Progress Report on the Canadian Multicentre Trial of Tetrahydroaminoacridine with Lecithin in Alzheimer's Disease

Abstract

Since the discovery of a significant depletion of acetylcholine in discrete areas of the brain of patients affected by Alzheimer's disease, attempts at symptomatic therapy have concentrated on acetylcholine supplementation, an approach that is based upon the efficacy of dopaminergic supplementation therapy for Parkinson's disease. Choline, then lecithin, used orally, failed to improve symptoms but the hypothesis that long-term choline supplementation might stabilize the course of Alzheimer's disease remains to be tested. Nerve growth factor may also offer that possibility. Bethanechol administered intracerebroventricularly did not help when a fixed dose was used but individual titration of more selective muscarinic agonists may prove more effective. In this article we report that tetrahydroaminoacridine (THA), given together with highly concentrated lecithin, appears to bring improvement in cognition and in functional autonomy using the Mini Mental State and the Rapid Disability Rating Scale-2 respectively, without change in behavior as reflected by the Behave-AD. Double-blind cross-over studies are in progress to establish its efficacy. Improvement in study design and means of assessment of cognition, functional autonomy and behavior have been made possible by these drug trials. RESUME: Rapport d'etape sur 1'etude multicentrique Canadienne avec tetrahydroaminoacridine et lecithine pour la maladie d'Alzheimer. Depuis la d6couverte d'une perte substantcielle d'acetylcholine dans certaines regions du cerveau de patients souffrant de maladie d'Alzheimer, les essais pour traitment symptomatique ont vis6 a supplier l'ac6tylcholine, une approche fondee sur le succes de la supplementation en dopamine pour la maladie de Parkinson. La choline, puis la lecithine orale n'ont pas ameliore de symptomes mais l'hypothese qu'un supplement a long-terme de choline pourrait stabiliser devolution de la maladie d'Alzheimer reste a verifier. Le facteur de croissance neuronale pourrait 6galement agir en ce sens. Le bethanechol administre par voie intraventriculaire n'a pas aide lorsqu'administre' a une dose fixe mais une titration individuelle utilisant des agonistes muscariniques plus selectifs pourrait s'aveYer plus efficace. Dans cette publication nous rapportons que la tetrahydroaminoacridine avec lecithine hautement concentree semble ameliorer l'intellect et l'autonomie fonctionnelle tel que reflate par le Mini Mental State et la Rapid Disability Rating Scale-2 respectivement. Des etudes en double-insu avec chasse-croise sont en cours pour confirmer son efficacite. Des ameliorations dans le design des etudes et les mesures de fonctions intellectuelles, dautonomie fonctionnelle, de comportement et d'humeur ont ete rendues possibles par ces essais cliniques.

Parallel Group Analysis of the Effects of Tacrine versus Placebo in Alzheimer's Disease

“…From this it would appear carers were able to detect similar changes as those demonstrated by the MMSE. Similar clinical changes have also been described by Gauthier et al [14], who described an increase in spontaneity of speech and of functional gestures (setting the table, answering the phone) while on THA and a withdrawal of these features during the washout phase. The fact that the mean global score averaged out to the middle of the scale seems to indicate that any observer bias such as the carer's or cli nician's expectations was corrected for in the rating pro cedure.…”

Psychometric Discrimination of Tetrahydroaminoacridine Responders in Alzheimer Patients

“…The mean duration of disease symptoms was 3.4 ± 0.8 years. The mean pre treatment Mini-Mental State Examination (MMSE) score [18] was 15.5 ± 1.2 (range: [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22].…”

Assessment of Functional Changes in Alzheimer's Disease

“…We recruited 38 subjects having a diagno sis of 'probable' or 'definite' AD, as defined by the NINCDS-ADRDA work group in a 9-month clinical trial to test the therapeutic value of THA with lecithin [5]. These pa tients were living at home with GDS scores of 4 and 5, and their caregiver was ques tioned at each visit.…”

“…The use of THA on an experimental basis has opened a door to many drug trials using cognitive enhancing agents, most of them acting on the central cholinergic sys tem. Data from the titration period of the Canadian Collaborative Study on the Use of THA with Lecithin in AD has shown that the RDRS-2 (ADL) is sensitive to drug-related effects: 46 subjects showed a significant im provement between baseline and the dose of 75 mg of THA/day (p = 0.02, Wilcoxon signed-rank test) [5], Data from the double blind phase of that study are currently being analyzed.…”