This is an application for a CMHAA on behalf of Maria Caserta, M.D., Ph.D., who is leaving Evanston Hospital Corporation and moving to Northwestern Memorial Hospital/Northwestern University Medical School. This revised application proposes a five year plan of research and education that is focused on developing non-invasive in vivo diagnostic techniques based on magnetic resonance spectroscopy (MRS) is for the early identification of Alzheimer's disease (AD). At the present time there is no accurate in vivo diagnostic test for any stage of AD. The availability of such a test would allow clinicians to accurately identify patients suitable for studying the biochemical processes of the disease in humans and for clinical trials of therapeutic agents. Dr. Caserta will study two animal models of Alzheimer's disease: an in vitro murine trisomy 16 model and an in vivo rat model of beta-amyloid deposition and neurotoxicity. The former will help elucidate the metabolic and biochemical abnormalities induced by the overexpression of genes known to cause AD neuropathology in individuals with Down's syndrome (DS). The latter will permit the study of the direct metabolic effects of injected beta-amyloid peptide into the hippocampus where the earliest signs of AD pathology occur and to determine if characteristic MRS signals can be identified from this brain region. Preliminary experiments with both animal models have shown an increase in scyllo- and myo-inositol. The MRS spectroscopic methods from these two models will be used in post-mortem specimens of AD and controls to determine if the results can be confirmed in human tissue, and then used with in vivo spectroscopy in human subjects with early signs of cognitive impairment and used to develop a diagnostic test for AD. Dr. Caserta is an Assistant Professor of Psychiatry, Neurology, and Neurobiology at Northwestern University, and will be moving from Evanston Hospital to the Medical School as Medical Director of the Geriatric Outpatient Psychiatry Program. She is familiar with the murine trisomy 16 model of DS and AD. She proposes to become proficient in the use of MRS imaging and spectroscopic techniques in brain extracts, animals, and in human subjects through a sequential plan that includes coursework, mentorship by experts in brain imaging and MRS spectroscopy at Evanston Hospital and Northwestern University Medical School, and visits to MRS research centers in Minneapolis and St. Louis. Dr. Caserta will participate in a clinic for the evaluation of dementias, including AD, which is directed by M.-Marsel Mesulam, M.D. and can be used to identify subjects or clinical research in AD, and as a teaching resource for psychiatry residents and graduate students in the Northwestern University system. She will develop didactic courses for residents and clinicians in the biology of AD, and will become a resource for clinical investigators in the field of AD at Northwestern during the five year period of this award.