Neil W. Kowall, MD - US grants

The purpose of the Boston University Alzheimer's Disease Center (BU ADC) is to promote research on Alzheimer's Disease (AD) at BU and throughout the country by providing information and materials from well characterized patient, control and caregiver populations drawn from the ambulatory and late-stage suburban population at the Bedord VA Medical Center and the racially, ethnically, and culturally diverse poor urban Registry of the Clinical Core are assessed annually with a standardized neurological examination and neuropsychological test battery. Blood is obtained and stored for molecular genetic studies. A detailed family neuropsychological test battery. Blood is obtained and stored for molecular genetic studies. A detailed family history is obtained and a separate Caregiver Registry collects annual standardized information on family and professional caregivers. This information is entered into a database for longitudinal comparisons and correlation with the progression of AD and its impact on caregivers. Subjects, data and blood/DNA are made available to qualified researchers to stimulate new research in AD and normal aging. The Neuropathology Core establishes accurate pathological diagnoses, rigorous documentation and quantitation of neuropathological changes, harvests endothelial cells, and collects, stores and disburses post-mortem tissue. The Education and Information Transfer Core supports the development of physicians and other professional caregivers to improve clinical and research skills related to AD and provide outreach programs to increase caregivers' and the lay public's knowledge of AD. Nationally, this Core collaborates with other ADCs, ADEAR Center, Alzheimer Association and other groups to advance AD care, education, and research. The Murine Breeding and Molecular Genetics Core maintains a transgenic mouse colony as well as several colonies of mice with AD-related phenotypes including: 1) increased or decreased susceptibility to oxidative injury 2) Calreticulin Knockout mice 3) over expression or under expression of APOE. This comprehensive breeding facility is a unique resource for investigators. The BU ADC funds pilot projects to promote new AD research and fosters the development of new AD investigators. These multiple activities are coordinated by the Administrative Core. The BU ADC has greatly strengthened and expanded AD research at BU and has facilitated the involvement of African Americans in aging and dementia research. The BU ADC has promoted and supported AD research on a comprehensive range of topics including pathogenesis, animal models, neuropathology, genetic and environmental risk and protective factors, late-stage dementia, and the impact of disease burden on caregivers and society.

medical outreach /case finding; Alzheimer's disease; human old age (65+); data collection; health science research; clinical research; human subject;

The Neuroanatomy Core will perform immunohistochemical, in situ hybridization, electron microscopic and computerized image analysis studies to define the organization of selected cellular classes in specific brain regions and determine how they are affected by perinatal nutritional manipulations in collaboration with individual research projects in the program. Qualitative neuroanatomical analyses will include the definition of the spatial distribution, cellular morphology and the localization of relevant molecules in selected cell classes. Quantitative analyses will include measurements of cell size, volume, axonal and dendritic branching patterns and the computation of cell density and unbiased cell counts. These procedures will be accomplished using computer-assisted image analysis, the capture of high-resolution digital images and confocal microscopy. These data will be stored in a relational Access database for the use of all investigators. The specific aims of the neuroanatomy core are: 1) to facilitate the accomplishment of the scientific aims delineated in all of the individual projects of the program by providing expertise in quantitative structural techniques and other technical support as needed. Genotyping of transgenic mice will be performed as required for all investigators. A relational database of anatomical results has been established and will be maintained for correlational studies. Anatomical studies have been prioritized to concentrate on the most scientifically important topics in each project. These comprise the other 2 aims of the core which are to determine the structure correlates of the observed effects of prenatal choline availability on rodent behavior and brain biochemistry and electrophysiology and to define the anatomical and neuropathological features of transgenic mice used in the program project. Preliminary studies strongly suggest that the hippocampus or its connections is a major locus of interest. The core will work with Project 0001 to determine the anatomical distribution of biochemical markers of plasticity and diet-related changes in gene expression defined by expression profiling during development and aging; with Project 0004 to quantify how prenatal availability of choline influences adult neurogenesis and survival; and with Project 0005 to examine selected markers in adult and aging brain that show diet-related alterations during fetal development. The anatomical and neuropathological features of transgenic mice strains used in the program project will be studied. CNS anatomy and pathology affecting many of these strains and the consequences of dietary manipulation have not been previously characterized.

laboratory mouse

PROJECT SUMMARY (See instructions): The primary goal of the BU ADC Clinical Core is to provide resources and infrastructure to facilitate clinical research in Alzheimer's disease (AD) and related disorders, such that data and well-characterized research subjects are widely available and shared with other investigators and institutions. During the current funding cycle of the BU ADC, Clinical Core faculty have made major contributions in several important and innovative areas of investigation, which include three general themes: (1) Alzheimer's disease (AD) genetics and genetic risk disclosure; (2) medical and environmental risk factors for cognitive aging; and (3) the longterm effects of repetitive head trauma in the development of neurodegenerative disease. Core faculty have led or participated in several high profile national studies and have facilitated and made possible major breakthroughs in AD-related research both locally and nationally. The longitudinal Patient/Control Registry is now fully subscribed with over 450 active participants and a wide variety of clinical research studies are being actively supported. Over this past cycle, there have been 1374 referrals of registry participants to other studies with 752 enrollments to a total of 38 unique research projects. The Specific Aims of the Clinical Core for the next five years are: Specific Aim 1: To support innovative clinical AD research by identifying, recruiting, and thoroughly characterizing subjects willing to participate in clinical trials and other cutting-edge clinical research studies. We will leverage our resources to promote and accomplish wodd-class AD-related research at BU through our partnerships with the Center for the Study of Traumatic Encephalopathy and the Framingham Heart Study and through our role as a leading site in national NIH and industry supported clinical research. Specific Aim 2: To establish research-quality diagnoses on all participants through multidisciplinary diagnostic consensus conferences and to collect and submit high quality data to the Data Management and Statistics Core (DMSC) for timely UDS submissions to the NACC database and for data sharing with qualified AD investigators engaged in cutting edge AD-related research. Specific Aim 3: To collect, store, analyze, and distribute biological samples from registry participants for APOE genotyping, DNA banking, and biomarker assays, to support high priority AD-related research. Specific Aim 4: To collaborate with the neuropathology and education cores to maximize CNS tissue donation for clinicopathological correlations and for other state of the art tissue-based research.

PROJECT SUMMARY (See instructions): The primary mission of the Boston University Alzheimer's Disease Center (BU ADC) Data Management and Statistics Core (DMSC) is to provide leadership and expertise in all phases of data management and statistical analyses, from research project development to publication of results. This collaborative assistance encompasses analytic plan development, database design, implementation of quality control procedures, technical support, creation of analytic datasets, statistical analyses, and manuscript preparation. DMSC faculty and staff maintain ongoing communication and interactions in collaborative relationship with members of all other BU ADC Cores and projects as well as the National Alzheimer's Coordinating Center (NACC). To continue accomplishing these goals into the next funding cycle, the DSMC will continue to leverage DMSC resources, including state-of-the-art hardware, software and expertise, to enable the appropriate management and analysis of data resulting from BU ADC. The specific aims of the DMSC are: Specific Aim 1. Provide data system expertise, assistance, and an enhanced infrastructure, including hardware, software, networks, and procedures, to ensure data security and integrity across the BU ADC. Specific Aim 2. Provide expertise and assistance in developing and updating existing data systems for data collection, participant and data tracking, data management, and quality control procedures for BU ADC activities, including the Uniform Data Set (UDS), neuropathology, NACC, and requests from local Investigators. Maintain and expand training of all BU ADC faculty and staff in use of data systems through written materials and in-person and web-based training sessions. Specific Aim 3. Continue to support and manage BU ADC data and resource sharing with NACC and local BU investigators. This support includes the transmittal of raw UDS and Neuropathology data to NACC as well as creation of analytic datasets, including calculated variables, for specific, approved analyses;and support and management of all resource requests, including data, participants, tissue, and animals. Specific Aim 4. Provide high-level data management and biostatistical expertise, support and consulting to BU ADC investigators and new BU ADC-affiliated proposals and pilot grant projects, including study design, implementation and interpretation of data analyses, preparation of funding applications, and manuscript development.

PROJECT SUMMARY (See instructions): Core Description: The Education and Information Transfer Core (EITC) leads outreach, recruitment, and retention activities that support the Boston University Alzheimer Disease Center's (BU ADC) clinical research portfolio. In addition, the EITC provides Alzheimer's disease (AD)-related education to both professional and lay audiences. During the current funding cycle, the EITC has developed two specialized areas that complement its Core functions, including: (1) developing and implementing innovative programs to increase our African American participants' involvement in the Center's brain donation program, and (2) enhancing our Center's long-standing professional education focus with the successful replication of a medical student education program developed by our Northwestern University EITC colleagues. The BU-based program (known locally as the PAIRS Program) partners first-year students with community-based patients with early stage AD for an experiential learning opportunity. These two areas of specialization will continue into the proposed renewal period and are well integrated into our EITC specific aims for the next cycle. Specifically, we aim to: (1) Facilitate and evaluate outreach efforts in the recruitment, referral, and retention of participants in the BU ADC research registry and BU ADC-sponsored clinical research projects with an emphasis on the recruitment and retention of individuals with mild cognitive impairment (MCI) and earlystage AD and the recruitment of African American participants into the Center's brain donation program; (2) Provide lay audience education about AD and related disorders through community-based outreach in collaboration with other BU ADC Cores and community partners; and (3) Facilitate education and a high quality training environment for professionals at all career levels interested in clinical and translational research and the clinical care of individuals with MCI, AD, and related disorders. These aims will be met through numerous academic and community partnerships, professional and lay audience educational events, formal professional education programs, a biannual newsletter, and an active and highly-utilized website.

DESCRIPTION (provided by applicant): This interdisciplinary post-doctoral training program will provide intensive, structured translational research training in Alzheimer's disease (AD) for a new cadre of talented basic PhD, clinical PhD, and physician scientists. Leveraging the existing infrastructure and research strengths of the NIA-funded Boston University Alzheimer's Disease Center and affiliated faculty, the program will eliminate barriers in communication, knowledge, and collaboration between basic and clinical scientists and train investigators to cross disciplinary boundaries at an early and formative period in their professional development. Through individualized and group didactics, the fellowship program will provide (1) integrated knowledge in the basic and clinical fundamentals of AD, focusing on environmental and genetic risk factors, prevention, mechanistic pathways, biomarkers, diagnostics, and therapeutics of AD, (2) training in essential research skills (e.g., conceptualization, development, and implementation of research studies, and creativity in developing new research directions), (3) training in critical professional skills for success in academic medicine (e.g., understanding available funding mechanisms and development of grant writing skills, oral presentation skills, and manuscript writing abilities), (4) training in the responsible conduct of research, emphasizing both animal and human subjects, and (5) a high quality jointly-mentored, interdisciplinary research experience that synthesizes the trainee's knowledge base, research and professional skill set, and appreciation of responsible conduct of research, and prepares the trainee for independence as an investigator. Trainees completing the program will be well-positioned for academic success in both conducting and securing funding for original research in AD. As a consequence, the program will fill an important need for an increased number of high quality investigators who are well equipped to advance the field of AD prevention, diagnostics, and therapeutics. PUBLIC HEALTH RELEVANCE: An estimated 5.1 million Americans have AD, and this number is expected to rise to 13.2 million by 2050. Advances in AD diagnostics and therapeutics rely on innovative translational research efforts;however, a recent report suggests there is a shortage of patient-oriented investigators well-trained in the fundamentals of translational research.

PROJECT SUMMARY (See Instructions): A strong and responsive Administrative Core is a key component of the Boston University Alzheimer's Disease Center (BU ADC). The Administrative Core consists of a formal administrative structure under the leadership of the BU ADC Director, Dr Kowall. Three standing administrative committees have been established: the Executive Committee, the External Advisory Committee, and the Community Action Council and an ad hoc Internal Advisory Committee. In conjunction with the Center Director, these committees are responsible for coordinating, planning, overseeing, and evaluating all BU ADC activities and ensuring the optimal utilization of BU ADC resources. The budget for the Administrative Core supports centralized administrative personnel and activities relevant to the overall mission of the BU ADC. The budgets for other administrative functions assigned to specific cores are included in individual core budgets. The aims of the BU ADC administrative core are: 1. To integrate, coordinate, direct and plan all BUADC activities and to ensure full compliance with all human subjects, animal welfare, scientific integrity, and financial policy requirements of NIH while promoting a culture that values and promotes the highest standards of ethics in clinical care and research guided by input from the scientific and lay communities. 2. To foster innovative AD research through a strong pilot project program, by facilitating cross-core interactions, and by maximizing resource utilization to support affiliated programs such as the Framingham Heart Study and the Center for the Study of Traumatic Encephalopathy. 3. To partner with the local, regional, national and international AD research community to support high impact research including the Framingham Heart Study, ADNI, ADCS, AD genetics consortium, and industry sponsored clinical trials. To ensure that all mandated data sets, such as the UDS, are submitted to NACC in an accurate and timely manner. 4. To support and inform the communities we serve regarding the benefits of the BU ADC and AD research. We have an active and engaged Community Action Council, have a longstanding and strong affiliation with the Massachusetts Alzheimer Association, and actively partner with Continuing Care Retirement Communities in the greater Boston area.

PROJECT SUMMARY (See instructions): Since 1996, the Boston University Alzheimer's Disease Center (BU ADC) Neuropathology Core has conducted and facilitated cutting-edge research on the neuropathology of Alzheimer's disease (AD) and is recognized internationally for outstanding contributions to neuropathological diagnosis and clinicopathological analysis. Under the consistent leadership of Dr. Ann McKee, the Core continues to provide advances in our understanding of preclinical AD, the contribution of microvascular injury to cognitive impairment, the effects of repetitive trauma on neurodegeneration, and the result of protracted aging on the brain. The BU ADC Neuropathology Core serves diverse brain donor cohorts, which include the internationally-renowned Framingham Heart Study (FHS), the Centenarian Study (CEN), and, most recently, the Center for the Study of Traumatic Encephalopathy (CSTE). Innovations include the collection of supplemental tissue, including eyes and spinal cord tissue, in addition to brain and cerebrospinal fluid. Our Neuropathology Core has pioneered standardized criteria for rating microvascular pathology to assess the contribution of gross and microvascular pathology to cognitive impairment. We were the first group to recognize the eariy neurofibrillary degeneration of the posterior visual association cortex in preclinical AD. Furthermore, the BU ADC Neuropathology Core infrastructure was leveraged to create the BU CSTE, which has provided groundbreaking research on the long-term neurodegenerative consequences of repetitive mild traumatic brain injury. We have defined the essential clinical and neuropathological features of Chronic Traumatic Encephalopathy (CTE), a progressive neurodegenerative disorder characterized by the accumulation of hyperphosphorylated tau and TDP-43 proteins. In the next cycle, we will assess the relationship between ischemic injury and cognitive status and validate the diagnostic criteria that distinguish CTE from other tauopathies and TDP-43 proteinopathies, including AD. Through institutional support from the Edith Nourse Rogers Memorial Veterans Hospital in Bedford, MA, the newly renovated neuropathology laboratories have doubled in size with state-of-the-art Leica equipment. Three histology technicians and a MD pathologist have been added, and we are currently recruiting an additional neuropathologist. Although there has been a dramatic expansion in the capabilities and institutional infrastructure in the past four years, none of these accomplishments could have taken place without the framework and personnel provided by the BU ADC Neuropathology Core, whose existence continues to be absolutely central to all our endeavors.

The mission of the Boston University Alzheimer's Disease Center (BU ADC) is to facilitate and promote high impact research on the etiology, pathogenesis, diagnosis, treatment, and prevention of Alzheimer's disease (AD), Chronic Traumatic Encephalopathy (CTE) and related disorders through the provision of well- characterized participants, brain tissue, biological specimens, and intellectual resources to qualified investigators. The prime directive of the Administrative Core is to deploy the administrative processes required to accomplish this mission. The Core manages and coordinates internal interactions between the ADC Director and Core Leaders, interactions between the BU ADC and investigators at BU and elsewhere, BU administration, staff at NIA, and local and national community organizations. The Administrative Core is under the leadership of BU ADC founder and Director, Dr. Neil Kowall supported by an Executive Committee comprised of BU ADC core leaders and other senior thought leaders at BUMC. An External Advisory Committee, ad hoc Pilot Project Review Committee, Community Action Council, and ad hoc Internal Advisory Committee help Dr. Kowall and the executive committee coordinate, plan, oversee, and evaluate BU ADC activities and ensure the optimal utilization of BU ADC resources. Ongoing, interactive communication and input is solicited from multiple sources, including our local research community, external AD and CTE experts, and NIA, to strengthen and improve performance. The Administrative Core budget supports centralized administrative personnel and activities relevant to promoting the BU ADC mission. The aims of the BU ADC Administrative Core are: 1) to integrate, coordinate, direct and plan all BU ADC activities and ensure full compliance with human subjects, animal welfare, scientific integrity, and financial policy requirements of NIH while promoting a culture that values and promotes the highest standards of ethics in clinical care and research guided by input from the scientific and lay communities; 2) to foster innovative AD and CTE research by providing visionary leadership and by facilitating cross-core interactions and coordinating the provision of resources including pilot project support to qualified investigators at BU and other local, national, and international research programs; 3) to partner with local, regional, national and international AD and CTE research communities to support high-impact research; and 4) to support and inform the communities we serve regarding the benefits of the BU ADC and AD and CTE research and to solicit feedback and advice from them. We have an active and engaged Community Action Council, a longstanding and strong affiliation with our local Alzheimer's Association, and an new partnership with the Concussion Legacy Foundation, a nonprofit group dedicated to advancing the study, treatment, and prevention of the effects of brain trauma in athletes and other at-risk groups through advocacy, education, policy development, and medical research.

Since 1996, the BU ADC has been a catalyst for research on brain aging and Alzheimer's disease (AD) at the local and national levels. The BU ADC is an active contributor to all major national AD initiatives through its contribution of large numbers of samples and standardized clinical data collected from well-characterized participants. The BU ADC also contributes participants to important national interventional AD clinical trials including the A4 study. Research supported by the BU ADC has helped to better define normal brain aging and the transition from normal aging to mild cognitive impairment (MCI) and to the earliest stages of dementia. In the current funding cycle, the BU ADC has been a leader for innovative research at the intersection between brain trauma, aging, and cognitive decline that paved the way for two new major NIH U01 programs on Chronic Traumatic Encephalopathy (CTE) based at BUSM. A major focus of BU ADC supported research over the next funding cycle will be to build on this strong foundation by: (i) differentiating AD and CTE in prodromal and later stages in aging subjects, and (ii) determining the role of repetitive head injury in the evolution of AD. The BU ADC is composed of 5 interactive and synergistic cores: Administrative, Clinical, Neuropathology, Data Management & Statistics, and Outreach and Recruitment, and a Research Education Component. The BU ADC actively partners with the Alzheimer Association in advancing AD-related research and the Concussion Legacy Foundation in advancing research on the long-term effects of brain injury. The overall specific aims of the BU ADC are: 1) to identify, recruit, and thoroughly characterize MCI, AD, CTE, and control subjects willing to participate in cutting-edge research studies and clinical trials. Research quality MRI, amyloid and tau PET scans, and CSF collection will be performed on a subset of participants; 2) to collect, store, analyze, and distribute biological samples from participants for APOE genotyping, DNA banking, biomarker assays to support high priority AD and CTE research; 3) to conduct state-of the-art diagnostic neuropathological evaluation and provide high-quality tissue for research on AD, CTE and related conditions; 4) to educate the next generation of research leaders through the Research Education Component and to foster the professional development of early-stage investigators and innovative AD and CTE related research through the BU ADC pilot project program; and 5) to collect and store high quality data, ensure data security and integrity, and provide biostatistical consultation for investigators affiliated with the BU ADC. The Administrative Core coordinates activities of the BU ADC cores to achieve the above aims and serves as the interface between internal ADC activities and external entities and ensures that BU ADC activities are consistent with the NIA ADC program mission. The BU ADC is unique in its research focus on the role of brain trauma in neurodegeneration and will make available to the research community unmatched resources to support research on AD and the role of brain trauma in age-related neurodegeneration.

Please refer to Research Strategy for all changes and additions to original Aims.

Summary As the number of Alzheimer's disease (AD) patients increases rapidly, a simple and specific blood test to diagnose AD is needed. Our recent research discovered that a single peripheral injection of pramlintide can move amyloid-? peptide (A?) from the brain into the blood in AD mouse models, and the level of A? increase in the blood correlates well with the existing amount of A? in the brain. Based on this finding, the proposed study is to further the development of a blood test for AD patients that we initiated by a single injection of pramlintide as the challenge for biomarker changes in blood. This challenge test will be a diagnostic test for AD similar in principle to the glucose tolerance test that shows abnormalities specifically in diabetic patients. The central hypothesis is that a single pramlintide injection will significantly induce a change in a group of AD-related factors in the blood of AD patients but not in those with normal cognition, and the signature of these changes will correlate with the AD biomarkers in the central nervous system (CNS). We will recruit 240 subjects from 3 clinical research centers to conduct the pramlintide challenge test. There will be three specific aims. Aim 1 is to investigate whether a single injection of pramlintide induces a dose-dependent increase in A? in the blood of AD patients. Aim 2 is to investigate whether the pattern of AD biomarker changes in the pramlintide challenge test correlates with AD biomarkers in CSF. Aim 3 is to determine whether the pattern of AD biomarker changes in the pramlintide challenge test correlate with amyloid burden in the brain. Pramlintide is non-amyloidogenic amylin analog, and is an FDA-approved drug for diabetes with a favorable safety profile. Should our proposed study support the concept of the amylin challenge test as a diagnostic test for AD, this test will be able to be conducted in a doctor's office. 1

The Boston University Alzheimer's Disease Research Center (BU ADRC) is committed to the goals and strategies of NAPA including: to prevent and effectively treat AD and AD related dementias (ADRD) by 2025 by expanding AD/ADRD research; to accelerate efforts to identify early and pre-symptomatic stages of AD/ADRD; and to educate the public about AD/ADRD. BU ADRC research themes are congruent with NIH AD/ADRD Research Summit recommendations including: 1) research on heterogeneity and the multifactorial nature of AD/ADRD; 2) molecular profiling of existing and new cohorts; and 3) developing new public-private partnerships. We operationalize our mission through 7 tightly integrated cores: Administrative, Clinical (CC), Data Management and Statistics (DMS), Biomarker, Neuropathology (NPC), Outreach/Recruitment, Engagement (ORE), Genetics and Molecular Profiling (GMP) and a research education component (REC). The Cores are focused on cutting edge research, proactive community engagement, training the next generation of AD/ADRD clinicians and researchers, and sharing key material, data, and expertise both among key partners and with the community at large. The BU ADRC has made significant contributions to the remarkable growth of AD/ADRD research nationally and has actively contributed participants, biological samples, clinical data, and scientific expertise to all major national AD/ADRD research initiatives. The BU ADRC has been the catalyst for exciting new research on genetic and lifespan environmental risk factors and AD/ADRD, particularly vascular risk and exposure to repetitive head impacts (RHI) from contact sports, military service and other sources. Major BU ADRC research themes include studies on RHI from contact sports and military service and risk for AD/ADRD, including chronic traumatic encephalopathy (CTE) and deep phenotyping AD/ADRD heterogeneity with a range of complementary innovative approaches including digital and EEG phenotyping; neuropathology; genetics; biostatistical modelling; biomarker discovery; and molecular profiling. The BU ADRC will build on this strong record of accomplishment to support new research and educate the next generation of AD/ADRD scientists. The BU ADRC will also support high risk high gain innovative developmental projects focused on NAPA and NIA strategic goals and utilize our collective expertise and experience to facilitate career development of investigators with diverse backgrounds. The BU ADRC will develop new partnerships and enhance current partnerships with other ADRCs and national research programs, foundations, advocacy groups and private organizations in our quest to prevent and treat AD/ADRD. Exposure to RHI is associated with CTE and a wide range of other AD/ADRD pathologies. As recognized leaders in this space, we are uniquely positioned to support research on genetic and other risks factors and study how RHI affects the clinical course, biomarker profile, and clinical-pathological features of AD/ADRD including CTE.