):67-74. 53. Lopez OL, Becker JT, Wahed AS, et al. Long-term effects of the concomitant use of memantine with cholinesterase inhibition in Alzheimer disease. J Neurol Neurosurg Psychiatry. 2009;80:600-607. 54. Howard R, McShane R, Lindesay J, et al. Donepezil and memantine for moderate-to-severe Alzheimer's disease. N Engl J Med. 2012;366(10):893-903. 55. Tariot PN. Cessation of donepezil is associated with clinical decline in patients with moderate-to-severe Alzheimer's disease compared to continuation of donepezil or addition or substitution of memantine. Evid Based Med. 2013;18(2):62-3. 6