Neuropathologic Correlates of Late-Onset Major Depression

Abstract

Late life major depression (LLMD) is frequently associated with cognitive impairment, and increases the risk for subsequent dementia. Cerebrovascular disease, Alzheimer's disease (AD), and dementia with Lewy bodies (DLB) have all been hypothesized to contribute to this increased risk, though prospective studies have yet to examine these hypotheses with autopsy confirmation of the clinical diagnoses. The aim of this study is to examine the rates of cerebrovascular, AD, and DLB pathology among the first 10 participants in an LLMD brain tissue donation program. Subjects' psychiatric diagnoses and cognitive status were prospectively determined during their participation in clinical research protocols of the Intervention Research Center for Late Life Mood Disorders. After death, final clinical diagnoses were made using all clinical information, while blind to neuropathologic diagnoses. Neuropathologic assessments were conducted blind to final clinical diagnoses. Rates of neuropathology were compared with those in a cohort of subjects with dementia, without a history of LLMD, participating in an Alzheimer Disease Research Center. Seven (70%) subjects had evidence of onset of a dementia prior to death. LLMD with dementia was significantly associated with a neuropathologic diagnosis of AD. Cerebrovascular disease and DLB pathology were also frequent in the LLMD subjects with dementia, and were found in an LLMD subject without dementia. Rates of AD, DLB, and cerebrovascular disease were similar to those in the comparison subjects. These preliminary findings suggest that AD is the predominant neuropathologic condition in LLMD subjects with dementia. Further assessment of the role of comorbid cerebrovascular disease and comorbid DLB is needed.

Translational Research in Late-Life Mood Disorders: Implications for Future Intervention and Prevention Research

“…The majority of these studies have been performed in younger patients and the extension of these observations into older patients represents an important area of investigation. Future studies of the neuropathology of late-life depression will extend the observations made by these initial studies (Sweet et al, 2004;Rajkowska et al, 2005) to larger sample sizes and further integrate the post-mortem findings with clinical and neuroimaging methods.…”

“…The initial, preliminary neuropathological studies of patients with geriatric depres-sion that have been clinically well characterized before death have been published (Sweet et al, 2004;Rajkowska et al, 2005). In a sample of patients, many of whom (70%) demonstrated cognitive deficits before death, evidence of cerebrovascular alterations, neurofibrillary tangles, amyloid plaques, and diffuse lewy bodies was observed (Sweet et al, 2004).…”

“…The initial, preliminary neuropathological studies of patients with geriatric depres-sion that have been clinically well characterized before death have been published (Sweet et al, 2004;Rajkowska et al, 2005). In a sample of patients, many of whom (70%) demonstrated cognitive deficits before death, evidence of cerebrovascular alterations, neurofibrillary tangles, amyloid plaques, and diffuse lewy bodies was observed (Sweet et al, 2004). To follow-up on reports of decreased orbitofrontal cortex volume identified on magnetic resonance scans (Lee et al, 2003), Rajkowska et al (2005) demonstrated a decreased packing density of pyramidal neurons and reductions to a greater extent in cortical layers IIIc and V, the source of prefrontal-striatal, prefrontal-cortical, and prefrontal-amygdala projections.…”

Mood, cognition and in vivo protein imaging: the emerging nexus in clinical neuroscience

“…MDD has been identified both as a risk factor and a prodrome of Alzheimer's disease (AD) in clinical and community samples (Reding et al, 1985;Kral and Emery, 1989;Kokmen et al, 1991;Jorm et al, 1991;Alexopoulos et al, 1993b;Speck et al, 1995;Devanand et al, 1996;Henderson et al, 1997;Steffens et al, 1997;Bassuk et al, 1998;Chen et al, 1999;Yaffe et al, 1999;Geerlings et al, 2000;Jorm, 2000;Lockwood et al, 2000;Visser et al, 2000;Jorm, 2001;Lockwood et al, 2002;Wilson et al, 2002;Green et al, 2003;Sweet et al, 2004;Cannon-Spoor et al, 2005;Gatz et al, 2006;Rapp et al, 2006;Steffens et al, 2006). Community based studies have identified clinical depression, including depressive symptoms as a risk factor for the subsequent development of dementia.…”

“…In a preliminary, but important, report on the neuropathological correlates of cognitive changes in patients initially diagnosed as having late-life MDD, Sweet et al examined post mortem brain tissue in nine patients diagnosed as having late-onset major depression and one patient diagnosed with bipolar disorder (Sweet et al, 2004). This sample of patients had MDD without clinical evidence of dementia during the initial assessment and participated in research protocols for patients with late-life major depression.…”