On neurodegenerative diseases, models, and treatment strategies: Lessons learned and lessons forgotten a generation following the cholinergic hypothesis

Experimental Neurology

Volumn 163, Issue 2, 2000, Pages 495-529

  Bartus, Raymond T ^a  

^a ALKERMES INC   (United States)

Author keywords

Age associated memory impairment (AAMI); Age related memory deficits; Alzheimer's disease; Animal models; Neurodegeneration; Pharmacological treatment

Indexed keywords

2 PHENYL 5H PYRAZOLO[4,3 C]QUINOLIN 3 ONE; APOMORPHINE; ARECOLINE; CHOLINE; CLONIDINE; LEVODOPA; MUSCIMOL; PHYSOSTIGMINE; TACRINE;

ALZHEIMER DISEASE; AMNESIA; ANIMAL EXPERIMENT; ANIMAL MODEL; CHOLINERGIC NERVE; CONTROLLED STUDY; DRUG EFFECT; HYPOTHESIS; MONKEY; NERVE DEGENERATION; NEUROTRANSMITTER RELEASE; NONHUMAN; PALLIATIVE THERAPY; PRIORITY JOURNAL; RECEPTOR BLOCKING; REVIEW; TASK PERFORMANCE;

EID: 0034125843     PISSN: 00144886     EISSN: None     Source Type: Journal    
DOI: 10.1006/exnr.2000.7397     Document Type: Review

References (247)

1. Bartus R., Dean R., Beer B., Lippa A. The cholinergic hypothesis of geriatric memory dysfunction. Science. 217:1982;408-417.
2. Bartus R. Web of Science (SM) Citation Indexes. 1988;Institute for Scientific Information, Inc. Philadelphia.
3. Bartus R. Cholinergic treatment for age-related memory disturbances: Dead or barely coming of age? Crook T. Treatment Development Strategies for Alzheimer's Disease. 1986;421-450 Powley Assoc. Madison.
4. Fibiger H. Cholinergic mechanisms in learning, memory and dementia: A review of recent evidence. Trends Neurosci. 14:1991;220-223.
5. Ridley R., Baker H., Fine A. Cholinergic controversies. Trends Neurosci. 14:1991;482.
6. Sarter M. J. Bruno, Dudchenko P. Cholinergic controversies. Trends Neurosci. 14:1991;483.
7. Perry E., Irving D., Perry R. Cholinergic controversies. Trends Neurosci. 14:1991;483.
8. Davis K. Future therapeutic approaches to Alzheimer's disease. J. Clin. Psychiatry. 59:1998;14-16.
9. Tariot P., Schneider L. Contemporary treatment approaches to Alzheimer's disease. Consult. Pharm. 11:1996;16-24.
10. Wisniewski H., Terry R. Neuropathology of the aging brain. Terry R., Gershon S. Aging: Neurobiology of Aging. 1976;265-280 Raven Press, New York.
11. Roth, M, 1978, Diagnosis of senile dementia and related forms of dementia. In, Alzheimer's Disease: Senile Dementia and Related Disorders, (, R. Katzman, Ed.), p, 25, Raven Press, New York.
12. Constantinidis J. Is Alzheimer's disease a major form of senile dementia? Clinical, anatomical, and genetic data. Katzman R. Alzheimer's Disease: Senile Dementia and Related Disorders. 1978;15-25 Raven Press, New York.
13. Flicker C., Bartus R., Crook T., Ferris S. Effects of aging and dementia upon recent visuospatial memory. Neurobiol. Aging. 5:1984.
14. Crook T., Bartus R., Ferris S., Whitehouse P., Cohen G., Gershon S. Age-associated memory impairment: proposed diagnostic criteria and measure of clinical change. Dev. Neuropsychol. 2:1986;261-276.
15. Bartus R., Fleming D., Johnson H. Aging in the Rhesus monkey: Debilitating effects on short term memory. J. NIH Res. 7:1995;69-77.
16. Bartus R., Fleming D., Johnson H. Aging in the Rhesus monkey: Debilitating effects on short-term memory. J. Gerontol. 33:1978;858-971.
17. Bartus R. Psychostimulants of the central nervous system: Effects on short term memory in young vs. aged monkeys. J. Am. Geriatr. Soc. 27:1979;11-19.
18. Sathananthan G., Gershon S. Cerebral vasodilators: A review. Gershon S., Raskin A. Aging. 1975;155-168 Raven Press, New York.
19. Lehmann H., Ban T. Central nervous system stimulants and anabolic substancees in geropsychiatric therapy. Gershon S., Raskin A. Aging. 1975;179-197 Raven Press, New York.
20. Spence K. Behavior Theory and Learning. 1960;Prentice Hall, Englewood Cliffs.
21. Watson J. Behavior: An Introduction to Comparative Psychology. 1967;Holt, Rinehart, & Winston, New York.
22. Bartus R., Dean R., Pontecorvo M., Flicker C. The cholinergic hypothesis: An historical overview, current perspective, and future directions. Olton D. Annals of the New York Academy of Science, Memory Dysfunctions: Integration of Animal and Human Research from Clinical and Preclinical Perspectives. 1985c;NY Acad. Sci. New York.
23. Drachman D., Leavitt J. Human memory and the cholinergic system: A relationship to aging? Arch. Neurol. 30:1974;113-121.
24. Hollister L. Chemical Psychoses. 1968;Charles Thomas, Springfield.
25. Longo V. Behavioral and electroencephalographic effects of atropine and related compounds. Pharmacol. Rev. 18:1966;965-996.
26. Bartus R., Dean R., Flicker C. Cholinergic psychopharmacology: An integration of human and animal research in memory. Usdin E. Psychopharmacology: A Third Generation of Progress. 1987;219-232 Raven Press, New York.
27. Bartus R. Aging in the Rhesus monkey: Specific behavioral impairments and the effects of pharmacological intervention. Orimo H. Recent Advances in Gerontology. 1978;225-228 Elsevier, Tokyo.
28. Bartus R. Physostigmine and memory: Effects in young and aged nonhuman primates. Science. 270:1979;1087-1089.
29. Davis K., Mohs R., Davis B., Levy M., Rosenberg G., Horrath T., DeNigris Y., Ross A., Decker P., Rothpearl A. Cholinomimetic agents and human memory: Clinical studies in Alzheimer's disease and scopolamine dementia. Crook T., Gershon R. Strategies for the Development of an Effective Treatment for Senile Dementia. 1981;Mark Powley Associates, New Caanan.
30. Smith C., Swash M. Possible biochemical basis of memory disorder in Alzheimer's disease. Ann. Neurol. 3:1978;471-473.
31. Flicker C., Dean R., Bartus R., Ferris S., Crook T. Animal and human memory dysfunctions associated with aging, cholinergic lesions and senile dementia. Olton D. Annals of the New York Academy of Science, Memory Dysfunctions: Integration of Animal and Human Research from Clinical and Preclinical Perspectives. 1985;515-517 NY Acad. Sci. New York.
32. Flicker C., Ferris S., Serby M. Hypersensitivity to scopolamine in the elderly. Psychopharmacology (Berlin). 107:1992;437-441.
33. Sunderland T., Tariot P., Murphy D., Weingartner H., Mueller E., Cohen R. Scopolamine challenges in Alzheimer's disease. Psychopharmacology. 87:1985;247-249.
34. Litvan I., Sirigu A., Toothman J., Grafman J. What can preservation of autobiographical memory after muscarinic blockade tell us about the scopolamine model of dementia? Neurology. 45:1995;387-389.
35. Bowen D., Smith C., White P., Davison A. Neurotransmitter-related enzymes and indices of hypoxia in senile dementia and other abiotrophies. Brain. 99:1976;459-496.
36. Davies P., Maloney J. Selective loss of central cholinergic neurons in Alzheimer's disease. Lancet. 2:1976;1403.
37. Perry E., Perry R., Blessed G., Tomlinson B. Necropsy evidence of central cholinergic deficits in senile dementia. Lancet. 1:1977;189.
38. Haubrich D., Chippendale T. Regulation of acetylcholine synthesis in nervous tissue. Life Sci. 20:1977;1465-1478.
39. Jenden D., Jope R., Weiler M. Regulation of acetylcholine synthesis: Does cytoplasmic acetylcholine control high affinity choline uptake? Science. 194:1976;635-637.
40. Arai H., Kosaka K. Changes of biogenic amines and their metabolites in postmortem brains from patients with Alzheimer-type dementia. J. Neurochem. 43:1984;388-393.
41. Cross A., Crow T., Johnson J., Joseph M., Perry E., Perry R., Blessed G., Tomilson B. Monoamine metabolism in senile dementia of Alzheimer type. J. Neurol. Sci. 60:1983;383-392.
42. Cross A., Crow T., Perry E., Pery R., Blessed G., Tomilson B. Reduced dopamine-beta-hydroxylase activity in Alzheimer's disease. Br. Med. J. 282:1981;93-94.
43. Soininen H., Macdonald E., Rekonen M., Riekkinen P. Homovanillic acid and 5-hydroxyindolacetic acid levels in cerebrospinal fluid of patients with senile dementia of Alzheimer type. Acta Neurol. Scand. 64:1981;101-107.
44. Whitehouse P., Price D., Clark A., Coyle J., Delong M. Alzheimer's disease: Evidence for selective loss of cholinergic neurons in the nucleus basalis. Ann. Neurol. 10:1981;122-126.
45. Whitehouse P., Price D., Struble R., Clark A., Coyle J., Delong M. Alzheimer's disease and senile dementia: Loss of neurons in the basal forebrain. Science. 215:1981;1237-1239.
46. Enna S., Samorajski T., Beer B. Aging: Brain Neurotransmitters and Receptors in Aging and Age-Related Disorders. 1980;Raven Press, New York.
47. Lippa A., Pelham R., Beer B., Critchett D., Rean R., Bartus R. Brain cholinergic dysfunction and memory in aged rats. Neurobiol. Aging. 1:1980;13-19.
48. Lippa A., Critchett D., Ehlert F., Yamamura H., Enna S., Bartus R. Age-related alterations in neurotransmitter receptors: An electrophysiological and biochemical analysis. Neurobiol. Aging. 2:1981;3-8.
49. Gallagher M. Effects of aging on cognition and hippocampal/cortical systems. Soc Neurosci. Abstr. 24:1998.
50. Smith D., Roberts J., Gage F., Tuszynski M. Age-associated neuronal atrophy occurs in the primate brain and is reversible by growth factor gene therapy. Proc. Natl. Acad. Sci. USA. 96:1999;10893-10898.
51. Davis K., Mohs R., Marin D., Purohit D., Perl D., Lantz M., Austin G., Haroutunian V. Cholinergic markers in elderly patients with early signs of Alzheimer's disease. JAMA. 281:1999;1401-1406.
52. Bartus R., Emerich D. Cholinergic markers in Alzheimer disease. JAMA. 282:1999;2208.
53. Davis K., Mohs R., Tinklenberg J., Pfefferbaum A., Hollister L., Kopell B. Physostigmine: Improvement of long-term memory processes in normal humans. Science. 201:1978;272-274.
54. Davis K., Mohs R., Tinklenberg J. Enhancement of memory by physostigmine. N. Engl. J. Med. 301:1979;946.
55. Davis K., Berger P. Pharmacological investigations of the cholinergic imbalance hypothesis of movement disorders and psychosis. Biol. Psychiatry. 13:1978;23-49.
56. Davis, K, and, P. Berger, 1979, Brain Acetylcholine and Neuropsychiatric Disease, Plenum, New York.
57. Davis, K., R. Mohs, B. Davis, G. Rosenberg, T. Horvath, and Y. DeNigris. 1981. Cholinomimetic agents in human memory: Preliminary observations in Alzheimer's disease. Cholinergic Mechanisms: Phylogenetic Aspects, Central and Peripheral Synapses, and Clinical Significance (G. Pepeu and H. Ladinsky, Eds.), pp. 929-936. Plenum, New York.
58. Davis K., Mohs R. Enhancement of memory processes in Alzheimer's disease with multiple-dose intravenous physostigmine. Am. J. Psychiatry. 139:1982;1421-1424.
59. Christie J., Shering A., Ferguson J., Glen A. Physostigmine and arecoline: Effects of intravenous infusions in Alzheimer's presenile dementia. Br. J. Psychiatry. 138:1981;46-50.
60. Thal L., Masur D., Sharpless N. Acute and chronic effects of oral physostigmine and lecithin in Alzheimer's disease. Prog. Neuropsychopharmacol. Biol. Psychiatr. 10:1986;617-636.
61. Mohs R., Davis B., Johns C. Oral physostigmine treatment of patients with Alzheimer's disease. Am. J. Psychiatry. 142:1985;28-33.
62. Stern Y., Sano M., Mayeux R. Long-term administration of oral physostigmine in Alzheimer's disease. Neurology. 38:1988;1837-1841.
63. Bartus R., Dean R., Beer B. Recent memory deficits in aged Cebus monkeys and facilitation with central cholinimimetics. Neurobiol. Aging. 1:1980;145-152.
64. Bartus R., Dean R., Beer B. An evaluation of drugs for improving memory in aged monkeys: Implication for clinical trials in humans. Psychopharmacol. Bull. 19:1983;168-184.
65. Summers W., Majovski L., Marsh G., Tachiki K., Kling A. Oral tetrahydroaminoacridine in long-term treatment of senile dementia. N. Engl. J. Med. 315:1986;1241-1245.
66. Davis K., Thal L., Gamzu E., Davis C., Woolson R., Gracon S., Drachman D., Schneider L., Whitehouse P., Hoover T., Morris J., Kawas C., Knopman D., Earl N., Kumar V., Doody R. A double-blind, placebo-controlled multicenter study of tacrine for Alzheimer's disease. N. Engl. J. Med. 327:1992;1253-1259.
67. Bartus R. The need for common perspectives in the development and use of animal models for age-related cognitive neurodegenerative disorders. Neurobiol. Aging. 9:1988;445-451.
68. Bartus R., Dean R. Animal models for age-related memory disturbances. Coyle J. Animal Models of Dementia: A Synaptic Neurochemical Perspective. 1987;67-79 Liss, New York.
69. Bartus R., Dean R. On possible relationships between Alzheimer's disease, age-related memory loss and the development of animal models. Altman H. Alzheimer's disease: Problems, Prospects, Perspectives. 1987;129-139 Plenum, New York.
70. Bartus R. Commentary on animal models of Alzheimer's and Parkinson's disease. Integr. Psychiatry. 4:1986;74-75.
71. Bartus R., Flicker C., Dean R., Fisher S., Pontecorvo M., Figueriredo J. Behavioral and biochemical effects of nucleus basalis magnocellularis lesions: Implications and possible relevance to understanding or treating Alzheimer's disease. Van Haaren Z. Progress in Brain Research. 1986;345-361 Elsevier Science, Amsterdam.
72. Bartus, R., C. Flicker, and R. Dean. 1983. Logical principles in the development of animal models of age-related memory loss. In Clinical and Preclinical Assessment in Geriatric Psychopharmacology (T. Crook, Ed.), pp. 263-299. Mark Powley Associates, New Caanan, CT.
73. Bartus, R., and R. Dean. 1985. Developing and utilizing animals models in the search for an efffective treatment for age-related memory disturbances. In Normal Aging, Alzheimer's Disease, and Senile Dementia (C. Gottfries, Ed.), pp. 231-267. Univ. of Brussels Press, Brussels, UK.
74. Bartus R., Flicker C., Dean R., Beer B. Behavioral and pharmacological studies using animal models of aging: Implications for studying and treating dementia of Alzheimer's type. Banbury Rep. 1515:1983;207-218.
75. Bartus R., Dean R., Fleming D. Aging in the Rhesus monkey: Effects on visual discrimination and reversal learning. J. Gerontol. 34:1979;209-219.
76. Bartus, R. 1979. The effects of aging on visual memory, sensory processing and discrimination learning in a nonhuman primate. In Aging: Sensory Systems and Communication in the Elderly (J. Ordy, Ed.), pp. 85-113. Raven Press, New York.
77. Bartus R., Dean R. Recent memory in aged nonhuman primates: Hypersensitivity to visual interference during retention. Exp. Aging Res. 5:1979;385-400.
78. Riopelle, A., and C. Rogers. 1965. Age changes in chimpanzees. In Behavior of Nonhuman Primates (A. Schrier, Ed.), pp. 449-462. Academic Press, New York.
79. Medin D., O'Neill P., Smeltz E., Davis R. Age differences in retention of concurrent discrimination problems in monkeys. J. Gerontol. 28:1973;63-67.
80. Arnsten A., Goldman-Rakic. Catecholamines and cognitive decline in aged nonhuman primates. Olton D. Annals of the New York Academy of Science. 1985;218-241 New York Academy of Science, New York.
81. Bachevalier J., Landis L., Walker L., Brickson M., Mishkin M., Price D., Cork L. Aged monkeys exhibit behavioral deficits indicative of widespread cerebral dysfunction. Neurobiol. Aging. 12:1991;99-111.
82. Bachevalier J. Behavioral changes in aged rhesus monkeys. Neurobiol. Aging. 14:1993;619.
83. Marriott J., Abelson J. Age differences in short-term memory in test-sophisticated rhesus monkeys. Age. 3:1980;7-9.
84. Moss M., Rosene D., Peters A. Effects of Aging on visual recognition memory in the Rhesus monkey. Primate Rep. 14:1986;133.
85. Moss M. D., Rosene A P. Effects of aging on visual recognition memory in the rhesus monkey. Neurolbiology of Aging. 9:1988;495-502.
86. Moss M., Killiany R., Lai Z., Rosene D., Herndon J. Recognition memory span in rhesus monkeys of advanced age. Neurobiol. Aging. 18:1997;13-19.
87. Presty S., Bachevalier J., Walker L., Struble R., Price D., Mishkin M., Cork L. Age differences in recognition memory of the rhesus monkey (Macaca mulatta). Neurobiol. Aging. 8:1987;435040.
88. Rapp P., Amaral D. Recognition memory deficits in a subpopulation of aged monkeys resem le the effects of medial temporal lobe damage. Neurolbiol. Aging. 12:1991.
89. Rapp P., Amaral D. Evidence for task-dependent memory sysfunction in the aged monkey. J. Neurosci. 9:1989;7.
90. Voytko M. Cognitive changes during normal aging in monkeys assessed with an automated test apparatus. Neurobiol. Aging. 14:1993;643.
91. Goldman-Rakic P. The prefrontal landscape: Implications of functional architecture for understanding human mentation and the central executive. Phil. Trans. R. Soc. London. 351:1996;1445-1453.
92. Hanninen T., Hallikainen M., Koivisto K., Partanen K., Laakso M., Riekkinen P., Soininen H. Decline of frontal lobe functions in subjects with age-associated memory impairment. Neurology. 48:1997;148-153.
93. Rapp P., Heindel W. Memory systems on normal and pathological aging. Curr. Opin. Neurol. 7:1994;294-298.
94. Rapp P. Neuropsychological analysis of learning and memory in the aged nonhuman primate. Neurobiol. Aging. 14:1993;627.
95. Arnsten A. Postsynaptic alpha-2 receptor stimulation improves memory in aged monkeys: Indirect effects of yohimbine versus direct effects of clonidine. Neurobiol. Aging. 14:1993;597-603.
96. Flicker C., Ferris S., Crook T., Bartus R. A visual recognition memory test for the assesment of cognitive function in aging and dementia. Exp. Aging Res. 13:1987;127-132.
97. Flicker C., Ferris S., Crook T., Bartus R., Reisburg B. Cognitive function in normal aging and early dementia. Traber J. Senile Dementia of the Alzheimer Type. 1985;1-16 Springer-Verlag, Berlin.
98. Mace N., Rabins P. The 36-Hour Day. 1991;Johns Hopkins Univ. Baltimore.
99. Albert M. The ageing brain: Normal and abnormal memory. Phil. Trans. R. Soc. London. 352:1997;1703-1709.
100. Luszcz M., Bryan J. Toward understanding age-related memory loss in late adulthood. Gerontology. 45:1999;2-9.
101. Crook T. Diagnosis and treatment of memory loss in older patients who are not demented. Levy R., Howard R., Burns A. Treatment and Care in Old Age Psychiatry. 1993;95-111 Wrightston Biomedical.
102. Am. Psychol. 53:1998;1298.
103. Diagnostic and Statistical Manual of Mental Disorders. 1994;APA, Washington.
104. Alhainon K., Helkala E., Riekkinin P. Psychometric discrimination of tetrahydroaminoacridine responders in Alzheimer patients. Dementia. 4:1993;54-58.
105. Lawrence A., Sahakian B. Alzheimer's disease, attention, and the cholinergic system. Alzheimer Dis. Assoc. Disord. 9:1995;43-49.
106. Voytko M., Olton D., Richardson R., Gorman L., Tobin J., Price D. Basal forebrain lesions in monkeys disrupt attention but not learning and memory. J. Neurosci. 14:1994;167-186.
107. Gallagher M., Colombo P. Aging: The cholinergic hypothesis of cognitive decline. Curr. Opin. Neurobiol. 5:1995;161-168.
108. Voytko M. Cognitive functions of the basal forebrain cholinergic system in monkeys: memory or attention? Behav. Brain Res. 75:1996;13-25.
109. Baxter M., Gallagher M. Cognitive effects of selective loss of basal forebrain cholinergic neurons - Implications for cholinergic therapies of Alzheimer's disease. Brioni, Decker. Pharmacological Treatment of Alzheimer's Disease. 1997;Wiley-Liss, New York.
110. Baxter M., Chiba A. Cognitive functions of the basal forebrain. Curr. Opin. Neurobiol. 1998.
111. Bartus R., Dean R. Recent memory in aged nonhuman primates: Hypersensensitivity to visual interference during retention. Exp. Aging. 5:1979;385-400.
112. Chiba A., Bushnell P., Oshiro W., Gallagher M. Selective removal of cholinergic neurons in the basal forebrain alters cued target detection in rats. NeuroReport. 1998.
113. Solomon P., Beal M., Pendlebury W. Age-related disruption of classical conditioning: A model systems approach to memory disorders. Neurobiol. Aging. 9:1988;535-547.
114. Gallagher M., Pelleymounter M. Spatial learning deficits in old rats: A model for memory decline in the aged. Neurobiol. Aging. 9:1988;548-557.
115. Kesner R. Reevaluation of the contribution of the basla forebrain cholinergic system to memory. Neurobiol. Aging. 9:1988;609-617.
116. Barnes C. Aging and the physiology of spatial learning. Neurobiol. Aging. 9:1988;563-569.
117. Landfield P. Hippocampal neurobiological mechanisms of age-related memory dysfunction. Neurobiol. Aging. 9:1988;571-581.
118. Olton D. Aging and spatial cognition. Neurobiol. Aging. 9:1988;569-571.
119. Dean R., Scozzafava J., Goas J., Beer. B., Bartus R. Age-related differences in behavior across the life span of the C57BL/6J mouse. Exp. Aging Res. 7:1981;427-451.
120. Bartus R. Cholinergic drug effects on memory and cognition in animals. Poon L. Aging in the 1980's: Psychological Issues. 1980;APA, Washington.
121. Semple S., Smith C., Swash M. The Alzheimer's disease syndrome. Corkin S. Alzhiemer's Disease: A Report of Progress in Research. 1982;93-107 Raven Press, New York.
122. John, E, 1967, Mechanisms of Memory, Academic Press, New York, NY.
123. Buchel C., Couell J., Friston K. The predictive value of changes in effective connectivity for human learning. Science. 283:1999;1538-1541.
124. Jarrard L., Moise S. Short-term memory in the monkey. Jarrard L. Cognitive Processes of Nonhuman Primates. 1971;1-24 Academic Press, New York.
125. Medin, D, and, R. Davis, 1974, Memory. In, Behavior of Nonhuman Primates: Modern Research Trends, (, S. A and F. Stollnitz, Eds.), Academic Press, New York.
126. Fletcher, H., and J. Davis. 1965. The delayed response problem. Behavior of Nonhuman Primates (A. M. Schrier, Ed.), pp. 129-165. Academic Press, New York.
127. Barnes C., McNaughton B., O'Keefe J. Loss of place specificity in hippocampal complex spike cells of the senescent rat. Neurobiol. Aging. 4:1983;113-119.
128. Barnes C., Nadel L., Honig W. Spatial memory deficit in senescent rats. Can. J. Psychol. 34:1980;29-39.
129. Shen J., Barnes C., Wenk G., McNaughton B. Differential effects of selective immunotoxic lesions of medial septal cholinergic cells on spatial working and reference memory. Behav. Neurosci. 110:1996;1181-1186.
130. Bartus R., Flicker C., Dean R., Pontecorvo M., Figueriedo J., Fisher S. Selective memory loss following nucleus basalis lesions: Long term behavioral recovery despite persistent cholinergic deficiencies. Pharmacol. Biochem. Behav. 23:1985;125-135.
131. Kesner R. P., Ragozzino M. E. Structure and dynamics of multiple memory systems in Alzheimer's disease. Decker B. A. Pharmacological Treatment of Alzheimer's Disease: Molecular and Neurobiological Foundations. 1997;3-35 Wiley-Liss, New York.
132. Gold, P., and J. McGauch. 1975. Changes in learning and memory during aging. In Advances in Behavioral Biology (J. Ordy, Ed.), pp. 145-148. Plenum, New York.
133. Kubanis P., Gobbel G., Zornetzer S. Age-related memory deficits in Swiss mice. Behav. Neur. Biol. 32:1981;241-247.
134. Bartus R. The one-trial passive avoidance procedure as a possible marker of aging. Schneider E., Reff M. Biological Markers of Aging. 1982;67-77 NIH, Washington.
135. Dean R. L., Bartus R. T. Behavioral models of aging in nonhuman primates. Handb. Psychopharmacol. 20:1988;325-326.
136. Bartus, R., T. Crook, and R. Dean. 1987. Current progress in treating age-related memory problems: A perspective from animal preclinical and human clinical research. In Geriatric Clinical Pharmacology (G. Wood and R. Strong, Eds.), pp. 71-94. Raven Press, New York.
137. Bartus R., Dean R., Beer B. Neuropeptide effects on memory in aged monkeys. Neurobiol. Aging. 3:1982;61-68.
138. Bartus, R., and R. Dean. 1988. Effects of cholinergic and adrenergic enhancing drugs on memory in aged monkeys. In Current Research in Alzheimer Therapy (E. Giacobini and R. Becker, Eds.), pp. 179-190. Taylor and Francis, New York.
139. Bartus R., Dean R. Lack of effect of clonidine on memory test in aged Cebus monkeys. Neurobiol. Aging. 9:1988;409-411.
140. Arnsten A., Goldman-Rakic P. Alpha-2-adrenergic mechanisms in prefrontal cortex associated with cognitive decline in aged nonhuman primates. Science. 230:1985;1273-1275.
141. Arnsten A., Cai J., Steere J., Goldman-Rakic P. Dopamine D2 receptor mechanisms contribute to age-related cognitive decline: The effects of quinpirole on memory and motor performance in monkeys. J. Neurosci. 15:1995;3429-3439.
142. Coull J. Pharmacological manipulations of the alpha 2-noradrenergic system. Effects on cognition. Drugs Aging. 5:1994;116-126.
143. Schlegel J., Mohr E., Williams J., Mann U., Gearing M., Chase T. Guanfacine treatment of Alzheimer's disease. Clin. Neuropharmacol. 12:1989;124-128.
144. Crook T., Wilner E., Rothwell A., Winterling D., McEntee W. Noradrenergic Intervention in Alzheimer's Disease. Psychopharmacol. Bull. 28:1992;67-70.
145. McEntee W., Crook T., Jenkyn L., Petrie W., Larrabee G., Coffey D. Treatment of adult-onset cognitive disorders: results of multicenter trials. Psychopharmacol. Bull. 27:1991;41-46.
146. Mohr E., Schlegel J., Fabbrini G., Williams J., Mouradian M., Mann U., Claus J., Fedio P., Chase T. Clonidine treatment in Alzheimer's disease. Arch. Neurol. 46:1989;376-378.
147. Bierer L., Aisen P., Davidson M., Ryan T., Schmeidler J., Davis K. A pilot study of clonidine plus physostigmine in Alzheimer's disease. Dementia. 5:1994;243-246.
148. Haroutunian V., Kanof P., Tsuboyama G., Davis K. Restoration of cholinomimetic activity by clonidine in cholinergic plus noradrenergic lesioned rats. Brain Res. 507:1990;261-266.
149. Haroutunian, V., A. Santucci, and K. Davis. 1997. Neurotransmitter interactions and responsivity to cholinomimetic agents. In Neurotransmitter Interactions and Cognitive Function (E. Levin, M. Decker, and L. Butcher, Eds.), pp. 119-143. Birkhauser, Boston.
150. Bartus R., Johnson H. Short-term memory in the Rhesus monkey: Disruption from the anticholinergic scopolamine. Pharmacol. Biochem. Behav. 5:1976;39-46.
151. McDonald M., Overmier J. Present imperfect: A critical review of animal models of the mnemonic impairments in Alzheimer's disease. Neurosci. Biobehav. Rev. 22:1998;99-120.
152. Penetar D., McDonough J. Effect of cholinergic drugs on delayed match-to-sample performance of rhesus monkeys. Pharacol. Biochem. Behav. 19:1983.
153. Bartus R. Evidence for a direct cholinergic imvolvement in the scopolamine-induced amnesia in monkeys: Effects of concurrent administration of physostigmine and methylphenidate with scopolamine. Pharmacol. Biochem. Behav. 9:1979;833-836.
154. Bartus R. Short-term memory in the Rhesus monkey: Effects of dopamine blockade via acute haloperidol administration. Pharmacol. Biochem. Behav. 9:1978;353-357.
155. Dean R., Bartus R. Drug induced memory impairments in nonhuman primates. Soc. Neurosci. Abstr. 8:1982;322.
156. Askew W., Kimball A., Ho B. Effect of tetrahydrocannabinols on brain acetylcholine. Brain Res. 69:1974;375-378.
157. Domino E. Cannabinoids and the cholinergic system. J. Clin. Pharmacol. 21:1981;249s-255s.
158. Ladinsky H., Consolo C., Bellantuono C., Garattini S. Interaction of benzodiazepines with known and putative neurotransmitters in the brain. Praag M. V. Handbook of Biological Psychiatry. 1981;Dekker, New York.
159. Clemmesen L., Mikkelsen P., Lund T. Assessments of the anticholinergic effects of antidepressants in a single-dose cross over study of salivation and plasma levels. Psychopharmacology. 82:1984;348-354.
160. Palmer A., DeKosky S. Monoamine neurons in Alzheimer's disease. Neural Transm. Gen. Sect. 91:1993;135-159.
161. Ogura H., A T. MK-801 impairs recogition memory in rhesus mondeys: comparison with cholinergic drugs. Pharmacol. Exp. Ther. 266:1993;60-64.
162. Matsuoka N., Aigner T. Cholinergic-glutamatergic interactions in visual recognition memory of rhesus monkeys. Neuroreport. 7:1996;565-568.
163. Aigner T. Pharmacology of memory: cholinergic-glutamatergic interactions. Curr. Opin. Neurobiol. 5:1995;155-160.
164. Herz A. Die Gedentung der Gahung fur die wirkung von scopolamin und ahnlichen. Z. Biol. 112:1960;104-112.
165. Meyers B., Domino E. The effect of cholinergic blocking drugs on spontaneous alteration in rats. Arch. Int. Pharmacodyn. 150:1964;3-4.
166. Meyers B., Roberts D., Ricputi R., Domino E. Some effects of muscarinc cholinergic blocking drugs on behavior and the electrocorticogram. Psychopharmacology. 5:1964;289-300.
167. Deutsch J., Hamburg M., Dahl H. Anticholinesterase-induced amnesia and its temporal aspects. Science. 151:1966;221-223.
168. Deutsch J. The cholinergic synapse and the site of memory. Science. 174:1971;788-794.
169. Kubanis P., Zornetzer S. Age-related behavioral and neurobiological changes: A review with an emphasis on memory. Behav. Neural. Biol. 31:1981;115-172.
170. Rigter H., Crabbe J. Modulation of memory by pituitary hormones and related peptides. Vitam Horm. 37:1979;153-241.
171. Beatty W., Butters N., Janowsky D. Patterns of memory failure after scopolamine treatment: Implications for cholinergic hypotheses of dementia. Behav. Neural. Biol. 45:1986;196-211.
172. Molchan S., Martinez R., Hill J., Weingartner H., Thompson K., Vitiello B., Sunderland T. Increased cognitive sensitivity to scopolamine with age and a perspective on the scopolamine model. Brain Res. Rev. 17:1992;215-226.
173. Newhouse P. Cholinergic studies in dementia and depression. Zandi T. New Directions in Understanding Dementia and Alzheimer's Disease. 1990;65-76 Plenum, New York.
174. Aigner T., Mitchell S., Aggelton J., DeLong M., Struble R., Price D., Wenk G., Mishkin M. Effects of scopolamine and physostigmine on recognition memory in monkeys with ibotenic-acid lesions of the nucleus basalis of Meynert. Psychopharmacology. 92:1987;292-300.
175. Flicker C., Dean R., Watkins D., Fisher S., Bartus R. Behavioral and neurochemical effects following neurotoxic lesions of a major cholinergic input to the cerebral cortex in the rat. Pharmacol. Biochem. Behav. 18:1983;973-981.
176. Dunnett S., Whishaw I., Jones G., Bunch S. Behavioal, biochemical, and histochemical effects of different neurotoxic amino acids injected into nucleus basalis magnocellularis of rats. Neuroscience. 20:1987;653-669.
177. Dunnett S., Everitt B., Robbins T. The basal forebrain-cortical cholinergic system: interpreting the functional consequences of excitotoxic lesions. Trends Neurosci. 14:1991;494-501.
178. Wenk G., Harrington C., Tucker D., Rance N., Walker L. Basal forebrain neurons and memory: A biochemical, histological, and behavioral study of differential vulnerability to ibotenate quisqualate. Behav. Neurosci. 106:1992;909-923.
179. Wenk G., Stoehr J., Quintana G., Mobley S., Wiley R. Behavioral, biochemical, histological, and electrophysiological effects of 192 IgG-saporin injections into the basal forebrain of rats. J. Neurosci. 14:1994;5986-5995.
180. Lashley K. Brain Mechanisms and Intelligence: A Quantitative Study of Injuries to the Brain. 1929;Dover Publishing, New York.
181. Bartus R., Pontecorvo M., Flicker C., Dean R., Figuerido J. Behavioral recovery following bilateral lesions of the nucleus basalis does not occur spontaneously. Pharmacol. Biochem. Behav. 24:1986;1287-1292.
182. Chappell J., MacMahan R., Chiba A., Gallagher M. A re-examination of the role of basal forebrain cholinergic neurons in spatial working memory. Neuropharmacology. 37:1998;481-487.
183. Berger-Sweeney J., Heckers S., Mesulam M., Wiley R., Lappi D., Sharma M. Differential effects on spatial navigation of immunotoxin-induced cholinergic lesions of the medial septal area and nucleus basalis magnocellularis. J. Neurosci. 14:1994;4507-4519.
184. Mishkin M. Memory in monkeys severely impaired by combined but not by separate removal of amygdala and hippocampus. Nature. 273:1978;297-298.
185. Mishkin M. Neural circuitry underlying behavioral deficits in aging. Neurobiol. Aging. 14:1993;615-617.
186. Fine A., Hoyle C., Mclean C., Levatte T., Baker H., Ridley R. Learning impairment following injection of a selective cholinergic immunotoxin, ME20.4 IgG-saporin, into the basal nucleus of Meynert in monkeys. Neuroscience. 81:1997;331-343.
187. Ridley R., Barefoot H., Maclean C., Pugh P., Baker H. Different effects on learning ability following injection of the cholinergic immunotoxin ME20.4gC-saporin into the diagonal band of Broca, basal nucleus of Meynert, or both in monkeys. Behav. Neurosci. 1998.
188. Irle E., Markowitsch H. Basal forebrain-lesioned monkeys are severely impaired in tasks of association and recognition memory. Ann. Neurol. 22:1987;735-743.
189. Gritti I., Mainville L., Mancia M., Jones B. GABAergic and other noncholinergic basa forebrain neurons, together with cholinergic neurons, project to the mesocortex and iscortex in the rat. J. Compar. Neurol. 383:1997;163-177.
190. Sparks D., Hunsacker J., Slevin J., DeKosky S., Kryscio R., Markesbery W. Monoaminergic and cholinergic snyaptic markers in the nucleus basalis of Meynert (nbM): Normal age-related changes and the effect of heart disease and Alzheimer disease. Ann. Neurol. 31:1992;611-620.
191. Backman C., Rose G., Bartus R., Hoffer B., Henry M., Friden P., Granholm A. Systemic administration of a nerve growth factor conjugate reverses age-related cognitive dysfunction and prevents cholinergic neuron atrophy. J. Neurosci. 16:1996;5437-5442.
192. Fischer W., Chen K., Gage F., Bjorklund A. Progressive decline in spatial learning and integrity of forebrain cholinergic neurons during aging. Neurobiol. Aging. 13:1992;2-23.
193. Fischer W., SIrevaag A., Wiegand S., Lindsay R., Bjorklund A. Reversal of spatial memory impairments in aged rats by nerve growth factor and neurotrophins 3 and 4/5 but not by brain-derived neurotrophic factor. Proc. Natl. Acad. Sci. USA. 91:1994;8607-8611.
194. Serrano-Martinez A. Long-term functional recovery from age-induced spatial memory impairments by nerve growth factor gene transfer to the rat basal forebrain. Proc. Natl. Acad. Sci. USA. 93:1996;6355-6360.
195. Chen K., Nishimura M., Armanini M., Crowley C., Spenser S., Philips H. Disruption of a single allele of the nerve growth factor gene results in atrophy of basal forebrain cholinergic neurons and memory deficits. J. Neurosci. 17:1997;7288-7296.
196. Selkoe D. Molecular pathology of amyloidgenic proteins and the role of vascular amyloidosis in Alzheimer's disease. Neurobiol. Aging. 10:1989;387-397.
197. Auld D., Kar S., Quiron R. Beta-amyloid peptides as direct cholinergic neuromodulators: A missing link? Trends Neurosci. 1998;43-49.
198. Moran R., Higgans L., Cordell B., Moser P. Age related learning deficits in transgenic mice expressing the 751-amino acid sioform of human B-amyloid precursor protein. Proc. Natl. Acad. Sci. USA. 92:1995;5341-5345.
199. McKee A., Kowell N., Schumacher J., Beal M. The neurotoxicity of amyloid beta protein in aged primates. Amyloid. 5:1998;1-9.
200. Alvarez A., Opazo C., Alarcon R., Garrido J., Inestrosa N. Acetylcholinesterase promotes the aggregation of amyloid-B-peptide fragments by forming a complex with the growing fibrils. J. Mol. Biol. 272:1997;348-361.
201. Alvarez A., Alarcon R., Opazo C., Campos E., Munoz F., Calderon F., Dajas F., Gentry M., Doctor B., DeMellow G., Inestrosa N. Stable complexes involving acetylcholinesterase and amyloid-B peptide change the biochemical properties of the enzyme and increase the neurotoxicity of Alzheimer's fibrils. J. Neurosci. 18:1998;3213-3223.
202. Reyes A., Perez D., Alvarez A., Garrido J., Gentry M., Doctor B., Inestrosa N. A monoclonal antibody against acetylcholinesterase inhibits the formation of anmyloid fibrils induced by the enzyme. Biochem. Biophys. Res. Commun. 232:1997;652-655.
203. Loring J., Paszty C., Rose A., McIntosh T., Murai H., Pierce J., Schramm S., Wymore K., Lee V., Trojanowski J., Peterson K. Rational design of an animal model for Alzheimer's disease: Introduction of multiple human genomic transgenes to reproduce AD pathology in rodent. Neurobiol. Aging. 17:1996;173-182.
204. Rogers S., Farlow M., Doody R., Mohs R., Friedhoff L. A 24-week double-blind placebo-controlled trial of donepezil in patients with AD. Neurology. 50:1998;136-145.
205. Bartus R. Drugs to treat age-related neurodegenerative problems: The final frontier of medical science? J. Am. Geriatr. Soc. 38:1990;680-695.
206. Layton B. Perceptual noise and aging. Psychol. Bull. 82:1975;875-883.
207. Sahakian B., Jones G., Levy R., Gray J., Warburton D. The effects of nicotine on attention, information processing, and short-term memory in patients with dementia of the Alzheimer type. Br. J. Psychiatry. 154:1989;797-800.
208. Nordberg A., Amberla K., Shigeta M., Lundquist H., Vittanen M., Hellstrom-Lindahl E., Johansson M., Andersson J., Hartvig P., Lilja A., Langstrom B., Winblad B. Long-term tacrine treatment in three mild Alzheimer patients: Effects on nicotinic receptors, cerebral blood flow, glucose metabolism, EEG, and cognitive abilities. Alzheimer Dis. Assoc. Disord. 12:1998;228-237.
209. Jones G., Sahakian B., Levy R., Warburton D., Gray J. Effects of acute subcutaneous nicotine on attention, information processing and short-term memory in Alzheimer's disease. Psychopharmacology (Berl). 108:1992;485-494.
210. Nordberg A., Winblad B. Reduced number of [3H]nicotine and [3H]acetylcholine binding sites in the frontal cortex of Alzheimer brains. Neurosci. Lett. 72:1986;115-119.
211. Flynn D., Mash D. Characterization of L-[3H]nicotine binding in human cerebral cortex: Comparison between Alzheimer's disease and the normal. J. Neurochem. 47:1986;1948-1954.
212. Pery E., Morris C., Court J., Cheng A., Fairbarn A., McKeith I., Irving I., Brown A., Perry R. Alteration in nicotine binding sites in Parkinson's disease, Lewy body dementia, Alzheimer's disease: Possible index of early neuropathology. Neuroscience. 64:1995;385-395.
213. Marutle A., Warpman U., Bogdanovic N., Lannfelt L., Nordberg A. Neuronal nicotinic recpetor deficits in Alzheimer patients with the Swedish amyloid precursor protein 670-671 mutation. J. Neurochem. 72:1999;1161-1169.
214. Whitehouse P., Martino A., Antuono P., Lowenstein P., Coyle J., Price D., Kellar K. Nicotinic acetylcholine binding sites in Alzheimer's disease. Brain Res. 371:1986;146-151.
215. Whitehouse P., Martino A., Wagster M., Price D., Mayeux R., Atack J., Kellar K. Reductions in [3H]nicotinic acetylcholine binding in Alzheimer's disease and Parkinson's disease: An autoradiographic study. Neurology. 38:1988;720-723.
216. Prendergrast M., Terry A., Jackson W., Marsh K., Decker M., Arneric S., Buccafusco J. Improvement in accuracy of depayed recall in aged and non-aged, mature monkeys after intramuscular or transdermal administration of the CNS nicotinic receptor agonist ABT-418. Psychopharmacology. 130:1997;276-284.
217. Jorm A. Effects of cholinergic enhancement therapies on memory function in Alzheimer's disease: A meta-analysis of the literature. Australian N. Z. J. Psychiatry. 20:1986;237-240.
218. Eagger S., Harvey R. Clinical heterogeneity: responders to cholinergic therapy. Alzheimer Dis. Assoc. Disord. 9:1995;37-42.
219. Alhainen K., Riekkinen J. Discrimination of Alzheimer's patients responding to cholinesterase inhibitor therapy. Acta. Neurol. Scand. Suppl 149:1993;16-21.
220. Farlow M., Lahiri D., Poirer J. Apolipoprotein E genotype and gender influence response to tacrine therapy. Ann. NY Acad. Sci. 802:1996;101-110.
221. Grothe D., Piscitelli S., Dukoff R. Penetration of tacrine into cerebrospinal fluid in patients with Alzheimer's disease. J. Clin. Psychopharmacol. 18:1998;78-81.
222. Lou G., Montgomery P., Sitar D. Bioavailability and pharmacokinetic disposition of tacrine in elderly patients with Alzheimer's disease. J. Psychiatry Neurosci. 21:1996;334-339.
223. Flicker L. Acetylocholinesterase inhibitors for Alzheimer's disease. Br. Med. J. 318:1999;615-616.
224. Stern Y., Sano M., Mayeux R. Effects of oral physostigmine in Alzheimer's disease. Ann. Neurol. 22:1987;306-310.
225. Mayeux R., Sano M. Treatment of Alzheimer's disease. N. Engl. J. Med. 341:1999;1670-1679.
226. Bartus R. Drugs to treat age-related cognitive disorders: on the threshold of a new era in the pharmaceutical industry? Crook T. Treatment Development Strategies for Alzheimer's Disease. 1986;Powley Associates, Madison.
227. Schumock G. Economic considerations in the treatment and management of Alzheimer's disease. Am. J. Health Syst. Pharm. 55:1998;S17-S21.
228. Schneider L., Tariot P. Emerging drugs for Alzheimer's disease: Mechanisms of action and prospects for cognitive enhancing medications. Med. Clin. North Am. 78:1994;911-935.
229. Somerset, P, 1997, Somerset Pharmaceuticals reports results of clinical trial in Alzheimer's disease, PR Newswire, November 3, 1997.
230. Rosler M., Anand R., Cicin-Sain A., Gauthier S., Agid Y., Dal-Bianco P., Stahelin H., Hartman R., Marguirguis G. Efficacy and safety of rivastigmine in patients with Alzheimer's disease: International randomised controlled trial. British Medical Journal. 318:1999;633-640.
231. Giacobini E. Therapy for Alzheimer's disease. Symptomatic or neuroprotective? Mol. Neurobiol. 9:1994;115-118.
232. Knopman D., Schneider L., Davis K., Talwalker S., Smith F., Hoover T., Gracon S. Long-term tacrine (Cognex) treatment. Neurology. 47:1996;166-177.
233. Crowley E. Big study hopes to find if Alzheimer's can be prevented in memory-impaired. Wall Street Journal. 1999.
234. van Duijn C., Hofman A. Relation between nicotine intake and Alzheimer's disease. Br. Med. J. 302:1991;1491-1494.
235. Cohen E., Wurtman R. Brain acetylcholine: Increases after systemic choline administration. Life Sci. 16:1975;1095-1102.
236. Bartus R., Dean R., Beer B. Cholinergic precursor therapy for geriatric cognition: It's past, present, and a question of its future. Ordy J. Nutrition in Gerontology. 1984;191-226 Raven Press, New York.
237. Bartus, R. T., R. L. Dean, K. S. Sherman, E. Friedman, and B. Beer. 1981. Profound effects of combining choline and piracetam on memory enhancement and cholinergic functions in aged rats. 2: 105-111.
238. Bartus R., Dean R., Goas J., Lippa A. Age-related changes in passive avoidance retention and modulation with chronic dietary choline. Science. 209:1980;301-303.
239. Schwarz R. Muscarinic receptor agonists under development for the treatment of Alzheimer's disease. Alzheimer's Dis. ID Res. Alert. 2:1997;5459-5465.
240. Pang D. Alzheimer's Disease. AAPS News. 1:1998;11-15.
241. Yaffe K., Sawaya G., Lieberburg I. Estrogen therapy in post-menopausal women: effects on cognitive function and dementia. JAMA. 279:1998;688-695.
242. Henderson V., Paganini-Hill A., Emanuel C., Dunn M., Buckwalter J. Estrogen replacement therapy in older women. Comparisons between Alzheimer's disease cases and nondemented control subjects. Arch. Neurol. 51:1994;896-900.
243. Gibbs R. Estrogen and nerve growth factor-related systems in brain. Effects on basal forebrain cholinergic neurons and implications for learning and memory processes and aging. Ann. NY Acad. Sci. 743:1994;165-196.
244. Hefti F., Hartikka J., Knusel B. Function of neurotrophic factors in the adult and aging brain and their possible use in the treatment of neurodegenerative diseases. Neurobiol. Aging. 10:1989;515-534.
245. Ingvar M., Ambros-Ingerson J., Davis M., Granger R., Kessler M., Rogers G., Scher R., Lynch G. Enhancement by an ampakine of memory encoding in humans. Exp. Neurol. 146:1997;553-559.
246. Kim S., Kim Y., Jeong S., Haass C., Kim Y., Suh Y. Enhanced release of secreted form of Alzheimer's amyloid precursor protein from PC12 cells by nicotine. Mol. Pharmacol. 52:1997;430-436.
247. James J., Nordberg A. Genetic and environmental aspects of the role of nicotinic recpetors in neurodegenerative disorders: Emphasis on Alzheimer's disease and Parkinson's disease. Behav. Genet. 25:1995;149-159.