This proposal is oriented to examine the relationship between the two most important CNS pathologies that occur in the elderly (Alzheimer's disease [AD] and vascular disease) during the pre-symptomatic phase of AD. We will specifically test the hypothesis that the clinical effects of amyloid deposition detected in vivo in the brain of normal individuals who progress to mild cognitive impairment (MCI) and later to AD is modulated by sub-clinical vascular disease. The central hypothesis of this study is that cognitively normal subjects with systemic and cerebral vascular disease will be less likely to mount a compensatory response to amyloid deposition. Elderly subjects with vascular disease, in whom the neuropathological cascade leading to AD has already started, will be less likely to maintain normal cerebral metabolism; they will have a shorter 'latency period', and a greater incidence of MCI. By contrast, cognitively normal subjects with less vascular disease will have more amyloid deposition, since they will be able to compensate and maintain a longer 'latency period.' This longitudinal study will examine the MRI, PET, and cerebral and systemic vascular characteristics of 70 cognitively normal subjects participating of the Ginkgo Evaluation of Memory Study (GEMS). The GEMS was conducted to determine effectiveness of ginkgo biloba versus placebo in lowering the incidence of all-cause dementia and AD in normal elderly subjects and those with MCI. The GEMS has conducted careful annual cognitive evaluations since 2001 (mean follow-up: 8.5 years) on 966 subjects in Pittsburgh, and the study was completed in 2008. As part of the last examination to be completed in 2010, all non-demented participants in Pittsburgh were invited to have an MRI of the brain and a PET scan with an amyloid ligand (Pittsburgh Compound B), and approximately 200 subjects will be entered in the last phase of GEMS. From this population, we will select 70 cognitively normal participants for the present study; 35 without and 35 with amyloid deposition. Consequently, by sampling from the GEMS, we will be in the unique position of examining the relationship between vascular disease, amyloid deposition and onset of cognitive changes in a normal elderly population.
The study of how amyloid deposition, cerebral blood flow, and systemic and cerebral vascular factors influence the transition from normalcy to AD has two important implications: 1) proper treatment of vascular disease in normal individuals may delay the onset of MCI and later AD, and 2) the understanding of this initial process will improve the outcome and design of clinical trials;future disease modifying treatments will target subjects at their pre-symptomatic stages.
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