Charles DeCarli, MD - US grants

This renewal will continue the analysis of the determinants of individual households' savings, but it will focus on how individual behavior will respond to potential changes in public policy. In particular, the projects' findings will be used to analyze the effect of potential changes in Social Security, Medicare, and disability insurance. A major aim of the program project is hence to use the analysis of the individual households' behavior to project the consequences of changes in public policy impinging on health and retirement. The program project has two cores and three projects. The Administrative Core (continuing Core A) will provide overall administrative support for the entire project. It will also provide support for research coordination and dissemination. The Database Core (continuing Core B) will continue to work on methods for improving the wealth data in the HRS and on issues of survey design (bracketing, question order, anchoring) that impinge on the preference and expectational measures as well as the wealth measures. The three projects include: (1) preference parameter project (continuing Project) will develop new measures quantifying the altruism and labor supply of individuals and extend the analysis of the existing parameters relating to risk tolerance. These estimates will be used to study bequests, portfolio choices, and the interaction between the retirement and wealth accumulation decision. (2) The earnings dynamics project (new Project 7) will use HRS Social Security earnings history to estimate the stochastic process followed by labor income. Such estimates are of interest in themselves, particularly in what they reveal about the persistence of shocks to earnings. The earnings process project will also make them the subject of analysis. It will treat the stochastic process for earnings a consequence of choices made by individuals instead of something exogenous. It will also examine how individuals adjust their consumption, saving, and labor supply follow shocks to earnings. And (3) the earnings expectations project (new Project 8) will collect and analyze probabilistic expectations data related to economic insecurity and lifetime earnings expectations and will integrate these measures with explicit questions bout the behavioral response to changes in Social Security and Medicare benefits.

The Clinical Core will develop the current strengths of the UC Davis Alzheimer's Disease Center (UCD ADC) in order to create a synergy between the research at UCD and the activities of the Clinical Core. This process will further the goals of supporting the AD research at UCD and of promoting thematic research on the roles of cerebrovascular disease and ethnicity in modifying the clinical expression of AD. While the Clinical Core proposes to continue to recruit; evaluate and longitudinally follow Alzheimer's disease patients in the usual manner, we also propose to develop new cohorts and to apply new methods developed during the previous funding cycle. The new cohorts will include larger numbers of African American and Hispanic subjects, as well as patients with cerebrovascular risk factors or disease. Additional emphasis will be placed on subjects with very mild cognitive symptoms who are cognitively impaired but not demented (CIND). In order to maximize resources, the Core will establish two separate groups, the Subject Pool and the Longitudinal Cohort. The Subject Pool will constitute a large group of clinically probably AD patients, who are evaluated once. It is designed to meet the specific needs of collaborating researchers who are mostly interested in cross-sectional studies of AD. The Longitudinal Cohort will constitute an ethnically diverse group of subjects with annual follow-up to autopsy, including controls, patients who have CIND, and clinically probable AD and possible AD patients with cerebrovascular disease. New recruitment strategies are proposed to obtain these measurement of cognitive deficit, will be used. The Clinical Core will work closely with the Neuroimaging Core to obtain quantitated MRI data, with the Biostatistics and Data Management Core to expand the data base and to refine statistical methodology, with the Neuropathology Core to obtain autopsies on Longitudinal Cohort members, and with the Education and Information Transfer Core to maximize our recruitment of ethnic minority subjects.

PROJECT SUMMARY/ABSTRACT ? Administrative Core The Administrative Core (AC) is responsible for overall governance and leadership of the UCD ADC as well as spearheading development of new research and initiatives and representing the UCD ADC within and outside the UC Davis community. The landscape of medical research has changed substantially over the last 5 years, challenging the AC to innovate strategic planning so as to optimize utilization of ADC resources to benefit the overall mission of the Center. As a consequence, the AC has developed new avenues of research support and collaboration through state and local partnerships as well as promoting greater philanthropy. The result has been an expanded and highly successful pilot project program, new collaborative research programs, the expansion of career development of diverse faculty that culminated in successful funding of the Latino Aging Research Resource Center, a new and unique Resource Center in Minority Aging Research (RCMAR) that focuses on diversity faculty development and Latino health disparities research. Finally, the AC has worked closely with the UDC School of Medicine (SOM) leadership to expand the reach and impact of UC Davis health care system into the East Bay through the creation of a new clinical facility in Walnut Creek that houses both the East Bay ADC site and an extension of the UCD transplant service. The AC also continues to work closely with Program Officers of the NIA Alzheimer's Disease Centers program to further the goals of research including expansion of NACC data through MRI analysis as well as emphasizing training and education (including sharing new scientific information with the ADEAR center) in accordance with their scientific and academic mandates.

[unreadable] DESCRIPTION (provided by applicant): Clinical studies of elderly individuals with memory impairment reveal a rapid rate of conversion to Alzheimer's disease (AD) reaching as high as 15% per year. This evidence suggests that significant memory impairment, short of dementia and often denoted as mild cognitive impairment (MCI) in the elderly may be a transition phase between the normal aging process and AD. Individual trajectories of cognitive decline can be quite variable, however, and not all older individuals with cognitive impairment have memory loss as the predominant symptom suggesting considerable clinical and etiological heterogeneity. Further support for etiological heterogeneity comes from recent studies that show significantly increased blood pressure, magnetic resonance imaging and pathological evidence of cerebrovascular disease (CVD) amongst patients with MCI. Given the apparent heterogeneity within the broadly define syndrome denoted as MCI, examination of the various etiologies amongst the varied clinical presentations of MCI could significantly alter our current understanding of the process by which individuals transition from normal aging to dementia. In addition, since CVD is common to an aging population and potentially treatable, understanding the role CVD plays in the expression of MCI and progression to dementia could also result in clinical therapeutic trials aimed at the prevention of cerebrovascular-related cognitive impairment. The prevalence and impact of CVD on the natural history, patterns of cognitive performance or longitudinal cognitive changes in MCI are currently unknown. To address this gap in current understanding, this proposed project will examine the clinical and neurobiological substrate of MCI in a large group of MCI patients selected to have both memory and non-memory cognitive impairments as well as a broad spectrum of CVD severity. [unreadable] [unreadable]

pathologic process; brain imaging /visualization /scanning; dementia; temporal lobe /cortex; frontal lobe /cortex; clinical research; positron emission tomography; human subject;

apolipoprotein E; genotype; Alzheimer's disease; cortisol; dementia; saliva; plasma; biomarker; cerebrospinal fluid; neural degeneration; clinical research; human subject;

DESCRIPTION (provided by applicant): Data from the initial funding period of this grant have substantially informed us regarding the interaction between CVD and AD pathologies as they relate to the transitions between normal aging, MCI and dementia. These data suggest that CVD affects cognition through impairment of executive function, which in turn, adversely affects episodic memory performance. Anatomical evidence from these data strongly suggests that CVD influences executive function through white matter injury along specific tracts connecting parietal and frontal lobes and that the AD process also injures parietal subcortical white matter integrity, in addition to the more commonly recognized neuronal pathology. This information serves as the basis for a hypothetical disease model whereby CVD may act alone to cause impaired executive function (and possibly episodic memory impairment) or acts to amplify the cognitive effects of AD pathology. In addition, we hypothesize that both CVD and AD disease processes affect parietal-frontal connections through different mechanisms, and when they both occur in a given individual, will significantly increase the likelihood of future dementia. An important principal to our research is the recognition that both AD and CVD pathologies cause cognitive impairment through neuronal death or dysfunction. We also recognize that both diseases cause overlapping structural brain changes. For example, there is evidence that brain atrophy and WMH are the consequence of both AD and CVD pathologies, whereas MRI infarctions are strictly CVD and hippocampal atrophy is a strong, but not entirely pure indicator of AD. Unfortunately, until recently, it was impossible to dissociate these two disease processes on the basis of neuroimaging tools alone. A major advantage of our current study design is that-through use of PiB imaging-we can determine the presence or absence of cerebral amyloid, thereby allowing us to test the joint contributions of the AD and CVD processes on cognition without relying solely on MRI to make specific inferences regarding which structural brain changes relate to AD and which relate to CVD. The significance of our proposal continues to rest on the fact that CVD is currently the only treatable disease associated with cognitive impairment. We hope further understanding of how CVD impacts cognition will soon be used to develop clinical therapeutic trials that may reduce the incidence of cognitive impairment and dementia among our aging population. PUBLIC HEALTH RELEVANCE: This project seeks to extend current work evaluating the heterogeneous causes of mild cognitive impairment (MCI). Current work strongly suggests that MCI, including the amnestic subtype, results from the additive effects of cerebrovascular and Alzheimer's pathologies. This project is designed to identify the unique contributions of both pathologies to cognitive aging, MCI and risk for dementia.

longitudinal human study; Alzheimer's disease; racial /ethnic difference; Hispanic Americans; African American; cardiovascular disorder; clinical research; human subject;

Clinical heterogeneity is one of the basic facts of Alzheimer's disease. With this renewal application the DC Davis ADC further defines its long-standing interest in that heterogeneity to focus on two interconnected sets of factors, which may modify the clinical expression of this disorder, namely cerebrovascular disease and ethnicity. The goal of the Clinical Core is to assemble the subjects and clinical data needed to support and expand the research programs of ADC investigators, to facilitate the work of other investigators at Davis, and to contribute to the larger research community. The aims of the Core are: 1) To create cohorts of subjects who may participate in dementia related studies, and to follow selected subjects to create a longitudinal cohort and to maximize autopsy rates. 2) Diversify our subject population by recruiting large numbers of African American and Hispanic subjects, increasing the number of subjects with vascular risk factors and cerebrovascular disease, and by substantially increasing the number of subjects with MCI and or normal cognitive function. 3) Acquire high quality clinical data, including diagnosis, the UDS, and measures well suited for longitudinal measure and to maintain quality control of the data. 4) Facilitate and promote dementia research at Davis by helping investigators recruit subjects and train clinical investigators. Three of the most basic functions of the Core are subject recruitment, diagnosis, and assignment of subjects to research protocols. Subjects are recruited to the ADC through two dementia clinics, one in Sacramento, one in Martinez, and through a sizeable community outreach effort. In the community outreach program ADC recruiters directly approach senior citizens in the community to ask their participation. This approach, new in the concluding grant cycle, resulted in much larger numbers of minority participants, and more persons with cerebrovascular risk factors. The number of subjects with MCI also greatly increased. Regardless of where they are recruited, all subjects receive the same diagnostic evaluation, which includes the UDS measures, and are diagnosed according to the same procedures. After diagnosis, subjects are assigned to either the cross sectional cohort, or the longitudinal cohort. Subjects entering the longitudinal cohort receive additional studies including MRI, DNA/serum banking, and special neuropsychological studies, and are followed to autopsy if possible. These two cohorts play complementary roles in the Center, the CSC providing subjects to studies that require only diagnosis and/or baseline characteristics, while the LC provides a powerful core of baseline brain imaging and longitudinal neuropsychological, functional, and other clinical indices for studies of change or conversion.

Research during the last 5 years has uniquely positioned the University of California, Davis Alzheimer's Disease Center (UCD ADC) to advance scientific understanding along the theme of how various risk and protective conditions differentially affect cognitive trajectories across the spectrum of cognitive ability. Our approach is enabled and enhanced by the unique experiences, skills, and methods facilitated by the UCD ADC Cores and their interactions. These skills include development or refinement of new methods along with development of new conceptual models and the coordinated application of these resources towards common goals. These efforts are further extended by extensive collaborations with other scientists, NACC and the NIA. Importantly, these efforts are part of an integrated and growing research program at UC Davis that is uniquely suited to studying the complex determinants of cognitive decline associated with diseases of aging and dementia. Consisting of 6 Cores, the UCD ADC approach to supporting ongoing research is based on the belief that AD exists within the wider context of other factors that affect cognitive function. Unraveling the multiple deleterious and protective factors that ultimately determine the variance in course of cognitive function with advancing age, however, remains an enormous challenge. To meet this challenge, the Clinical Core developed methods to enhance subject diversity amongst the participants within the longitudinal cohort of the UCD ADC leading to recruitment of a highly diverse study population that varies across multiple dimensions. We also developed novel assessment tools which were used to acquire further research funding in support of the general themes and available resources of the UCD ADC. This approach, built around a diverse and longitudinally followed cohort of subjects, serves as the core resource for an integrated research effort that is guided by five essential principals: innovation, integration, leverage, growth and training. In this application we present successful progress over the previous grant cycle and propose nbvel and unique approaches to guide the succeeding five years in order to continue to productively contribute to advancing our understanding of conditions the influence cognitive aging and incident dementia.

community; university

The Clinical Core (CC) maintains our Longitudinal Cohort (LC), an ethnically and demographically diverse cohort which is the central scientific resource of the UCD ADC. The CC supports the research mission of the ADC to assess how various risk and protective conditions differentially affect cognitive trajectories across the spectrum of cognitive ability. The Core has achieved target enrollment in the LC (n ~530) and now has 2 or more visits on 88% of participants; approximately one-half of LC participants are of minority ethnicity, generally African American or Hispanic. In order to facilitate study of early AD and clinical transitions, about 50% of the LC is cognitively normal, 20% MCI. and 30% demented (59% of whom were non-demented at entry). The CC recruits participants primarily through direct, outreach based community recruitment, and also through ADC clinics. Recruitment now focuses on replenishing the cohort and meeting particular needs of associated scientific projects. It works closely with the Education and Information Transfer Core on recruitment and retention of the LC. The CC consents, evaluates participants in the LC. obtains autopsy preconsents and annual follow-up. The Core provides reliable and valid diagnoses for each participant. It implements standardized clinical data collection protocols, obtaining clinical data including all elements of the UDS. In concert with the Neuropathology Core, it arranges collection of biospecimens (e.g. plasma. DNA. RNA) and works closely with the Neuroimaging Core to obtain research MRI and other brain imaging studies. In addition, it coordinates, enables and monitors the collection of additional data that are crucial to a variety of thematically connected, independent research projects supported by the ADC. Because the Core is so tightly, and synergistically. integrated with independent projects, all participants in the LC also participate in a variety of R01s. The Core implements numerous procedures to maintain data quality and reliability, including monthly clinicopathological case conference (conducted with the Neuropathology Core). The Core supports recruitment for studies by ADC investigators, including pilot studies. The Core maintains a Clinical Trials Unit that carries out industry and academically sponsored diagnostic and treatment trials.

PROJECT SUMMARY (See Instructions): The Neuroimaging Core (NC) plays an integral role in addressing the UCD ADC scientific theme by providing imaging-based biological markers of disease processes that damage brain structure and function and ultimately impact cognitive trajectories across a broad spectrum of ability. Building on the success of our two previous cycles of funded activities, the NC will continue to provide a set of core services related to acquisition, post-processing, storage, and dissemination of imaging data. In addition, the NC will continue to collaborate with neuroimaging institutions at UC Davis to incorporate novel state-of-the-art methods that further its scientific mission to make precise measurements of the natural course of late-life brain injury. The Aims of the NC reflect a steady progression of the capabilities of the NC over time, and the Core is now a tightly-integrated component of the Center that enriches the other Cores and the AD research community. Specifically, the NC now provides raw images to the Clinical and Neuropathology Cores (CC and NPC) to support diagnostic activities, and provides validated, state-of-the-art measurements of brain structure and function to the Data Management and Statistics Core (DMSC) in support of research projects. The NC also participates in large-scale multi-site imaging studies and provides imaging data that promotes novel AD research. The NC also works with the Education and Information Transfer Core (EITC) to train investigators in neuroimaging methods and disseminate imaging related research advances. While the NC has limited resources, the images and imaging-based numerical measurements it collects are widely disseminated and utilized. This leveraging of resources enhances research productivity broadly and amplifies the initial investment in image acquisition. Thus, the NC provides benefits that extend far beyond the level of Core funding or support from individual research projects.

PROJECT SUMMARY (See Instructions): The Neuropathology Core (NPC) supports the clinical and research missions of the UCD ADC by providing (1) expert neuropathological (NP) analysis; and (2) well-preserved brain tissue, along with blood and DNA samples from the clinically well-characterized participants of our longitudinal cohort. In addition, the NPC plays an important role in bolstering basic and translational research on AD and related disorders by providing tissue samples, NP techniques, and NP tools. The UCD NPC has established expertise in postmortem NP analysis, with a special focus on assessment of vascular brain injury. The NPC works closely with the Clinical Core and the Neuroimaging Core to provide clinico-imaging-pathological correlation. The NPC works closely with the Data Management and Statistics Core to incorporate the NP data and tissue information to the web-based UCD ADC database, facilitating research. In collaboration with the Education and Information Transfer Core, the NPC promotes consenting to autopsy by our study subjects, and the use of the NPC resource for research. In the current funding period, we have accomplished all the proposed Aims. We have streamlined our brain and tissue procurement and processing procedures, and obtained more research-grade brain samples. We have collected and banked serum, plasma, and peripheral blood DNA from over 750 individuals participating in UCD ADC-sponsored research protocols. We have made substantial progress in obtaining minority autopsies. We have also developed new research tools such as tissue microarray and multiplex quantification method. Due to our enhanced infrastructure for research, the UCD NPC has become an essential player in the overarching UCD ADC research goal and have contributed to several multi-center projects involving sharing of neuropathological data and samples. Furthermore, there has been a substantial increase in the use of our biological samples by investigators within UCD and outside the ADC. and as a result we supported numerous grants and papers. In this reapplication. we propose to continue all the current aims, with new perspectives and opportunities building on the progress achieved during the current grant cycle.

PROJECT SUMMARY (See Instructions): The Education Core (EITC) supports the overall mission of the ADC through activities related to recruitment and retention, autopsy consent, lay and professional education, and research training. The EITC has considerable expertise in minority outreach and supports the Clinical Core in recruiting and retaining an ethnically and demographically diverse cohort in multiple ways, including staff trainings, collaboration with community agencies, development of outreach materials, publication and dissemination of semi-annual newsletters. The EITC works closely with the Clinical and Neuropathology Cores to monitor and promote minority participation in the brain donation program. For example, together with three other ADCs, the EITC is conducting a study of barriers to brain donation among minorities through a National Alzheimer's Coordination Center Collaborative Grant. The EITC, in collaboration with the Alzheimer's Association and other groups, educates lay communities about Alzheimer's disease and healthy brain aging by cosponsoring major conferences, such as the Spanish Mini-Medical School, African American Wellness Forum on Healthy Aging and Sacramento Caregiver Conference. The EITC helps coordinate activities to educate professionals including web-based CME presentations on clinical topics and presentations at conferences and workshops. The EITC also educates professionals about culturally-appropriate initial assessment and treatment of ethnically diverse elders. The EITC uses innovative approaches to evaluate profession and lay educational activities based on self-reported behavioral change. The EITC works with the Administrative Core, Biostatistics Core, and NPC to support research training and interest in Alzheimer's disease research through an annual Advanced Psychometric Methods Conference and through the coordination of mini internships and regular research forums (e.g., Basic Science Journal Club) as well as a monthly clinical pathological case conference. Finally, the EITC maintains the ADC website, supporting other Cores and the Center as a whole. The activities of the EITC are leveraged through a set of collaborative relationships both within and outside the ADC, as well external funding from NIH and foundation support.

PROJECT SUMMARY (See instructions): The DSMC maintains a central data base, ensures its quality and security, arranges linkage of data from the various cores, facilitates linkage with projects, identifies potential subjects for new and ongoing studies based on eligibility criteria, compiles analytic datasets, and carries out statistical analysis of the data. Core statisticians develop new methodology to meet the challenges of the longitudinal studies of the UCD ADC and to support new applications. The Core also provides intellectual leadership through collaboration with investigators, analysis and reporting of data, and mentoring and training in biostatistics. We have developed a state-of-the-art centralized web-accessed database that integrates data and tracking from all cores. DSMC leadership organized a strategic plan and process for developing publications that has been highly successful in disseminating results from our unique clinical sample and longitudinal data resources. We have developed innovative analytic methodology for the challenges of longitudinal data and complex multidimensional information about participants. We play an ongoing role in training new investigators in the psychometric and statistical issues for cognitive research and aging. Our goal for the renewal period is to build on this substantial track record to advance the goals of the UCD ADC through 1) continued oversight of data management, 2) providing statistical design and analysis support, 3) fostering development of new statistical methodology for specific ADC analysis challenges, and 4) working with the EITC to train students and new researchers in the area of AD.

PROJECT SUMMARY (See instructions): The Administrative Core (AC) is the unit responsible for overall governance and leadership of the UCD ADC as well as a resource for developing new research initiatives, new training initiatives and representing the UCD ADC within and outside the UC Davis community. In addition, the AC interacts closely with the UCD School of Medicine (SOM) Leadership and the Program Officers of the NIA Alzheimer's Disease Centers program to further the goals of research, training and education in accordance with their scientific and academic mandates. In pursuit of these general goals, the Administrative core emphasizes four major themes that encompass 1) supporting scientific innovation, 2) leveraging available resources through integration of research effort and pursuit of research funding, 3) program growth through seeking local, national and international collaborations and initiation of new programs, and, finally, 4) pursuit of funding sources for training of junior scientists so as to expand and provide continuity for our program of research on aging, Alzheimer's disease and associated dementias. Our success over the last four years has positioned the AC to respond further to the new requirements of the RFA as well as the challenges and opportunities presented by today's scientific research environment. As such the AC will continue to provide strong leadership along with the infrastructure and the administrative support needed to meld the various Cores and geographically dispersed units of the UCD ADC into a true, coherent Center. At the UCD ADC, this is accomplished primarily through strong leadership and an effective management structure that emphasizes clear communication and can establish workable policies and procedures to optimize effort toward successful completion of the aims and evolving needs of the UCD ADC.

Located within one ofthe most ethnically and racially diverse areas in the country, UG Davis serves the health care needs of a large Latino population and is the site of the Sacramento Area Latino Study on Aging (SALSA). In addition, UC Davis hosts multiple clinical-translational training programs to support faculty development and minority research, and has created the UC Davis Mentoring Academy to focus on developing the next generation of independent, highly successful academic faculty. Moreover, UC Davis has ample supporting programs that actively participate in research related to Latino health and healthcare and serve as catalysts and resources for new research initiatives. Despite this rich environment, however, the numberof faculty, particulariy under-represented faculty involved in research on minority aging, remains quite limited. The Investigator Development Core (IDC) will ameliorate these disparities by working closely with the Administrative Core (AC; which will identify and solicit qualified applicants) to offer research training, skills development, and mentoring to support achievement of independent funding and an independent research career in the study of cognitive health and healthcare among older Latinos. The recognized need for the RCMAR has also drawn substantial financial support from a wide variety of programs, enhancing the impact of a funded RCMAR at UC Davis. The goal of the IDC is to identify and support excellent researchers focused on reducing disparities in cognitive heaith among older Latinos through mentoring, training, and leveraging of existing UC Davis resources to advance their academic careers.

DESCRIPTION (provided by applicant): White Matter Hyperintensities (WMH) are areas of discrete high signal intensity on T2 and FLAIR brain MRI. They are associated with increasing age, vascular disease and other factors and cause cognitive decline, depression and gait impairment. Since accrual of WMH may diminish with treatment of vascular risk factors, there is a potential for therapeutic intervention Recent studies of mutant mice show that knockout of the Nrf2 (Nuclear factor erythroid-derived 2-like 2) gene results in loss of brain myelin with a vacuolar leukoencephalopathy that occurs with advancing age. Nrf2 activates antioxidant response elements (ARE) to modulate downstream anti-oxidant target genes. These findings, coupled with our preliminary data showing increased expression of Nrf2 target genes in the blood of patients with WMH, has led us to focus this study on Nrf2 and propose these aims. Aim #1a: Demonstrate that the number of OLIGOs and OPCs in WMH identified by post-mortem MRI are decreased in WMH compared to distant unaffected white matter. Aim# 1b. Show that markers of oxidative stress, F2-isoprostane (myelin) and 8-OH-2dG (DNA), stain myelin sheaths and OLIGO nuclei in WMH compared to no staining in distant unaffected white matter. Aim# 1c. Demonstrate increased nuclear Nrf2 protein and increased Nrf2 target gene expression in WMH and at the margins of WMH as compared to distant unaffected white matter. Aim #2a: Demonstrate that expression of Nrf2 target genes in blood using qRT-PCR is increased in subjects with large volume WMH compared to those with low volume WMH as measured using in vivo MRI. Aim# 2b: Demonstrate that the expression of Nrf2 target genes using qRT-PCR is either persistently elevated or markedly increases in blood of subjects whose WMH volumes increase the most over 2 years compared to matched subjects who have the smallest changes in WMH volumes over 2 years. Aim #3. Demonstrate that brain pathological changes and Nrf2 target gene expression changes in blood and WMH in Aims #1 and #2 are present in the blood and brain obtained from the same individual. In this study we will determine whether systemic and brain oxidative stress correlate with WMH damage, large WMH volumes and progression of WMH volumes over time. Systemic ROS damage brain endothelial cells allowing pro-oxidant molecules into brain that increase brain ROS that contribute to WMH. This study will begin to identify novel Nrf2 therapeutic targets for decreasing or preventing WMH. It will also begin to provide the rationale and preliminary data needed before antioxidant trials would be undertaken to reduce WMH with the goal of delaying or preventing cognitive decline.

DESCRIPTION (provided by applicant): Advancing age is associated with changes in brain structure and widely varying trajectories of cognitive performance. At least some of these differences are attributable to Alzheimer's disease (AD) and a major effort is underway to delineate the effects of brain amyloid on age related cognitive change and incident dementia. However, approximately 75 percent of cognitively normal individuals aged 70-79 do not have significant brain amyloid retention. These data suggest that factors other than amyloidosis are associated with declining cognitive performance amongst older individuals. Epidemiological studies repeatedly show that cerebrovascular disease (CVD) is extremely common and associated with decreased cognitive performance as well as incident MCI and dementia, independent of AD pathology. This is particularly true for African American and Hispanic communities where CVD is more prevalent. Evidence for CVD-related cognitive change has led to the hypothesis that the population burden of age-related cognitive decline may be considerably lessened through prevention and treatment of vascular risk factors. However, this hypothesis has been difficult to assess. Both Alzheimer's and CVD pathologies commonly co-occur in the brains of demented individuals making the independent effects of each pathology on cognitive decline difficult to discern. Amyloid imaging, however, allows for the measure of at least one component of AD pathology thereby creating the opportunity to assess cognitive trajectories, brain differences and risk factors for cognitive decline amongst individuals free of extensive amyloidosis. The premise of this study is that structural brain changes, ranging from infarction to WMH, loss of white matter integrity and brain atrophy are extremely common with aging. Further, these changes are associated with cognitive decline and increased risk for dementia. Therefore, it is critically important to identify the extent and consequences of brain injury in the absence of extensive amyloid. To accomplish this goal, we will characterize non-amyloid related changes in brain structure and cognitive trajectories in a diverse group of older individuals. In so doing, we will advance understanding of the impact of vascular factors on brain structure and cognition that will provide new insights into the course of cognitive aging and susceptibility to future cognitive impairment in a community based, ethnically and racially diverse cohort.

? DESCRIPTION (provided by applicant): A primary objective of the 2012 National Alzheimer's Plan Act was to decrease racial disparities of dementia. While it is known that certain ethnoracial groups such as Blacks have higher rates of dementia, reasons for disparities are unknown. The NIH State of the Science on Preventing Cognitive Decline recommended a life course approach to identifying modifiable risk and protective factors. Whether early life factors contribute to ethnic disparities in dementia and cognitive decline and how these variables relate to brain changes that may mediate disparities is not well understood. Further, effects of risk and protective factors may vary across ethnoracial groups. Most of what is known about risk and protective factors and brain mechanisms for dementia is from studies of non-Hispanic whites. We propose an unprecedented lifecourse study of disparities in late life cognitive decline and dementia using a large multi-ethnoracial sample of current Kaiser Permanente health system members who participated in the Multiphasic Health Study (MHS) extending from 1964-1991. MHS data, joined with electronic medical records from 1996-present, provide up to 50 years of comprehensive, prospectively collected data. Eighteen hundred (450 Black, 450 Hispanic, 450 White, 450 Asian) MHS participants aged 65+ will receive cognitive and clinical evaluations at 3 time points to rigorously characterize prevalence and incidence of dementia and measure cognitive decline using well-validated tests for ethnoracially diverse older adults. Structural MRI and Amyloid PET will be obtained on a random sub sample of 400 non-demented individuals to characterize cerebral amyloid burden, vascular lesions, and neuronal injury (atrophy). Our objectives are to delineate why there are racial/ethnic disparities in dementia and how life course risk and protective factors and brain mechanisms differ across ethnoracial groups. We will do so with three Specific Aims: 1) Evaluate ethnoracial differences in dementia incidence and cognitive decline, 2) Evaluate how early life experience, life course health, and genetics influence ethnoracial differences in cognitive decline and dementia, 3) Characterize paths by which ethnicity/race and cumulative vascular risk influence brain status (amyloid, vascular brain injury, atrophy) and cognitive decline.

? DESCRIPTION (provided by applicant): Modern neuroscience has the potential to significantly contribute to meeting current and future social challenges related to the advancing age of the population. In order to maintain health and autonomy in old age, understanding of the basic mechanisms of aging processes are of the utmost urgency. Deciphering the changes in neural structure and function of the healthy brain throughout the entire life span is essential for developing new approaches for diagnostics, prevention, therapy and health care. Based on newly acquired knowledge about the basic mechanisms of aging appropriate training measures and interventions can be developed. As a consequence, the need for the infusion of new and highly creative young scientists into this area of research has never been more acute. The aim of this T32 training application, therefore, is to develop a highly diverse, but integrated program of neuroscience research that aims to understand the biological underpinnings of the aging brain as it relates to cognition across the spectrum of human brain aging. To accomplish this goal, we propose to bring together the outstanding neuroscience research and education resources of UC Davis in a synergistic and collaborative manner to train new post-doctoral students (3 per year - 3-year training programs, total of 6 trainees over 5 years). These trainees will serve as catalysts for translational neuroscience research on cognitive aging, and this program will bring added value to the UC Davis aging research community by bringing together disparate but complimentary faculty and laboratories and generating newly funded research related to advancing science to improve human health.

Project Summary /Abstract Small vessel cerebrovascular disease and Alzheimer's disease are the two most common causes of cognitive decline in the elderly, but methods for determining the relative contributions of both these pathologies to functional impairment, understanding their interactions, predicting progression and defining targets for clinical trials remain underdeveloped. The overarching goal of this proposal is to further develop novel neuroimaging and serologic biomarkers of cerebrovascular disease. Accomplishing this goal will improve early detection, diagnosis, and prognosis of small vessel cerebrovascular disease in older subjects, and provide better targets and outcome metrics for clinical trials. We propose to longitudinally study 400 well characterized older subjects from ongoing projects at UCSF and UCD who present with a range of cerebrovascular burden and functional decline. Our search for biomarkers will focus on novel neuroimaging variables and measures of endothelial dysfunction. Our aims will address the relationships between these markers and measures of amyloid burden, cognition, and change over time.

DESCRIPTION (provided by applicant): The Framingham Heart Study (FHS) has, during the 33 years that the Precursors of Stroke Incidence and Prognosis (PSIP) grant has been funded, prospectively identified 2290 incident stroke and TIA events in 15,442 participants and made landmark contributions to the our understanding of stroke risk factors. It has also described 50-year temporal trends in stroke risk, and crafted a widely used Framingham Stroke Risk Profile (FSRP). In parallel, FHS has prospectively accrued data on incident mild cognitive impairment and dementia, 1-3 rounds of brain MRI and detailed cognitive assessment (N~7000 persons) and a wealth of genomic, lifestyle, vascular risk factor and biomarker data. In this renewal we propose to continue stroke surveillance, to identify additional stroke risk factors and temporal trends, especially in adults <55 years, and to use the rich data available in FHS to understand vascular contributions to dementia. The burden of stroke is dwarfed by the burden of subclinical vascular brain injury (VBI). VBI assessed with objective imaging measures, is a risk factor for stroke and for vascular cognitive impairment and dementia (VCID). However, there is considerable heterogeneity in the association between conventional MRI measures of VBI and cognitive performance. We hypothesize that some of this discrepancy will be due to differences in brain blood flow (imaged with pseudocontinuous arterial spin labeling [pCASL]), white matter integrity (detectable by diffusion tensor imaging [DTI]), functional connectivity (assessed by fcMRI) and concomitant AD pathology (assessed using PIB-PET amyloid burden). We also posit that variability in risk of VCID might be further explained by exploring individual differences in genetic susceptibility, lifestyle and exposure to risk factors. Finally, we postulate that factors determining VCID in persons with and without stroke will overlap. We propose the following Specific Aims: Aim 1: To continue surveillance for stroke and transient ischemic attack (TIA) in surviving FHS participants (n~8000, aged 28-107 years), using existing standardized protocols and introducing web-based physician examinations. We will further explore clinical, risk factor, biomarker and (in conjunction with large consortia) genetic risk factors associated with stroke allowing us to expand and refine the FSRP. We propose to especially focus on young stroke and the study of TIA with diffusion-weighted abnormalities. Aim 2: To examine the burden of VBI after stroke/TIA using 3TMRI, MRA, pCASL, fcMRI and PIB-PET at 6 months and 2 years after the event in 75 cases, and in 75 age- and sex-matched controls. We will relate these measures to VCID assessed with a 60 min detailed cognitive assessment, repeatedly used in prior FHS exams. Aim 3: To assess the range of VBI and VCI in 200 persons without clinical stroke, selecting 100 each from the two extremes of the stroke risk (FSRP) spectrum, using the same imaging and cognitive measures as in Aim 2. Aim 4: To identify genetic, lifestyle, vascular and biomarker determinants of VBI, VCI, VCID among FHS participants, utilizing traditional and novel, targeted and exploratory statistical modeling.

The Framingham Heart Study (FHS) is a prospective, community-based 3-generational study that enrolled participants between ages 20-50 and has examined them every 2-4 years to collect extensive lifestyle, vascular, biomarker data; 9300 have GWAS. Embedded in this cohort are 1036 multigenerational families. Surveillance for AD dementia (and MCI) has been ongoing for over 4 decades. We have identified 1421 incident AD, 1767 MCI, enrolled 800+ in a brain donation program, obtained 7000+ 1.5T brain MRI, and repeated, detailed neuropsychological assessments. We have recently obtained extensive omics in ~6000 (gene expression, methylation, miRNA, metabolomics and proteomics) and genomics (50X whole genome sequences [WGS] in 4197 with pedigree-based imputation to 6554) through the NHLBI funded SABRe CVD (omics) and TOPMed (WGS) programs. We seek to leverage these rich resources (>$25 million). We propose these specific aims: AIM 1 is to examine and explain temporal trends in clinical AD dementia in the FHS cohorts. The age-specific incidence of dementia has declined over the past 4 decades among FHS participants (in press). However, the reasons for this decline remain unclear. We thus propose to continue tracking temporal trends in AD dementia and MCI through intensive surveillance, and verifying diagnoses at autopsy. We hypothesize that better education, treatment of some vascular factors and protective lifestyle changes (diet, activity, social engagement) may partially explain these trends. AIM 2 is to identify the patterns and predictors of preclinical AD within FHS families by obtaining (i) a novel circulating biomarker (plasma tau on 8000+ persons, using samples collected 5-15 years ago and repeat assay in 450) to supplement 1000+ biomarkers already available, and (ii) brain imaging with tau- and amyloid- PET, 3TMRI, including assessment of functional connectivity, tractography and blood flow, in 450 dementia- and stroke-free, FHS participants age 35-75 on whom we have (a) directly verified familial cognition and AD dementia status (both parents and all 4 grandparents were FHS participants), and also (b) have WGS and omics data. AIM 3 is to utilize the available WGS and extensive `omics' data for deep molecular phenotyping of AD. We will undertake conventional family-based WGS analyses of AD dementia and preclinical AD endophenotypes and novel high dimensional (co-expression, network, systems-based) analyses in collaboration with Drs. DeJager (PI of Accelerated Medicine Partnerships-AD, with omics data in 1200 brains), Witten (award-winning mathematician in applying graphical analysis to omics) and Levy (PI of SABRe-CVD at FHS). We will validate our findings in unrelated and multi-ethnic (Omni) FHS participants, through collaborations with other cohorts, and share all data through dbGaP and BioLINCC for analyses by others. We expect to identify new biologic pathways, drug targets and biomarkers for AD, especially those applicable to the preclinical stage of AD and those explaining promising trends in AD risk; such pathways should prove most useful for AD prevention.

PROJECT SUMMARY/ABSTRACT - Neuroimaging Core The Neuroimaging Core (NC) plays an integral role in the UC Davis ADC (UCD ADC) scientific mission by providing imaging-based biological markers of disease processes in brain structure and function. In vivo imaging of cerebral pathology and brain status provides measures that are central to the overarching scientific theme of the UCD ADC which seeks to use demographic diversity to understand the multiple life course factors that influence brain and cognitive trajectories in old age and transitions to dementia. Building on the success of our previous cycles of funded activities, the NC will continue to provide a comprehensive and expanded set of neuroimaging services ranging from image acquisition and storage to post-processing, creation of standard and customized analytic data sets, and dissemination of imaging data. In addition, the NC will continue to collaborate with other neuroimaging institutions as well as researchers at UC Davis to develop novel state-of- the-art methods for measuring the natural course of late-life brain injury.

PROJECT SUMMARY/ABSTRACT Increasing racial and ethnic diversity is the hallmark of United States demography. For example, in 2011, 13% of the population classified themselves as African American and nearly 17% classified themselves of Hispanic or Latino origin and these percentages are expected to increase substantially in the near future. Diversity among older individuals is similarly increasing with self-identified minorities expected to increase to 20% with most minority adults being of Latino origin by 2020. Increasing diversity of the population has significant

PROJECT SUMMARY/ABSTRACT As reflected in recent budget increases in the National Institutes of Health, and in line with the National Alzheimer?s Project Act, there is a need to enhance and leverage resources to decrease dementia disparities and change the trajectory of Alzheimer?s disease and related dementias. To fill this gap, we seek to enhance the University of California Davis Alzheimer?s Disease Center (UCD ADC), which contains a diverse ethnoracial cohort (having Hispanic, Black, and non-Hispanic White decedents), through implementation of digital pathology within our Neuropathology Core. This implementation will allow for rapid transmission of pathological data for consultation and collaborations, distribution of materials for educational purposes, tissue specimen archiving, and image analysis. In addition, by having a digital pathology with immunofluorescent capabilities will allow for viewing of the distribution (including overlap) of multiple proteins at one time within a tissue specimen. This can enhance biological studies by providing spatial relationships of proteins resulting in a deeper phenotype of disease. This supplement application is designed to support equipment and leverage and enhance infrastructure to allow the UCD ADC the ability to 1) purchase a whole slide image system to digitize existing and future histologically stained samples 2) leverage and enhance current servers and database systems to allow for storage and rapid retrieval of digital images and their data and 3) leverage and enhance hardware to develop and deploy pipelines for quantitative computational methodologies for pathologies found within a diverse ethnoracial cohort of Alzheimer?s disease brains. The UCD ADC continues to excel and expand in its research initiatives to collect and provide brain specimens and pathological data on a diverse population of individuals at various stages of cognitive ability and dementia risk. This supplement will further enable suitable infrastructure for enhancement of current collaborations and facilitate emerging collaborations by providing a means to share and analysis pathology on digitized whole slide images.

By 2060, the CDC projects that the Latino population will experience the largest increase in Alzheimer's disease and related dementia (ADRD) cases of all US ethnic/racial groups. The main, if not only, explanation oft echoed for disparately high Latino ADRD is attributed to early and excess cardiovascular disease (CVD) morbidity contributing to disparately high ADRD. CVD risk factors emerge earlier among Latinos in midlife, thereby increasing deleterious exposures to exquisitely sensitive and highly vascularized brain tissue. Yet, to- date there has not been any study of Latinos with sufficiently deep CVD phenotyping and genotyping to adequately address this significant public health question. This scientific knowledge gap is a significant impediment to the field and public health given continued and rapid Latino population growth projections, particularly for older adults. Latinos now represent nearly one-fifth of the US and 40% of its two most populous states, California and Texas. In coming decades, the older Latino population (>65 years) will quadruple (391%) and US public health is ill-prepared for forthcoming demographic and health-related shifts in the population. The Study of Latinos-Investigation of Neurocognitive Aging (SOL-INCA) is the only large, representative and ongoing longitudinal study of CVD, genomics and cognitive aging and ADRD in diverse Latinos. In this SOL- INCA renewal, we will leverage 10-years of deep CVD phenotyping, multi-layered -omics and rich sociocultural data to fill these neglected scientific gaps in our current understanding of ADRD in diverse Latinos.

PROJECT SUMMARY/ABSTRACT - Overall The mission of the UC Davis Alzheimer?s Disease Research Center (UCD ADRC) is to promote a highly innovative and enriched research environment focused on understanding the heterogeneity of brain aging among diverse populations that will ultimately lead to effective therapies to prevent or mitigate dementia. This approach stems from the premise that emphasizing diversity enhances discovery and contributes to translational science as well as reducing disparities in brain health and care. To accomplish this mission, the UCD ADRC has developed innovative methods and a unique study design to recruit and retain a highly demographically diverse clinical and autopsy cohort. All UCD ADRC participants are longitudinally followed and deeply phenotyped with extensive clinical, blood and imaging biomarker measures as well as developing state-of-the-art quantitative neuropathology. The UCD ADRC succeeds at these efforts through a robust research infrastructure, state-of-the-art database management and a highly collaborative environment consisting of seven well integrated resource cores and one research education component (REC) designed to facilitate new research efforts and interventions, dissemination of research findings, education and training as well as encouraging researcher development. Our approach addresses several milestones set by the National Alzheimer?s Project Act to effectively treat Alzheimer?s disease and associated disorders (ADRD) by 2025. These include, but are not limited to: 1) M1.L., evaluating disparities among ethnic and racial minority populations that are at higher risk for AD to mitigate risk and improve cognitive outcomes, 2) M2.H., fully characterizing mixed pathologies and identifying unique risk factors,3) M5-7., accelerating the development of treatments that would prevent, halt, or reverse the course of Alzheimer?s disease (AD), 4) M9., improving early diagnosis through discovery of novel imaging and blood biomarkers, 5) M8., developing novel dementia prevention strategies, and 6) M13.E.,supporting caregiving through funded caregiver research. The UCD ADRC also directly supports multiple epidemiological studies of diverse communities through use of research methods and personnel to gain further insights into dementia risk reduction, early diagnosis, and the impact of various neuropathologies on aging and dementia. Our efforts reflect the evolving needs of an increasingly older and more diverse US population, which is expected to rise to nearly 14 million by midcentury. Moreover, while AD continues to be the major pathological cause of dementia, more recent studies?including one from the UCD ADRC?find that dementia pathology is multifactorial and highly heterogeneous, due in part to the co-occurrence of AD and vascular disease, which varies by ethnoracial characteristics, is emphasized as part of dementia prediction and which can be modified by treatment even in later life. The UCD ADRC is uniquely qualified to support this research focus with a considerable impact on future ADRD diagnosis and treatment.