ABSTRACT
We describe events spanning over 20 years that have shaped our approach to identification of interventions that may delay symptoms in Alzheimer's disease (AD). These events motivated the development of a new Centre for Studies on Prevention of AD that includes an observational cohort of cognitively normal high-risk persons and INTREPAD, a nested two-year randomized placebo-controlled trial of the non-steroidal anti-inflammatory drug naproxen sodium. INTREPAD enrolled 217 persons and will follow 160 in a modified intent-to-treat analysis of persons who remained on-protocol through at least one follow-up evaluation. The trial employs dual endpoints: 1) a composite global cognitive score generated by a battery of 12 psychometric tests organized into five subscales; and 2) a summary Alzheimer's Progression Score derived from latent variable modeling of multiple biomarker data from several modalities. The dual endpoints will be analyzed by consideration of their joint probability under the null hypothesis of no treatment effect, after allowing appropriately for their lack of independence. We suggest that such an approach can be used economically to generate preliminary data regarding the efficacy of potential prevention strategies, thereby increasing the chances of finding one or more interventions that successfully prevent symptoms.
ABSTRACT
N-Methyl-D-aspartate (NMDA) antagonists reduce ischemic brain damage and associated hypermotility. Two potent, selective and competitive NMDA antagonists, cis-4-(phosphonomethyl)-2-piperidine-carboxylic acid (CGS 19755) and 4-(3-phosphonopropyl)-2-piperazine-carboxylic acid (CPP), were characterized in the gerbil ischemia model with respect to dose-response and time course effects. Both drugs were effective in reducing ischemia-induced hippocampal brain damage as well as hypermotility. In this model, CGS 19755 was more potent than CPP, and had protective effects when given after longer delays between ischemia and drug administration.
Subject(s)
Aspartic Acid/analogs & derivatives , Brain/physiopathology , Ischemic Attack, Transient/physiopathology , Motor Activity/drug effects , Pipecolic Acids , Piperazines/pharmacology , Piperidines/pharmacology , Animals , Aspartic Acid/antagonists & inhibitors , Brain/drug effects , Brain/physiology , Female , Gerbillinae , Hippocampus/physiopathology , N-Methylaspartate , Neurons/drug effects , Neurons/physiologyABSTRACT
The N1 and P2 components of the auditory evoked magnetic field were shown to be modified by the benzodiazepines diazepam and triazolam. Previous studies indicate that the electrical sources of these components are located in the auditory cortex, implying that benzodiazepines have a direct or indirect effect on neuronal activity at this level. The recorded changes were comparable to those previously reported using auditory evoked potential measurements. These results suggest that magnetic recordings may eventually be used as a sensitive, supplementary and location-specific measure of the central action of psychoactive substances.
