Victor W. Henderson - US grants

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common cause of dementia, and effective treatment options are distressingly limited. Raloxifene, a selective estrogen receptor modulator (SERM), is approved for treatment and prevention of osteoporosis in postmenopausal women. Its clinical profile is well known, and drug side-effects are generally well tolerated. In animal studies, this compound affects neural activity in ways that might be expected to improve cognitive function, and recent clinical data support the hypothesis that raloxifene could ameliorate dementia symptoms in women with AD. Over a three-year period of time, we will undertake a parallel-groups, randomized, double-blind, placebo-controlled pilot trial of raloxifene for the treatment of women with AD. Eligible participants must have been on an effective dose of a cholinesterase inhibitor (donepezil) for at least six months prior to randomization. A total of 72 women with mild to moderate dementia due to AD will be enrolled in this pilot study, and treatment duration will be for 12 months. Studies will be conducted at two performance sites, the University of Arkansas for Medical Sciences and Indiana University. Our first specific aim is to assess effect sizes of raloxifene on study outcomes as a guide to future clinical trials with this agent for women with AD. Our second aim is to determine if raloxifene compared to placebo substantially improves cognitive function and other specified outcomes. The hallmark of AD is cognitive deterioration, and our primary outcome instrument is the cognitive subscale of the Alzheimer's Disease Assessment Scale. Secondary outcomes are global change, function in activities of daily living, behavior, measures of specific cognitive skills, caregiver burden, and select biomarkers. The primary outcome will be assessed at three, six, nine, and 12 months. Primary analyses will be based on the month 12 assessment using an intention to treat analysis. It is anticipated that findings from this pilot study will provide useful guidance to plan and conduct future studies of raloxifene in women with mild to moderate symptoms of dementia due to AD.

DESCRIPTION (provided by applicant): A widely-held distinction between "usual aging" and "successful aging" implies that a variety of extrinsic factors influence how we age, including how cognitive abilities change with age. There is convincing evidence that physical activity, mental activity, and social engagement have great potential to ameliorate age-related cognitive decline, and that these factors contribute independently and additively to reducing the impact of usual cognitive aging. Using a parallel groups design, we will conduct a pilot randomized controlled trial among healthy older adults aged 70 and above, to assess behavioral interventions predicted to remediate age-related cognitive decline. Prior behavioral interventions in older adults that improved cognitive skills usually failed to show transfer to untrained activities, perhaps reflecting the narrowness of such interventions, a lack of complexity, or both. For these reasons, we have selected experimental interventions that engage multiple pathways linked to cognitive aging. These were also chosen to be easy to implement, appeal to older adults, have intrinsic value, and have the potential for long-term sustainability. The selected interventions are (1) Tai Chi, a moderate-intensity low-impact Eastern exercise program that combines physical activity and intense mental concentration, (2) Guided Autobiography, a complex mental activity performed in a setting that promotes a high level of social engagement, (3) a combined intervention that thus incorporates physical activity, two distinct forms of mental activity, and social engagement, and (4) a general health education control group. We hypothesize that structured programs in Tai Chi, Guided Autobiography, and Tai Chi and Guided Autobiography combined are feasible to implement and maintain in an older population, and - in comparison to a health education control program - will improve neuropsychological measures of executive function and episodic memory. Our research goals are to establish the feasibility of the two experimental interventions alone and combined in healthy older adults, assess which of the experimental interventions is most likely to be successful in a full- scale randomized controlled trial, and to estimate immediate (3 month) and short-term (12 month) parameters needed to guide the design of such a larger trial. PUBLIC HEALTH RELEVANCE: Thirty-seven million Americans are aged 65 and older, and their numbers will nearly double by 2030. Cognitive aging is an important, widespread concern in this age group. We will conduct a pilot randomized controlled trail among healthy older adults to assess whether innovative programs in Tai Chi exercise, guided autobiographical writing, or a combination of both are feasible interventions for remediation of age- related cognitive decline.

SUMMARY, Core A The Stanford Alzheimer's Disease Research Center (ADRC) will serve as a shared resource to facilitate and enhance multidisciplinary and interdisciplinary research in Alzheimer's disease and related disorders; our mission is to specialize in the collection, analysis and dissemination of data sets that is relevant to both Alzheimer's disease and Parkinson's disease research. The Administrative Core (Core A) serves as an administrative structure to direct, facilitate and support the goals of the Stanford ADRC. It assures compliance with NIH policy requirements and provides a forum for planning. It will accomplish its goals through the following specific aims: (1) Coordinate activities of the ADRC Cores, committees, and research projects; (2) Establish advisory committees, which will support Center aims through recommendations, guidance, and critiques; (3) Oversee, monitor, and ensure compliance with reporting procedures, policies, and guidelines of the NIH, institutional review board, university, and other relevant bodies; (4) Stimulate innovative research in Alzheimer's disease and related disorders by existing and new investigators; and (5) Promote research and educational collaborations with other Alzheimer's Disease Centers, universities, health professionals, Alzheimer and Parkinson caregivers, and the wider community.

Abstract Within the Stanford ADRC, the Clinical Core (Core B) provides well-characterized, longitudinally followed patient and control participants for research supported by the ADRC and additional external funding. The Clinical Core fulfills this role through human subjects recruitment, evaluation, data collection, registry, and analyses. The Stanford ADRC focuses on patients with mild changes of Alzheimer s disease, Parkinson s disease or both, and on cognitively normal older adults, optimizing the ability of investigators to discover early markers of disease specificity. We will create innovative research opportunities focusing on the overlapping spectrum of these two common neurodegenerative disorders, facilitating interdisciplinary investigations that make use of standardized clinical data, biospecimens, novel biomarkers, and neuroimaging (via Core F). In association with Core D, there is a strong emphasis on autopsy participation. Specific aims are to: (1) recruit participants within specified diagnostic categories to support anticipated research needs of participating ADRC investigators (we target 20% Hispanic/Latino participation, a group traditionally under-represented in medical research); (2) characterize participants neurological, cognitive, behavioral, and biomarker status; provide consensus diagnoses; and follow participants longitudinally: (3) perform Uniform Data Set assessments at entry and annually; and to collaborate with the Database Management & Biostatistics Core on the efficient transmission of these de-identified data to the National Alzheimer s Coordinating Center; (4) collaborate with the Imaging Core to facilitate innovative neuroimaging research by ADRC participating investigators; (5)ensure availability of biospecimens and postmortem tissues, in collaboration with the Neuropathology & Biospecimen Core, from well-characterized participants within a Normal Alzheimer s disease Parkinson s disease spectrum and from other clinical populations as needed to facilitate participating investigators research; and (6) support ADRC small R01 Project 2, pilot research projects, clinical trials, and research needs of externally funded investigators who could benefit from Clinical Core resources.

DESCRIPTION (provided by applicant): Overall We will establish an Alzheimer's Disease Research Center (ADRC) at Stanford University to serve as a shared resource to facilitate and enhance multidisciplinary and interdisciplinary research in Alzheimer's disease and related disorders. Our mission is to specialize in the collection, analysis and dissemination of data sets that are relevant to two common neurodegenerative illnesses, Alzheimer's disease and Parkinson's disease. The new Stanford ADRC will emphasize particular strengths in neuroimmunity and synapse biology, as well as strengths in imaging, clinical assessment and clinical research, biostatistics, and caregiver outreach. Outreach activities will focus specificaly on underserved urban Hispanic/Latino and American Indian communities. To accomplish these goals, we will establish core resources for human studies; make available biospecimens and biomarker data; provide structural and functional neuroimaging; maintain an administrative structure and consultative resources appropriate for these goals; provide community-based outreach and educational programs and research participation opportunities; support Center-sponsored research projects and pilot projects on these disorders; and support national efforts to understand disease mechanisms and find effective forms of therapy and prevention.

PROJECT SUMMARY?OVERALL COMPONENT: The NIH has long recognized the necessity to aggressively leverage emerging methodologies like precision medicine, digital health, biomedical data science and virtual reality & simulation based interventions approaches to ameliorate health disparities in racial and ethnic minorities. However, relatively fewer efforts have attempted to conduct trans- disciplinary aging research integrating biological, social and behavioral sciences utilizing emerging methodologies. The overarching goal of the proposed Stanford Aging and Ethnogeriatrics Transdisciplinary Collaborative Center (SAGE) is to increase the diversity of the aging research workforce by mentoring new leaders in aging research and promoting advances in behavioral and social sciences aging research using emerging methodologies including precision medicine, digital health, biomedical big data science and virtual reality and simulation based interventions. By identifying, mentoring and supporting (through dedicated pilot funds and methodological and recruitment support) junior investigators from underrepresented groups (SAGE Scientists) we propose to create a culturally sensitive and culturally competent research workforce focused on promoting equity in healthcare and mitigating disparities in diverse older populations using emerging methodologies. We have in place outstanding strengths in the three principal scientific elements requisite to form a coordinated, sustainable, and far-reaching `aging research to practice collaboration' integrating behavioral, social and biological sciences using emerging methodologies: 1) Behavioral and social scientists and disparities researchers, spanning psychology, psychiatry, demography, epidemiology, evolutionary biology, health services research & economics, computer science, social media science, virtual reality/simulation interventions and digital health; 2). Extensive experience with trans-disciplinary translational research that integrates laboratory assessment of genetic markers, their relationships to both disease risk and treatment relevance with psychosocial research approaches; and 3) Novel and outstanding analytic and high-performance `big-data' computing capabilities, consolidated in our Department of Biomedical (`Big Data') Data Science. With Stanford's setting in one of the most racially, ethnically and socially diverse aging populations in the US, and leveraging the seven-school campus-wide ?Precision Health? initiative that integrates biomedical data science, engineering, business, design, digital health technology, virtual reality interventions and patient care under the recently endowed Center for Population Health Sciences we feel uniquely situated to make game-changing breakthroughs in aging research using emerging methodologies, and to lead such research efforts nationally.

1. SUMMARY (Administrative Core) The Stanford Alzheimer's Disease Research Center (ADRC) will support goals of the National Alzheimer's Project Act by serving as a shared resource to facilitate and enhance interdisciplinary and multidisciplinary research on Alzheimer's disease and Alzheimer's disease related dementia (AD/ADRD). At the Stanford ADRC, the focus will be on AD and a common ADRD, namely cognitive impairment and dementia linked to Lewy bodies, Lewy neurites, and the abnormal accumulation and propagation of alpha-synuclein (the Lewy body spectrum of neurodegenerative cognitive impairment). The Stanford ADRC has adopted a strategy of deep phenotyping, which draws together multiple levels of biological data on individual participants followed over time and culminating in brain donation. The Administrative Core provides the administrative structure needed to direct, facilitate and support the Stanford ADRC mission. It establishes the overall scientific direction, provides a forum for planning, ensures optimal resource utilization, and assures compliance with institutional and NIH policy requirements. It will accomplish these goals during the next five years through four specific aims: (1) Provide an infrastructure that establishes priorities and goals of the P30 Stanford ADRC: coordinate activities of ADRC cores and committees; ensure compliance with reporting procedures, policies, and guidelines of the NIH, institutional review board, and other relevant bodies; oversee data transfer to the National Alzheimer's Coordinating Center (NACC) and other entities; and oversee the transfer of biological specimens and genetic data to the National Centralized Repository for Alzheimer's Disease (NCRAD), National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS), and other collaborating groups; (2) Stimulate innovative research on AD/ADRD by existing and new investigators, including the solicitation, evaluation, selection, and monitoring of development projects supported by the Center; (3) Provide leadership opportunities for the next generation of ADRC leaders; and (4) Promote research, training, and educational collaborations with other ADRCs, universities, health professionals, caregiver organizations, and the wider scientific and lay communities.

Are phenotyping algorithms fair for underrepresented minorities within older adults? According to the latest population estimates by the US Census bureau, the United States population is growing older and more diverse, with their projections indicating that in 2035 there will be more people 65-and-older than 18-and-younger. In terms of diversity, the US Census Bureau projects that by 2060 the non-Hispanic White-alone population will shrink by 20 million, leading to the increased representation of currently underrepresented minority groups. These future population milestones paired with the rise of artificial intelligence (AI) use in medicine, present a very unique and problematic problem: determining if AI solutions are fair for underrepresented populations within older adults. This has been a very debated issue, with opinion pieces in the New York times making it clear that when done incorrectly, AI solutions can actually worsen health disparities in underrepresented populations due to the nature of the training sets for said AI solutions. It is intuitive to understand how dermatology AI systems could be biased to perform better for lighter skinned individuals, due to the prevalence of said patients in the training datasets. Other biases come from the fact that there is simply a lack of diverse research subjects, which is why their mortality outcomes are considerably worse. Electronic phenotyping algorithms are the cornerstone for automatic identification of selected patient groups for tasks like disease classification, epidemiological studies and clinical-trial recruitment. These algorithms are both rule-based or probabilistic in nature (machine learning models), and are usually built by using bundled patient populations (everybody put together), with very few exceptions (due to the nature of the phenotype) having some sort of stratification of populations. This proposed project seeks to identify bias in probabilistic electronic phenotype algorithms for older populations and create best-practices and software tools to overcome them in order to lead to better health outcomes.

1. SUMMARY (Clinical Core) In support of the goals of the National Alzheimer's Project Act, the Stanford ADRC will focus on the Alzheimer's disease (AD) spectrum and the Lewy body (LB) spectrum of neurodegenerative cognitive impairment. Recognizing that critical answers will emerge more readily when investigators can delve deeply within and across multiple levels of participant data, we have adopted a strategy of deep phenotyping. Stanford ADRC participants are characterized intensively and followed over time. The AD spectrum includes cognitively impaired patients with AD dementia and mild cognitive impairment due to AD, as well as preclinical AD inferred from biomarker data. The LB spectrum encompasses dementia with Lewy bodies and Parkinson's disease dementia and Parkinson's disease patients with mild cognitive impairment. Healthy adults without cognitive or motor impairment can serve as an age-equivalent comparison population, as an asymptomatic at-risk population, and as a potential preclinical population in which mechanisms of cognitive aging and preclinical transition can be studied. Within the LB spectrum, Parkinson's disease patients without cognitive impairment serve as age-equivalent comparators and as an at-risk transitional population for the development of LB- spectrum cognitive impairment. Stanford ADRC resources will enable the parallel study of these AD and LB spectrum disorders. Opportunities for investigators to compare and contrast can provide unique insights into pathogenesis, resistance and resilience, and therapeutic approaches. The Clinical Core will be responsible for participant enrollment and for clinical, cognitive, and behavioral assessments. In support of a strategy that emphasizes the deep phenotyping of individual participants, the Clinical Core is also responsible for biospecimen procurement, imaging referral, and brain donation consent. It is responsible for participant retention and for longitudinal follow-up. Most new participants in the Stanford ADRC will be asked to provide disease-defining biomarkers measured in CSF, imaged by amyloid-PET/MRI, or both; to consent to longitudinal follow-up; and to agree to brain donation through the Neuropathology Core. The Clinical Core will work with other ADRC Cores to accomplish four aims focused on the AD spectrum and the LB spectrum of neurodegenerative cognitive impairment: (1) Enroll participants into longitudinal research protocols of the Stanford ADRC; characterize their neurological, cognitive, and behavioral status; provide consensus diagnoses; follow participants longitudinally; and promote adherence; (2) support the efforts of other ADRC Cores; (3) support ADRC development project grants and research needs of qualified externally funded investigators who could benefit from Core resources; and (4) support the Research Education Component by providing a rich training environment for medical and graduate students, residents, fellows, and junior faculty.