The Pathophysiology Core (PA Core) has evolved from the Neuropsychology Core as a consequence of CRC findings of the previous funding period. We have identified evidence of at least two clinically and biologically meaningful subgroups of geriatric depression: 1. A group with predominant frontal systems impairment which is characterized by a distinct clinical presentation and a chronic course; and 2. A group with predominant memory impairment which is responsive to antidepressant treatment but at high risk for dementia (Alzheimer's or vascular). We argue that these subtypes are relevant to the pathophysiology of geriatric depression rather than randomly occurring comorbid states. The mission of the PA Core is to orchestrate for the CRC a program of targeted investigations into the above hypothesis using the science and techniques of four specialized laboratories: 1. neuropsychology; 2. evoked potentials; 3. structural MR neuroimaging; and 4. functional neuroimaging. Conceptual and operational integration of these laboratories provides a coordinated plan using complementary techniques to pursue biological hypothesis in a way that would be difficult, if not impossible to do, outside a CRC environment. Finally, the shared scientific goal of the PA Core provides its laboratories a coherent strategy for development of investigative methodology so that they can continue to make essential contributions to the pathophysiology of geriatric mood disorders. The findings and assessments of the PA Core will be sued by other Cores of the CRC in hypotheses examining heterogeneity in outcomes, mechanisms, and treatment of geriatric mood disorders. To accomplish its mission, the PA Core takes advantages of a unique geriatric population with a wide range of cognitive and medical morbidity necessary for testing the CRC hypotheses. Moreover, the PA Core draws upon the expertise and measures of other CRC Cores, such as Chronobiology, Psychopharmacology, and Psychosocial, to widen its scope. The PA Core will remain a central training resource in biological theory and techniques for senior and junior investigators of the CRC and for the research training programs of the Department of Psychiatry and the Medical College, including an NIMH research fellowship in geriatric mood disorders.