The overall goal of this program of research is to identify the neurobiological substrates of cognitive impairment (CI) in late life depression (LLD). CI represents one of the most debilitating and costly aspects of LLD and occurs in up to 60% of depressed older adults. While it is recognized that: 1) LLD is a relapsing-remitting disorder, 2) CI in some cognitive domains improves following remission of LLD (remediable CI) but the majority of CI persist, 3) LLD is a commonly co-occurring feature of several neurodegenerative diseases in older adults, and 4) LLD is associated with accelerated cognitive decline in older adults;the cause(s) of CI in LLD are not well understood. Therefore the identification of neurobiological substrates of CI represents a significant opportunity to improve health and disability outcomes for older adults with depression. Previous work has focused primarily on the association of white matter signal hyperintensities (WMSH) and CI in LLD but recent findings demonstrating prominent cortical thickness and cerebral blood flow abnormalities in LLD suggest these brain abnormalities may also be primary mechanisms contributing to CI. However, differentiating the impact of concurrent neurodegenerative disease(s) such as cerebrovascular disease and incipient Alzheimer's disease (AD) on CI in LLD has represented a significant obstacle. With the advent of new MRI techniques, including radioligands to evaluate amyloid deposition in vivo and the establishment of national research consortiums developed to identify neural substrates of CI in older adults there is now a tremendous opportunity to clarify the neurobiological substrates of CI in LLD. The specific goals of this investigation are: 1) To clarify the impact of cerebral blood flow, cortical thickness, and amyloid deposition on CI in LLD, and 2) To determine the impact of depression on course of cognitive decline in older adults. These goals will be achieved by enrolling 120 subjects with LLD into an adjunct arm of the Alzheimer's Disease Neuroimaging Initiative study (ADNI-II). ADNI-II is a five-year 69 million dollar study conducted to identify neuroimaging abnormalities and biomarkers of Alzheimer's disease and cognitive decline in older adults. For the proposed five year study, 120 LLD subjects will be enrolled at three recruitment sites and will participate in two evaluations. At baseline LLD participants will be evaluated to obtain neuroimaging and clinical data (depression, cognitive, genetic). After 2.5 years a clinical follow up assessment (cognitive, depression) will be conducted. Data from 300 non-depressed and non-demented older adults will be obtained from the ADNI-II study for between group comparisons. All data collected would be made available to scientists worldwide.

Public Health Relevance

Cognitive impairment (CI) represents one of the most debilitating and costly aspects of late life depression (LLD) and CI occurs in up to 60% of depressed older adults. The purpose of this project is to identify the impact of specific neurobiological characteristics on CI and accelerated cognitive decline in LLD, including cerebral blood flow, cortical atrophy, and amyloid deposition. The information obtained from this study will lead to improved diagnostic approaches and treatment trials aimed at cognitive impairment and LLD, which will ultimately lead to improved health outcomes and reduced healthcare costs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH098062-02
Application #
8706968
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Evans, Jovier D
Project Start
2013-08-01
Project End
2018-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Psychiatry
Type
Schools of Medicine
DUNS #
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Mohlenhoff, Brian S; O'Donovan, Aoife; Weiner, Michael W et al. (2017) Dementia Risk in Posttraumatic Stress Disorder: the Relevance of Sleep-Related Abnormalities in Brain Structure, Amyloid, and Inflammation. Curr Psychiatry Rep 19:89
Parthasarathy, Vishnu; Frazier, Darvis T; Bettcher, Brianne M et al. (2017) Triglycerides are negatively correlated with cognitive function in nondemented aging adults. Neuropsychology 31:682-688
Taylor, Alexander N W; Kambeitz-Ilankovic, Lana; Gesierich, Benno et al. (2017) Tract-specific white matter hyperintensities disrupt neural network function in Alzheimer's disease. Alzheimers Dement 13:225-235
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
Araque Caballero, Miguel Ángel; Brendel, Matthias; Delker, Andreas et al. (2015) Mapping 3-year changes in gray matter and metabolism in A?-positive nondemented subjects. Neurobiol Aging 36:2913-2924
Mattsson, Niklas; Insel, Philip S; Aisen, Paul S et al. (2015) Brain structure and function as mediators of the effects of amyloid on memory. Neurology 84:1136-44
Insel, Philip S; Mattsson, Niklas; Donohue, Michael C et al. (2015) The transitional association between ?-amyloid pathology and regional brain atrophy. Alzheimers Dement 11:1171-9
Insel, Philip S; Mattsson, Niklas; Mackin, R Scott et al. (2015) Biomarkers and cognitive endpoints to optimize trials in Alzheimer's disease. Ann Clin Transl Neurol 2:534-47
Mackin, R Scott; Insel, Philip; Zhang, Jing et al. (2015) Cerebrospinal fluid ?-synuclein and Lewy body-like symptoms in normal controls, mild cognitive impairment, and Alzheimer's disease. J Alzheimers Dis 43:1007-16
Jack Jr, Clifford R; Barnes, Josephine; Bernstein, Matt A et al. (2015) Magnetic resonance imaging in Alzheimer's Disease Neuroimaging Initiative 2. Alzheimers Dement 11:740-56

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