Meryl Butters, Ph.D. - US grants

This is a resubmission of K01MH01684-01A1 requesting support to provide the applicant with the skills necessary to conduct research that bridges geriatric neuropsychology with neuroimaging and longitudinal data analysis. Career development activities will focus on structural and functional MRI methods and data interpretation, and multivariate and longitudinal data analytic skills. These skills will be applied to research on the course of cognitive functioning in late-life depression (LLD), under the auspices of the Mental Health Interventions Research Center in Late-Life Mood Disorders. The Center provides subjects with broad-based clinical assessments, including neuropsychological evaluation, at baseline, after treatment of acute depressive episodes, and at yearly follow-up. The cognitive course of 250 LLD and 90 elderly control subjects will be studied over four years, using clinical neuropsychological and structural MRI data collected through the Center, as well as supplementary cognitive and functional MRI data collected under the auspices of this MRSDA. Treatment-related cognitive changes will be characterized. Risk factors for cognitive dysfunction will be determined. The functional integrity of the dorsolateral prefrontal cortex will be examined in a subset of subjects, using a valid and reliable functional MRI probe. Over a four-year follow-up period, this research will identify and characterize LLD sub-groups based on cognitive course, and examine risk factors for future dementia. This award will provide the applicant with the resources to obtain the training necessary to initiate a line of programmatic research and to develop into an independent scientist.

[unreadable] DESCRIPTION (provided by investigator): The goal of this revised R01 application is to investigate the relationships among late-life depression (LLD), cognitive impairment and progressive neurodegeneration. The guiding hypothesis is that LLD patients have evolving cognitive impairments as a consequence of distinct underlying neuropathological changes, which frequently are expressed as Mild Cognitive Impairment (MCI). These neuropathological and cognitive changes are risk modifiers, lowering brain reserve capacity, and in turn, increasing risk of developing Alzheimer's Disease (AD). In order to pursue this goal we will enroll LLD, MCI, and normal control subjects to enrich our existing cohort (gathered through Dr. Butters' existing K01 Award (MH01684), "The Course of Cognitive Functioning in Late-Life depression" to include a total of 150 elderly, non-demented, non-depressed subjects, 60 nondepressed MCI subjects and 270 LLD subjects. Using the joint infrastructure of the University of Pittsburgh's Intervention Research Center for Late-Life Mood Disorders (MH52247) and the Alzheimer's Disease Research Center (AG05133) we will complete a detailed neurobehaviora! evaluation, including clinical, neuropsychological, neuroimaging and biological markers, using these data to evaluate the factors associated with the development of MCI or dementia. Subjects will be studied annually for at least three years, allowing us to use longitudinal data to evaluate a series of linked hypotheses that postulate the pathways by which elderly, depressed patients develop cognitive impairment, and which may lead some to develop dementia. [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): This R01 resubmission from a new principal investigator focuses on generalized anxiety disorder (GAD) in elderly persons, a significant public health issue because of the high prevalence and burden of GAD in this age group. However, the treatment evidence in late life GAD is inadequate, and the illness remains vastly under treated. This study is a 12 week randomized, double-blind, placebo-controlled examination of escitalopram, an SSRI that is well-tolerated and highly specific for the serotonin transporter (SERT). We will recruit 176 subjects aged 60 and older from primary care practices for treatment. Subjects will have GAD without current major depressive disorder. The study will allow inclusion of comorbidity commonly seen in anxious elderly, including depression. We will examine symptomatic response. As secondary, exploratory analyses, we will examine treatment-attributable changes in functional disability and neuropsychological measures. We will genotype subjects in terms of a SERT polymorphism which has been posited as a moderator of SSRI treatment outcome, and we will determine whether allelic variation in the SERT contributes to the variability of treatment response. Our first goal is to demonstrate SSRI efficacy for late life GAD in the primary care sector. It is our expectation that demonstration of medication efficacy in this population (and dissemination of the results) would lead to increased utilization of pharmacotherapy for this disorder. Efficacy evaluation will include examination of functional and neuropsychological improvements from treatment. The second goal is the examination of a genetic moderator of treatment response - such findings could lead not only to improvements in the individualization of treatment for late life GAD, but also to a greater understanding of the neurobiological sources of heterogeneity in this disorder. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The goal of this R01 application is to investigate the relationships among late-life depression (LLD), cognitive impairment and progressive neurodegeneration with two imaging approaches: a novel PET ligand (Pittsburgh Compound-B;PiB) that binds to amyloid and volumetric MRI of white matter hyperintensities (WMH). The guiding hypothesis is that individuals who develop LLD have evolving cognitive impairments as a consequence of distinct underlying neuropathologic changes that frequently are expressed as Mild Cognitive Impairment (MCI). Amyloid and WMH are major neuropathologic features that lower brain reserve capacity, and in turn, increase risk of expressing clinical Alzheimer's disease. To pursue this goal, using the joint infrastructure of the University of Pittsburgh's Advanced Center for Intervention and Services Research for Late-Life Mood Disorders (MH071944) and the Alzheimer's Disease Research Center (AG05133), individuals with remitted depression will undergo PiB-PET imaging for amyloid pathology and MRI to determine WMH volume. We will study 100 remitted depressed subjects with a range of cognitive classifications (50 cognitively normal, 50 MCI) and follow them for 3 years with longitudinal clinical, cognitive and laboratory data collection through Dr. Butters'R01 (MH072947;"Pathways Linking Late-Life Depression to MCI &Dementia"). WMH and PiB-PET data from these subjects will be compared with similar data on 25 never-depressed non-amnestic MCI subjects gathered through the proposed research along with 75 never-depressed subjects with a range of cognitive classifications (50 cognitively normal, 25 amnestic MCI), collected under the auspices of two other funded awards (Program Project Grant AG025204 "In Vivo PiB-PET Amyloid Imaging: Normals, MCI &Dementia" and MERIT Award AG025516 "Brain Amyloid and Cognition in Normal Elderly"). We will test a series of linked hypotheses that postulate the neuropathologic substrates of some of the pathways by which elderly, depressed patients develop cognitive impairment and lead some to Alzheimer's disease. PUBLIC HEALTH RELEVANCE: This research study will gather information that will improve understanding of why elderly depressed individuals have an increased risk of developing dementia. To meet this goal we will study participants from related studies, with new brain scanning methods that detect cerebrovascular disease and amyloid, one of the key substances that accumulates in the brains of individuals with Alzheimer's disease. If we can better identify individuals at risk for developing specific types of dementia, such as Alzheimer's disease, then they can be candidates for treatment at the earliest disease stages, as new dementia treatments become available.

Mild cognitive impairment (MCI) is a transitional state between normal cognitive function and dementia. Depression frequently co-occurs with MCI and each increases the risk of developing the other.(192-196) Cognitive loss may act as a stressor (much like any chronic and potentially progressive medical illness), associated with a constellation of psychosocial factors that have been linked to increased depression risk.(197199) Once older adults develop major depression, multiple pathologic mechanisms (i.e., vascular, neurodegenerative, stress hormone toxicity(200-201) likely mediated by neuroinflammation, increase the risk of cognitive decline (in the case of depression risk of progression to dementia is doubled).(202)

DESCRIPTION (provided by applicant): The goal of this R01 application is to investigate the relationships among late-life depression (LLD), cognitive impairment and progressive neurodegeneration with two imaging approaches: a novel PET ligand (Pittsburgh Compound-B; PiB) that binds to amyloid and volumetric MRI of white matter hyperintensities (WMH). The guiding hypothesis is that individuals who develop LLD have evolving cognitive impairments as a consequence of distinct underlying neuropathologic changes that frequently are expressed as Mild Cognitive Impairment (MCI). Amyloid and WMH are major neuropathologic features that lower brain reserve capacity, and in turn, increase risk of expressing clinical Alzheimer's disease. To pursue this goal, using the joint infrastructure of the University of Pittsburgh's Advanced Center for Intervention and Services Research for Late-Life Mood Disorders (MH071944) and the Alzheimer's Disease Research Center (AG05133), individuals with remitted depression will undergo PiB-PET imaging for amyloid pathology and MRI to determine WMH volume. We will study 100 remitted depressed subjects with a range of cognitive classifications (50 cognitively normal, 50 MCI) and follow them for 3 years with longitudinal clinical, cognitive and laboratory data collection through Dr. Butters' R01 (MH072947; Pathways Linking Late-Life Depression to MCI & Dementia). WMH and PiB-PET data from these subjects will be compared with similar data on 25 never-depressed non-amnestic MCI subjects gathered through the proposed research along with 75 never-depressed subjects with a range of cognitive classifications (50 cognitively normal, 25 amnestic MCI), collected under the auspices of two other funded awards (Program Project Grant AG025204 In Vivo PiB-PET Amyloid Imaging: Normals, MCI & Dementia and MERIT Award AG025516 Brain Amyloid and Cognition in Normal Elderly). We will test a series of linked hypotheses that postulate the neuropathologic substrates of some of the pathways by which elderly, depressed patients develop cognitive impairment and lead some to Alzheimer's disease.

PROJECT SUMMARY DESCRIPTION: Dementia, especially Alzheimer's dementia (AD), is a growing public health problem with a prevalence of 5M in the US alone (33M worldwide). Despite a decrease in incidence rates, with the aging of the population, the prevalence of dementia is expected to increase to 16M in the US (115M worldwide) with associated costs rising to $1T. Delaying long-term care by 1 month for older Americans would save $60B annually in direct care cost. Efforts to prevent or delay dementia have been largely unsuccessful. However, major depressive disorder in late life (?late-life depression?, LLD) has been identified as one of six treatable risk factors for dementia, especially AD and vascular dementia. The depression-dementia relationship may be magnified in elders who do not respond to antidepressant treatment and experience persistent symptoms. Thus, resolving whether those with treatment-resistant late-life depression (TRLLD) are at higher risk of cognitive decline and progression to dementia compared to those with treatment-responsive LLD is critically important. Leveraging a Patient-Centered Outcomes Research Institute (PCORI)-funded treatment study of N=1500 people with LLD, across 5 sites, we propose to comprehensively delineate neurocognitive and neuroimaging biomarkers associated with progression to dementia in people with persistent LLD (i.e., TRLLD) compared to those whose LLD remits with treatment. We anticipate enrolling 750 elders with LLD and characterizing their symptomatic trajectory over 24 months. We will assess each participant at three time points with neurocognitive and advanced neuroimaging. We hypothesize that changes in executive functions and the executive control network, as well as changes in episodic memory and the default mode/cortico-limbic network, will be greater in those with TRLLD than in those who respond to treatment and stay well. We also hypothesize that changes over two years in executive function and episodic memory will be specifically associated with changes in executive- control and cortico-limbic circuitry, respectively. Based on our recent findings that inflammatory and related molecular markers can differentiate those with neurocognitive impairment and LLD from those with LLD alone, we will build a predictive multivariate model combining baseline neurocognitive, neuroimaging, and plasma protein data to determine who is at greatest risk for cognitive decline and dementia. Finally, we will also explore whether latent class trajectories of depressive symptoms can go beyond the dichotomy of remission/non-remission to identify subsets of elders with LLD at highest risk of cognitive decline, neural circuit change, and progression to dementia. This work will set the stage for neural circuit- targeted preventive care to delay dementia in subsets of older patients with LLD. If successful, our work can accelerate therapeutic efforts and innovation targeting the depression- dementia pathway and reduce suffering for large numbers of elders and their families.