This application responds to PA-99- 134, using the Exploratory/Development Grant for Intervention Pilot Research (R2 1) mechanism. The overarching goal of this proposal is to investigate how cognitive enhancing agents affect functional brain activity in elderly subjects early in the course of cognitive decline. This study will also determine whether a novel combination of agents may have enhanced or distinct effects on brain activity and cognition. Specifically, we propose a placebo-controlled trial of the cholinesterase inhibitor donepezil in the treatment of elderly subjects with mild cognitive impairment. We will also test whether augmentation with another agent, ginkgo biloba extract (GBE), may increase the therapeutic benefit. Outcome measures will include cognitive testing as well as an assessment of functional brain activity during a verbal recall activation task using H20 positron emission tomography (PET). Treatment effects on cognition, cerebral blood flow (CBF) and cerebrovascular reserve capacity (CVR) in elderly adults (over 65 years) will be examined. The treatment trial will be encompass a one year period, with initially a six month placebo-controlled donepezil trial followed by randomization to donepezil with and without GBE augmentation for a subsequent six month treatment period. PET imaging will be performed at intake, six months and one year to isolate the effects of each treatment condition. The PET imaging will assess brain activity during a specific memory activation task, and also during an acetazolamide challenge to measure total vasodilatory capacity. This will allow the investigators to determine whether treatment is associated with increased CBF during the cognitve task and/or associated with changes in cerebrovascular reserve (CVR). At the present time, there are no defmitive treatments for cognitive deterioration. The poor prognosis of dementia necessitates that every therapeutic option be investigated with rigorous scientific methods. The therapeutic effects of cholinesterase inhibitors have not yet been definitively mapped to regional changes in cerebral activity, nor have they been mapped to specific cognitive tasks. Similarly, GBE is currently being used widely, both in the context of dementia in the healthy adult population, yet the effects of this agent on cerebral blood flow and its relationship to cognition have not been quantified. The possible therapeutic effects of GBE should be tested through placebo-controlled, double-blinded research designed to objectively measure relevant disease parameters. This study will add to a foundation for future research on the use of cholinesterase inhibitors and/or GBE in specific neurodegenerative states (e.g., vascular dementia) by establishing their effects on CNS hemodynamics and cognitive function in the elderly adult. This study will specifically examine subjects with early cognitive impairment with the idea that clinical benefits may be detectable over long-term treatment due to both neuroprotective and direct flow effects, and that this particular population may benefit to the greatest extent.
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NIH ExPorter