Hostname: page-component-848d4c4894-jbqgn Total loading time: 0 Render date: 2024-06-16T11:07:18.191Z Has data issue: false hasContentIssue false

Cognitive Enhancing Agents: Current Status in the Treatment of Alzheimer's Disease

Published online by Cambridge University Press:  18 September 2015

Cheryl Waters*
Affiliation:
Divisions of Neurology and Clinical Pharmacology, University of Toronto, Toronto
*
University of Southern California School of Medicine, Department of Neurology, 2025 Zonal Ave., Los Angeles, CA, U.S.A. 90033
Rights & Permissions [Opens in a new window]

Abstract:

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

Extensive recent literature on drugs used to enhance cognitive functioning, reflects the growing social problem of dementia. Many clinical trials have been undertaken with variable success. In most cases the disorder studied has been Alzheimer's disease. The pharmacological approach has been designed to rectify the presumed pathophysiological processes characteristic of the condition. Agents tested include cerebral vasodilators, cerebral metabolic enhancers, nootropics, psychostimulants, neuropeptides and neurotransmitters with a special emphasis on drugs used to enhance cholinergic function. Ethical and practical issues concerning clinical drug trials in dementia will be discussed.

Type
Special Features And Reviews
Copyright
Copyright © Canadian Neurological Sciences Federation 1988

References

REFERENCES

1.Byrne, J, Arie, T: Rational drug treatment of dementia. Br Med J 1985; 290: 18451846.CrossRefGoogle ScholarPubMed
2.Cook, P, James, I: Cerebral vasodilators. N Engl J Med 1981; 305: 15081513, 1560–1564.Google ScholarPubMed
3.Kopelman, MD, Lishman, WA: Pharmacological treatments of dementia (non-cholinergic). Brit Med Bull 1986; 42: 101105.CrossRefGoogle ScholarPubMed
4.Ferris, SH, DeLeon, MJ, Wolf, AP, et al. Positron emission tomography in the study of aging and senile dementia. Neurobiol Aging 1980; 1: 127131.CrossRefGoogle Scholar
5.Drachman, DA, Leavitt, J: Human memory and the cholinergic system. A relationship to aging?. Arch Neurol 1974; 30: 113121.CrossRefGoogle ScholarPubMed
6.Peters, BH, Levin, HS: Effects of physostigmine and lecithin on memory in Alzheimer’s disease. Ann Neurol 1979; 6: 219221.CrossRefGoogle Scholar
7.Ezrin-Waters, C, Resch, L: The nucleus basalis of Meynert. Can J. Neurol Sci 1986; 13: 814.CrossRefGoogle ScholarPubMed
8.Yesavage, JA, Hollister, L, Buriane, E: Vasodilators in senile dementia. A review of the literature. Arch Gen Psychiatry 1979; 36: 220224.CrossRefGoogle ScholarPubMed
9.Davies, G, Hamilton, S, Hendrickson, E, et al. The effect of cyclandelate in depressed and demented patients: a controlled study in psychogeriatric patients. Age and Ageing 1977; 6: 156162.CrossRefGoogle ScholarPubMed
10.Wittenborn, JR: Pharmacotherapy for age-related behavioural deficiencies. J Nerv Ment Dis 1981; 169: 139156.CrossRefGoogle ScholarPubMed
11.Goodnick, P, Gershon, S: Chemotherapy of cognitive disorders in geriatric subjects. J. Clin Psychiatry 1984; 45: 196209.Google ScholarPubMed
12.Jarvik, LF: Hydergine as a treatment for organic brain syndrome in late life. Psychopharmacol Bull 1981; 17: 4041.Google Scholar
13.Branconnier, RJ: The efficacy of the cerebral metabolic enhancers in the treatment of senile dementia. Psychopharmacol Bull 1983; 19: 212219.Google ScholarPubMed
14.Herrman, WM, Kern, U, Rohmel, J: On the effects of pyritinol on functional deficits of patients with organic mental disorders. Pharmacopsychiatria 1986; 19: 378385.CrossRefGoogle Scholar
15.Giurgea, CE: 1980 Fundamentals to a pharmacology of the mind. Charles C. Thomas. Springfield, III.Google Scholar
16.Growdon, JH, Corkin, S, Huff, FJ: Clinical evaluation of compounds for the treatment of memory dysfunction. Ann NY Acad Sci 1985; 444: 437449.CrossRefGoogle ScholarPubMed
17.Chouinard, G, Annable, L, Ross-Chouinard, A, et al. A doubleblind placebo-controlled study of piracetam in elderly psychiatric patients. Psychopharmacol Bull 1981; 17: 129.Google ScholarPubMed
18.Stegink, AJ: The clinical use of piracetam , a new nootropic drug. Arzneimittelforsch 1972; 22: 975977.Google ScholarPubMed
19.Ferris, SH, Reisberg, B, Crook, T, et al. Pharmacologic treatment of senile dementia: choline, L-DOPA, piracetam and choline plus piracetam. In: Corkin, S, ed. Alzheimer’s Disease: A Report of Progress (Aging, Volume 19. Raven Press, New York 1982: 475481.Google Scholar
20.Bartus, RT, Dean, RL III, Sherman, KA, et al: Profound effects of combining choline and piracetam on memory enhancement and cholinergic function in aged rats. Neurobiol Aging 1981; 2: 105111.CrossRefGoogle ScholarPubMed
21.Friedman, E, Sherman, KA, Ferris, S, et al, Schneck MK: Clinical response to choline plus piracetam in senile dementia: relation to red-cell choline levels. N Engl J Med 1981; 304: 14901491.Google ScholarPubMed
22.Wurtman, RJ, Magil, SG, Reisntein, DK: Piracetam diminishes hippocampal acetylcholine levels in rats. Life Sci 1981; 28: 10911093.CrossRefGoogle ScholarPubMed
23.Poschel, BPH, Marriott, JG, Gluckman, MI: Pharmacology underlying the cognition - activating properties of pramiracetam (CI-879). Psychopharmacol Bull 1983; 19: 720721.Google Scholar
24.Pugsley, TA, Poschel, PH, Downs, DA, et al: Some pharmacological and neurochemical properties of a new cognition activator agent, pramiracetam (Cl-879) Psychopharmacol Bull 1983; 19: 721726.Google Scholar
25.Branconnier, RJ, Cole, JO, Dessain, EC, et al: The therapeutic efficacy of pramiracetam in Alzheimer’s disease: preliminary observations. Psychopharmacol Bull 1983; 19: 726730.Google Scholar
26.Schwam, E, Keim, K, Cumin, R, et al: The effects of aniracetam on primate behaviour and EEG. Ann NY Acad Sci 1985; 444: 482484.CrossRefGoogle ScholarPubMed
27.Vincent, G, Verderese, A, Gamzu, E: The effects of aniracetam (Ro 13–5057) on the enhancement and protection of memory. Ann NY Acad Sci 1985; 444: 489491.CrossRefGoogle ScholarPubMed
28.Cumin, R, Bandle, EF, Gamzu, E, et al: Effects of novel compound aniracetam (Ro 13–5057) upon impaired learning and memory in rodents. Psychopharmacology 1982; 78: 104111.CrossRefGoogle ScholarPubMed
29.Sourander, LB, Portin, R, Molsa, P, et al: Senile dementia of the Alzheimer’s type treated with aniracetam. Psychopharmacology 1987; 91: 9095.CrossRefGoogle ScholarPubMed
30.Banfi, S, Dorigotti, L: Activity of ISF 2522 on learning rate in rats using water maze test CNS report No. 26 ISF S.p.A. Trezzano, Italy.Google Scholar
31.Banfi, S, Dorigotti, L: Activity of ISF 2522 on the amnestic effect induced by maximal electro shock, cerebral edema, and administration of diazepam, assessed on the basis of passive avoidance tests in mice CNS Lab and Pharmacobiological Res. Lab Report No. 35 ISF S.p.A. Trezzano, Italy.Google Scholar
32.Itil, TM, Gopi, N, Menon, GN, et al. The effects of oxiracetam (ISF 2522) in patients with organic brain syndrome (a double-blind controlled study with piracetam). Drug Dev. Res. 1982; 2: 447461.CrossRefGoogle Scholar
33.Moglia, A, Sinforiani, E, Zandrini, C, et al. Activity of oxiracetam in patients with organic brain syndrome: A neuropsychological study. Clin Neuropharmacol 1986; 9 (suppl3): 573578.CrossRefGoogle ScholarPubMed
34.Villardita, C, Parini, J, Grioli, S, et al: Clinical and neuropsychological investigation on oxiracetam in patients in mild to moderate degree dementia. Clin Neuropharmacol 1986; 9 (suppl14): 301303.Google Scholar
35.Pepeu, G, Spignoli, G: Effect of oxiracetam on cognition and brain cholinergic mechanisms. Clin Neuropharmacol 1986; 9 (suppl14): 298300.Google ScholarPubMed
36.Itil, TM, Mukherjee, S, Michael, ST, et al: Clinical and electrophysiological effects of suloctidil in elderly patients with multiinfarct dementia (a double-blind placebo-controlled study). Psychopharmacol Bull 1983; 19: 730733.Google Scholar
37.Kaplitz, SE: Withdrawn, apathetic geriatric patients responsive to methylphenidate. J Am Geriatr Soc 1975; 23: 271276.CrossRefGoogle ScholarPubMed
38.Crook, T, Ferris, S, Sathananthan, G, et al: The effect of methylphenidate on test performance in the cognitively impaired aged. Psychopharmacology 1977; 52: 251255.CrossRefGoogle ScholarPubMed
39.Turek, I, Kurland, AA, Ota, KY, et al: Effect of pipradol hydrochloride on geriatric patients. J Am Geriatr Soc 1969; 17: 408413.CrossRefGoogle ScholarPubMed
40.Eisdorfer, C, Conner, JF, Wilkie, FL: The effect of magnesium pemoline on cognition and behaviour. J Gerontol 1968; 23: 283233.CrossRefGoogle Scholar
41.DeWied, D: The importance of vasopressin in memory. Trends Neurosci 1984; 7: 6263.Google Scholar
42.Chase, TN, Durso, R, Fedio, P, et al: Vasopressin treatment of cognitive deficits in Alzheimer’s disease. In: Corkin, S, Davis, KL, Growdon, JH, Usdin, E, Wurtman, RJ, eds. Alzheimer’s Disease: A report of Progress (Aging Volume 19). Raven Press, New York 1982: 457461.Google Scholar
43.Durso, R, Fedio, P, Brouwers, P, et al. Lysine vasopressin in Alzheimer’s disease. Neurology 1982; 32: 674677.CrossRefGoogle Scholar
44.Weingartner, H, Gold, P, Ballenger, JC, et al: Effects of vasopressin on human memory functions. Science 1981; 211: 601603.CrossRefGoogle ScholarPubMed
45.Jenkins, JS, Mather, HM, Coughlan, AK: Effect of desmopressin on normal and impaired memory. J Neurol Neurosurg Psychiatry 1982; 45: 830831.CrossRefGoogle ScholarPubMed
46.Tinklenberg, JR, Pigache, R, Pfefferbaum, A, et al: Vasopressin peptides and dementia. In: Corkin, S, Davis, KL, Growdon, JH, Usdin, E, Wurtman, RJ, eds: Alzheimer’s disease: A report of Progress (Aging Volume 19) Raven Press, New York 1982: 462468.Google Scholar
47.Legros, JJ, Gilot, P, Seron, X, et al: Influence of vasopressin on learning and memory. Lancet 1978; 1: 41–2.CrossRefGoogle ScholarPubMed
48.Oliveros, JC, Jandali, MK, Timsit-Berthier, M, et al: Vasopressin in amnesia. Lancet 1978; 1: 42.CrossRefGoogle ScholarPubMed
49.Blake, RD, Dodd, MJ, Evans, JG: Vasopressin in amnesia. Lancet 1978; 1: 608.CrossRefGoogle ScholarPubMed
50.Peabody, CA, Thiemann, S, Pigache, R, et al: Desglycinamide9-arginine-8-vasopressin (DGAVP, Organon 5667) in patients with dementia. Neurobiol Aging 1985; 6: 95100.CrossRefGoogle ScholarPubMed
51.DeWied, D, Van Ree, JM: Neuropeptides, mental performance and aging. Life Sci 1982; 31: 709719.CrossRefGoogle Scholar
52.Reisberg, B, London, E, Ferris, SH, et al: Novel pharmacologic approaches to the treatment of senile dementia of the Alzheimer’s type (SDAT). Psychopharmacol Bull 1983; 19: 220225.Google Scholar
53.Reisberg, B, Ferris, SH, Anand, R, et al: Effects of naloxone in senile dementia: a double-blind trial. N Engl J Med 1983; 308: 721722.Google ScholarPubMed
54.Blass, J, Reding, M, Drachman, D, et al: Letter to the editor. N Engl J Med 1983; 309: 556.Google Scholar
55.Steiger, WA, Mendelson, M, Jenkins, T, et al: Effects of naloxone in treatment of senile dementia. J Am Geriatr Soc 1985; 33: 155.CrossRefGoogle ScholarPubMed
56.Tariot, PN, Sunderland, T, Weingartner, H, et al: Naloxone and Alzheimer’s disease. Cognitive and behavioural effects of a range of doses. Arch Gen Psychiatry 1986; 43: 727732.CrossRefGoogle ScholarPubMed
57.Pomara, N, Roberts, R, Rhiew, HB, et al: Multiple, single-dose naltrexone administration fail to effect overall cognitive functioning and plasma Cortisol in individuals with probable Alzheimer’s disease. Neurobiol Aging 1985; 6: 233236.CrossRefGoogle ScholarPubMed
58.Hyham, BT, Eslinger, PJ, Damasio, AR: Effect of naltrexone on senile dementia of the Alzheimer’s type. J Neurol Neurosurg Psychiatry 1985; 48: 11691171.Google Scholar
59.Serby, M, Angrist, B, Corwin, J, et al: Cholecystokinin octapeptide in dementia. Psychopharmacol Bull 1984; 20: 546–7.Google ScholarPubMed
60.Cutler, NR, Haxby, JV, Narang, PK, et al: Evaluation of an analogue of somatostatin (L363.586) in Alzheimer’s disease. N Engl J Med 1985; 312: 725.Google ScholarPubMed
61.Davies, P, Katzman, R, Terry, RD: Reduced somatostatin-like immunoreactivity in cerebral cortex from cases of Alzheimer disease and Alzheimer senile dementia. Nature 1980; 288: 279280.CrossRefGoogle Scholar
62.Goldman-Rakic, PS, Arnstem, AFT: Adrenergic agonists are cognitive enhancers in nonhuman primates. Clin Neuropharmacol 1986; 9 (Suppl4): 292294.Google Scholar
63.Adolfsson, R, Brane, G, Bucht, G, et al: A double-blind study with levodopa in dementia of Alzheimer type. In: Corkin, S, Davis, KL, Growdon, JH, Usdin, E, Wurtman, RJ, eds. Alzheimer’s disease: A report of Progress (Aging Volume 19) Raven Press, New York 1982: 469481.Google Scholar
64.Fleischhacker, WW, Buchgeher, A, Schubert, H: Memantine in the treatment of senile dementia of the Alzheimer type. Prog Neuropsychopharmacol 1986; 10: 8793.CrossRefGoogle ScholarPubMed
65.Mohr, E, Bruno, G, Foster, N, et al: GABA-agonist therapy for Alzheimer’s disease. Clin Neuropharmacol 1986; 9: 257263.CrossRefGoogle ScholarPubMed
66.Smith, DF, Stromgren, E, Petersen, HN, et al: Lack of effect of tryptophan treatment in demented gerontopsychiatric patients. Acta psychiatr Scand 1984; 70: 470477.CrossRefGoogle ScholarPubMed
67.Dehlin, O, Hedenrud, B, Jansson, P, et al: A double-blind comparison of alaproclate and placebo in the treatment of patients with senile dementia. Acta psychiatr Scan 1985; 71: 190196.CrossRefGoogle ScholarPubMed
68.Cutler, NR, Haxby, J, Kay, AD, et al: Evaluation of zimeldine in Alzheimer’s disease. Arch Neurol 1985; 42: 744748.CrossRefGoogle ScholarPubMed
69.Bartus, RT, Dean, RL, Pontecorvo, MJ, et al: The cholinergic hypothesis: a historical overview, current perspective, and future directions. Ann NY Acad Sci 1985; 444: 332358.CrossRefGoogle ScholarPubMed
70.Hollander, E, Mohs, RC, Davis, KL: Cholinergic approaches to the treatment of Alzheimer’s disease. Br Med Bull 1986; 42: 97100.CrossRefGoogle Scholar
71.Crook, T: Clinical drug trials in Alzheimer’s disease. Ann NY AcadSci 1985; 444: 428436.CrossRefGoogle ScholarPubMed
72.Johns, CA, Greenwald, BS, Mohs, RC, et al: The cholinergic treatment strategy in aging and senile dementia. Psychopharmacol Bull 1983; 19: 185197.Google ScholarPubMed
73.Growdon, JH, Corkin, S, Huff, FJ, et al: Piracetam combined with lecithin in the treatment of Alzheimer’s disease. Neurobiol Aging 1986; 7: 269–76.CrossRefGoogle ScholarPubMed
74.Thal, LJ, Fuld, PA, Masur, DM, et al: Oral physostigniine and lecithin improve memory in Alzheimer’s disease. Ann Neurol 1983; 13: 491496.CrossRefGoogle Scholar
75.Christie, JE, Shering, A, Ferguson, J, et al: Physostigniine and arecoline: effects of intravenous infusions in Alzheimer’s presenile dementia. Br J Psychiatry 1981; 138: 4650.CrossRefGoogle Scholar
76.Mohs, RC, Davis, BM, Johns, CA, et al: Oral physostigniine treatment of patients with Alzheimer’s disease. Am J Psychiatry 1985; 142: 2833.Google ScholarPubMed
77.Beller, SA, Overall, JE, Swann, AC: Efficacy of oral physostigniine in primary degenerative dementia. Psychopharmacology 1985; 87: 147151.CrossRefGoogle ScholarPubMed
78a.Sano, M, Stern, Y, Mayeux, R: Consistent improvement in memory with long-term oral physostigmine therapy in Alzheimer’s disease. Neurology 1987; 37 (Suppl1): 33.Google Scholar
78b.Stern, Y, Sano, M, Mayeux, R: Effects of oral physostigniine in Alzheimer’s disease. Ann Neurol 1987; 22: 306310.CrossRefGoogle ScholarPubMed
79.Summers, WK, Majovski, LV, Marsh, GM, et al: Oral tetrahydroaminoacridine in long-term treatment of senile dementia, Alzheimer’s type. N Engl J Med 1986; 315: 12411245.CrossRefGoogle Scholar
80.Summers, WK, Viesselman, JO, Marsh, GMCandelora, K: Use of THA in treatment of Alzheimer-like dementia: pilot study in twelve patients. Biol Psychiatry 1981; 16: 145153.Google Scholar
81.Kaye, WH, Sitaram, N, Weingartner, H, et al: Modest facilitation of memory in dementia with combined lecithin and anticholinesterase treatment. Biol Psychiatry 1982; 17: 275280.Google Scholar
82.Pirozzolo, FJ, Baskin, DS, Swihart, AA, et al: Oral tetrahydroaminoacridine in the treatment of senile dementia, Alzheimer type. N Engl J Med 1987; 316: 1603–4.Google Scholar
83.Hermann, N, Sadavoy, J, Steingart, AA. Ibid.Google Scholar
84.Kopelman, M. Ibid.Google Scholar
85.Tariot, PN, Caine, ED: Ibid.Google Scholar
86.Wettstein, A, Spiegel, R: Clinical trials with cholinergic drug RS-86 in Alzheimer候s disease (AD) and senile dementia of the Alzheimer type (SDAT). Psychopharmacology 1984; 572573.CrossRefGoogle ScholarPubMed
87.Bruno, G, Mohr, E, Gillespie, M, et al: Muscarinic agonist therapy of Alzheimer’s disease. A clinical trial of RS-86. Arch Neurol 1986; 43: 659661.CrossRefGoogle ScholarPubMed
88.Davous, P, Lamour, Y: Bethanechol decreases reaction time in senile dementia of the Alzheimer type. J Neurol Neurosurg Psychiatry 1985; 48: 12971299.CrossRefGoogle ScholarPubMed
89.Wessling, H, Agostin, S: Effects of 4-aminopyridine in elderly patients with Alzheimer’s disease.. N Engl J Med 1984; 40: 988989.Google Scholar
90.Harbaugh, RE, Roberts, DW, Coombs, DM, et al: Preliminary report: Intracranial cholinergic drug infusion in patients with Alzheimer’s disease. Neurosurgery 1984; 15: 514518.CrossRefGoogle ScholarPubMed
91.Harbaugh, RE: Intracranial drug administration in Alzheimer’s disease. Psychopharmacol Bull 1986; 22: 106109.Google ScholarPubMed
92.McKhann, G, Drachman, D, Folstein, M, et al: Clinical diagnosis of Alzheimer’s disease: Report of the N1NCDS-ADRDA work group under the auspices of department of health and human services task force on Alzheimer’s disease. Neurosurgery 1985; 34: 939944.Google Scholar
93.Rosen, WG, Terry, RD, Fuld, PA, et al: Pathological verification of ischemic score in differentiation of dementias. Ann Neurol 1980; 7: 486488.CrossRefGoogle ScholarPubMed
94.Warren, JW, Sobal, J, Tenney, JH, et al: Informed consent by proxy. An issue in research with elderly patients. N Engl J Med 1986; 315: 11241128.CrossRefGoogle ScholarPubMed
95.Louis, TA, Lavori, PW, Bailar, JC III, et al: Crossover and selfcontrolled designs in clinical research. N Engl J Med 1984; 310: 2431.CrossRefGoogle ScholarPubMed
96.Wechsler, D, Stone, C: Wechsler Memory Scale. The psychological corporation 1945. New York.Google Scholar
97.Buschke, H, Fuld, PA: Evaluating storage; retention and retrieval in disordered memory learning. Neurology 1974; 24: 10191024.CrossRefGoogle Scholar
98.Goodglass, H, Kaplan, E: The assessment of aphasia and related disorders. Lea and Febriger Philadelphia, 1983.Google Scholar
99.Lezak, M: Neuropsychological assessment. Oxford University Press. New York, 1983.Google Scholar
100.Money, J, Alexander, D, Walker, HT: Manual for a standardized road-map test of direction senset. Johns Hopkins University Press. Baltimore, 1965.Google Scholar
101.Honigfeld, G, Klelt, C: Nurses observation scale for inpatient evaluation. J Clin Psychol 1965; 21: 6571.3.0.CO;2-I>CrossRefGoogle ScholarPubMed
102.Lawton, MP, Brody, E: Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist 1969; 9: 179–86.CrossRefGoogle ScholarPubMed
103.Schmuker, DL: Aging and drug disposition: an update. Pharmacol Rev 1985; 37: 133148.Google Scholar