While we now know on average how symptoms change in sporadic Alzheimer's disease (AD), we can't predict yet how rapidly dementia will progress in an individual, and we don't understand why the disease course is so much more malignant in some patients than in others. Positron emission tomography with [18F]fluorodeoxyglucose (FDG-PET) provides a window to observe the development of brain pathology in AD. Thus far, molecular imaging studies have focused almost exclusively on group changes. However, FDG-PET can identify individual changes before symptoms become manifest and thus serve as a biomarker for predicting individual disease progression. In this project, we will compare images in new subjects to a unique set of reference FDG-PET scans in normal elderly and autopsy confirmed AD subjects we have acquired already to confirm and extend preliminary data showing that dementia progresses more slowly when areas of cerebral hypometabolism are less extensive. We will perform FDG-PET and MRI scans at baseline and two years later and perform annual clinical and neuropsychological examinations in a prospective group of patients with mild dementia due to AD and mild cognitive impairment (MCI), a frequent prodrome of AD. Autopsies will be performed to confirm clinical diagnoses whenever possible. Individual global and regional metabolic changes will be compared to individual rates of change in global dementia and specific cognitive domains. If validated as a predictor of individual disease course in mild AD, it will be possible to use FDG-PET to select more homogeneous patient groups for clinical trials, assess the benefits of potential disease-modifying treatments, and permit individualized patient management. By identifying individuals with the most permissive genetic and environmental background for disease expression, it will be possible to study determinants of progression, which themselves could become targets for new AD treatments.
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