Brianne M. Bettcher, Ph.D. - US grants

DESCRIPTION (provided by applicant): This is an application for a K23 award for Dr. Brianne Bettcher, a neuropsychology fellow at the University of California, San Francisco Memory and Aging Center (MAC). Dr. Bettcher is establishing herself as a young investigator who conducts patient-oriented clinical research on the role of inflammation in cognitive aging. This K23 award will provide Dr. Bettcher with the support necessary to accomplish the following goals: (1) to garner expertise in the cognitive neuroscience of aging; 2) to advance her knowledge of the immunological contributions to healthy and pathological aging by translating innovative findings from basic science; (3) to acquire proficiency in structural and diffusion neuroimaging; (4) to develop proficiency in advanced statistical methods; and (5) to develop an independent research career. To achieve these goals, Dr. Bettcher has assembled a mentoring team that includes one primary mentor: Dr. Kramer (a clinical neuropsychologist and international leader in the cognitive neuroscience of aging); three co-mentors: Drs. Kristine Yaffe (a neurologist with expertise in immunological biomarkers and biostatistics), Maria Luisa Gorno-Tempini (a neurologist with expertise in structural MRI, specifically diffusion tensor imaging analyses), and Bruce Miller (a neurologist with expertise in behavioral neurology and clinical research); and one consultant: Dr. Tony Wyss-Coray (an immunologist with basic science expertise in inflammation). The proposed research study focuses on the cognitive and neural correlates of inflammation in healthy older adults. Dr. Bettcher will use laboratory indices of inflammation to assess the association between inflammation and cognitive functions, specifically memory consolidation, executive functions, and processing speed (Aim 1). Dr. Bettcher will employ structural and diffusion neuroimaging data to explicate the neural correlates of inflammation, and further identify whether these neural systems mediate the relation between inflammation and cognition (Aim 2). In order to isolate a novel mechanism of immune dysfunction, Dr. Bettcher will also examine the role of an upstream regulator of inflammation (i.e. progranulin) in cognitive functions and its association with brain structure (Aim 3). The proposed research will utilize the existing infrastructure of the MAC to investigate this new program of study. Public health relevance: The results from this study will provide integral information regarding the relationship between inflammation, cognition and brain structure in healthy older adults, and inform the cognitive neuroscience of healthy versus pathological aging. Dr. Bettcher's K23 training will prepare her to conduct multimodal studies of cognitive aging and implement future longitudinal studies that investigate modifiable risk factors for cognitive decline. PUBLIC HEALTH RELEVANCE: Recent evidence indicates that inflammation may confer risk for accelerated aging and may precede early stages of neurodegenerative disease; yet, strikingly little is known about the relationship between inflammation, cognition, and brain structure in healthy older adults. Results gleaned from this project will inform the cognitive neuroscience of healthy versus pathological aging, identify potential mechanisms of inflammation- associated alterations in brain structure and cognition, and provide a platform for identification of individuals at risk for cognitive decline. This work will also translate basic science studies of inflammation and aging to humans and will utilize a cutting edge marker of inflammation to pinpoint a potential mechanism of immune dysfunction.

Project Summary/Abstract The overarching hypothesis of this project is that peripheral immune dysregulation, independent of central nervous system (CNS) immune dysregulation, is a critical driver of cognitive decline, and this relationship is exacerbated by higher Alzheimer's Disease (AD)-related pathology and by recent immune health events. Epidemiological studies indicate that elevated levels of peripheral immune markers are evident years prior to clinical manifestation of Alzheimer's Disease. Although peripheral immune dysfunction is a risk factor for cognitive decline, many key unanswered how to effectively measure peripheral and CNS immune changes; 2) how to disentangle the mechanistic role of peripheral and CNS immune dysregulation on aging outcomes, and 3) how to evaluate the effect of immune-related health events on cognitive decline. To address gaps in the field, we propose to use longitudinal, multimodal measurements of peripheral and CNS immune markers. In addition to examining immune markers in circulating blood and CSF, we will employ a cutting-edge method to analyze immune markers carried by periphery- and CNS- derived extracellular vesicles (EVs). EVs play key roles in cell-to-cell communication and EV methodologies also allow for specification of the originating cells. Our primary aims for this study are: to determine how peripheral immune markers relate to CNS immune markers over time (Aim 1); to determine whether peripheral and CNS immune markers show independent associations with cognitive outcomes, and to delineate how AD- related pathology influences these associations (Aim 2); and to evaluate the role of immune health history on the relationship between peripheral and CNS immune markers and cognitive decline (Aim 3). To test our hypotheses, we will prospectively assess 180 AOAs enriched for preclinical AD (i.e., AOAs with positive amyloid PET brain scans) with baseline and 24-month follow-up measurements of peripheral immune markers (i.e., in circulating blood and in periphery-derived blood EVs) and of CNS immune markers (i.e., in CSF and in CNS-derived blood EVs), and correlate these markers with metrics of cognition and biomarkers of AD (i.e., amyloid and p-tau). We will employ both a targeted and an exploratory immune marker panel, and will record recent immune health events to determine their potential impact on the relationship between immune dysregulation and cognitive decline. Importantly, this study will establish the most comprehensively immunophenotyped aging cohort to date and will allow us to address critical questions regarding the role of the peripheral immune system in typical and pathological aging. By determining the contribution(s) of peripheral- versus CNS-derived immune signals to cognitive aging trajectories, we will be poised to better understand, predict, and ultimately treat early pathogenic immune events that may drive AD pathogenesis. questions remain, including: 1)

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