The Impact of Drugs against Dementia on Cognition in Aging and Mild Cognitive Impairment

Objective: To define the actual knowledge of the impact of drugs for the treatment of dementia on the improvement of cognition in aging and mild cognitive impairment. Method: We conducted a Medline search for studies with the parameters drug and cognition. Only drugs that had demonstrated cognition improvements in dementia according to actual methodological standards were included. Drugs had to be approved in at least one American or European nation. Results: Donepezil, galantamine, Ginkgo biloba EGb 761® (definition see editorial), memantine and rivastigmine fulfilled these criteria. There were no systematic investigations on the effects of these drugs on cognition in healthy adults or patients with mild cognitive impairment (MCI). Regarding Ginkgo biloba, two studies on MCI patients could be identified. In healthy adults, we could only include one study investigating donepezil and seven investigating Ginkgo biloba EGb 761®. According to the findings, donepezil significantly increased the percentage of REM sleep and REM density, whereas REM latency was reduced. This was interpreted as a sign of improved cognition. Ginkgo biloba EGb 761® improved cognition in healthy controls according to Delayed Free Recall and Delayed Recognition of the WAIS-III and the Color Naming of the Stroop Test as well as in MCI in Digit Copying, Dual Coding Task and speed of response on a computerized version of a classification task. The highest effects were observed after 6 weeks of treatment with 180 mg/d. Conclusions: Due to the lack of standard procedures for investigating cognition improvement in healthy aging, results have to be interpreted cautiously. In healthy adults as well as in individuals categorized as having MCI, Ginkgo biloba EGb 761® improved cognition in some but not all neuropsychological tests. The single positive result with donepezil raises hope that other drugs may also contribute to cognitive improvement, even in healthy adults. However, the data do not allow any conclusions regarding an improvement following a specific ”neuropsychological cluster.” Studies on prevention have not been completed so far.

• 1 Allain H, Raoul P, Lieury A, LeCoz F, Gandon J M, d’Arbigny P. Effect of two doses of Ginkgo biloba extract (EGb 761®) on the dual-coding test in elderly subjects.  Clin Ther. 1993;  15 549-558
• 2 Anokhin A P, Birbaumer N, Lutzenberger W, Nikolaev A, Vogel F. Age increases brain complexity.  Electroencephalogr Clin Neurophysiol. 1996;  99 63-68
• 3 Berger H. Über das Elektroenzephalogramm des Menschen.  Arch Psychiatr Nervenkr. 1931;  94 16-60
• 4 Birks J, Grimley E J, lakovidou V, Tsolaki M. Rivastigmine for Alzheimer’s disease.  Cochrane Database Syst Rev. 2000;  4 CD001191
• 5 Birks J S, Melzer D, Beppu H. Donepezil for mild and moderate Alzheimer’s disease. Cochrane Database Syst Rev 2000: CD001190
• 6 Burns A, Rossor M, Meeker J, Gauthier S, Petit H, Moller H J. et al . The effects of donepezil in Alzheimer’s disease - results from a multinational trial.  Dement Geriatr Cogn Disord. 1999;  10 237-244
• 7 Corey-Bloom J, Anand R, Veach J. for the EN A 713 B352 Study Group . A randomized trial evaluating the efficacy and safety of ENA713 (rivastigmine tartrate), a new acetylcholinesteraseinhibitor, in patients with mild to moderately severe Alzheimer’s disease.  International Journal of Geriatric Psychopharmacology. 1998;  1 55-65
• 8 Duffy F H, Albert M S, McAnulty G. Brain electrical activity in patients with presenile and senile dementia of the Alzheimer type.  Ann Neurol. 1984;  16 439-448
• 9 Erkinjuntti T, Kurz A, Gauthier S, Bullock R, Lilienfeld S, Damaraju C V. Efficacy of galantamine in probable vascular dementia and Alzheimer’s disease combined with cerebrovascular disease: a randomised trial.  Lancet. 2002;  359(9314) 1283-1290
• 10 Ernst E, Pittler M H. Ginkgo biloba for dementia - a systematic review of double-blind placebo controlled trials.  Clin Drug Invest. 1999;  4 301-308
• 11 Fillit H M, Butler R N, O’Connell A W, Albert M S, Birren J E, Cotman C W. et al . Achieving and maintaining cognitive vitality with aging.  Mayo Clin Proc. 2002;  77 681-696
• 12 Homma A, Takeda M, Imai Y, Udaka F, Hasegawa K, Kameyama M. et al . Clinical efficacy and safety of donepezil on cognitive and global function in patients with Alzheimer’s disease. A 24-week, multicenter, double-blind, placebo-controlled study in Japan. E2020 Study Group.  Dement Geriatr Cogn Disord. 2000;  11 299-313
• 13 Ihl R, Brinkmeyer J. Differential diagnosis of aging, dementia of the Alzheimer type and depression with EEG-segmentation.  Dement Geriatr Cogn Disord. 1999;  10 64-69
• 14 Jelles B, van Birgelen J H, Slaets J P, Hekster R E, Jonkman E J, Stam C J. Decrease of non-linear structure in the EEG of Alzheimer patients compared to healthy controls.  Clin Neurophysiol. 1999;  110 1159-1167
• 15 Jorm A F, Christensen H, Henderson A S, Korten A E, Mackinnon A J, Scott R. Complaints of cognitive decline in the elderly: a comparison of reports by subjects and informants in a community survey.  Psychol Med. 1994;  24 365-374
• 16 Kanowski S, Herrmann W M, Stephan W, Wierich W, Hörr R. Proof of efficacy of the Ginkgo biloba special extract EGb 761® in outpatients suffering from mild to moderate primary dementia of the Alzheimer type or multi-infarct-dementia.  Pharmacopsychiatry. 1996;  29 47-56
• 17 Korten A E, Henderson A S, Christensen H, Jorm A F, Rodgers B, Jacomb P. et al . A prospective study of cognitive function in the elderly.  Psychol Med. 1997;  27 919-930
• 18 LeBars P L, Katz M M, Berman N, Itil T M, Freedman A M, Schatzberg A F. A placebo-controlled double-blind randomized trial of an extract of Ginkgo biloba for dementia.  Journal of the American Medical Association. 1997;  278 1327-1332
• 19 LeBars P L, Kieser M, Itil K Z. A 26-week analysis of a double-blind, placebo-controlled trial of the Ginkgo biloba extract EGb 761® in dementia.  Dement Geriatr Cogn Disord. 2000;  11 230-237
• 20 Lindenberger U, Baltes P B. Sensory functioning and intelligence in old age: a strong connection.  Psychol Aging. 1994;  9 339-355
• 21 Luthringer T, d’Abigny P, Macher J P. Ginkgo biloba extract (EGb 761®), EEG and event related potentials mapping profile. In: Advances in Ginkgo biloba Extract Research, vol. 4. Effects of Ginkgo biloba Extract (EGb 761®) on Aging and Age-Related Disorders. 1995
• 22 McCurry S M, Edland S D, Ten L, Kukull W A, Bowen J D, McCormick W C. et al . The cognitive abilities screening instrument (CASI: data from a cohort of 2524 cognitively intact elderly).  Int J Geriatr Psychiatry. 1999;  14 882-888
• 23 Meyer-Lindenberg A. The evolution of complexity in human brain development: an EEG study.  Electroencephalogr Clin Neurophysiol. 1996;  99 405-411
• 24 Mix J A, Crews WD J r. An examination of the efficacy of Ginkgo biloba extract EGb 761® on the neuropsychologic functioning of cognitively intact older adults.  J Altern Complement Med. 2000;  6 219-229
• 25 Mix J A, Crews W A. A double-blind, placebo controlled, randomized trial of Ginkgo biloba Extract EGb 761® in a sample of cognitively intact older adults: neuropsychological findings.  Human Psychopharmacology: Clinical and Experimental. 2002;  17 267-277
• 26 Mundy-Castle A C. The electroencephalogram and mental activity.  Electroencephalography and Clinical Neurophysiology. 1957;  9 643-655
• 27 Obrist W D, Busse E W. The electroencephalogram in old age. In: Wilson WP, editor Applications of electroencephalography in psychiatry. Durham, N.C.; Duke University Press 1964: 185-205
• 28 Olin J, Schneider L. Galantamine for Alzheimer’s disease (Cochrane Review).  Cochrane Database Syst Rev. 2001;  4 CD001747
• 29 Oken B S, Storzbach D M, Kaye J A. The efficacy of Ginkgo biloba on cognitive function in Alzheimer disease.  Arch Neurol. 1998;  55 1409-1415
• 30 Orgogozo J M, Rigaud A S, Stoffler A, Mobius H J, Forette F. Efficacy and safety of memantine in patients with mild to moderate vascular dementia: a randomized, placebo-controlled trial (MMM 300).  Stroke. 2002;  33 1834-1839
• 31 Rai G S, Shovlin C, Wesnes K A. A double-blind, placebo controlled study of Ginkgo biloba extract (‘tanakan’) in elderly outpatients with mild to moderate memory impairment.  Curr Med Res Opin. 1991;  12 350-355
• 32 Raskind M A, Peskind E R, Wessel T, Yuan W. Galantamine in AD: A 6-month randomized, placebo-controlled trial with a 6-month extension. The Galantamine USA-1 Study Group.  Neurology. 2000;  54 2261-2268
• 33 Reisberg B, Windscheif U, Ferris S H, Hingorani V H, Stoeffler A, Moebius H J. Memantine in moderately severe to severe Alzheimer’s disease (AD): results of a placebo-controlled 6-month trial. Neurobiol Aging 21(1S): S275. Abstract
• 34 Ritchie K, Touchon J. Mild cognitive impairment: conceptual basis and current nosological status.  Lancet. 2000;  355(9199) 225-228
• 35 Ritchie K, Ledesert B, Touchon J. Subclinical cognitive impairment: epidemiology and clinical characteristics.  Compr Psychiatry. 2000;  41 Suppl 1 61-65
• 36 Rösler M, Anand R, Cicin-Sain A, Gauthier S, Agid Y, Dai-Bianco P. et al . Efficacy and safety of rivastigmine in patients with Alzheimer’s disease: international randomised controlled trial.  British Medical Journal. 1999;  318 633-640
• 37 Rogers S L, Friedhoff L T. The efficacy and safety of donepezil in patients with Alzheimer’s disease: results of a US Multicentre, Randomized, Double-Blind, Placebo- Controlled Trial. The Donepezil Study Group.  Dementia. 1996;  7 293-303
• 38 Rogers S L, Farlow M R, Doody R S, Mohs R, Friedhoff L T. A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer’s disease. Donepezil Study Group.  Neurology. 1998;  50 136-145
• 39 Rosen W G, Mohs R C, Davis K L. A new rating scale for Alzheimer’s disease.  American Journal of Psychiatry. 1984;  11 1356-1364
• 40 Schaffler K, Reeh P W. Double blind study of the hypoxia protective effect of a standardized Ginkgo biloba preparation after repeated administration in healthy subjects.  Arzneimittelforschung.. 1985;  35 1283-1286
• 41 Schredl M, Weber B, Leins M L, Heuser I. Donepezil-induced REM sleep augmentation enhances memory performance in elderly, healthy persons.  Exp Gerontol. 2001;  36 353-361
• 42 Solomon P R, Adams F, Silver A, Zimmer J, DeVeaux R. Ginkgo for memory enhancement: a randomized controlled trial.  JAMA. 2002;  288 835-840
• 43 Subhan Z, Hindmarch I. The psychopharmacological effects of Ginkgo biloba extract in normal healthy volunteers.  Int J Clin Pharmacol Res. 1984;  4 89-93
• 44 Tariot P N, Solomon P R, Morris J C, Kershaw P, Lilienfeld S, Ding C. A 5-month, randomized, placebo-controlled trial of galantamine in AD. The Galantamine USA-10 Study Group.  Neurology. 2000;  54 2269-2276
• 45 van Dongen M C, van Rossum E, Kessels A G, Sielhorst H J, Knipschild P G. The efficacy of Ginkgo for elderly people with dementia and age-associated memory impairment: new results of a randomized clinical trial.  J Am Geriatr Soc. 2000;  48 1183-1194
• 46 Warot D, Lacomblez L, Danjou P h, Weiler E, Payan C, Puech A J. Comparaison des effets déxtraits de Ginkgo biloba sur les performances psychometrices er al mémoire chez le sujet sain.  Therapie. 1991;  46 36
• 47 Wilcock G K, Lilienfeld S, Gaens E. Efficacy and safety of galantamine in patients with mild to moderate Alzheimer’s disease: multicentre randomised controlled trial. Galantamine lnternational-1 Study Group.  BMJ. 2000;  321(7274) 1445-1449
• 48 Winblad B, Poritis N. Memantine in severe dementia: results of the 9M-Best Study (Benefit and efficacy in severely demented patients during treatment with memantine.  Int J Geriatr Psychiatry. 1999;  14 135-146
• 49 Winblad B, Engedal K, Soininen H, Verhey F, Waldemar G, Wimo A, Wetterholm A L, Zhang R, Haglund A, Subbiah P. A 1-year, randomized, placebo-controlled study of donepezil in patients with mild to moderate AD.  Neurology. 2001;  57 489-495

1 A heterogeneous group of individuals was investigated in 37 retirement homes. Only 39 or 40 individuals (different numbers were reported) were classified as suffering from dementia. However, no imaging was performed. This means that in the mean, one individual with dementia was investigated by an undefined ”rater” in each retirement home. These results will show an extraordinary variance, making every outcome random. In fact, no efficacy of the drug could be demonstrated in a huge amount of statistical tests.