The primary objective of our study was to examine the role of atrophy, high intensity lesions and medical comorbidity in the pathophysiology of major depressive disorder in the elderly (late-life MDD). Our sample was comprised of 51 patients with late-life MDD and 30 non-depressed controls.All subjects were scanned on 1.5 tesla magnetic resonance imaging scanner (MRI) Depression is one of the most common mental disorders in the elderly (Alexopolous et al. 1988;Beck and Koenig 1996;Blazer et al. 1987;Blazer 1989Blazer , 1994Koenig et al. 1993;Oxman et al. 1987;Parmalee et al. 1989;Ruegg et al. 1988;Sherbourne et al. 1994). The prevalence of major depressive disorder (MDD) is estimated to be approximately 1-2 percent in community settings and strikingly higher in inpatient and long term care settings (Blazer et al. 1987;Koenig et al. 1993;Parmalee et al. 1989). The prevalence of other clinically significant forms of depression, that do not meet the severity criteria for MDD, lies between 5 and 15 percent in all major clinical settings (Beck and Koenig 1996;Blazer et al. 1987, Blazer 1994Parmalee et al. 1989). Anatomical and physiological neuroimaging approaches have been utilized to study the neurobiological correlates of MDD and minor depression in the elderly (Coffey et al. 1990;Coffey et al. 1993;Greenwald et al. 1996;Krishnan et al. 1988;Krishnan 1993;Kumar et al. 1997a;Lesser et al. 1994;Sackheim et al. 1993;Sheline et al. 1996). Glucose hypometabolism and Lesser et al. 1994;Sackheim et al. 1993). Using magnetic resonance imaging (MRI), investigators have demonstrated neuroanatomical abnormalities including smaller focal brain volumes and larger high intensity lesion volumes in patients with both late-life major and minor depression when compared with non-depressed controls (Coffey et al. 1990;Coffey et al. 1993;Greenwald et al. 1996;Krishnan et al. 1988;Krishnan 1993;Kumar et al. 1997aKumar et al. , 1997bKumar et al. , 1998Sheline et al. 1996).Despite these observations, the precise nature and extent of the neuroanatomical changes in elderly patients with MDD remains unresolved (Jeste et al. 1988;Morris and Rapoport 1990).Late-life MDD is also consistently associated with medical comorbidity (Berkman et al 1986;Gierz and Jeste 1993;Katz et al. 1994;Katz 1996;Lacro and Jeste 1994;Rodin and Voshart 1986). A broad spectrum of medical disorders including cardiovascular, musculoskeletal, gastrointestinal, pulmonary and metabolic disturbances are associated with both major and minor forms of depression (Alexopolous et al. 1988;Katz et al. 1994;Koenig et al. 1993;Lacro and Jeste 1994). Despite this association, the relationship between neuroanatomical abnormalities and medical disorders in late-life and their relative contributions to the pathophysiology of mood disorders remain unknown.In an earlier report, we demonstrated that the odds of developing MDD in late-life increased with overall medical burden and larger whole brain cerebrospinal fluid (CSF) volume (Kumar et al. 1997a). However, only global measures ...