In 60 patients with Alzheimer's Disease (AD), a cross-sequential design will be used to examine longitudinally regional Cerebral Blood Flow (rCBF) abnormalities at rest and in response to cognitive challenge. Patients will be crossed on the factors of age of disease onset (below and above 65) and on a combined measure of duration, behavioral and cognitive severity of disease (early/mild and late/severe). Neurologically-intact controls will be matched to the four patient subgroups. rCBF, neurological, psychiatric and neuropsychological evaluations will be performed semiannually in patients over a three year period, while controls will participate in annual examinations. Autopsy data will be obtained in cases of patient death during the study period. Previous research has established characteristic rCBF abnormalities at late stages and/or severe manifestations of AD. A major goal of this project is to evaluate the sensitivity of abnormal rCBF patterns as quantitative, in vivo, physiological markers for AD at short disease duration and mild symptomatological manifestation and to track changes in this putative marker with disease progression. In healthy subjects, cognitive challenges during rCBF measurement elicit localized """"""""activation responses,"""""""" i.e., flow increases. A second goal of this project is to determine whether the use of cognitive challenge, appropriate in difficulty level for AD patients, enhances the utility of rCBF indices as a stage marker of AD. Specifically, we hypothesize that whereas performance accuracy on our activation tasks and resting blood flow will decrease with advancing age in controls and moreso with AD progression in patients, the cognitive activation response of early/mild AD cases will be greater than that observed in controls. This hyperreactivity will disappear at later stages of disease progression. More generally, we will systematically examine resting and activated rCBF as markers of disease severity. By carefully controlling sample composition on behavioral and cognitive severity indices, illness duration, and age at onset, we create four groups of high internal homogeneity and large inter-group differences. The design will allow a robust test of rCBF as a marker of severity in AD. Finally, there is substantial evidence that under resting conditions global CBF decreases with normal aging. The effects of aging on cognitive activation response is for the most part unknown. The study design calls for considerable variance in the age of controls, permitting for examination of this issue.
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