James B. Brewer - US grants

DESCRIPTION (provided by applicant): This is a K23 Mentored Patient Oriented Career Development Award Application. The primary goal of the proposed research is to examine medial temporal lobe (MTL) structure and function in healthy subjects and in older individuals with varying degrees of memory difficulty - from the normal elderly to patients with mild Alzheimer's disease (AD). Four projects are proposed. One project will involve diffusion tensor imaging (DTI) measurements of anisotropy in MTL fiber tracks, which will be evaluated in young, healthy subjects (NC), elderly controls (EC), subjects with mild cognitive impairment (MCI) and patients with mild AD in order to evaluate the structural features that are specific to each group. Three interrelated event-related fMRI projects are proposed that are designed to differentially activate entorhinal, perirhinal and para-hippocampal cortices. Paradigms will be developed in young, healthy subjects and applied to each of the groups of older individuals. The candidate for this Career Development Award has experience in functional imaging of MTL function in young, healthy subjects, but wishes to gain expertise in the use of this and other emerging technologies in magnetic resonance imaging for the evaluation of clinical populations. As part of this proposal, the candidate will receive training in: 1) the clinical design and analysis of ethically sound studies focusing on comparisons between normal elderly, MCI and AD patients, 2) AD neuroanatomy, pathophysiology, neuropsychiatry and potential therapeutic strategies, 3) statistical approaches to the study of clinical populations and time course data sets, and 4) the acquisition and processing of measures of brain anisotropy using DTI.

Dementia with Lewy bodies (DLB) may account for 10-15 percent of all cases of dementia in the elderly, yet accurate recognition of the disorder remains a challenge. Diagnostic criteria that include typical DLB features lead to high specificity, but may fail to identify up to 50% of cases later diagnosed at autopsy. Advances in brain volumetry, which have shown promise in initial analysis of data from the Alzheimer's Disease (AD) Neuroimaging Inititative, and diffusion tensor imaging (DTI) may be used to quantify changes in brain atrophy and connectivity resulting from DLB, AD, and healthy aging. The primary goal of the proposed research is to identify brain structural changes that best differentiates these categories and to further examine the bases of such changes using magnetic resonance (MR) microscopy. To achieve this goal, four interrelated experiments are proposed. 1) Quantitative structural imaging will be used to identify the cross- sectional regional volumetric differences that best differentiate DLB, AD and healthy aging. 2) Probabilistic- atlas-based analyses will be used to identify the cross-sectional regional connectivity differences that best differentiate DLB, AD and healthy aging. 3) Assessment of within-subject change in regional volumes and connectivity will be used to identify differences in regional atrophy rates between DLB, AD and healthy aging. 4) MR microscopy will be used to identify the histopathological bases for such regional differences in MR signal. The proposal is based upon a wealth of data suggesting that structural MR imaging may be used to differentiate DLB from AD and upon preliminary studies showing that high-throughput, multi-region quantitative measures may be used to extend previous findings that used qualitative measures or limited- region volumetric assessment using manual tracing. The projects benefit from a convergence of recognized expertise in the neuropsychological assessment of DLB, in the neuropathological assessment of regional synuclein deposition, and in the application of quantitative structural MR imaging to neurodegenerative disorders, including high-field MR microscopy of post mortem tissue. In sum, results from these proposed experiments should provide important insights into the neuropathological bases of differences in MR measures of regional atrophy and connectivity in DLB, AD and healthy aging. RELEVANCE (See instructions): The proposed experiments will evaluate structural changes in the brain that differentiate DLB, AD, and healthy aging. The findings will improve understanding about the effects of neurodegenerative disease on the brain and the neuropathological bases for regional MR changes observed in DLB and AD relative to healthy aging.

DESCRIPTION (provided by applicant): ABSTRACT: In this K02 Independent Scientist Career Development Award, the candidate seeks to build upon his background in functional and structural neuroimaging and use multimodal neuroimaging to understand the evolution of cognitive disorders, such as Parkinson's disease dementia (PDD) and Alzheimer's disease (AD). The K02 will provide the candidate protected time for research and career development activities that will enhance the clinical applicability of his imaging expertise and assure excellence in the responsible conduct of human subject research. The proposed projects use multimodal magnetic resonance imaging (MRI) to examine structural and functional differences in the brains of patients with PDD and AD relative to elderly controls. The overall goal of the research is to better understand the selective vulnerability of brain regions to synuclein and amyloid pathology and to understand how cognitive deficits in dementia relate to underlying damage in brain structure and circuitry. Specifically, clinically and neuropsychologically characterized controls and subjects with PDD and AD will undergo a baseline and followup resting MRI protocol of around 30 minutes that will allow the following measurements: 1) regional volume of cortical and subcortical structures, 2) white matter integrity in tracts identified using probabilistic atlas-based diffusion tensor tractography, 3) functional connectivity within anatomically-defined regions of the default network, and 4) interval change in volume of cortical and subcortical structures using nonlinear registration of serial image datasets. High throughput processing streams are in place for efficiently capturing the structural measures obtained from each procedure, and the candidate's laboratory has added expertise in functional connectivity analysis. Thus, the proposed research will allow new insight into the structural and functional consequences of neurodegenerative disease.

DESCRIPTION (provided by applicant): The Alzheimer's Disease Cooperative Study (ADCS) has an established organizational infrastructure to conduct large scale clinical trials in Alzheimer's disease (AD) in the academic setting. Over the 19 years since its inception, the ADCS has completed multiple seminal AD studies by coordinating clinical trial activity across more than 80 participant sites. By the end of 2011, recent ADCS trials will have collected nearly 3000 brain magnetic resonance imaging (MRI) and positron emission tomography (PET) scans. The Biomedical Informatics Research Network (BIRN) provides an ideal resource for sharing ADCS clinical and brain imaging data with the broader research community. The primary goal of the proposed work is to use BIRN tools to analyze and share cross-sectional and longitudinal brain imaging data from prior and ongoing ADCS clinical trials. To achieve this goal, the investigators will 1) Assemble clinical and brain imaging data using BIRN tools and procedures for quality assurance and de-identification. 2) Provide regional volumetric brain imaging data using BIRN tools for cross-sectional volumetry, cortical parcellation, and cortical thickness measurements, combined with MRI-PET registration for quantification of regional metabolic activity when PET imaging data is available. 3) Provide measurements of regional atrophy using longitudinal brain imaging data and a novel procedure to quantify subregional volumetric change over time. 4) Provide data modeling and links between data objects with adherence to existing ontologies. 5) Share all raw and processed brain images as well as linked volumetric, metabolic, and clinical data using BIRN infrastructure. The project leverages the existing infrastructure and expertise assembled at the University of California, San Diego for large scale AD clinical trials and for large scale analyses of brain imaging data. Nevertheless, the richness of the dataset is far too great for researchers at a single university to fully exploit, and the importance of the data calls for collaboration across universities that the BIRN infrastructure enables. In summary, the proposed work will make a valuable dataset accessible to researchers otherwise unable to study this topic on such a scale, and will facilitate collaborative research likely to greatly advance knowledge about the structural and functional consequences of AD on the brain.

Quantitative brain imaging biomarkers now play a central role in clinical trials for AD, as they may permit a more direct assessment of the effects of a therapy on brain function, amyloid load, and rate of neurodegeneration. Such information complements clinical and cognitive data points to provide a more complete picture of an intervention's putative disease-modifying effects. Further, clinical brain imaging and central clinical overread may be required for monitoring patient safety during a trial. However, the complexity of imaging data requires ready access to specialized neuroimaging expertise to assist in developing and maintaining state-of-the-art approaches in study design as well as data management, analysis, and sharing. No single institution houses such a wide array of expertise, and the rapid evolution of the field calls for an organizational structure that allows project leaders flexibility in selecting best available design and analysis approaches, while maintaining consistency through centralized data upload and management.

? DESCRIPTION (provided by applicant): This proposal aims to validate cognitive event-related brain potential (ERP) biomarkers of disease progression in populations eligible to enroll in AD clinical drug trials. We will use a comprehensive ERP protocol which elicits 5 cognitive ERP components (P50, P300, N400, LPC and Frontal Positivity (FP)), each with demonstrated high sensitivity to early Alzheimer disease (AD). A systematic study which compares the relative sensitivity and stability of these ERP components is needed, in this era of validated amyloid biomarkers sensitive to early AD. We will study >200 elderly participants (60 pre-clinical AD, 50 amyloid biomarker - normal elderly, 50 amnestic MCI & 40 mild AD study completers) with longitudinal cognitive ERP/EEG, brain MRI and neuropsychological testing. The project will test the feasibility of multicenter ERP studies, develop infrastructure, refine methodology, and determine how ERPs can be best used to detect the AD pathophysiologic process and to measure changes over time. This study will advance our knowledge of how to use ERPs in AD treatment trials, e.g. for sample enrichment in prevention trials, and as outcome measures. Specific Aims: 1) To validate the utility of baseline ERPs in predicting longitudinal trajectories n cognitive decline and brain atrophy. 2) To test the hypothesis that our comprehensive ERP battery will assist the in vivo staging of the AD pathophysiologic process. 3) To test the hypothesis that ERPs are highly sensitive to changes in the AD pathophysiologic process over time and will provide useful biomarkers for tracking disease progression. Methods: We will recruit elderly subjects (age 60-90; n =252, 74 with Preclinical AD (Pre-AD), 62 amyloid biomarker-negative Normal Old (NO) subjects, 62 amnestic MCI, and 54 mild AD dementia). All enrolled subjects will receive an amyloid PET study, longitudinal ERP/EEG and brain MRI. All subjects will be studied with repeat annual ERP testing for 2 years and MRI 1 year after the baseline study, providing longitudinal ERP, structural MRI, neuropsychological and functional data. 32 channel ERP/EEG will be obtained using a comprehensive ERP battery which assesses automatic (P50) and controlled (P300) attention, language (N400) and memory (verbal and visual, with LPC and FP measures) processes. Significance: Sensitive, reliable markers of synaptic dysfunction and incipient AD in its preclinical stages are needed. This proposal, by validating ERP biomarkers of disease progression in populations most relevant to current AD clinical drug trials, will have important applications to primary prevention trials, disease-modifying and targeted cognitive therapies. This study will allow the rational application of specific ERP paradigms, best suited to preclinical vs. prodromal vs. demented populations. More wide application of sensitive ERP/EEG techniques could have major impact on reducing the requisite sample sizes and costs of AD treatment trials.

Alzheimer's Disease (AD), the most common cause of dementia in the elderly, affects over 4 million Americans, a number projected to grow in coming decades; current overall costs for their care exceeds $100 billion per year. Current treatment options at best provide only temporary stabilization. Failures of clinical trials in AD have led to a focus on intervening earlier, when there is less structural damage to the brain. Characterizing and intervening in pre-dementia stages of AD is a research imperative. The UCSD Alzheimer's Disease Research Center (ADRC) has contributed greatly to research progress in the past 30 years. To continue to facilitate and conduct research into the causes, treatment and prevention of AD and related disorders, overall aims of this renewal application, which has been revised in August 2015, are: 1) To support research efforts by maintaining resources that include cohorts of subjects with normal cognition, Mild Cognitive Impairment (MCI), AD and other dementias (particularly Lewy Body Disease); neuropathology tissue from well-characterized subjects; biological samples (DNA, plasma and CSF); MRI and other brain images; and to maintain a comprehensive database. This will be carried out by six well- integrated Cores: Administrative, Clinical, Hispanic Satellite, Pathology, Outreach/Recruitment/Education (ORE) and Data Management/Biostatistics. 2) To support 3 research Projects: i) Probing SORL1 Risk Factors with Human Induced Pluripotent Stem Cell Technology ii) Disease Mechanisms in Frontotemporal Dementia Linked to C9orf72 Expansion. iii) Genomic mosaicism underlying posterior cortical atrophy (PCA) [new project, part of P50 revision] Three Pilot Project awards related to AD, aging or neurodegeneration will also be issued each year. 3) Interact widely with researchers at UCSD, the VA Medical Center, and nearby research institutions (Salk Institute, Scripps Research Institute, Sanford-Burnham Institute, San Diego State University). 4) To collaborate with other AD Centers, NACC, and other national research efforts. The ADRC will follow about 500 subjects, using annual standardized evaluations that include the Uniform Data Set components. The ADRC will provide data to the National Alzheimer's Coordinating Center, and DNA to NCRAD. ADRC subjects will be offered participation in clinical trials organized by the Alzheimer's Disease Cooperative Study (ADCS) and by pharmaceutical companies, and participation in biomarker studies such as ADNI and PPMI. We will share subjects, data, brain images and biosamples with other researchers. 5) To continue to support innovative research, and to train new investigators 6) To foster professional education and training, improve public knowledge and awareness about aging and AD, and provide innovative support efforts for patients and families affected by AD.

DESCRIPTION (provided by applicant): Alzheimer's Disease (AD), the most common cause of dementia in the elderly, affects over 4 million Americans, a number projected to grow in coming decades; current overall costs for their care exceeds $100 billion per year. Current treatment options at best provide only temporary stabilization. Failures of clinical trials in AD have led to a focus on intervening earlier, when there is less structural damage to the brain. Characterizing and intervening in pre-dementia stages of AD is a research imperative. The UCSD Alzheimer's Disease Research Center (ADRC) has contributed greatly to research progress in the past 30 years. To continue to facilitate and conduct research into the causes, treatment and prevention of AD and related disorders, overall aims of this renewal application are: 1) To support research efforts by maintaining resources that include cohorts of subjects with normal cognition, Mild Cognitive Impairment (MCI), AD and other dementias (particularly Lewy Body Disease); neuropathology tissue from well-characterized subjects; biological samples (DNA, plasma and CSF); MRI and other brain images; and to maintain a comprehensive database. This will be carried out by six well- integrated Cores: Administrative, Clinical, Hispanic Satellite, Pathology, Outreach/Recruitment/Education (ORE) and Data Management/Biostatistics. 2) To support 3 research Projects: i) APP trafficking and endosomal sorting. ii) Probing SORL1 Risk Factors with Human Induced Pluripotent Stem Cell Technology; iii) Disease Mechanisms in Frontotemporal Dementia Linked to C9orf72 Expansion. Three Pilot Project awards related to Alzheimer's disease, aging or neurodegeneration will also be issued each year. 3) Interact widely with researchers at UCSD, the VA Medical Center, and nearby research institutions (Salk Institute, Scripps Research Institute, Sanford-Burnham Institute, and San Diego State University). 4) To collaborate with other AD Centers, NACC, and other national research efforts. The ADRC will follow about 500 subjects, using annual standardized evaluations that include the Uniform Data Set components. The ADRC will provide data to the National Alzheimer's Coordinating Center, and DNA to NCRAD. ADRC subjects will be offered participation in clinical trials organized by the Alzheimer's Disease Cooperative Study (ADCS) and by pharmaceutical companies, and participation in biomarker studies such as ADNI and PPMI. We will share subjects, data, brain images and biosamples with other researchers. 5) To continue to support innovative research, and to train new investigators 6) To foster professional education and training, and to improve public knowledge and awareness about aging and AD, as well as to provide innovative support efforts for patients and families affected by AD.

ADMINISTRATIVE CORE SUMMARY/ ABSTRACT Administrative Core provides scientific leadership, fiscal management, operations oversight, and administrative support to the Center?s 7 Cores and training program: the Clinical, Data, Neuropathology, Biomarker, Outreach Recruitment and Engagement (ORE), induced pluripotent stem cell (iPSC), and Latino Cores as well as the UCSD ADRC Research Education Component (REC). In addition to determining the overall priorities, the Administrative Core facilitates interactions with affiliated researchers, trainees, community partners, and advisors to advance Center goals and to ensure that efforts and resources are provided to support multicenter initiatives. These objectives are accomplished through a series of specific aims: 1) Create a leadership structure and culture that promotes the mission of the Shiley-Marcos ADRC to prevent, treat, and cure Alzheimer?s disease; 2) Set and review the scientific agenda, priorities and productivity; 3) Report progress and ensure responsiveness to funding agencies and other authorities; 4) Facilitate communication across cores, projects, trainees, and affiliated researchers; 5) Foster collaborations to advance team-based Alzheimer?s Disease and Related Disorders (ADRD) research and bring new investigators to the field with awareness of NAPA goals; 6) Communicate the latest research findings. To promote the Center?s mission and theme the Administrative Core supports integration across all departments, scientists, and community partners. Guidance is provided by the Administrative Core with input incorporated from the Executive Committee and Internal, External and Community Advisory. We provide sound fiscal management to the Center that is grounded in a solid understanding of operations and organizational strategy to amplify productivity and innovation in priority scientific areas. The Center?s development research and training grants are selected and awarded by the Administrative Core as one way to build synergy and collaborations with clinicians and researchers at UCSD and continue and strengthen collaboration with researchers at other outstanding biomedical research institutions in San Diego. Results of the latest research findings as well as new ways to become involved with the UCSD ADRC are disseminated by the Administrative Core.

OVERALL ? SUMMARY/ ABSTRACT Alzheimer?s disease and related dementias (ADRD) together constitute a paramount and growing public health issue with tremendous cost and unfathomable aggregate suffering. Unless the diseases can be effectively treated or prevented, increased prevalence with changing demographics will lead to costs the country will find difficult to bear. Reflecting this national imperative, the National Alzheimer?s Project Act (NAPA) created a roadmap and goal to impact this disease by 2025. The current proposal for renewed funding of the UCSD Shiley-Marcos Alzheimer?s Disease Research Center (ADRC) explicitly aligns with NAPA and leverages the center?s deep roots and engagement built over the past 35 years. The center?s rich academic and community environment make it well positioned to synergize with the ADC network toward achievement of NAPA goals and milestones, particularly along the theme of examining heterogeneity of ADRD through the study of models, markers, and mechanisms in a diverse cohort of volunteers. Specifically, the center proposes work that will bring world-class advanced translational neurosciences to the study of heterogeneity and diversity in ADRD using new models and new, tailored community engagement approaches. including innovative disease in a dish models fostered by its new iPSC Core, and increased engagement with the Latino Amerindian community through the establishment of a Latino Core. Efforts are tightly integrated with functions of other cores bolstered by tremendous resources and experience gained over the center?s longstanding existence, while incorporating the most innovative, disruptive and cutting-edge science available on the multi- faceted UCSD campus. The center will achieve the following overarching aims unifying its broad-based activity in research, education, engagement, and sharing and synergizing with the ADC network: The center will 1) apply well-developed and interactive cores to foster cross-disciplinary, integrative, and innovative clinical and translational science, 2) educate and train a diverse workforce, 3) Provide a hub for scientific and community exchange and support, optimizing core efforts and synergies to best serve the local and broader patient, caregiver, and research communities and 4) engage in collaborative research across centers, with special emphasis on applying center strengths to complement the ADC network and extend its impact.

PROJECT SUMMARY/ABSTRACT This new application for an institutional T32 program is designed to provide advanced translational research training on Alzheimer's disease and AD related dementias (ADRD). This proposal builds on the outstanding research and training environment of UCSD and participating neighboring institutions (The Salk Institute, Sanford-Burnham-Prebys Institute, and The Scripps Research Institute) as well as leveraging the resources of the UCSD Alzheimer's Disease Research Center, the AD Collaborative Study, and other affiliated programs. To take advantage of the unique opportunities of our research community, we will offer focused but also multidisciplinary approaches to training four pre- and four postdoctoral (MD, PhD, or MD/PhD) trainees to prepare them to tackle the challenges of ADRD due to population aging. The program has three key features: 1. Academic bridging - A principal focus will be to provide the predoctoral students and postdoctoral fellows with concepts and research tools necessary to address issues at the interfaces of basic, translational, and clinical questions in ADRD research. This bridging will be reflected in the diverse interests and expertise of the participating faculty, the nature of the projects proposed by the trainees, and the training plan itself which includes formal didactic teaching and less formal seminars, journal clubs, interactive sessions with faculty, and scientific retreat. 2. Multidisciplinary Approach - By its very nature, neurosciences is a multidisciplinary field of investigation. The training faculty brings to this Program expertise, experience, and technical knowledge in a variety of approaches and disciplines. Our goal is to train future investigators who are to work and think effectively in several of these areas. This will be achieved by choosing the best faculty, by bringing together trainees and mentors who are open to interdisciplinary exchange of ideas and approaches, and providing them a forum for instruction, discussions, and interactions. In addition, we hope to draw into the ADRD community faculty members who have recently expanded their research efforts into ADRD or who have expertise in related areas or in technologies that can expand the scope of ADRD research. 3. Mentorship ? An integral aspect proposed for this Training Program is the attention to mentorship. In addition to the trainee's own research mentor/supervisor, each trainee will select a co-sponsor chosen to provide more multidisciplinary input and oversight into his/her research. Junior faculty members will also be assigned a mentor chosen from the Executive Committee of the Training Program to provide advice and support in order to advance their academic trajectory and enhance the success of their laboratory trainees.

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.