2012 — 2021 |
Bendlin, Barbara Brigitta |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
White Matter Degeneration: Biomarkers in Preclinical Alzheimer's Disease @ University of Wisconsin-Madison
ABSTRACT Loss of myelinated axons is a feature of symptomatic Alzheimer's disease (AD). Our research group has also detected degeneration of myelinated axons in the preclinical phase. A major theme of our ongoing work has been to leverage the information derived from measures of myelin and axonal degeneration to improve the understanding of AD. This is a renewal application for ?White matter degeneration: biomarkers in preclinical Alzheimer's Disease?. Participants comprise cognitively unimpaired adults from the Wisconsin Alzheimer's Disease Research Center and the Wisconsin Registry for Alzheimer's Prevention who have been followed longitudinally with neuroimaging and CSF collection. In this renewal application, we propose to continue to follow enrolled participants as well as recruit additional participants to enrich for AD, including cognitively unimpaired biomarker positive participants, individuals with mild cognitive impairment (MCI), and participants with dementia due to AD. Participants will undergo comprehensive neuroimaging every two years. The hypothesis is that that degeneration of myelinated axons is a critical facet of the AD process, and that measures of white matter degeneration (myelin and axonal) can serve as sensitive markers of neurodegeneration in the context of plaque and tangle accumulation. We will examine measures of axons, including the primary measures neurofilament light protein in CSF and blood, and neurite density derived from multi-shell diffusion MRI. We will also evaluate myelin via CSF biomarkers and quantitative myelin imaging with mcDESPOT MRI. Our three aims are to 1) Define norms for white matter maturation/degeneration and determine the temporal ordering of AD pathology and neurodegeneration, using quantile regression and pattern mixture modeling approaches, 2) Determine the extent to which degeneration of myelinated axons predicts cognitive decline in the context of AD, and 3) Determine the cause(s) of myelin and axonal degeneration. This program of research is expected to inform upon the temporal course of AD development, disease severity, and the development of new treatment strategies.
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0.964 |
2014 — 2018 |
Bendlin, Barbara Brigitta |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Midlife Insulin Resistance and Obesity: Risk Factors For Ad-Related Brain Change @ University of Wisconsin-Madison
PROJECT 2 - PROJECT SUMMARY/ABSTRACT Insulin resistance (IR) and central obesity at midlife are associated with cognitive decline and greater risk for developing Alzheimer's disease (AD). Converging evidence suggests amyloid and neural injury mediate this effect. Yet, the impact of IR and central obesity on the brain remains poorly understood in humans, especially at the preclinical stage of the disease. The objective of Project 2 is to determine the effect of IR and central obesity on longitudinal brain and cognitive change in people at risk for AD. Our overall hypothesis is that central obesity and IR affect multiple pathways which ultimately contribute to a critical burden of neural pathology manifesting as cognitive decline. Our hypothesis is based on our own pilot data (presented herein) showing that central obesity and IR affect amyloid deposition, gray matter atrophy, glucose metabolism, and memory function. To carry out our objective and test our hypothesis, we propose 3 Specific Aims: 1) Determine the extent to which IR and central obesity are linked with midlife beta amyloid, 2) determine the effect of IR and central obesity on neural health in late-midlife, and 3) determine the mediating effect of amyloid and neural injury on memory function. We will achieve these aims by enrolling 100 participants from the Wisconsin ADRC IMPACT cohort into Project 2. The IMPACT cohort is an asymptomatic group of middle-aged adults enriched on risk for AD. We will utilize existing data and samples, in addition to prospectively collected MRI (T1- weighted), CSF (to be assayed for P-Tau, A?42, sAPP-?, and insulin) cognitive, laboratory and clinical data; culminating in at least three time points. Half of the participants in Project 2 will be enrolled into a PET sub- study and will undergo [F18]FDG-PET, and [F18]Florbetapir imaging at two time points. Following completion of this study, we will have a) determined the extent to which IR and central obesity affect the ?-secretase pathway of APP cleavage, and longitudinal amyloid deposition, b) determined the effect of IR and central obesity on longitudinal brain amyloidosis as indexed by [F18]Florbetapir, c) determined the effect of IR and central obesity on structural neural injury and glucose uptake, d) determined whether glucose hypometabolism is due to neural injury or central hypoinsulinemia, and e) determined the extent to which amyloid and neural injury mediate the relationship between IR, central obesity, and hippocampal-based memory decline. The proposed research is fully integrated with the resources and expertise at the Wisconsin ADRC. This project depends on the Clinical Core (IMPACT cohort) and the Neuropathology Core (fluid sample management), and will utilize other resources including services provided by the Neuroimaging Core and the Data Management and Statistics Core. Synergy with the Wisconsin ADRC ensures the strong feasibility of the proposed research. The metabolic abnormalities to be studied in Project 2 affect more than half of all older adults, while also being established AD risk factors that have the potential to be modified. Understanding the mechanisms that impact trajectories of brain and cognitive aging is expected to lead to strategies that delay and prevent AD.
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0.964 |
2016 — 2019 |
Bendlin, Barbara Brigitta Li, Shi-Jiang [⬀] |
UF1Activity Code Description: To support a discrete, specific, circumscribed project to be performed by the named investigator(s) in an area representing specific interest and competencies based on the mission of the agency, using standard peer review criteria. This is the multi-year funded equivalent of the U01 but can be used also for multi-year funding of other research project cooperative agreements such as UM1 as appropriate. |
Alzheimer's Disease Connectome Project @ Medical College of Wisconsin
? DESCRIPTION (provided by applicant): The long-term goal of this proposal is to apply the Human Connectome Project (HCP) data collection protocol and develop robust technology to accurately stage Alzheimer's disease (AD) across the full spectrum of its progression on an individual subject basis. The onset of AD is insidious, and significant irreversible brain damage is already present by the time clinical symptoms appear. One difficulty in the field of AD research is that we have not yet established firm links between the appearance of any specific biomarker in asymptomatic individuals and the subsequent emergence of clinical symptoms. In this proposed study, we will utilize the HCP approach to determine when, where, and how the dysfunctional networks occur during disease development, and establish links by integrating HCP connectome biomarkers with well-studied molecular, genetic, and cognitive biomarkers to stage preclinical AD risks and subsequent AD progression. The success of the proposed project will open a crucial window of opportunity to intervene with disease-modifying therapy. Specifically, we hypothesize that HCP connectome biomarkers can predict and stage the full spectrum of AD dementia from the preclinical phase to dementia onset using a novel event-based probabilistic model on an individual subject basis. To test this hypothesis, we will conduct the following four aims. Aim 1. HCP compatibility. We will implement the HCP LifeSpan protocols with additional anatomical, functional, and positron emission tomography (PET) sequences tailored for aging and AD. Aim 2. Aberrant connectivity in AD. We will acquire and quantitatively characterize the connectome biomarkers in the AD connectome project (ADCP) cohort and determine their individual stages in AD progression. Aim 3. We will measure longitudinal changes in brain connectome, diseases stage development, and cognitive changes in the ADCP cohort and prospectively validate the probability distribution of biomarker-based AD stages on an individual subject basis using Markov chain estimation. Aim 4. Determine the extent to which connectome biomarkers are predicted by amyloid (A?) and tau pathologies. The completion of this Aim 4 will shed light on the molecular neurobiology of connectivity dysfunction and clarify the pathophysiology of AD development. This study will have significant impact to transform AD research paradigms in three ways. It will 1) allow for selection of individuals at high risk in order to enrich clinical trials, 2) identify the earliest preclinical disease stage atthe individual subject level, and 3) be a critical step toward the goal of developing personalized medicine for AD prevention and treatment.
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0.906 |
2016 |
Benca, Ruth M (co-PI) [⬀] Bendlin, Barbara Brigitta |
R56Activity Code Description: To provide limited interim research support based on the merit of a pending R01 application while applicant gathers additional data to revise a new or competing renewal application. This grant will underwrite highly meritorious applications that if given the opportunity to revise their application could meet IC recommended standards and would be missed opportunities if not funded. Interim funded ends when the applicant succeeds in obtaining an R01 or other competing award built on the R56 grant. These awards are not renewable. |
Apnea and Local Sleep: Mechanism and Intervention in Preclinical Alzheimer's @ University of Wisconsin-Madison
? DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is reaching epidemic proportions, and in the absence of effective treatments, prevention strategies are needed. Accumulating evidence suggests that sleep plays an important role in regulating amyloid deposition, a hallmark of AD pathology. Both sleep disturbance and obstructive sleep apnea (OSA), a disorder characterized by frequent pauses in breathing during sleep and leading to hypoxemia and sleep fragmentation, are highly prevalent in AD and are associated with progression of AD pathology. Work from our group and others has shown that sleep disruption is associated with increased amyloid deposition in preclinical AD. Our group has pioneered the use of high density EEG (hdEEG, 256 channels) to demonstrate that sleep is not uniform throughout the brain, but is locally regulated and related to plastic changes during waking; different parts of the brain fall asleep at different times, such that certain brain regions may experience chronic deficits in local sleep. Further, this phenomenon has been shown by our group to occur in a variety of neuropsychiatric disorders. Importantly, we have recently shown that OSA is associated with a local deficit in sleeping brain activity in the posterior cingulate region, in precisely the same area where peak amyloid deposition occurs in AD, suggesting a mechanism by which OSA exacerbates AD pathology. Our overarching research objective is to identify AD risk factors and mechanisms that can be modified in midlife to prevent or delay progression to AD. Sleep provides such a target. The 3 Specific Aims of this study are to determine over a 2 year period (1) the association of OSA with amyloid deposition and neural damage; (2) whether OSA treatment decreases progression of AD pathology and memory loss; and (3) the effect of local sleep deficits in the cingulate cortex on AD pathology and memory loss. The proposed study will clarify which aspects of OSA-apnea/hypopnea index, hypoxemia or sleep fragmentation-contribute to AD pathology and tests the novel hypothesis that OSA-related local sleep deprivation mediates AD progression. This study will add comprehensive imaging, sleep and activity recordings including hdEEG and amyloid-PET collection to the extensive battery of data already being collected in participants enrolled in the Wisconsin Alzheimer's Disease Research Center, comprising a cohort of asymptomatic, middle-aged subjects (50-65 yrs) at risk for AD based on parental family history. The proposed study provides an unprecedented opportunity to assess the effects of OSA, sleep features, and treatment in a well characterized and longitudinally followed group of participants at increased risk for AD. Results will also provide valuable preliminary data for a large-scale pragmatic clinical trial to test the value of OSA screening and treatment to prevent progression of AD pathology in at-risk individuals.
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0.964 |
2016 — 2017 |
Bendlin, Barbara Brigitta Gretebeck, Randall J |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Diet and Exercise Trial to Improve Insulin Resistance, Increase Cerebral Blood Flow, Alter Metabolomic Biomarkers, and Decrease Alzheimer's Disease Risk @ University of Wisconsin-Madison
Project Summary Metabolic syndrome (MetS) is associated with the development of diabetes and cardiovascular disease; however it is also linked with cognitive decline and dementia. We have shown that MetS is associated with lower cerebral blood flow (CBF) and memory function in late middle-aged adults at increased risk for developing Alzheimer?s disease (AD). Insulin resistance (IR) is at the core of MetS, and a hallmark feature of IR is higher fasting blood glucose (FBG) as well as post prandial hyperglycemia. While we and others have demonstrated links between IR and CBF as well as cognition from an observational perspective, no studies have investigated CBF and cognition after an intervention involving exercise and a carbohydrate restricted diet (CRD) designed to improve or normalize IR and glucose homeostasis. We propose to determine the effect of improving or normalizing glucose homeostasis on CBF and cognition, through diet and exercise, in individuals with IR and at risk for the development of AD. While exercise and a CRD have been shown to improve IR and glycemic control, we have only limited knowledge of the mechanisms behind these improvements. Nutritional metabolomics, the global measurement and interpretation of metabolic profiles, assesses the interaction of diet with the endogenous gene-protein cascade and the gut microbiome. Additionally, exercise has been shown to have an impact on the human metabolome. Finally, numerous metabolites have been specifically linked to IR and impaired fasting glucose (IFG). We propose to use metabolomics to measure changes in metabolites as individuals normalize or improve IR and glucose homeostasis. Should this exploratory study reveal increased brain blood flow and improved memory in response to diet and exercise, then early treatment of these individuals at risk might offer new avenues for disease-course modification. Strategies towards early and effective risk factor management could be of value in reducing the risk of metabolic as well as cognitive decline. In addition, should this study reveal changes in metabolic abnormalities consistent with early indications of diabetes, metabolomics could be an effective approach to complement disease risk analysis in our goal toward precision care.
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0.964 |
2017 |
Bendlin, Barbara Brigitta Kind, Amy Jo Haavisto |
RF1Activity Code Description: To support a discrete, specific, circumscribed project to be performed by the named investigator(s) in an area representing specific interest and competencies based on the mission of the agency, using standard peer review criteria. This is the multi-year funded equivalent of the R01 but can be used also for multi-year funding of other research project grants such as R03, R21 as appropriate. |
Neighborhood Socioeconomic Contextual Disadvantage and Alzheimer's Disease @ University of Wisconsin-Madison
Abstract: Dementia due to Alzheimer's Disease (AD) disproportionately impacts racial and ethnic minorities and the socioeconomically disadvantaged?populations often exposed to neighborhood disadvantage, a condition associated with education, health behaviors, mortality and disease. Although studies have linked neighborhood to diseases such as diabetes and cancer, very little is known about the effect of neighborhood disadvantage on development of dementia. A better understanding of the interactions among social and biological processes is necessary to design effective interventions to ameliorate AD disparities. We have created and validated neighborhood-level quantifications of socioeconomic contextual disadvantage for the full US?over 34 million Zip+4 codes?employing the latest American Community Survey data. This metric--the Area Deprivation Index (ADI)--incorporates poverty, education, housing and employment indicators; predicts disparity-related health outcomes; and can be used to establish a `dose' and timing of exposure to lifetime neighborhood disadvantage. Our long-term objective is to examine the impact, mediators and moderators of exposure to socioeconomic contextual disadvantage on the development of AD-specific pathologic features, vascular burden and cognitive decline. Our short-term objective is to establish the necessary preliminary assessments, infrastructure and methods to enable us to further our long-term goal. In addition to capitalizing on the data available through the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center (ADRC), we will create detailed residential histories for each subject (N~1918). Furthermore, since post-mortem brain tissue allows for characterization of AD neuropathological burden, we will work with the US Census to validate a novel technique for the creation of lifetime residential histories for specimens housed within two ADRC?based brain banks (N~2745). Aim 1: Determine the impact of the cumulative dose and timing of neighborhood disadvantage exposure, by ADI, on cognitive function and cognitive change over time; and Aim 2: on AD-specific markers indexed by neuroimaging (amyloid and tau PET) and CSF (P-tau, A?42). Secondary outcomes include volumetric MRI and markers of neurovascular health. Exploratory Aims 1a, 2a: Using existing data, define the extent to which race/ethnicity, age, gender and APOE4 status modify, and income, education, comorbidity and health-behaviors mediate, these relationships. Aim 3: Validate a novel technique for the creation of lifetime residential histories for brains within two ADRC based brain banks (Wisconsin and University of California-San Diego) in partnership with the US Census. Exploratory Aim 3a: Using existing brain bank data, define the extent to which the cumulative dose and timing of neighborhood disadvantage exposure, by ADI, impacts neuropathologic diagnosis, features. Impact: The project will better understanding of the fundamental mechanistic linkages between neighborhood disadvantage and AD, providing a potential pathway to new therapeutics and directly responsive to NIA mission.
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0.964 |
2017 |
Bendlin, Barbara Brigitta |
R56Activity Code Description: To provide limited interim research support based on the merit of a pending R01 application while applicant gathers additional data to revise a new or competing renewal application. This grant will underwrite highly meritorious applications that if given the opportunity to revise their application could meet IC recommended standards and would be missed opportunities if not funded. Interim funded ends when the applicant succeeds in obtaining an R01 or other competing award built on the R56 grant. These awards are not renewable. |
White Matter Degeneration: Biomarkers in Preclinical Alzheimer's Disease @ University of Wisconsin-Madison
Structural connectivity is substantially altered in Alzheimer?s disease (AD). Post-mortem studies show loss of myelinated axons, as well as loss of dendrites which correlates with cognitive severity. Interestingly, the development of AD neuropathology, including amyloid plaque and neurofibrillary tangle (NFT) development appears to occur in brain regions that are characterized by thin myelin. However, the extent to which this information can be leveraged in the preclinical stages of AD to predict future cognitive decline and development of dementia due to AD is unknown. The objective of the proposed renewal project is to determine, in vivo, the extent to which structural disconnection predicts cognitive decline, the temporal and spatial relationship between myelin degeneration and development of AD neuropathology in vivo, and the effect of processes that contribute vulnerability to structural connectivity (i.e. neuroinflammation). The central hypothesis is that that structural disconnection (loss of myelinated axons) is an early and critical feature in the neuropathologic process, is impacted by inflammation, and leads to cognitive decline and dementia due to AD. This will be tested by pursuing three specific aims: Aim 1: Determine the extent to which structural connectivity loss (myelin, axonal, and dendritic degeneration) predicts cognitive decline in preclinical AD. This will be accomplished by utilizing existing and prospectively collected CSF to be assayed for markers of structural connectivity and neural injury. Statistical models will test the extent to which connectivity markers improve prediction of cognitive decline when used with markers of classic AD neuropathology. Aim 2: Determine the temporal ordering of structural connectivity loss in relation to regional plaque/NFT development. This will be accomplished by collecting longitudinal [C11]PIB PET to assess amyloid deposition, [F18]THK5351 PET to assess NFT burden, and quantitative myelin imaging with mcDESPOT MRI to assess myelin degeneration in asymptomatic late-middle-aged adults. Longitudinal modelling on these in vivo data will be used to determine the temporal and spatial ordering of these pathologic processes. Aim 3: Determine the contribution of neuroinflammation to neurodegeneration. Existing and prospectively collected CSF will be assayed for markers of neuroinflammation and neural injury and models will test the extent to which loss of structural connectivity is due to elevated inflammation. We expect the results of this project to provide new knowledge concerning the utility of connectivity markers for predicting cognitive decline in preclinical AD, as well as informing the biology of AD. This in turn is expected to lead to earlier diagnosis of AD, contribute to the development of new prevention and treatment strategies, and reduce the prevalence of AD. This project has a high likelihood of success because it will capitalize on the large amount of existing data collected during the prior project period as well as prospectively collected data in well-characterized preclinical participants in the Wisconsin Registry for Alzheimer?s Prevention study and the Wisconsin Alzheimer?s Disease Research Center.
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0.964 |
2019 |
Bendlin, Barbara Brigitta Singh, Vikas [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Algebraic Formulations For Characterizing Structural Brain Connectivity Changes and Pathology Transmission Networks in Preclinical Alzheimer's Disease @ University of Wisconsin-Madison
PROJECT SUMMARY: Accumulating evidence suggests that measuring loss of structural connectivity together with markers of core Alzheimer's disease (AD) pathology such as amyloid plaques and neurofibrillary tangles may facilitate identification of individuals with the greatest risk of progressing to dementia. The primary focus and overarching goal of this project is to improve prediction of cognitive decline in the preclinical stage, prior to irreversible disease stages by utilizing novel wavelets based multi-scale brain connectivity signatures (WaCS) and deriving mechanisms that characterize the propagation of plaque and tangle pathology in the brain over time. We will accomplish this goal by using longitudinal cognitive and diffusion weighted magnetic resonance and positron emission tomography (PET) imaging data acquired from asymptomatic middle-aged participants enrolled in the Wisconsin Registry for Alzheimer's Prevention study and the Wisconsin Alzheimer's Disease Research Center clinical core. The analyses will be driven by (a) the ?Wavelets on graphs? transforms which allow us to simultaneously operate on multiple scale representations of brain connectivity and yield very sensitive detection of weak but real disease-specific signals with rigorous statistical confidence and (b) novel algebraic formulations that parameterize the dynamics of molecular pathology progression at the subject-specific level using an exquisite spatial mapping of amyloid and tau pathology with PiB and MK6240 PET. The proposed project comprises of three aims. Specific Aim 1: Derive structural connectivity phenotypes of preclinical AD by extending wavelet based multi-scale representations of brain connectivity graphs with improved microstructural specificity offered by biophysical diffusion models beyond classical diffusion tensor imaging (DTI). We will utilize ?? these representations to identify statistical associations between connectivity, cerebrospinal fluid based AD biomarkers (e.g., A 42, phosphorylated tau), and cognitive trajectories. Specific Aim 2: Develop techniques to characterize the subject-specific propagation dynamics of amyloid and tau pathology as measured on PET images and evaluate their associations with structural connectivity, total pathology burden and cognitive scores. Specific Aim 3: Design frameworks for predicting cognitive trajectories at the individual level using structural connectivity and molecular pathology propagation networks. Significance: This project is expected to transform three distinct areas of AD research, it will (1) deliver the impact of multi-resolution analysis of brain connectivity networks derived from diffusion models beyond the classical DTI for preclinical AD, (2) characterize how amyloid plaque and tangle pathology propagate over time in a subject-specific manner in early AD stages and (3) how such information sources can be utilized to jointly predict endpoint diagnostic status at the level of individual subjects, for monitoring disease progression and as a first step towards criteria that could inform the design of secondary prevention trials.
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0.964 |
2019 — 2021 |
Bendlin, Barbara Brigitta |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
Research Education Component @ University of Wisconsin-Madison
PROJECT SUMMARY ? RESEARCH EDUCATION COMPONENT (REC) The goal of the Research Education Component (REC) of the Wisconsin Alzheimer's Disease Research Center (ADRC) is to support educational activities that complement and enhance the training of a workforce to meet the nation's biomedical, behavioral, and clinical needs in Alzheimer's Disease (AD)-related research. The Wisconsin ADRC REC will achieve this goal by providing a program of training to all ADRC-affiliated trainees in addition to identifying exceptional junior investigators who will be specifically supported in their development into independent Alzheimer's researchers (ADRC REC Scholars). The REC will provide trainees with individualized career coaching and mentorship to support their growth and training to achieve proficiency in core research competencies and eight Wisconsin ADRC content areas (Basic Science & Neuropathology, Neuroimaging, Community Based Outreach, Clinical and Biomarker Research, Neuropsychology, Data Analytics, Care Research, and Omics). Training will occur through seminars, degree and certificate programs, workshops, and mentored research experiences. To develop the next generation of research leaders, we must attract trainees and junior faculty to this field. Accordingly, we will work with training programs across the University of Wisconsin (UW)-Madison campus to infuse AD-related research concepts into predoctoral, postdoctoral, and junior faculty training programs. By exposing early stage investigators to these topics, we will increase the interest in and understanding of aging research and enlarge an already robust pipeline of future researchers. The REC will evaluate the effectiveness of the research training program through a collaboration with the Wisconsin Center for Education Research, a national leader in education evaluation. We will use mixed methods approaches to assess the quality and value of the REC. Collaboration with education experts will allow us to educate trainees using innovative best practices. We will achieve these goals by leveraging the vast resources available at UW, one of the academically most productive institutions in the country.
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0.964 |
2019 — 2021 |
Bendlin, Barbara Brigitta Christian, Bradley T (co-PI) [⬀] Johnson, Sterling C (co-PI) [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Sv2a Pet Imaging in Alzheimer's Disease @ University of Wisconsin-Madison
ABSTRACT Synaptic loss is a major feature of symptomatic Alzheimer?s disease (AD). New positron emission tomography (PET) radioligands have been developed which bind to synaptic vesicle glycoprotein 2A (SV2A), a synaptic vesicle protein found in presynaptic nerve terminals throughout the brain. While development of these tracers is a major advance for the field of AD, very little is yet known about synapse loss across the clinical and pathological spectrum of AD, and longitudinal studies in large cohorts are lacking. In order to address this gap in knowledge, we propose to perform longitudinal SV2A PET imaging with [C-11]UCB-J in participants recruited from the Wisconsin Alzheimer?s Disease Research Center. The sample will include cognitively unimpaired AD biomarker negative participants, cognitively unimpaired biomarker positive participants, individuals with mild cognitive impairment (MCI), and participants with dementia due to AD. Participants will be imaged at baseline and at two- year follow-up. The hypothesis is that regional synaptic loss will serve as a sensitive marker of neurodegeneration in the context of plaque and tangle accumulation and will explain cognitive decline. In order to address this hypothesis, we propose the following three specific aims: 1) determine the extent to which [C- 11]UCB-J provides unique information from MRI regarding neurodegeneration; 2) determine the rate of synapse loss as reflected by [C-11]UCB-J signal; and 3) determine the extent to which [C-11]UCB-J associates with cognitive decline. In addition to [C-11]UCB-J PET, we will acquire [C-11]PIB PET to determine spatial amyloid plaque burden, as well as [F-18]MK6240 PET to determine tau tangle burden. This study will be the first to obtain these three markers in tandem, which will allow?for the first time?the ability to determine how these pathologies evolve in AD, and determine how they are spatially and temporally related to one another. The National Institute on Aging has called SV2A PET imaging a ?potentially game-changing biomarker in AD and AD-related dementias?. Synapse loss is expected to be the most closely associated with cognitive decline, yet no large human studies have yet been undertaken to examine regional synapse loss across the spectrum of AD. The proposed project addresses this gap in knowledge. This program of research is expected to improve early detection of AD, improve prediction of cognitive decline, and inform the development of new treatment strategies.
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0.964 |
2021 |
Bendlin, Barbara Brigitta Rey, Federico E (co-PI) [⬀] Ulland, Tyler Kent (co-PI) [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Gut Barrier Function in Alzheimer?S Disease @ University of Wisconsin-Madison
The age-related processes that contribute to Alzheimer's disease (AD) development, particularly in the prodromal period, are incompletely understood. Age-related reduction in gut microbiome alpha-diversity is apparent in the majority of older adults, and is suspected of contributing to brain changes, including the development of neurodegenerative disease. Our team published the first comprehensive report describing differences in the gut microbiome observed in AD dementia, including reduced diversity in gut microbiota and altered composition in people with AD dementia compared to age-matched controls. Furthermore, we found that differentially abundant genera were associated with cerebrospinal fluid biomarkers of AD, even among individuals who were cognitively unimpaired. Several studies in mouse models of AD indicate that gut microbiota play a role in the development of AD neuropathology, however to date, the mechanisms underlying these effects are virtually unknown. Recently it has also become clear that the innate immune response in AD plays a critical role in mediating the pathology associated with AD; however the interplay between systemic changes and the innate immune response in AD are not well understood, nor is it known how these factors impact the progression of AD pathology. Our overarching goal is to determine the extent to which alterations in the composition of gut microbiome exacerbate and/or accelerate the development of AD pathology. This proposal is based on the central hypothesis that age-associated gut dysbiosis and inflammation weaken gut barrier function, which in turn leads to the systemic dissemination of microbial components, driving an immune response and system wide changes that worsen AD pathology. To test this hypothesis we propose to study well-characterized participants enrolled in the Wisconsin Alzheimer's Disease Research Center as well as conventional and gnotobiotic APPPS1 mice, to address the following specific aims: 1. Determine the longitudinal relationship between gut microbiome (metagenome), gut inflammation and permeability, and the development of AD pathology in human participants, and 2. Determine the effects of modifying gut permeability on AD pathology in mice. We expect that alterations in gut microbiome composition and gut permeability exacerbate AD pathology in humans, and that impairment of intestinal barrier function and increased gut permeability alters brain homeostasis and exacerbates AD progression in mouse models of AD. Our research group has been working to determine the role of gut microbiome in the development of AD pathology for the past 5 years, and we are perfectly poised to address the proposed aims. We will leverage our expertise in clinical AD, neuroimmunology, and gut microbiology/gnotobiotic mouse models to successfully carry out the proposed project. Completion of the proposed experiments is expected to lead to the development of novel therapeutic strategies for AD and related dementias.
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0.964 |
2021 |
Bendlin, Barbara Brigitta Kind, Amy J. [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
The Neighborhoods Study: Contextual Disadvantage and Alzheimer?S Disease and Related Dementias (Adrd) @ University of Wisconsin-Madison
Dementia due to Alzheimer?s disease and related dementias (ADRD) disproportionately impacts racial/ethnic minorities and the socioeconomically disadvantaged. Development of effective interventions require mechanistic understanding of distal fundamental forces, including socioeconomic context (i.e. ?neighborhood disadvantage? or the social determinants of health of a given area), that put people at ?risk for [more proximal] risks? such as individual-level income, education, health behaviors and comorbidity. Prior research supports that contextual disadvantage is modifiable and interacts with biological processes to produce disease, yet little is known of its impact on ADRD. Towards this, we created validated quantifications of neighborhood disadvantage for the full US. This Area Deprivation Index (ADI) incorporates poverty, education, housing and employment indicators; predicts disparity-related health outcomes; and is freely shared through our public platform (the Neighborhood Atlas). We have validated survey and public data-based residential history tracing methodologies that establish dosage and timing of neighborhood disadvantage exposure across a life-course for both living and deceased persons. We have demonstrated that even after adjustment for individual risk factors, neighborhood disadvantage is strongly associated with cognitive function, neurodegeneration shown on MRI, and post-mortem AD plaque neuropathology. However, our current sample is lacking in geographic diversity and is of insufficient size to conduct a more robust multi-factor phenotypic risk assessment of social-biological interactions and their mechanisms; a necessary foundation towards developing new therapeutic intervention. This proposal employs collaboration with 22 Alzheimer?s Disease Research Centers (ADRC) and their existing cognitive, neuroimaging and neuropathology data. We take on the substantial work to create detailed residential histories for each ADRC subject (N~9,234 living, N~10,469 brain bank) to establish a dosage and timing of neighborhood disadvantage exposure across each life-course. Hypothesis: Larger and earlier exposures to neighborhood disadvantage will predict lower cognitive function, faster cognitive decline and greater disease burden including AD neuropathology among the targeted sample. Aim 1: Determine the impact of the cumulative dose and timing of neighborhood disadvantage exposure (indexed by ADI), on cognitive function and change over time; Aim 2: on AD-specific markers indexed by neuroimaging (amyloid and tau PET) and the secondary outcome of volumetric MRI; and Aim 3: on neuropathologic tissue features and diagnosis. Aim 4: Using existing ADRC data and newly collected survey data, define the extent to which individual race/ethnicity, age, sex, income, education, comorbidity and health-behaviors mediate these relationships. The proposed project, if funded, will be the largest study of its kind on social determinants of health in the context of AD. Successful completion will result in the development of a novel collaborative infrastructure of contextual exposure for future social-biological phenotypic evaluation, providing a potential pathway to new therapeutics, and directly responsive to the NIA mission.
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0.964 |