The proposed supplemental study is submitted in response to PA-04-158, """"""""Ancillary Studies to the AD Neuroimaging Initiative"""""""". It will test the hypothesis that rosiglitazone, a peroxisome proliferator-activated receptor-y (PPAR-y) agonist with insulin-sensitizing and anti-inflammatory properties, attenuates rates of hippocampal atrophy, whole brain atrophy and ventricular expansion as measured with magnetic resonance imaging (MRI) in persons with amnestic mild cognitive impairment (MCI), a presumed prodromal phase of Alzheimer's disease (AD). We predict that atrophy attenuation will be related to cognitive and metabolic indices of treatment response. This study will significantly expand the scope of our Pilot Clinical Trial, in which subjects receive rosiglitazone or placebo for 18 months, with cognitive assessment at 6-month intervals. We also proposed that subjects undergo pre- and post-treatment structural MRI with a standard clinical protocol to assess whole brain atrophy. However, recent work suggests that while whole brain atrophy is a non-specific correlate of several neurodegenerative diseases, hippocampal atrophy is a sensitive index of pathology specific to AD and MCI. Furthermore, the recently launched AD Neuroimaging Initiative (ADNI) has assembled considerable expertise in imaging to develop acquisition and analytic protocols that will provide the greatest sensitivity to detect AD-related changes. Therefore, in this supplement, in collaboration with ADNI Principal Investigator Dr. Michael Weiner, we propose to use methods developed by ADNI to assess rosiglitazone's effects on hippocampal atrophy in persons with MCI. ? The parent trial will elucidate the effects of improved insulin sensitivity on cognition and peripheral disease markers in MCI and examine the efficacy of a novel treatment that may prevent or postpone the onset of AD. ADNI methodology will add a powerful tool for quantifying hippocampal atrophy, one of the most sensitive measures of disease progression in MCI and AD, and provide evidence regarding potential diseasemodifying effects of rosiglitazone. Additionally, treatment-related imaging data from the trial will strengthen the ADNI data repository. ? ? ?
