Lon White - US grants

[unreadable] DESCRIPTION (provided by applicant): Building upon the network foundation established by BRIN, INBRE proposes to expand and to develop Hawaii's competitive biomedical research capacity. The expansion will center on three thematic projects exploring the cellular basis of immunological and neurological diseases from the perspective of immunology, cell biology, and developmental biology. Each project will be led by a well-established senior investigator who will mentor junior investigators at both the lead and the affiliated baccalaureate institutions. This will extend into the state's community colleges where participating faculty will collaborate with established researchers at the lead institution. Each investigator - senior, junior, and Outreach - will recruit and mentor undergraduate and graduate students as well. The development will concentrate on not only individual research careers but also the network's overall approach to competitive research. This involves the establishment of rigorous standards and performance expectations coupled with attentive mentoring to assist network investigators and students in meeting these challenging criteria. Organizationally, INBRE will [unreadable] consist of four major cores: Administrative, Research, Bioinformatics, and Outreach. The Administrative [unreadable] Core will provide overall administrative support, including maintenance of the network's web site, evaluation efforts, and training and mentoring workshops and seminars. The Research Core will be comprised of the three thematic research projects with a Core leader to ensure project coordination. The Outreach Core extends the research thrust into the community colleges by promoting research and student participation through collaborations with the lead and the baccalaureate institutions. The Bioinformatics Core will also provide unique opportunities by emphasizing academic work force development. To facilitate this, the Core will be housed within the University of Hawaii at Manoa's Department of Information and Computer Sciences. [unreadable] [unreadable]

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The Administrative Core coordinated and administered general program implementation. This included provision of clerical and fiscal support for the grant as a whole and for the other cores, compliance with federal and university regulations governing research on human subjects and vertebrate animals, and oversight of the grant's post-award management by the University's fiscal officer. This includes preparation and submission of all NIH- and university-mandated reports and documents. In addition, the Core orchestrated meetings of the External and other advisory committees and served as liaison with partner institutions. The Core also assigned and retained three Senior Investigators who served as mentors to the six Junior Investigators.

DESCRIPTION (provided by applicant): Population demographics suggest that with the expected dramatic increase in age-associated dementias a public health crisis is looming. Current emphasis is on disease prevention with a focus on elderly individuals who express some cognitive impairment. We propose to identify authoritatively the risk and protective factors for cognitive decline in older persons. We have shown how to define these impaired states retrospectively, how to account for reverse transitions, how to distinguish prevalence from incidence, and how to account for competing risks by using a unique statistical (Markov) model. But sufficient longitudinal and neuropathological data is currently not available to distinguish among different types of dementia. No single Alzheimer's Disease Center (ADC) or cooperative study has an adequate sample size to reliably track transitions to dementia and differentiate Alzheimer's disease (AD) from other prevalent brain diseases that include vascular dementia (VaD) and Lewy body disease (LBD). This project will pool data from six well established longitudinal cohorts to identify risk factors for (1) preservation of intact cognition in those meeting neuropathological criteria for varying types of dementia and MCI and (2) specific forms of dementia (clinical and neuropathological). This will improve our understanding of intervening impaired states and factors that promote resistance to clinical symptoms despite the presence of neuropathology. These considerations lead to the specific aims below. Specific Aim 1: To merge databases from six large projects that follow cohorts of cognitively intact subjects to dementia, for the purpose of rigorous, statistical, biologically-informed analyses that accentuate longitudinal follow-up: BRAiNS (University of Kentucky), Nun Study (University of Minnesota), Memory and Aging Project (Washington U), Kuakini Honolulu-Asia Aging Study, Religious Orders Study (ROS, Rush Medical University), and the OHSC ADC (Oregon Health &Science University). The database would be made publicly accessible. Specific Aim 2: To identify appropriate intervening states between intact cognition and dementia based on periodic assessments of cognition and functional skills from data collected at these centers. Specific Aim 3: To study transitions and associated risk factors (e.g., genetic, medical, time in an impaired state) using novel statistical methods. Specific Aim 4: To standardize the neuropathological findings across databases (including quantitative neuropathological assessments) to enable the analysis of novel pathogenetic determinants of outcomes. This aim allows us to evaluate how actual brain pathology (e.g., microinfarcts, Lewy bodies, hippocampal sclerosis, and mixed pathologies) relates to antemortem states in the subset of participants coming to autopsy. This aim could support proposed revisions of current neuropathological and clinical research diagnostic criteria in dementia and preclinical dementia conditions. PUBLIC HEALTH RELEVANCE: With the graying of America the cost of caring for demented elderly will rise substantially in the next few decades. Current emphasis is on preventing this disease. This project will identify risk factors for various forms of dementia as well as impaired states that precede this disease.

DESCRIPTION (provided by applicant): Population demographics suggest that with the expected dramatic increase in age-associated dementias a public health crisis is looming. Current emphasis is on disease prevention with a focus on elderly individuals who express some cognitive impairment. We propose to identify authoritatively the risk and protective factors for cognitive decline in older persons. We have shown how to define these impaired states retrospectively, how to account for reverse transitions, how to distinguish prevalence from incidence, and how to account for competing risks by using a unique statistical (Markov) model. But sufficient longitudinal and neuropathological data is currently not available to distinguish among different types of dementia. No single Alzheimer's Disease Center (ADC) or cooperative study has an adequate sample size to reliably track transitions to dementia and differentiate Alzheimer's disease (AD) from other prevalent brain diseases that include vascular dementia (VaD) and Lewy body disease (LBD). This project will pool data from six well established longitudinal cohorts to identify risk factors for (1) preservation of intact cognition in those meeting neuropathological criteria for varying types of dementia and MCI and (2) specific forms of dementia (clinical and neuropathological). This will improve our understanding of intervening impaired states and factors that promote resistance to clinical symptoms despite the presence of neuropathology. These considerations lead to the specific aims below. Specific Aim 1: To merge databases from six large projects that follow cohorts of cognitively intact subjects to dementia, for the purpose of rigorous, statistical, biologically-informed analyses that accentuate longitudinal follow-up: BRAiNS (University of Kentucky), Nun Study (University of Minnesota), Memory and Aging Project (Washington U), Kuakini Honolulu-Asia Aging Study, Religious Orders Study (ROS, Rush Medical University), and the OHSC ADC (Oregon Health & Science University). The database would be made publicly accessible. Specific Aim 2: To identify appropriate intervening states between intact cognition and dementia based on periodic assessments of cognition and functional skills from data collected at these centers. Specific Aim 3: To study transitions and associated risk factors (e.g., genetic, medical, time in an impaired state) using novel statistical methods. Specific Aim 4: To standardize the neuropathological findings across databases (including quantitative neuropathological assessments) to enable the analysis of novel pathogenetic determinants of outcomes. This aim allows us to evaluate how actual brain pathology (e.g., microinfarcts, Lewy bodies, hippocampal sclerosis, and mixed pathologies) relates to antemortem states in the subset of participants coming to autopsy. This aim could support proposed revisions of current neuropathological and clinical research diagnostic criteria in dementia and preclinical dementia conditions.

DESCRIPTION (provided by applicant): The development of strategies to prevent Alzheimer's disease (AD) and related dementing illnesses will depend on an understanding of the underlying pathologic processes. In recent years it has become apparent that in older persons, these illnesses are usually the result of two or more fundamental pathogenic processes, often interacting additively. This complexity has been recognized largely as a result of neuropathological research in the context of longitudinal epidemiologic projects such as the Nun Study and the Honolulu-Asia Aging Study (HAAS), both now completed. The proposed project will compile accrued data and images from 854 HAAS autopsies and approximately 500 Nun Study autopsies, develop a common dataset and archive of photographic images of brain sections, and will be employed in parallel assessments of newly revised neuropathologic criteria for the identification and measurement of the AD disease process, which will be compared to previous criteria. In addition, these same data will be utilized for in an in-depth analysis of the interdependent and independent roles of AD brain lesions and brain atrophy as proximate causal factors responsible for dementia. These efforts are expected to: (1) provide a foundation for future analytic use of the accrued resources of the two projects, (2) examine the likely impact and utility of the revised neuropathologic AD assessment criteria for future research addressing the dementing illnesses of late life, and (3) facilitate a conceptual convergence of our understanding of the causes and importance of brain atrophy from neuroimaging and neuropathological perspectives.

Abstract/Summary The proposed work will investigate the pathogeneses of late life cognitive and motor impairments attributed to Alzheimer's disease, closely allied cerebrovascular and neurodegenerative diseases, brain aging, and their common patterns of co-occurrence in three existing cohorts: the Honolulu-Asia Aging Study, the Nun Study, and the 90+ Study. Our focus will be on relationships among objective, longitudinal measures of motor function and cognition?with the last obtained proximate to death?and a defined set of neuropathologic substrates identified at autopsy. Parallel and merged analyses will be carried out using existing resources provided from these three large population-based longitudinal studies composed of participants with distinctly different gender, age, and ethnicity. We will leverage these substantial existing resources to test the hypothesis that cognitive and motor impairments that occur with advancing age are syndromic and derive from a partially overlapping mix of diseases that vary among individuals in part by age, sex, and ethnicity, and that can be identified best at the current time by their neuropathologic features. This will allow the identification of common patterns for the singular, concurrent, or sequential development of cognitive and/or motor impairments in persons with and without dementia. The informational wealth of these three studies (all established and supported with NIA funding) will be further expanded and available to teams of collaborating researchers for continuing analyses.