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Predicting Response to Cholinesterase Inhibitors in Alzheimer’s Disease

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Summary

Cholinesterase inhibitors have been more extensively investigated for the treatment of Alzheimer’s disease than other medications. Currently, tacrine is the only Cholinesterase inhibitor that is approved for marketing in the US, Australia and several European countries. Other Cholinesterase inhibitors that are currently in phase II and III clinical trials are likely to become available in the next few years. Although these agents have not been as effective as originally expected, they modestly improve cognitive function and functional activities in a subset of patients with Alzheimer’s disease.

Potential predictors or response modifiers to Cholinesterase inhibitors include demographic, clinical and biological characteristics of patients. The most impressive determinants of clinical response seem to be sufficient dosage, plasma concentrations and Cholinesterase inhibition, or the effect on the CNS as indicated by elec troencephalography, cerebral blood flow or positron emission tomography (PET).

At present, the best approach to the early prediction of response is to treat patients with adequate doses of Cholinesterase inhibitor, and to assess for early response within 4 weeks of instituting adequate dosage. However, there is no published basis for withholding medication from a patient because he or she is deemed to have a poor probability of response.

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References

  1. Hefti F, Schneider LS. Rationale for the planned clinical trials with nerve growth factor in Alzheimer’s disease. Psychiatr Dev 1989;7:297–315

    PubMed  CAS  Google Scholar 

  2. Becker RE, Giacobini E. Mechanisms of Cholinesterase inhibition in senile dementia of the Alzheimer type: clinical, pharmacological, and therapeutic aspects. Drug Dev Res 1988; 12: 163–95

    Article  CAS  Google Scholar 

  3. Thal LJ, Fuld PA, Masur DM, et al. Oral physostigmine and lecithin improve memory in Alzheimer’s disease. Ann Neurol 1983; 13:491–6

    Article  PubMed  CAS  Google Scholar 

  4. Mohs RC, Davis BM, Johns CA, et al. Oral physostigmine treatment of patients with Alzheimer’s disease. Am J Psychiatry 1985; 142: 28–33

    PubMed  CAS  Google Scholar 

  5. Stern Y, Sano M, Mayeux R. Long-term administration of oral physostigmine in Alzheimer’s disease. Neurology 1988; 38: 1837–41

    Article  PubMed  CAS  Google Scholar 

  6. Harrell LE, Jope RS, Falgout J, et al. Biological and neuropsychological characterization of physostigmine responders and nonresponders in Alzheimer’s disease. J Am Geriatr Soc 1990; 38: 113–22

    PubMed  CAS  Google Scholar 

  7. Jorm AF. Effects of cholinergic enhancement therapies on memory function in Alzheimer’s disease: a meta-analysis of the literature. Aust NZ J Psychiatry 1986; 20: 237–40

    Article  CAS  Google Scholar 

  8. Davis KL, Thal LJ, Gamzu E, et al. Tacrine in patients with Alzheimer’s disease: a double-blind, placebo-controlled multi-center study. N Engl J Med 1992; 327: 1253–9

    Article  PubMed  CAS  Google Scholar 

  9. Farlow M, Gracon SI, Hershey LA, et al. A 12-week, double-blind, placebo-controlled, parallel-group study of tacrine in patients with probable Alzheimer’s disease. JAMA 1992; 268: 2523–9

    Article  PubMed  CAS  Google Scholar 

  10. Knapp MJ, Knopman DS, Solomon PR, et al. Controlled trials of high-dose tacrine in patients with Alzheimer’s disease. JAMA 1994; 271:985–91

    Article  PubMed  CAS  Google Scholar 

  11. Antuono PG. Efficacy and safety of velnacrine for Alzheimer’s disease: a double-blind, placebo-controlled study. Arch Intern Med. In press

  12. Forette F, Bert P, Breuil V, et al. Therapeutic drug trials and heterogeneity of Alzheimer’s disease. In: F Boller, F Forette, Z Khachaturian, et al., editors. Clinical heterogeneity in Alzheimer’s disease. New York: Springer-Verlag, 1992: 67–73

    Chapter  Google Scholar 

  13. Bartus RT, Dean RL. Tetrahydroaminoacridine, 3,4-diamino-pyridine and physostigmine: direct comparison of effects on memory in aged primates. Neurobiol Aging 1988; 9: 351–6

    Article  PubMed  CAS  Google Scholar 

  14. Goa KL, Fitton A. Velnacrine in Alzheimer’s disease: an initial appraisal of its clinical potential. CNS Drugs 1994; 1: 232–40

    Article  Google Scholar 

  15. Nordberg A, Nilsson-Hakansson L, Adem A, et al. Multiple actions of THA on cholinergic neurotransmission in Alzheimer’s brains. Prog Clin Biol Res 1989; 317: 1169–78

    PubMed  CAS  Google Scholar 

  16. Robinson TN, De Souza RJ, Cross RJ, et al. The mechanism of tetrahydroaminoacridine-evoked release of endogenous 5-hydroxytryptamine and dopamine from rat brain tissue prisms. Br J Pharmacol 1989; 98: 1127–36

    Article  PubMed  CAS  Google Scholar 

  17. Drukarch B, Leysen JE, Stoof JC. Further analysis of the neuro-pharmacological profile of 9-amino-1, 2, 3,4tetrahydroacrid-ine (THA), an alleged drug for the treatment of Alzheimer’s disease. Life Sci 1988; 42: 1011–7

    Article  PubMed  CAS  Google Scholar 

  18. Soininen H, Unni L, Shillcutt S. Effect of acute and chronic Cholinesterase inhibition on biogenic amines in rat brain. Neurochem Res 1990; 15: 1185–90

    Article  PubMed  CAS  Google Scholar 

  19. Åhlin A, Nybäck H, Junthé T, et al. Tetrahydroaminoacridine (THA) in Alzheimer’s dementia [abstract]. Neurobiol Aging 1990; 11: 344

    Google Scholar 

  20. Chui HC, Lyness S, Sobel E, et al. Extrapyramidal signs and psychiatric symptoms predict faster rate of progression in Alzheimer’s disease. Arch Neurology 1994; 51: 676–81

    Article  CAS  Google Scholar 

  21. Summers WK, Majovski LV, Marsh GM, et al. Oral tetrahydro-aminoacridine in long-term treatment of senile dementia, Alzheimer type. N Engl J Med 1986; 315: 1241–5

    Article  PubMed  CAS  Google Scholar 

  22. Fitten LJ, Perryman KM, Gross PL, et al. Treatment of Alz heimer’s disease with short- and long-term oral THA and lecithin: adouble-blind study. Am J Psychiatry 1990; 147: 239–42

    PubMed  CAS  Google Scholar 

  23. Davies B, Andrewes D, Stargatt R, et al. Tetrahydroaminoacridine in Alzheimer’s disease. Int J Geriatr Psychiatry 1990; 5: 317–21

    Article  Google Scholar 

  24. Gauthier S, Bouchard R, Lamontagne A, et al. Tetrahydro-aminoacridine-lecithin combination treatment in patients with intermediate-stage Alzheimer’s disease: results of a Canadian double-blind, crossover, multicenter study. N Engl J Med 1990; 322: 1272–6

    Article  PubMed  CAS  Google Scholar 

  25. Chatellier G, Lacomblez L, on behalf of Groupe Francais d’Etude de la Tetrahydroaminoacridine. Tacrine (tetrahydroaminoacridine; THA) and lecithin in senile dementia of the Alzheimer’s type: a multicentre trial. BMJ 1990; 300: 495–9

    Article  PubMed  CAS  Google Scholar 

  26. Weinstein HC, Teunisse S, van Goog WA. Tetrahydroaminoacridine and lecithin in the treatment of Alzheimer’s disease. Effect on cognition, functioning in daily life, behavioral disturbances and burden experienced by the carers. J Neurol 1991; 238: 34–8

    Article  PubMed  CAS  Google Scholar 

  27. Murphy MF, Hardiman ST, Nash RJ, et al. Evaluation of HP 029 (velnacrine maleate) in Alzheimer’s disease. Ann NY Acad Sci 1991; 640: 253–62

    PubMed  CAS  Google Scholar 

  28. Eagger SA, Levy R, Sahakian BJ. Tacrine in Alzheimer’s disease. Lancet 1991; 337: 989–92

    Article  PubMed  CAS  Google Scholar 

  29. Siegfired K. A placebo-controlled crossover study of velnacrine in patients with Alzheimer’s disease [abstract]. Neurology 1992; 42 Suppl. 3: 141

    Google Scholar 

  30. Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer’s disease. Am J Psychiatry 1984; 141: 1356–64

    PubMed  CAS  Google Scholar 

  31. Folstein MF, Folstein SE, McHugh PR. ‘Mini-mental state’ a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12: 189–98

    Article  PubMed  CAS  Google Scholar 

  32. Eagger S, Morant N, Levy R, et al. Tacrine in Alzheimer’s disease: time course of changes in cognitive function and practice effects. Br J Psychiatry 1992; 160: 36–40

    Article  PubMed  CAS  Google Scholar 

  33. Holford NHG, Peace K. Results and validation of a population pharmacodynamic model for cognitive effects in Alzheimer patients treated with tacrine. Proc Natl Acad Sci 1992; 89: 11471–5

    Article  PubMed  CAS  Google Scholar 

  34. Schneider LS, Farlow MK, Henderson VW, et al. Estrogen replacement therapy may enhance response to tacrine in women with Alzheimer’s disease [abstract]. Presented at the 47th Annual Meeting of the American Academy of Neurology; 1995 May 10; Seattle

    Google Scholar 

  35. Nordberg A, Lilja A, Lundqvist H, et al. Tacrine restores cholinergic nicotinic receptors and glucose metabolism in Alzheimer patients as visualized by positron emission tomography. Neurobiol Aging 1992; 13: 747–58

    Article  PubMed  CAS  Google Scholar 

  36. Perryman KM, Fitten LJ. Delaying matching-to-sample performance during a double-blind trial of tacrine (THA) and lecithin in patients with Alzheimerś disease. Life Sci 1993; 53: 479–86

    Article  PubMed  CAS  Google Scholar 

  37. Farlow MR, Brashear A, Hui S, et al. The effects of tacrine in patients with mild versus moderate stage Alzheimer’s disease. Neurobiol Aging 1994; 15 S81: 331

    Google Scholar 

  38. Kaufer DI, Cummings JL. Does dementia severity predict response to tacrine in Alzheimer’s disease? [abstract]. Presented at the 47th Annual Meeting of American Academy of Neurology; 1995 May 11; Seattle

    Google Scholar 

  39. Olin JT, Schneider LS. Assessing response to tacrine using the factor analytical structure of the Alzheimer’s Disease Assessment Scale (ADAS)-Cognitive subscale. Int J Geriatr Psychiatr. In press

  40. Sahakian BJ, Coull JT. Tetrahydroaminoacridine (THA) in Alzheimer’s disease: an assessment of attentional and mnemonic function using CANTAB. Acta Neurol Scan 1993; 149 Suppl.: 29–35

    CAS  Google Scholar 

  41. McKeith I, Fairbairn A, Perry R. Neuroleptic sensitivity in patients with senile dementia of Lewy body type. BMJ 1992; 305: 673–8

    Article  PubMed  CAS  Google Scholar 

  42. Perry RH, Irving D, Blessed G, et al. Senile dementia of Lewy body type, a clinically and neuropathologically distinct form of Lewy body dementia in the elderly. J Neurol Sci 1990; 95: 119–39

    Article  PubMed  CAS  Google Scholar 

  43. Levy R, Eagger S, Griffiths M, et al. Lewy bodies and response to tacrine in Alzheimer’s disease [letter]. Lancet 1994; 343: 176

    Article  PubMed  CAS  Google Scholar 

  44. Wilcock GK, Scott M, Pearsall T. Long-term use of tacrine [letter]. Lancet 1994; 343:294

    Article  PubMed  CAS  Google Scholar 

  45. Cummings JL, Gorman DG, Shapira J. Physostigmine ameliorates the delusions of Alzheimer’s disease. Biol Psychiatry 1993; 33(7): 536–41

    Article  PubMed  CAS  Google Scholar 

  46. Eagger S, Levy R. Serum levels of tacrine in relation to clinical response in Alzheimer’s disease. Int J Geriatr Psychiatry 1992; 7: 115–9

    Article  Google Scholar 

  47. Food and Drug Administration PCNS Drugs Advisory Committee meeting; 1991 Mar 15

  48. Nybäck H, Hassan M, Junthe M, et al. Clinical experiences and biochemical findings with tacrine (THA). Acta Neurol Scand 1993; 149 Suppl.: 36–8

    Google Scholar 

  49. Davis KL, Levy R, Murphy MF, et al. Clinical trials of THA and HP 029 in Alzheimer’s disease [abstract]. Presented at the American College of Neuropsychopharmacology Annual Meeting; 1991 Dec 11; San Juan

    Google Scholar 

  50. Becker RE, Giacobini E. Pharmacokinetics and pharmacody namics of acetylcholinesterase inhibition — can acetylcholine levels in brain be improved in Alzheimer’s disease? Drug Dev Res 1988; 14: 235–46

    Article  Google Scholar 

  51. Imbimbo BP, Lucchelli PE. A pharmacodynamic strategy to optimize the clinical response to eptastigmine (MF-201). In: Giacobini E, Becker R. Alzheimer disease: therapeutic strategies. Boston: Birkhäuser Verlag AG, 1994: 103–7

    Google Scholar 

  52. Ebmeier KP, Hunter R, Curran SM, et al. Effects of a single dose of the acetylcholinesterase inhibitor velnacrine on recognition memory and regional cerebral blood flow in Alzheimer’s disease. Psychopharmacology 1992; 108: 103–9

    Article  PubMed  CAS  Google Scholar 

  53. Alhainen K, Helkala EL, Riekkinen P. Psychometric discrimination of tetrahydroaminoacridine responders in Alzheimer patients. Dementia 1993; 4: 54–8

    PubMed  CAS  Google Scholar 

  54. Perryman KM, Fitten LJ. Quantitative EEG during a double-blind trial of THA and lecithin in patients with Alzheimer’s disease. J Geriatr Psychiatry Neurol 1991; 4: 127–33

    Article  PubMed  CAS  Google Scholar 

  55. Gasnault J, Gueguen B, Bourdel MC, et al. THA effects on EEG activity in a double-blind cross-over study in Alzheimer’s disease [abstract]. Electroencephalogr Clin Neurophysiol 1990; 75: S49

    Google Scholar 

  56. Alhainen K, Partanen J, Reinikainen K, et al. Discrimination of tetrahydroaminoacridine responders by a single dose phar-maco-EEG in patients with Alzheimer’s disease. Neurosci Lett 1991; 127: 113–6

    Article  PubMed  CAS  Google Scholar 

  57. Riekkinen P, Alhainen K, Soininen H, et al. The effect of THA on cognitive functions and spectral power EEG in AD [abstract]. Neurobiol Aging 1990; 11: 342

    Google Scholar 

  58. Shigeta M, Persson A, Viitanen M, et al. EEG regional changes during long-term treatment with tetrahydroaminoacridine (THA) in Alzheimer’s disease. Acta Neurol Scand 1993; 149 Suppl.: 58–61

    CAS  Google Scholar 

  59. Alhainen K, Riekkinen PJ. Discrimination of Alzheimer patients responding to Cholinesterase inhibitor therapy. Acta Neurol Scand 1993: 149 Suppl.: 16–21

    CAS  Google Scholar 

  60. Margolin RA, Schneider LS, Ge Y. Velnacrine raises brain metabolism in Alzheimer’s disease [abstract no. 407]. Presented at the American Psychiatric Association Annual Meeting; 1991 May 15; New Orleans

    Google Scholar 

  61. Tune L, Brandt J, Frost JJ, et al. Physostigmine in Alzheimer’s disease: effects of cognitive functioning, cerebral glucose metabolism analysed by single photon emission tomography and cerebral blood flow analysed by single photon emission tomography. Acta Psychiatr Scand 1991; 366 Suppl.: 61–5

    Article  CAS  Google Scholar 

  62. Minthon L, Gustafson L, Dalfelt G, et al. Oral tetrahydroaminoacridine treatment of Alzheimer’s disease evaluated clinically and by regional cerebral blood flow and EEG. Dementia 1993; 4: 32–42

    PubMed  CAS  Google Scholar 

  63. Schneider LS, Lyness SA, Pawluczyk S, et al. Does blood pressure and age predict response to tacrine? A preliminary report. Psychopharmacol Bull 1991; 27: 309–14

    PubMed  CAS  Google Scholar 

  64. Pomara N, Deptula D, Singh R. Pretreatment postural blood pressure drop as a possible predictor of response to the Cholinesterase inhibitor velnacrine (HP 029) in Alzheimer’s dis ease. Psychopharmacol Bull 1991; 27: 301–7

    PubMed  CAS  Google Scholar 

  65. Alhainen K, Helkala EL, Reinikainen K, et al. The relationship of cerebrospinal fluid monoamine metabolites with clinical response to tetrahydroaminoacridine in patients with Alzheimer’s disease. J Neurol Transm 1993; 5: 185–92

    Article  CAS  Google Scholar 

  66. Åhlin A, Nyback H, Junthe T, et al. THA in Alzheimer’s dementia: clinical biochemical and pharmacokinetic findings. In: Iqbal K, McLachlan DCR, Winblad B, et al., editors. Alzheimer’s Disease: basic mechanisms, diagnosis and therapeutic strategies. Chichester: Wiley & Sons Ltd, 1991: 522–32

    Google Scholar 

  67. Gottfries CG. Neurochemical aspects on aging and disease with cognitive impairment. J Neurochem Res 1990; 27: 541–7

    CAS  Google Scholar 

  68. Reinikainen KJ, Soininen H, Riekkinen PJ. Neurotransmitter changes in Alzheimer’s disease: implications to diagnostics and therapy. J Neurosci Res 1990; 27: 576–86

    Article  PubMed  CAS  Google Scholar 

  69. Kumar V, Smith RC, Sherman KA, et al. Cortisol responses to cholinergic drugs in Alzheimer’s disease. Int J Clin Pharmacol Ther Toxicol 1988; 26: 471–6

    PubMed  CAS  Google Scholar 

  70. Hardiman S, Miller K, Murphy M. Clinical trials with velnacrine: (PROPP) The physician reference of predicted probabilities — a statistical model for the estimation of hepatotoxicity risk with velnacrine maleate. Acta Neurol Scand 1993; 149 Suppl.: 46–52

    CAS  Google Scholar 

  71. Tavitian B, Pappata S, Planas AM, et al. In vivo visualization of acetylcholinesterase with positron emission tomography. NeuroReport 1993; 4(5): 535–8

    Article  PubMed  CAS  Google Scholar 

  72. Sunderland T, Tariot PN, Cohen RM, et al. Anticholinergic sensitivity in patients with dementia of the Alzheimer type and age-matched controls. Arch Gen Psychiatry 1987; 44: 418–26

    Article  PubMed  CAS  Google Scholar 

  73. Becker RE, Moriearty P, Sunbeck R, et al. Second and third generation Cholinesterase inhibitors: clinical aspects. In: Giacobini E, Becker RE. Alzheimer’s disease: therapeutic strategies. Boston: Birkhäuser Verlag AG, 1994: 172–8

    Google Scholar 

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Schneider, L.S., Farlow, M.R. Predicting Response to Cholinesterase Inhibitors in Alzheimer’s Disease. CNS Drugs 4, 114–124 (1995). https://doi.org/10.2165/00023210-199504020-00004

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