treatment with vitamin E, donepezil, or placebo

         Approximately 720 participants with MCI are currently being randomized to treatment with vitamin E, donepezil, or placebo for 3 years, with roughly an equal number of participants (240) in each treatment group.
      From previous data, it is known that individuals who meet criteria for MCI convert to AD at a rate of approximately 12% to 15% per year (Petersen, Smith, Ivnik, et al, 1995; Grundman, Petersen, Morris, et al., 1996b; Petersen et al., 1999). Additional data suggest that this conversion rate may be even higher (up to approximately 20% per year over the first 3 years) in MCI participants who are screened with a memory test assessing delayed recall. Based on these figures, it is expected that at the end of the 3 years, 45% to 60% of placebo-treated participants may develop AD.

     The trial is designed to evaluate whether the two treatment interventions are effective at reducing the rate of conversion to AD by approximately one third over the course of the 3 years. The MRI component of the protocol stipulates that MRI scans are obtained on participants at entrance into the trial, upon completion of the trial 3 years later, and at the time of diagnostic crossover to AD. In all participants the MRI study is performed according to a defined set of imaging sequences that are sufficiently generic so that they can be executed across a variety of MRI vendors. The cornerstone of the planned volumetric analyses includes a 3-dimensional (3D) volumetric imaging sequence that provides optimal spatial resolution in all three anatomic dimensions.

     Guidelines for the storage and archival procedures are provided to each of the individual participating sites. Magnetic resonance imaging data cassettes from participating sites are sent to the central data repository at the Mayo Clinic in Rochester, Minnesota, where imaging data are downloaded, checked for compliance with the prescribed imaging sequences, and then catalogued. Catalogued images are cross-checked with case report forms forwarded from participating clinical sites to the ADCS coordinating
center in San Diego, California. After the images are analyzed, the data are merged with other clinical data on each participant residing in the ADCS central database.

    The proposed analyses focus primarily on the medial temporal lobe, particularly the hippocampal formation. Nevertheless, with the imaging sequences outlined in the study protocol, the capability exists to measure serial whole brain, lobar, sublobar, and ventricular volumes, as well as gray and white matter volumes, and leukoaraiosis. Based on prior studies, we anticipate that the hippocampal volume or other baseline measurements on the baseline MRI scans will predict which participants are most likely to develop AD. Analyses of the serial images obtained over the course of the study will examine whether treatment with either vitamin E or donepezil alters the rate of atrophy in the whole brain, lobar and sublobar-medial temporal lobe, entorhinal cortex, as well as the gray and white matter. Similar analyses will examine whether there are treatmen differences in the rate of ventricular enlargement.