Cognitive Remediation of Cognitive Control in Late-Life Depression

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Dr. Manning is a licensed clinical neuropsychologist who specializes in the cognitive evaluation of older adults. The focus of his clinical practice and clinical-research is cognitive disorders and depression in the elderly. This K23 Award is a critical step toward his career as an independent investigator focused on understanding and modifying pathophysiologic processes of late-life depression (LLD). LLD is a risk state for later dementia. It is thought that frontolimbic brain changes result in both depression and cognitive weaknesses that interact to increase the likelihood of dementia in LLD. Mild impairments in executive functions (EF) appear especially relevant to LLD. Weaknesses in EF are common in LLD and predictive of treatment resistance and a later dementia diagnosis. The process appears to be dynamic, in the sense that decrements in EF promote depressive symptoms, and increases in depression lead to greater impairment in EF. One way to intervene would thus be to address depressive symptoms, e.g., with antidepressants and / or psychotherapy. However, antidepressants have rather limited efficacy and a delayed clinical response in LLD. Furthermore, antidepressants and psychotherapy do not consistently improve EF post-treatment. The other means to intervene, then, would be to target EF. We propose to use computerized cognitive remediation to change EF, depression, and executive control connectivity and explore whether this change is associated with changes in limbic connectivity and long-term cognitive decline in LLD. With the resubmission of this Award application, Dr. Manning proposes a training and research plan that provides a foundation from which to study mechanisms related to treatment response and cognitive decline in LLD. He has four training goals: 1) Expand his knowledge of mechanisms affecting treatment response and cognitive decline in LLD. 2) Develop expertise in the acquisition and analysis of structural and functional MRI. 3) Obtain training in the utilization and evaluation of cognitive remediation interventions, and 4) Learn clinical trial design and analysis of mechanisms of therapeutic change in LLD. In response to the Reviewers' thoughtful critiques, the training plan now emphasizes coursework in clinical neuroscience, MRI analysis, and randomized trials, as well as workshops in preclinical dementia identification. Dr. Manning pays close attention to the use of structural and functional MRI, sensitive cognitive assessment, and longitudinal follow-up as a means to identify LLD patients at risk for cognitive decline. Beyond providing excellent training, this research approach has the strong potential to shed light on the pathophysiology of LLD.