The overarching goal of this K08 Career Development Award project proposal is to delineate the relative contributions of cognitive deficits and brain abnormalities on disability for individuals with late life depression (LLD). This research will facilitate the development of interventions to minimize the burden of disability in LLD and will also inform studies of disability in neurodegenerative diseases. Depression is the fourth leading cause of disability worldwide and elderly depressed individuals are particularly at risk to become disabled. LLD has been strongly linked to cerebrovascular disease (CVD) and cognitive deficits of executive dysfunction (ED) and both CVD and ED confer additional risk for disability. However, to date, the relative contributions of cognitive and neurobiological factors on disability in LLD remain under-investigated. The specific focus of the proposed study is to determine the independent effects of depression severity, ED, and changes in brain structure and white matter integrity on disability in LLD. The stated research goal will be achieved by recruiting 60 individuals over the age of 65 with LLD,ED, and risk factors for CVD. Participants will be enrolled in the study for one year to determine factors associated with disability at baseline and at follow-up. The predictor variables will be depression severity, measures of ED, and brain Magnetic Resonance Imaging (MRI) measures obtained at 4 Tesla. MRI measures will include conventional structural MRI measures to evaluate structural brain abnormalities and diffusion tensor imaging (DTI) measures utilized to assess white matter integrity. Outcome variables will be measures of functional disability that are sensitive to physical, emotional, and cognitive factors. Disability will be assessed by patient self-report and by report of an informant. Measures of medical comorbidity, physical impairment, social support and medication use will be obtained to further clarify the impact of the primary predictor variables on disability status. Longitudinal measures of disability status, depression severity, and cognitive functioning will be obtained at a one-year follow-up assessment to evaluate factors associated with poor course of disability. Data from non-depressed older adults with isolated ED (n=46) and cognitively normal, non-depressed older adults (n=40) will be available for comparison to LLD individuals for disability severity, cognitive functioning, MRI measures, and depression severity at baseline and one-year follow up evaluations. This research design will offer the opportunity to test our hypothesis that depression severity, ED, and structural brain abnormalities each represent independent pathways to disability in LLD.

Public Health Relevance

Further, we expect that measures of white matter integrity (DTI) will be stronger predictors of disability than traditional neuroimaging markers. Importantly, this research proposal is accompanied by complimentary career development and training plan to facilitate the development of the applicant's career as an independent academic researcher.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Clinical Investigator Award (CIA) (K08)
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Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Chavez, Mark
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Insel, Philip S; Mattsson, Niklas; Mackin, R Scott et al. (2016) Accelerating rates of cognitive decline and imaging markers associated with ?-amyloid pathology. Neurology 86:1887-96
Sacuiu, Simona; Insel, Philip S; Mueller, Susanne et al. (2016) Chronic Depressive Symptomatology in Mild Cognitive Impairment Is Associated with Frontal Atrophy Rate which Hastens Conversion to Alzheimer Dementia. Am J Geriatr Psychiatry 24:126-35
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Lindqvist, Daniel; Mueller, Susanne; Mellon, Synthia H et al. (2014) Peripheral antioxidant markers are associated with total hippocampal and CA3/dentate gyrus volume in MDD and healthy controls-preliminary findings. Psychiatry Res 224:168-74
Mackin, R Scott; Insel, Philip; Truran, Diana et al. (2014) Neuroimaging abnormalities in adults with sickle cell anemia: associations with cognition. Neurology 82:835-41

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