While knowledge about the longitudinal course of Alzheimer's disease (AD) is expanding, little is known about patients who present with cognitive impairment but do not meet criteria for dementia and initial evaluation. This broad category of patients will be referred to as Questionable Dementia or QD. Some have suggested that these patients have a benign course, while others have proposed that on follow-up, virtually all such patients will eventually meet criteria for dementia, predominantly Alzheimer's disease. In a preliminary longitudinal study, we found that some QD patients worsened and met criteria for dementia, predominantly Alzheimer's disease, while others were judged to be not demented. A small minority continued to be classified as QD. This heterogeneity makes it feasible to study predictors of long-term outcome. We found that baseline Clinical Dementia Rating (0 or 0.5) was unrelated to final diagnosis on follow-up. Baseline rating of level of independent functioning, degree of cognitive impairment on some measures, and a parietotemporal deficit on blind evaluation of regional cerebral blood flow were associated with the final diagnosis of AD. Several lines of evidence in our preliminary data strongly indicated that patients who did not meet criteria for AD at follow-up would not have done so even if followed for a much longer period of time. 120 QD patients will be studied longitudinally. The clinical characteristics and course of these patients will be determined during a 2-5 year follow-up period. In addition, a normal control group of 60 subjects will be recruited over the same time span, and followed with the same set of assessment procedures as the QD sample. This study will test the predictive accuracy (sensitivity and specificity) of specific clinical features, neuropsychological test results, and functional brain imaging (SPECT) abnormalities in predicting which QD patients will meet diagnostic criteria for possible and probable Alzheimer's disease, with the aim of developing a predictor model for AD in patients of this type. QD patients and their families are presenting in markedly increased numbers, and are looking for early, accurate diagnosis to reduce anxiety and to make reasonable plans for the future. The implications of this study may also be of value in the design of future clinical trials for therapeutic agents that might be effective only in the very early stages of the dementing process, particularly in AD. Therefore, a systematic longitudinal study of patients with QD, which has hitherto never been conducted, will be considerable value. The proposed studies will also help to improve the overall efficiency and accuracy of physician's judgements in patients of this type.
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