Sterling C. Johnson - US grants

Deficits in acquisition and retention of new information, two core features of early Alzheimer disease (AD), are generally observed before the clinical onset of dementia. Mild cognitive impairment (MCI) is a descriptive term that has been used to describe the transitional or borderline state between normal aging and onset of Alzheimer disease. Earlier identification and treatment of MCI is of urgent clinical interest since the elderly are the fastest growing segment of the U.S. population, and approximately 12-15 percent of MCI cases convert to AD each year. This pilot-project is a functional MRI (fMRI) study of learning and forgetting in normal aging and MCI. With recent advances in the cognitive neuroscience of memory and statistical processing of functional images, it is now possible to detect dynamic changes in neural activation associated with the acquisition and retention of new information. In this pilot project, we propose to study 15 MCI and 15 demographically matched healthy, cognitively normal adults between ages 60 and 85 with an event- related verbal learning paradigm during fMRI scanning. Subjects will also receive neuropyschological testing with emphasis on aspects of memory. Specific Aims: 1. Characterize the neural response during learning of temporally spaced, repeating information in MCI and healthy controls. We expect that in normal controls activations associated with repeated exposure will decrease over time, a phenomenon known as repetition suppression or adaptation; this 'learning' effect will be evident in the left anterior hippocampus. In contrast, MCI patients will not show this effect-thus, each word will be perceived as novel despite repeated presentation. The learning effect will be assessed with linear as well as exponential models of adaptation. 2. Neuropsychological functioning (verbal memory scores) will be related to activation in the MCI group: Greater severity of psychometric memory deficit will be related to less adaptation within the hippocampus. Once patterns of activation are established in MCI and controls, longitudinal designs can be implemented and other patient groups such as those with depression and various forms of mild dementia can be investigated. Thus, we expect that the results from this pilot grant will be useful in guiding hypotheses for future funded experiments that further our understanding of the neural substrates of memory and its breakdown in MCI and related disorders. Such knowledge may be useful in identifying subjects at risk for AD for earlier intervention as treatments become available.

Awareness (accurate, conscious understanding) of one's own cognitive, emotional, and social abilities and limitations is among the highest of all cerebral functions. This aspect of consciousness is often impaired several months to years after a moderate to severe traumatic brain injury (TBI) and often interferes with treatment and adjustment following injury. The neural correlates of deficits in self-awareness are not well understood, and progress in this area may be helpful in predicting recovery and designing optimal treatment strategies. In this application we propose to use BOLD contrast functional MRI (fMRI) and diffusion tensor imaging (DTI) to probe the neural substrates of self-awareness, as well as executive functions and episodic memory in TBI cases and matched trauma controls (orthopedic, non-brain trauma). We will examine the presence and degree of resolution of injury-induced cognitive and psychosocial deficits, and relate these to neural activity using fMRI during cognitive tasks, and to axonal integrity as measured by DTI. We will examine all subjects (60 moderate, 60 severe TBI cases, and 60 matched trauma controls) at 4 months post-injury, and again at 18 months in order to test the following hypotheses: 1. The anterior medial prefrontal cortex subserves self-reflective thought. Activation in this region will be related to the patient's level of self-awareness, and to the degree of white matter integrity underlying that region. 2. Improvement of executive and memory abilities will be related to longitudinal changes in activation in the lateral prefrontal cortex and mesial temporal cortex respectively. Improvement in cognition, together with a longitudinal change in activation, and a difference from control group activity, will be considered evidence for cerebral reorganization. 3. Functional imaging findings will improve prediction of neurobehavioral outcome. Approach. We will characterize patients with neuropsychological and neurological evaluation, neurobehavioral outcomes, and functional MR imaging. Depth and duration of coma will be used as primary measures of injury severity. MRI activation and tensor data will be analyzed using the general linear model with a voxel-based approach. This technique will allow direct and simultaneous assessment of the relationship between MR data and other measurements such as injury severity, outcome and scores on cognitive tests. We expect that successful completion of this project will provide greater understanding of patients with debilitating brain injury, and that these probes of neurobehavioral function may be useful in the future to guide and monitor treatment interventions.

[unreadable] DESCRIPTION (provided by applicant): This investigation will focus on two key brain regions suggested by recent studies to be vulnerable in people at risk for Alzheimer Disease (AD)-the mesial temporal lobe, and the posterior cingulate cortex (PC). The role of the mesial temporal lobe in forming new memories has been well established with lesion studies and neuropsychological investigation. The role of the PC is only beginning to be understood (through functional imaging) as important in retrieval processes. Recent imaging studies suggest that both of these regions are affected in AD even before clinical symptoms appear, consistent with the very early memory symptoms in AD. In this project we will study middle age and older adults with one or more risk factors for AD including first-degree family history, ApoE genotype, or memory difficulty. Group one will be selected based on family history and genetic risk for AD (presence or absence of at least one APOE e4 allele) compared with age-matched controls. A second risk group will be patients identified with Mild Cognitive Impairment-amnestic type (MeIa) (and age matched controls), who will be enrolled over the first two years, imaged at baseline and monitored with cognitive testing until conversion to AD or until the end of the funding period. Half of the MCI patients are expected to convert over the five years of support. Aims: Using high-field (3Tesla) functional MRI (fMRI) and extensive clinical and cognitive characterization, our aims are 1) To determine the independent contributions of age, APOE status, and presence or absence of family history of AD, to the cerebral response in the mesial temporal lobe and posterior cingulate during learning and retrieval tasks in cognitively healthy adults age 46 to 65. 2) To show that patients with MCI differ from age-matched controls in the MTL and PC response, and that conversion to incident AD is predicted by the baseline PC and MTL fMRI response. Methods: Voxel-based image processing methods will be applied to regions of interest for the fMRI data using clinical characteristics as grouping variables and covariates within the general linear model to accomplish the above aims. Significance: Examining learning and retrieval functions in asymptomatic and symptomatic persons with risk factors for AD may provide rich insight into the organization of learning and memory systems and how they may begin to fail in preclinical AD. In the future this information may lead to improved methods for earlier detection of the disease. [unreadable] [unreadable]

In many mammals, including humans and some non-human primate species, the aging brain undergoes a number of large-scale changes that can be observed with imaging and cognitive approaches. These agerelated changes include structural atrophy, increased mineral deposition, decline in neurotransmitter production, periventricular ischemia, decline in glucose metabolism (and concomitant decline in certain higher cognitive functions, particularly in the domains of memory, cognitive speed, and executive function). The dramatic effect of diet restriction (DR) to increase lifespan in many species and its salutary effects on metabolic processes such as oxidative stress, suggest that this intervention may also be good for the brain. In this project, we propose to test the hypothesis that rhesus monkeys undergoing chronic DR will exhibit less pronounced age-related brain structural and functional changes than their ad libitum fed age-matched controls. We propose to test this hypothesis using high-resolution volumetric and microstructural Magnetic Resonance Imaging (MRI) techniques of the brain and cognitive tests. Our emphasis is on structures and cognitive functions that may change with age. We plan to accomplish the following specific aims: 1) determine if baseline differences exist between DR and control animals on tissue volume and integrity such as regional gray and white matter volume, T2 relaxation time (gray matter mineralization), magnetization transfer, and diffusion tensor imaging (white matter integrity). 2) determine whether cognitive differences exist between DR and control groups using computerized non-human primate behavioral paradigms that have previously been shown to be sensitive to age. 3) determine whether the rate of structural change has been slowed in the DR group. These aims will be accomplished utilizing the expertise and excellent resources of the Wisconsin Primate Research Center and the Keck Laboratory's 3-Tesla MRI. Analyses will examine the groups for baseline and longitudinal differences. The unique opportunity to study these animals with a comprehensive MRI imaging and cognitive battery should provide much needed information regarding global aging processes in the brain, and extend the evaluation of the effects of the DR intervention in domains of great significance to humans.

Seeinstructions): A major emphasis of the Wisconsin ADRC is identifying features and avenues for early intervention in the preclinical state of AD. Project 1 of the Wisconsin ADRC is about early characterization of AD using a fibrillar amyloid positron emission tomography imaging method with Pittsburgh Compound B [C11]PiB. We seek to determine the relationship between amyloid binding measured with PiB,and neural activity where neural activity is indexed by a) cognitive function/decline, b) BOLD activity during a memory task, and c) resting cerebral blood flow (CBF) imaging in a cohort of cognitive decliners at high risk for AD. The overall hypothesis is that fibrillar amyloid binding to [C11JPIB will be related to markers of neural function in cognitive decliners at high risk for AD. We will focus on the posterior cingulate/precuneus brain region (which is known to have high amyloid burden in AD) and probe this region with 1) a functional MRI task previously shown to activate the region, 2) resting cerebral blood flow (CBF) using a whole-brain pseudo- continuous arterial spin labeling technique (ASLCBF),and [C11]PIB imaging. Specific Aim 1: To determine whether PIB binding in the posterior cingulate is associated with cognitive decline to MCI in a cohort of subjects who we have followed over a 4-year interval. Furthermore we will determine whether PIB binding in the posterior cingulate predicts subsequent decline. Specific Aim 2: To determine whether PIB binding in the posterior cingulate is associated with imaging markers of neural function (BOLD fMRI during a memory task, and resting cerebral blood flow). Specific Aim 3: To determine if the relationship between PIB binding in the posterior cingulate is related to cerebral spinal fluid levels of amyloid-beta42 andtau. To accomplish these aims we will identify 30 subjects who have declined over the prior four years to MCI and match them to 30 cognitively-stable subjects over the same interval. All will participate in a single study visit to include PiB,fMRI, ASL CBF, and a lumbar puncture for CSF collection. All will be subsequently followed annually by the Clinical Core of the Wisconsin ADRC to determine their cognitive status including decline to AD. The data collected in this project will be analyzed to determine the relationship of PiB with prior and subsequent cognitive decline and imaging markers of neural function using voxel-wise statistics. RELEVANCE (Seeinstructions): By the time a patient exhibits symptomatic dementia, devastating neural loss has already occurred. New methods for characterizing brain dysfunction are needed to facilitate early detection and early intervention. By applying advanced imaging to a well-characterized high-risk longitudinally-followed cohort, we are in a unique position to provide a greater understanding of early brain changes that occur in prodromal AD.

DESCRIPTION (provided by applicant): The theme of this ongoing R01 project is that risk factors for Alzheimer's disease (AD) are associated with presymptomatic changes in brain function that can be detected well in advance of symptom onset. Previously we studied an AD risk cohort known as the Wisconsin Registry for Alzheimer's Prevention (WRAP) and have shown functional MRI (fMRI) associated changes due to family history of AD and apolipoprotein E genotype. In this project we will investigate associations that may shed light on explanatory mechanisms of our previously observed findings by measuring amyloid burden using [C11]PiB, regional cerebral metabolic rate of glucose (rCMRglu) using [F18]fluoro-deoxyglucose (FDG) positron emission tomography (PET), neural function, rate of atrophy and ischemic lesion burden using MRI. Our prior study had a cross-sectional design; thus, a second major goal is to investigate the longitudinal course of brain change in a group of at risk subjects who were cognitively normal at baseline; some are now declining toward MCI. This proposed ongoing project represents a unique opportunity to comprehensively follow high-risk patients from cognitively normal to pre-MCI, and eventually to MCI and AD. Our studies are centered around three Specific Aims: A) to examine potential mechanisms (by way of association) of the BOLD risk effect we have observed in the prior funding period; B) To investigate longitudinal presymptomatic evolution of AD related brain changes and cognitive decline in people who are at high risk for AD, and determine whether PiB predicts decline in people at risk; C) Examine the direct relationship between brain changes and the best available known biomarkers consisting of CSF A242, t-tau and p-tau181. We will study 250 subjects longitudinally and use integrated path and regression analyses to accomplish these cross-sectional and longitudinal aims. PUBLIC HEALTH RELEVANCE: By the time a patient exhibits symptomatic dementia, devastating neural loss has already occurred, and the time window for most effective intervention already past. If a preclinical signal can be reliably observed and is predictive of cognitive decline, this will greatly strengthen the rationale for earlier intervention rather than waiting for symptomatic AD to present itself.

DESCRIPTION (provided by applicant): This proposal is to continue our studies of brain aging in rhesus macaques that have been calorically restricted since 1989 or 1994. We will investigate processes and mechanisms that may explain why caloric restriction (CR) exerts a salutary effect on the brain. The key hypothesis is that a metabolic shift occurs due to CR. In this study we will employ a powerful array of investigative tools: MRI to examine longitudinal change in brain morphology, FDG PET to examine glucose metabolic function, detailed cognitive and behavioral testing to examine executive, memory and fine motor dexterity, and on the animals that have died due to natural causes throughout the course of the long-running study, we will examine the brain in fine detail for neuropathologic features and for key indicators of metabolic changes. Aim 1 of this study examines longitudinal change on brain MRI including volumetric changes, and iron deposition changes. In addition we will employ newer scan sequences to obtain greater characterization of white and gray matter. Aim 2 will examine cognitive and motor function using an already existing touch screen response system. Aim 3 examines fine-grained neurohistopathology features including histological characterization of beta amyloid, tau, p-tau, synaptic density, and reactive astrocytes (GFAP). Aim 4 examines the central hypothesis that CR induces an upregulated state of energy metabolism in the brain assessed in vivo with PET FDG and in situ with assays of key metabolic regulators PGC-1a, SIRT1, mTOR, and AMPK. Finally Aim 5 provides an integrative Aim examining associative convergence among the various markers in the study that would lead us to conclude that CR retards the aging process in multiple domains. The significance of this project is quite high since body weight is a modifiable risk factor for disease. In order for CR or CR mimetics to be applied in humans it is critical to understand the effect of CR on the brain in a primate model. In this project we will attain a comprehensive and completely novel set of data on the long-term (18-23 years) effects of CR on the brain and behavior. The powerful combination of the metabolic and structural imaging, cognitive assessment and in-situ brain assays obtained in this multidisciplinary and translational project will lead to better understanding of the mechanisms by which CR affects the brain. PUBLIC HEALTH RELEVANCE: The elderly are the fastest growing segment of the U.S. population and this will only increase as baby boomers began turning 65 in 2011. Thus, functional, cognitive and physical declines associated with brain aging and age-related neuro-diseases will also rise, as will health care burden and costs required to treat these conditions. CR and/or CR-mimetics may be a viable means to prolong healthy brain function if it can be shown to be effective in a primates model of aging (which is the goal of this project), and ultimately in humans.

DESCRIPTION (provided by applicant): An estimated 5.3 million Americans currently have Alzheimer's disease (AD), and the number is expected to increase rapidly with the aging of the baby boom generation. There is a growing consensus that AD represents an advanced state of brain failure that is preceded by many years of pathological changes. The limited effectiveness of current therapies and the failure of recent clinical trials to identify effective therapies for D suggest that current treatments are intervening at a late stage of the disease when significant improvement is less likely. A major barrier to early intervention is our lack of knowledge about which biologic or environmental factors are associated with cognitive decline and eventually result in the clinical syndromes of mild cognitive impairment (MCI) or AD. The Wisconsin Registry for Alzheimer's Prevention (WRAP) is a longitudinal cohort study of 1,527 middle-aged persons with and without a family history of AD that is designed to identify genetic and environmental factors that are associated with the earliest signs of AD. The purpose of this research is to conduct cognitive, laboratory and neuroimaging assessments at 2-year intervals to identify the health, lifestyle and genetic risk factors that influence biomarker expression of A in persons who are currently asymptomatic, but are at an increased risk of developing the disease. This study will combine biomarker measurements collected over the past 10 years with biomarker, genetic and environmental data collected with this renewal to describe the neurobiology of preclinical AD. At the present time, the temporal course of biomarker changes in preclinical AD, and the factors that influence change during the decade before the development of clinical symptoms are unknown. This information is essential for the development of clinical trials evaluating disease-modifying therapies designed to delay the onset or slow the progression of AD.

NEUROIMAGING CORE (CORE G)- PROJECT SUMMARY A major focus of the Wisconsin ADRC research agenda is multi-disciplinary translational neuroscience research in humans with evidence of AD or with risk factors. In-vivo neuroimaging assessments and sophisticated analytic techniques are increasingly being utilized or sought by our investigators to gain further insights about the neurobiology of AD. Thus, a NeuroImaging Core, constituting an MRI service, PET service and Data Informatics and Analysis service is proposed whose purpose will be to provide necessary infrastructure and resources for investigators to successfully implement imaging outcomes in an efficient manner. This will reduce duplication of effort and resources, while at the same time maximizing the possibilities of collaboration and the leveraging of data across ADRC affiliated projects through standardization of a select subset of core scan sequences. Over the prior funding period we developed a highly successful imaging service within the Neuropathology and Biomarkers Core (Core D) with extensive utilization and growth that exceeded projections resulting in support for 41 funded projects, the majority were funded federally. This occurred largely by emphasizing support of new faculty and faculty who were not imaging experts per se, but nevertheless desired to enhance the significance and impact of their studies by incorporating state of the art imaging outcomes. The breadth and depth of Wisconsin ADRC supported and pending/planned imaging projects warrant more comprehensive infrastructure and service delivery to improve our ability to collaborate and enhance the scientific mission and impact of the Wisconsin ADRC. The Specific Aims of the Core are: Aim 1. Primary ADRC support) To provide imaging support for the ADRC cohorts (MRI) and support the MRI and amyloid imaging needs in Project 2. This includes support for data acquisition, data management, pipeline programming for image preprocessing, and data analysis. All newly enrolled ADRC participants are asked to have an MRI at baseline. All IMPACT and MCI participants will be invited to have a follow-up MRI scan every two years in conjunction with their regular ADRC visit; these cohorts were selected for repeat imaging because of their high local programmatic scientific value to many of our projects. Approximately 1170 MRI scans are projected for the ADRC alone. Aim 2) To provide imaging informatics support for all ADRC-affiliated projects including tools for cataloging and interacting with imaging data in a project specific manner. We will use these tools to continue to actively manage the many ADRC-affiliated neuroimaging projects that use our infrastructure. This includes management of the existing repository of 2300 MRI exams and 520 PET exams spanning 39+ projects, as well as an expected 3000 additional imaging exams during the renewal funding period. Aim 3: Methodology infrastructure: To make available the latest advanced PET and MRI imaging methods and data analysis capabilities in support of ADRC affiliated projects. We will assist projects obtain regular high quality data acquisition, continue to develop and deploy pipelines for preprocessing and also assist with the project-specific image analysis as needed. As new developments in imaging and analysis develop we will integrate these into our repertoire. The core will optimize imaging protocols, implement quality improvement processes, and evolve our pipelines to accommodate new approaches and sequences. Aim 4) Consultation and Training: Provide training to investigators and staff in the ADRC and University of Wisconsin-Madison campus at large on neuroimaging methods and analysis techniques pertaining to neuro- disorders. This includes regular seminars and formal courses as well as individual and small group instruction. We will also provide pre- and post-award consultation to investigators who are implementing/planning imaging studies, and assist in grant preparation, study design, and startup.

DESCRIPTION (provided by applicant): An estimated 5.3 million Americans currently have Alzheimer's disease (AD), and the number is expected to increase rapidly with the aging of the baby boom generation. There is a growing consensus that AD represents an advanced state of brain failure that is preceded by many years of pathological changes. The limited effectiveness of current therapies and the failure of recent clinical trials to identify effective therapies for D suggest that current treatments are intervening at a late stage of the disease when significant improvement is less likely. A major barrier to early intervention is our lack of knowledge about which biologic or environmental factors are associated with cognitive decline and eventually result in the clinical syndromes of mild cognitive impairment (MCI) or AD. The Wisconsin Registry for Alzheimer's Prevention (WRAP) is a longitudinal cohort study of 1,527 middle-aged persons with and without a family history of AD that is designed to identify genetic and environmental factors that are associated with the earliest signs of AD. The purpose of this research is to conduct cognitive, laboratory and neuroimaging assessments at 2-year intervals to identify the health, lifestyle and genetic risk factors that influence biomarker expression of A in persons who are currently asymptomatic, but are at an increased risk of developing the disease. This study will combine biomarker measurements collected over the past 10 years with biomarker, genetic and environmental data collected with this renewal to describe the neurobiology of preclinical AD. At the present time, the temporal course of biomarker changes in preclinical AD, and the factors that influence change during the decade before the development of clinical symptoms are unknown. This information is essential for the development of clinical trials evaluating disease-modifying therapies designed to delay the onset or slow the progression of AD.

The goal of this ongoing R01 is to chart the progression of pathobiologic markers of presymptomatic Alzheimer's Disease (AD) and their effect on neural function and cognition in a late-middle-aged cohort enriched with risk for AD. There is an appreciable gap in knowledge about the temporal disease course in this age range that this ongoing project has been directly addressing with serial multimodal imaging including amyloid, cerebrospinal fluid (CSF) collection, and serial cognitive measurement. In the next funding cycle we will add a new positron emission tomography (PET) imaging technique sensitive to fibrillar tau [F-18]THK5351 indexing neurofibrillary pathology. In the prior funding period we recruited 179 individuals from a registry of 1,545 people at risk for AD known as WRAP (Wisconsin Registry for Alzheimer's Prevention). We found that [C-11]PIB amyloid burden is detectable in 20% of people with parental history of AD at a mean age of 60. Baseline amyloid is more extensive in the presence of higher CSF total tau levels, and 2-year increases in PiB amyloid are significantly predicted by higher baseline CSF tau. The hypothesis for this renewal is that tau- related neurofibrillar pathology begins early (in accord with the neuropathology literature) in people at AD risk and its strategic spatial burden explains changes in amyloid, neural function and cognitive decline. Aim 1: To test the premise that amyloid burden is necessary but not sufficient to evoke preclinical cognitive change. We will examine effects of longitudinal amyloid and tau change on episodic memory trajectories over time in 235 at risk individuals including all subjects we previously enrolled and follow them over 2 years with advanced multimodal imaging and CSF. Aim 2: To assess the effects of tau and amyloid imaging on MRI and CSF indicators of neural injury and function. Aim 3: To develop a multimodal disease marker to maximize efficiency of clinical trials in preclinical AD. Following our work in creating tools for efficient clinical trials in MCI, we will extend these concepts to the pre-MCI phase of disease utilizing deep learning architectures with tau, amyloid and structural imaging inputs. We will also examine change over time in tau, amyloid and cognition as outcomes. As any of these features considered singularly may be affected by age, and as amyloid and tau may be `necessary but not sufficient' by themselves, a derived multimodal marker may have eventual clinical utility in enriching prevention trials with those most likely to progress, and increasing power to detect change attributable to preclinical interventions. Significance: Relative tau and amyloid imaging profiles have not been empirically established in the presymptomatic time frame and this information is urgently needed to identify incipient disease. No comparable studies exist regarding the evolution of tau and amyloid signal in the critical late-middle-age time frame of preclinical AD. This ongoing project represents a unique opportunity to examine the earliest determinants of AD progression, when treatments may be most meaningful.

Project Summary The ability to quantitatively characterize incipient Alzheimer's disease (AD) pathology in its preclinical stage is a critical step for early interventions involving disease modifying therapy and for designing efficient clinical trials to test therapy efficacy. This project focuses on deriving statistical image analysis methods for identifying the relationship of morphometric changes in this early stage with direct indicators of AD pathology (such as amyloid deposition) and various risk factors such as family history in late midlife adults who are cognitively healthy. The proposed analysis will be conducted on the largest preclinical AD cohort assembled to date and help elucidate how clinical-cognitive-imaging AD phenotypes emerge in asymptomatic individuals at risk for AD. The core of our analyses is a set of algorithms that allow operating directly on powerful ?manifold-valued? representations of morphometric change and consequently yield high sensitivity in picking up real but statistically weak multi-modal patterns of the disease process. Hypothesis: 1) Detecting precise associations between morphometric changes in preclinical AD subjects with amyloid burden and various risk factors is possible using new algorithms that work directly with representations of the Jacobians of the deformation fields derived from longitudinal imaging data. 2) Conducting such analyses on a large multi-site cohort of asymptomatic at-risk preclinical AD individuals with identified AD pathology will a) reveal important insights into early disease processes when dementia is 15+ years away, b) provide preclinical AD biomarkers and c) provide frameworks for predicting clinical endpoints at the level of individual subjects. Specific Aims: 1) To develop new algorithms for performing statistical analysis of manifold representations of morphometric changes concurrently with multiple covariates representing risk factors, AD pathology markers, and clinical/cognitive measures. 2) Conducting an end-to-end analysis of two independent preclinical AD cohorts to identify the relationship of morphometric changes with various predictors as well as test/retest validation across sites. 3) Analyzing the largest preclinical AD cohort to date for characterizing the relationship of the entire spectrum of predictors to clinical endpoints for late midlife individuals. 4) Providing industry- strength open-source software implementing the full suite of models, integrated with existing software toolboxes, for deployments on a workstation, a high throughput cluster or the cloud. Significance: This project will have a significant impact across three distinct areas of brain imaging research: 1) characterization of how clinical-cognitive-imaging AD phenotypes emerge in asymptomatic individuals in the earliest stages of AD, 2) rigorous algorithms for morphometric change analysis in neuroimaging and neuroscience, 3) open-source end-to-end implementations of the algorithms for use within the community.

NEUROIMAGING CORE PROJECT SUMMARY A major focus of the Wisconsin ADRC research agenda is multi-disciplinary translational neuroscience in humans with evidence of AD pathology with or without clinical features. In-vivo neuroimaging assessments, including new tau and amyloid imaging, and sophisticated analytic techniques are increasingly being utilized or sought by our investigators to gain further insights about the neurobiology of AD. The NeuroImaging Core was created to provide necessary infrastructure and resources for investigators to successfully implement imaging outcomes in an efficient manner. The Core reduces duplication of effort and resources, while at the same time maximizing the possibilities of collaboration and the leveraging of data across ADRC affiliated projects through standardization of select scan modalities/sequences. The Core has experienced extensive utilization and growth that exceeded projections resulting in support for over 45 funded projects, the majority were funded federally. This occurred largely by emphasizing support of new faculty and faculty who were not imaging experts per se, but nevertheless desired to enhance the significance and impact of their studies by incorporating state of the art imaging outcomes. The Core now proposes to add [F18]THK5351 tau imaging and [C11]PiB amyloid PET imaging for 300 participants. The original Specific Aims are: 1) To provide imaging support for the ADRC cohorts (MRI) and support the imaging needs in Project 2. 2) To provide imaging informatics support for ADRC-affiliated projects including tools for cataloging and interacting with imaging data in a project specific manner. 3) Make available the latest advanced PET and MRI imaging methods and data analysis capabilities to ADRC affiliated projects. 4) Provide training to investigators and staff in the ADRC and University at large on neuroimaging methods and analysis techniques pertaining to neuro-disorders. We also provide pre- and post-award consultation to investigators who are implementing/planning imaging studies, and assist in grant preparation, study design, and startup. The major goals of this supplemental proposal are to 1) Describe the spatial patterns of tau and amyloid across stages of AD, and identify those spatial pre- dementia disease profiles most associated with subsequent decline. 2) Determine the concordance between CSF metrics of AD pathology and tau and amyloid imaging. 3) To completely integrate amyloid and tau imaging information into our center's infrastructure, process, and data sharing initiatives. This award will significantly enhance the overall impact of the center by establishing crucial tau and amyloid molecular imaging endophenotypes. The field has suffered from a lack of clarity on preclinical AD, because we have not had the tools to spatially characterize amyloid plaque and NFTs. This project represents a unique opportunity to examine the earliest determinants of AD progression, which is a central scientific theme of the Wisconsin ADRC. The unique data collected will be made available immediately to the research community.

ABSTRACT The Wisconsin Registry for Alzheimer?s Prevention (WRAP) is a longitudinal observational cohort study of 1,561 middle-aged persons with and without a parental family history of AD. The study conducts cognitive, laboratory and now molecular neuroimaging assessments at 2-year intervals to identify the health, lifestyle and genetic risk factors that influence biomarker expression of AD in persons who are currently asymptomatic, but are at an increased risk of developing the disease. This study will combine the data collected over the past 15 years with new biomarker, cognitive, lifestyle and laboratory data collected with this renewal to establish longitudinal trajectories and describe the neurobiology of preclinical AD. Currently the temporal course of preclinical AD, and the factors that influence change during the decade before the development of clinical symptoms are unknown. This information is essential for the development of clinical trials evaluating disease- modifying therapies designed to delay the onset or slow the progression of AD. In the prior funding period we: Began to develop and apply new approaches to identify mild cognitive decline using internal robust norms; Developed polygenic risk scores associated with health and cognitive phenotypes; Demonstrated that lifestyle and health features in midlife impact overall brain health and specific AD pathophysiologic markers and thus may confer resilience to cognitive decline and AD pathology; Demonstrated differential rates of cognitive decline by AD biomarker pathology status in a subset of WRAP using cerebrospinal fluid (CSF) and/or imaging markers of amyloid, tau, neurodegeneration and vascular disease; and established participation in a consortium of several adult children cohorts, which has enhanced data sharing and will improve rigorousness in research using confirmatory methodologies across large cohorts. WRAP is now uniquely positioned to address major knowledge gaps in the next funding period: A) develop and validate longitudinal change standards for identifying when an individual?s cognitive decline exceeds the pace of normal aging; B) identify modifiable and nonmodifiable characteristics that predict midlife cognitive trajectories and development of abnormal cognition (e.g., MCI or dementia); C) understand the early effects of the two most common diseases causing cognitive dysfunction in this age group?1) the dual AD pathologies of amyloid and tau (via CSF Ab42 and ptau181, and/or molecular PET imaging of amyloid with [C-11]PiB and tau with [F-18]MK6240) and 2) neurovascular pathology (with novel measures of cerebral arterial and venous pulsatility and flow), on domain- specific cognitive trajectories and abnormal cognitive outcomes; and D) elucidate the effect of modifiable and nonmodifiable features on the relationship between AD and vascular pathology and cognition.

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.

PROJECT SUMMARY- BIOMARKER CORE (CORE G) The Biomarker Core (BMC) of the Wisconsin Alzheimer's Disease Research Center (ADRC) represents the capability and infrastructure for peering into the brain in vivo to obtain biological markers of Alzheimer's disease (AD) and related disorders and non-disease-specific qualities characterizing brain health and resilience. Since the pre-clinical time frame of AD is a major emphasis of the ADRC, and since it is increasingly understood that AD pathology occurs well before its symptoms, the charge of this core is to provide the necessary capabilities, tools, and infrastructure to investigators to characterize as accurately as possible the early in-vivo changes of AD, effect of risk and resilience factors, and effect of prevention strategies on relevant biomarkers. The core will focus on collecting, quality checking, and curating several types of AD-relevant biomarkers including a) markers indicative of AD - defined by amyloid plaques and neurofibrillary tangles, and ascertainable by molecular PET imaging or cerebrospinal fluid (CSF) assays; b) markers of cerebrovascular diseases - the second most common etiology (or etiologies) of cognitive decline and ascertainable by new MRI methods; c) markers of other neurodegenerative diseases as they become available via CSF or PET; and d) markers of general brain health including synaptic density, neuronal injury, atrophy, connectivity, inflammation, and blood flow that are possible through PET, MRI and CSF modalities. To meet these goals, we will accomplish the following aims: Aim 1: Obtain biological markers of AD's hallmark neuropathological features - amyloid plaques and neurofibrillary tangles with CSF and/or molecular PET imaging. Aim 2: Collect biomarkers of concomitant features, such as vascular disease, inflammation, and neuronal death. Aim 3: Develop method for interpreting biomarker readouts, particularly for Amyloid (A), tau (T) and neurodegeneration (N). Aim 4: Support ADRC investigators with infrastructure and analytic support. Aim 5: Share images, fluid, and derived data with the National Alzheimer's Coordinating Center (NACC), local investigators, and other qualified investigators throughout the world. Aim 6: Expand the Center's biomarker capability, including a) adopting new methods and modalities in this fast-changing field, and b) for harmonizing previously collected data or multi-site data with current or future collection methods. The BMC will work interactively with the other ADRC cores to serve the needs of the ADRC investigators as efficiently as possible and deliver high quality data to NACC and other users so we, as a field, can come to answers faster in detecting and intervening effectively in AD.