Thomas J. Grabowski - US grants

Studies in neurological patients with brain lesions suggest that the normal process of retrieving words which denote concrete entities depends in part on multiple regions of the left cerebral hemisphere, located outside classic language areas, in higher-order association cortices. The findings also indicate that, at the level of large-scale systems, there appears to be an intriguing and principled relationship between the anatomical region and the kind of item being named. These findings open the possibility of investigating further the nature of the lexicon and its neural underpinnings, and that is the aim of this project, focused on the issue of lexical retrieval pertaining to concrete entities. We will test three principal hypotheses in a series of [150]H2O PET experiments conducted in 60 normal native English speaking adults. We will begin by testing the idea that the retrieval of words denoting concrete entities pertaining to diverse conceptual categories depends on anatomically separable regions. We will then test the idea that such regions are the same regardless of the sensory mode (e.g., visual [pictures] versus auditory [associated sounds]) of presentation of the concrete entities to be named. Finally, we will test the idea that the same regions operate not only for, retrieval of words, given the concepts, but also for the retrieval of concepts, given the words. In addition to contributing to a better understanding of the neural basis of language processing, the findings are also likely to contribute to the understanding of the neural architectures which subserve cognition, at large-scale systems level, and will have a direct application in the diagnosis and management of disorders of communication and memory.

[unreadable] DESCRIPTION (provided by applicant): FMRI has become a tool for mapping brain function because of its high spatial and temporal resolution and noninvasiveness. In addition, it is applicable to single subjects and thus could play a role in the clinical realm. These properties are appealing for use in clinical populations, for research, treatment and disease monitoring. However, in contrast to normal volunteers, clinical populations are more likely to move, more likely to fail to conform to the task and are less tolerant to long imaging sessions. Thus, these subjects may generate less data and of lower quality than normal making it more difficult to detect the low signal changes inherent in BOLD contrast fMRI. In addition, qualified patients are more difficult to come by than normal making it critical to insure that useful data has been acquired. Timely feedback from results is also necessary for treatment planning. Thus, we have set out to develop a clinical competent fMRI system that is more flexible and more efficient that existing systems. The goal of the system is to provide time efficient estimation of activation in the presence of multiple concurrent effects, track processes that lead to confounding effects (motion, speech, cardiac pulsatility, respiration, etc) and adapt the processing to the subject's performance rather than the expected task. Major components of this system such as the timeaware architecture, measurement and filtering of physiologic data (speech, cardiac, respiration, skin conductance) and real-time multiple linear regression have been completed. We will extend the system by incorporatingdetection of and correction for motion, modeling of physiologic noise and development of real-time speech detection for use in a paradigm where both the timing of paradigm delivery and processing of the data is driven by the subject's response.

[unreadable] DESCRIPTION (provided by applicant): Event-related fMRI is appealing for augmenting diagnosis, planning treatment, and monitoring course in clinical populations. However, fMRI must be able to accommodate variable performance success, failure to conform to task protocol, and reduced tolerance for the physical demands of an imaging session. We propose to exploit a "time aware" data acquisition and processing system to implement an interactive approach to fMRI, tailored to individual subject performance. The system allows real-time paradigm control featuring interaction of the subject with an examiner. The paradigm chosen for proof of concept is cue-facilitated word retrieval, in which aphasics perform naming to visual confrontation, and are given phonemic cues when they fail to name an item. The software architecture permits generation of statistical contrasts that take account of actual performance, in real time, and incremental monitoring of the statistical quality of the data. The goal is to generate standardized results for longitudinal studies of speech production in aphasia. We will evaluate the stability of these measures in chronic aphasics and in normal subjects. The results will provide a basis for assessing feasibility and power of future applications of fMRI in aphasia rehabilitation. The tools developed here will be made available to the research community. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Studies of normal subjects and neurological patients show that the integrity of the left inferior and polar temporal cortex is critical to normal lexical-semantic processes, and that the anatomic substrates of these processes are partially segregated by conceptual category. We will probe the role of these regions in lexical processing using two empirical effects (the semantic interference and word frequency effects) that arise from differential demands on lexical selection and phonological code activation, respectively. The physiologic correlates of these effects, measured with functional magnetic resonance imaging (fMRI), will illuminate the role of the left extrasylvian temporal lobe in normal lexical processing, and clarify whether neural regions specifically involved in lexical processing are segregated by conceptual category. Finally, we will take advantage of a unique Patient Registry including subjects with acquired left temporal lobe damage and anomia. We will examine the correlates of the semantic interference and word frequency effects in these subjects using fMRI techniques that isolate the correlates of successful naming trials. The results will clarify the neural basis for residual lexical retrieval after damage to preferred neural systems. The studies undertaken here address wider issues of plasticity, recovery, and the interplay of systems related to language and memory, and will promote adaptation of fMRI imaging technology to language-impaired patients, in whom it may be used to track the course of disease and recovery, as well as responses to treatment.

DESCRIPTION (provided by applicant): The lesion method, which identifies consistent relationships between sites of brain damage and acquired impairments of cognition and behavior, continues to be an indispensable approach in neuroscience for identifying the neural basis of higher function. The overall goal of this project is to put the lesion method on a rigorous, quantitative footing, and to determine and extend its limits, especially with respect to the specificity and interpretability of localization. We will introduce methods for formally integrating connectivity information, from diffusion tensor imaging, into group-level voxel-based lesion-deficit analyses. We will investigate the validity, reliability, and anatomic accuracy of existing and new methods, with particular attention to the impact of the subject group, non-uniform lesion coverage, and the different roles of gray and white matter damage. We will validate voxel-based statistical methods for lesion studies in two ways: 1) with simulations based on a large set of real brain lesions, that capture the effects of the complex structure of the natural lesion sample;and 2) in a well characterized database of lesions in the retinotopically organized visual system, for which there will be multispectral MRI data and extensive functional assessment (retinotopic fMRI, multifocal visual evoked potentials, quantitative visual fields, and metabolic PET data). Another overarching goal is to determine best practices for the lesion method, including identification of the optimal (efficient, sensitive, valid) forms of analysis and generation of resources for evaluating future improvements in the methods. Finally, we will disseminate methods, software, validation data sets, and performance benchmarks generated in this Project to the brain mapping community. The work proposed here will enable the lesion method to be used with unprecedented confidence to identify the essential components of neural systems for normal cognition and behavior. PUBLIC HEALTH RELEVANCE Studying the behavioral and cognitive consequences of focal brain damage provides information about the brain basis of cognitive abilities that can be gained from no other source. The proposed work will help establish best practices for the lesion method, making it easier to study and understand the impairments that result from stroke and other neurologic diseases.

DESCRIPTION (provided by applicant): The objective of the project is to accelerate discovery and a new program for multidisciplinary interaction across cognitive neuroscience, human neuroimaging and medicine at the University of Washington (UW). The project uses the infrastructure of the Integrated Brain Imaging Center to partner with existing established Centers and groups whose scientific programs can immediately investigate basic and translational questions in neurodegenerative disease, brain aging, epilepsy, and rehabilitation of paralysis with new systems neuroimaging approaches. The UW is a premier biomedical research institution and a particularly strong institutional setting for using imaging to elucidate biological mechanisms and biomarkers of disease, and for conducting translational studies. The theme of this proposal is the application of emerging systems neuroimaging approaches to key basic problems in neurologic disease pathophysiology, and key translational settings. One project cluster centers around novel uses of systems neuroimaging and MR spectroscopy to understand mechanisms in degenerative disease (Alzheimer disease, Parkinson disease). One goal is to understand and detect the early vulnerability of the default mode network in Alzheimer disease. For this work, we will use two subject groups: well characterized mild cognitive impairment, which often reflects incipient Alzheimer disease, and aging individuals who have been rigorously stratified with respect to their cognitive trajectories in midlife and old age. A second goal is to understand cognitive impairments in Parkinson disease, which arise in the setting of disturbances primarily in ascending systems. A third goal is understanding factors governing prognosis for language and other cognitive impairments after epilepsy surgery. A second cluster project cluster is driven by outstanding UW expertise in human neurophysiology, electrophysiology and sensorimotor engineering, and focuses on integration of imaging with electrophysiology to understand the neurophysiologic dynamics of clinically relevant large scale systems (default mode network, dorsal attentional network), and to improve brain-computer interfaces for rehabilitation of paralysis. For each collaboration we propose an initial high impact study and future directions. PUBLIC HEALTH RELEVANCE: This project will develop new collaborative scientific teams at the University of Washington to work in partnership with the Integrated Brain Imaging Center and apply new imaging methods to degenerative dementia, brain aging, epilepsy, and rehabilitation of paralysis. One cluster of projects will investigate the biological basis of early Alzheimer disease, disorders of attention and concentration in Parkinson disease, and language problems in epilepsy surgery. A second cluster of projects will used EEG and imaging to understand signaling in brain systems and how to extract signals for controlling brain-computer interfaces. )

The objective of this award is to develop a computational framework for identifying the critical network topology of brain connectivity in neuroimaging data, specifically functional magnetic resonance imaging (fMRI). In this framework, network optimization modeling and mathematical programming algorithms will be employed to characterize connectivity patterns in fMRI data from different brain regions. Machine learning techniques will be employed to construct a pattern recognition model used to detect biomarkers and predict the brain disease conditions (i.e., abnormals vs. controls). An information-theoretic approach will be used to select the most informative brain regions to improve the generalizability and to increase the accuracy of the diagnosis prediction model.

If successful, the results of this research will lead to improvements in efficiency and efficacy of brain functional connectivity modeling and new developments of optimization methods for handling large-scale spatio-temporal data. The developed computational framework will be extremely useful for neuroscientists and neurologists to identify abnormal functional connectivity in the brain and to gain a greater understanding of the brain function. The framework will be employed and tested as a novel biomarker for differential diagnoses of brain disorders. Alzheimer?s disease (AD), autism spectrum disorder (ASD), and Parkinson?s disease (PD) will be the case points in this project to test if our computational framework is a sensitive enough tool to detect alterations in brain connectivity associated with brain disorders. Accurate diagnosis can substantially extend a patient?s lifespan and some treatments have different outcomes at different disease stages. Additionally, the developed computational framework can be applied to other real-life large-scale spatio-temporal data that arise in other research areas such as manufacturing, medicine, bioinformatics, neuroscience, finance, and geosciences.

DESCRIPTION (provided by applicant): This is an application to fund travel awards for trainees to attend the 2013 annual meeting of the Organization for Human Brain Mapping (www.humanbrainmapping.org), to be held in Seattle, WA, and for which I am the Local Organizing Committee Chair and a Program Committee member. The Organization for Human Brain Mapping (OHBM) is the primary international organization dedicated to noninvasive neuroimaging research and the functional organization of the human brain, and its Annual Meeting is regarded as a premier venue for the integration of innovative brain imaging methods and cognitive neuroscience. It is primarily an educational forum for the exchange of up-to-the-minute and groundbreaking research in this area. The meeting will gather more than 2500 scientists, working with all brain imaging modalities. The R13 proposal is for the purpose of supporting travel awards for trainees who are first authors on the most highly ranked abstracts. Trainees include medical students, graduate students, residents in clinical neuroscience (neurology, psychiatry, neurosurgery) and post-doctoral fellows in fields related to human brain mapping. Travel awards have been a regular and effective feature of this meeting. In past years, awardees have typically given more than 1/3 of all oral presentations at the annual meeting. Recent past meetings of OHBM were in: Toronto Canada, 2005; Florence Italy, 2006; Melbourne Australia 2007; Chicago, Ill 2008; San Francisco CA 2009, Barcelona Spain 2010, Quebec City, Canada 2011, and Beijing China, 2012. This meeting has relevance for the NINDS in the following ways. First, virtually every presentation relates to the function and structure of the human brain, in both health and disease. Better understanding of the organization of the human brain is directly relevant to treating neurological disease. Moreover the use of noninvasive imaging methods is increasingly important to translational investigation in clinical neuroscience. The program will highlight emerging structural and functional MRI imaging approaches to tracking brain systems organization, connectivity and plasticity, and imaging genetics. By bringing together scientists interested in basic systems neuroscience, noninvasive imaging technology, and neurologic medicine, the meeting affords an outstanding interdisciplinary, and international, educational and scientific experience for trainees interested in the organization of the human brain.

PROJECT 3 - ABSTRACT Alzheimer's disease (AD) pathologic change develops in an orderly anatomic sequence but the level of pathologic change varies among and within preclinical and dementia stages of AD. Moreover, multiple pathological processes, primarily AD and cerebral microvascular disease, varyingly conspire to cause memory problems and dementia. Although very successful and critically important in research settings, and likely to remain part of tiered assessment protocols, CSF biomarkers and PET imaging are likely to encounter barriers as initial screens or serial treatment monitors for millions of people. We seek to address this anticipated barrier to health care effectiveness by developing functional MRI (fMRI)-based approaches that are informative in preclinical stages of dementia. Functional connectivity fMRI (fcMRI) studies show altered functional connectivity in the default mode network (DMN) as a marker of preclinical AD, but it is not known how specific the changes are to AD, or how predictive DMN functional connectivity is of memory decline or AD progression. Moreover, current data derive mostly from research cohorts and have not focused on the likely large contribution from cerebral microvascular disease as indicated by autopsy. Indeed, the Adult Changes in Thought (ACT) study, a community-based study of brain aging and incident dementia in the Seattle area, has demonstrated in large autopsy studies that the population-attributable risk of dementia in ACT was 45% from AD and 33% from cerebral microvascular disease. Using a cohort of ACT participants that is part of the UW ADRC Clinical Core (ACT-Plus), we will evaluate the specificity of DMN functional connectivity changes in preclinical AD, as well as MRI measures of the impact of cerebral microvascular disease. Specific Aim 1. By determining novel fcMRI correlates of preclinical AD as defined by CSF biomarkers in participants without dementia, we will test the hypothesis that functional connectivity measures can discriminate individuals with CSF profiles of AD from those without, and will compare functional connectivity measures to commonly used parameters including hippocampal volume and cortical thickness, as well as to proxy measures of regional cerebral metabolism. Specific Aim 2. By determining novel fcMRI correlates of cognitive impairment and decline in individuals without dementia at baseline, and analyzing them with respect to established and experimental leading measures of cognitive decline, we will test the hypothesis that dynamic functional connectivity, using an approach we developed, is a more sensitive and informative biomarker than existing imaging approaches or stationary functional connectivity for identifying present and predicting future cognitive impairment. When successfully completed, this Project will have determined the utility of novel fMRI approaches to brain aging and preclinical AD in a sample that more closely reflects the ultimate target population.

PROJECT 2 (GRABOWSKI): ABSTRACT MR-based systems imaging of PD-related cognitive impairment and inherited variants in APOE or GBA. Emerging evidence indicates that variability in cognitive impairment in Parkinson Disease (PD) in part reflects fundamental biological heterogeneity. We hypothesize that the difference is mediated by differential compromise of intrinsic cortical systems, and that functional connectivity fMRI will demonstrate specific systems-level alternations in neurophysiologic relationships that vary depending upon the specific molecular driver of disease. The findings that APOE ?4 and GBA variants are robust genetic predictors of dementia in PD, and that they may modify the profile of the cognitive impairment, justify a focus on these genetically- defined groups. We will apply novel dynamic and established functional connectivity fMRI methods in APOE ?4 and GBA variant carriers, and healthy comparison subjects. These analyses will be conducted in the practical dopaminergic OFF state. We expect that APOE ?4 disproportionately affects memory-related systems including the parietal and temporal components of the default mode network, while GBA variants accelerate pathological effects on dopaminergic targets in the mesial frontal wall and the basal ganglia, and their functionally integrated lateral frontoparietal networks. Using the same genetically-defined participants, we will test the hypothesis that dynamic functional connectivity and network kernel analyses, approaches we have developed for both resting and task state fMRI, can sensitively predict the development and progression of cognitive impairment in PD. These analyses will be conducted with fMRI data taken ON dopaminergic medication. We will also evaluate whether functional connectivity predicting cognitive diagnosis and/or progression are invariant to dopaminergic replacement status. Finally we will investigate profiles of cortical systems change associated with biomarkers of different pathophysiologic mechanisms of cognitive impairment in PD. Our preliminary studies establish that omnibus and regional measures of system disruption increase in proportion to the (pathologic) reduction of ?-synuclein or A?42 concentration in CSF. We will replicate this finding in a separate group of PD participants and go on to analyze whether omnibus and regional measures of system disruption mediate the relationship between CSF biomarkers of cortical pathology and cognition. In secondary analyses informed by the other Projects in this Center, we will extend this novel approach to other markers of disease mechanisms: SAI (a measure of cholinergic tone, Project 3) and quantitative molecular pathology, Project 1. The new knowledge gained in this Project will be foundational to precision medicine for different molecular drivers of cognitive impairment in PD.

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a major global public health threat for which we have very limited responses. Solutions will come only though research. The AD Centers (ADC) Program is a leading effort by the US under the responsibility of the National Institute on Aging (NIA) to develop solutions for AD. The central research strategy of NIA is Seeking the Earliest Interventions. The University of Washington (UW) ADC is one of fifteen AD Research Centers (ADRCs), and we contribute uniquely to this premier program through our vision of precision medicine for AD: comprehensive classification of an individual's risk; surveillance with accurate and early detection of patho-physiologic processes while still preclinical; and interventions tailored to an individual's molecular drivers of disease All components of UW ADRC are focused on this vision and our 5-year mission of creating the knowledge and tools needed to advance preclinical biomarkers and develop experimental therapeutics, while also enthusiastically participating in (inter)national collaborations in clinicl trials, AD genetics, brain aging, diagnostics, and outreach to disparities populations. UW ADRC balances stability with innovation. Stability in the leadership of our required Cores assures highest quality outcomes for the ADC Program. Innovation draws on the vast resources of UW to develop three new Projects, a new Satellite Core, and a new component of our Clinical Core to fuel discoveries. UW ADRC resonates strongly with the three principles of National Plan to Address Alzheimer's Disease, especially its third: transform the way we approach AD. Successful completion of our 5-year mission will hasten this transformation to the right intervention for the right person at the right time - precision medicine for AD.

ABSTRACT (modified form Parent Proposal) Alzheimer's disease (AD) is a major public health threat. Along with better diagnostic tools and treatments, a pressing need exists for more information on AD in diverse populations. The AD Centers Program is a landmark effort to develop solutions sponsored by the National Institute on Aging. The University of Washington AD Research Center will contribute to this Program through our vision of precision medicine for AD, namely, comprehensive classification of an individual's risk; early detection of pathophysiologic processes, especially while manifestations are preclinical; and interventions tailored to an individual's molecular drivers of disease. Our Cores and Projects are focused on this vision, as well as our 5-year mission to create the requisite knowledge and tools to advance research on preclinical biomarkers and experimental therapeutics. We will collaborate on a wide range of topics pertinent to AD such as clinical trials, genetics, brain aging, diagnostics, and outreach to disparities populations. The AD Research Center balances stability with innovation. Stability in the leadership of the Cores assures that we will achieve the best outcomes. Innovation draws on the vast resources of the University and our partners to develop 3 new Projects, a new Satellite Core, and a new component of our Clinical Core to fuel discoveries. The Satellite Core is recruiting 100 American Indians from the Southern Plains (Oklahoma) who participated in the Strong Heart Stroke Study, an enormous effort that administered cognitive tests and MRIs in 1,033 American Indians from 12 communities in 3 states. Our Specific Aims are to 1) Enlarge the sample size of the Satellite Core by initiating recruitment in 2 other field sites that participated in the Strong Heart Stroke Study: the Southwest and Southern Plains field sites; 2) Use the same cognitive function and structural MRI protocols to re-examine participants and document changes over time; 3) Collaborate with the Clinical Core to assign cognitive diagnoses and collect samples for future research; 4) Work with the Outreach, Recruitment, and Education Core to raise awareness of AD and provide education to AIs; and 5) Enhance the overall University of Washington AD Research Center and AD Centers Program by pursuing an unparalleled opportunity to advance AD research with a dramatically understudied and underserved population. These efforts resonate strongly with the principles of National Plan to Address Alzheimer's Disease to ?transform the way we approach AD? and the equally important goal of increasing the diversity and representativeness of populations in the AD Centers Program. Successful completion of our Center's 5-year mission will hasten the transformation to offer the right intervention for the right person (including American Indians) at the right time.

Cognitive abilities such as memory and attention are supported by specialized brain networks made up of specific patches of the cerebral cortex called cortical fields. Cortical fields are thought to be anatomically distinct, with neurons connecting between them. Until recently, cortical fields could only be identified after death, by microscopic examination of autopsy brain tissue. Their number, function, and location in individual brains have been unknown. Now however, Magnetic resonance imaging (MRI) can detect neural activity in the cerebral cortex with relatively high resolution, and diffusion MRI (dMRI) can detect white-matter fibers that connect brain regions. Networks made up of cortical fields become active when individuals accomplish a task, and also spontaneously, when the mind is "at rest." We will use all this information to delineate the specific cortical fields in individual brains as well as patterns of connectivity between them. Cortical fields vary in size up to threefold from person to person, and we intend to study whether this variability is reflected in individual abilities or susceptibilities. The overarching goal is to test the idea that the size of cortical fields matters to the strength and vulnerability of brain networks. We use the MRI approaches outlined above to measure network strength, and we temporarily disrupt networks with transcranial magnetic stimulation (TMS) to assess network vulnerability. The work is important because it will allow us to better understand the reasons people have variable mental abilities.

The project focuses on two established brain networks: the default mode network (DMN) and the lateral frontoparietal network (LFPN), which have components in the inferior parietal lobes. Connectivity-based parcellation distinguishes two angular gyrus fields, PgA and PgP, which are nodes within the LFPN and DMN networks, respectively. We will use dMRI to parcellate the cortex using a probabilistic parcel atlas of the Human Connectome Project data as prior information. Using functional connectivity, we will evaluate if PgP belongs to DMN, and PgA to LFPN. We will also analyze the strength of functional connectivity across network nodes in resting state fMRI using the dual-regression approach and ascertain the degree to which cortical field size variability across subjects is correlated with network-size variability. We will evaluate whether connectivity-defined cortical parcels maximize fMRI task contrast and show higher levels of EEG gamma and theta activities. Finally we relate the variability of cortical parcel size to task vulnerability by applying transcranial magnetic stimulations (TMS) to PgP and PgA. We hypothesize that low-frequency repetitive TMS (rTMS) over PgA will impair task performance on a working memory task and on a flanker task, and more so for individuals with smaller surface area of PgA. Furthermore, because endogenous reduction of DMN activity is associated with successful deployment of attentional resources, we also hypothesize that rTMS over DMN nodes will positively affect performance on the same tasks, and more so for individuals with smaller surface areas of these nodes. This project is funded by Integrative Strategies for Understanding Neural and Cognitive Systems (NSF-NCS), a multidisciplinary program jointly supported by the Directorates for Computer and Information Science and Engineering (CISE), Education and Human Resources (EHR), Engineering (ENG), and Social, Behavioral, and Economic Sciences (SBE).

PROJECT SUMMARY   The overall purpose of this proposal is to upgrade a research-­dedicated, Philips 3T Achieva MRI scanner at  the University of Washington Medical Center to support state of the art signal acquisition. The upgrade will  incorporate a digital signal transmission system, a multi-­transmit system, and the Philips implementation of  simultaneous multislice (multi-­band) acquisition.  This upgrade will enable (i) a 15-­40% increase in signal-­to-­ noise ratio, (ii) increased RF homogeneity and low RF power deposition, and (iii) high spatial and temporal  resolution for functional and anatomical imaging.  Extensive neuroimaging research is conducted at this  scanner, especially with functional MRI and supporting modalities, Research activity also encompasses  cardiac MRI, fetal imaging, coil design and optimization, and advanced spectroscopy. The proposed upgrade  will benefit essentially all neuroimaging research, in humans and animals alike, through a fundamental  improvement in the fidelity (signal to noise characteristics) of the instrument.  Imaging science has become  simply critical, and increasingly so, for understanding biological systems, detecting and controlling disease,  and translating basic discovery. The Diagnostic Imaging Science Center (DISC) and the closely partnered  Integrated Brain Imaging Center (IBIC) are the necessary and primary neuroimaging resources for NIH-­funded  investigators at the University of Washington, who are interested in brain organization and function in health  and disease. The upgrade will enable them to advance multimodal (functional and diffusion connectivity,  vascular and structural MRI) imaging methods in clinical populations, including children and elders with  neurodegenerative diseases. Multiband acquisition will support superior spatiotemporal resolution in fMRI,  make multi-­shell diffusion MRI feasible routinely, and enable Human Connectome Project-­ compatible data  acquisition protocols that are becoming a standard requirement for some cognitive neuroscience programs.  The scanner is housed at DISC and maintained under the supervision of expert MRI physicists and  technologists. We have outlined a detailed financial, technical, and safety plan for the smooth operation of the  scanner. Institutional commitment includes the differential costs required in excess of the grant award to  complete this upgrade.   

Abstract The Administrative Core provides the overarching leadership that sets the tone, philosophy, and scientific vision of the University of Washington Alzheimer's Disease Research Center (UW ADRC) for the next 5 years and beyond. It ensures that the UW ADRC supports the needs of UW, regional, and national Alzheimer's disease and related dementias (ADRD) investigators and their projects. It does so by providing expertise and well-developed research resources. We enable clinical research which might not otherwise be possible to accomplish due to the time, expense, and expertise it takes to obtain well-characterized and deeply phenotyped human participants and the biospecimens obtained from them. The Core administers a vibrant developmental research project program, focused on young investigators, and closely linked to the Research Education Component. The Administrative Core situates and advocates for the ADRC in its overall institutional setting, and optimizes its impact locally, at our university, within the Alzheimer's Disease Centers Program, and within the broader community of investigators focused on developing solutions for ADRD. The Core also fosters a timely and visionary collaboration with Partnerships for Native Health (P4NH) to build research resources for investigating ADRD in American Indians and Alaska natives.

Cognitive impairment is the most disabling non-motor feature of Parkinson Disease (PD) and causes the greatest degree of caregiver distress. The large majority of patients with PD will eventually suffer cognitive impairment, and although treatment of motor parkinsonism has improved, cognitive impairment has proven more difficult to treat. When cognitive impairment appears, it tends to have a profile of more affected and less affected domains that suggests differential regional cortical involvement. Measurement of cognitive performance through neuropsychological tests tells us what functions are impaired but not why. A better understanding of the causes of impairment would help identify therapeutic targets for cognitive symptoms. This would lay the groundwork for developing biomarkers of brain (patho)physiology that would advance the goal of precision medicine for treatment of PD. This project exploits the discovery that regional spontaneous cortical activity measured by fMRI at rest has a spatial structure that includes the same cognitive networks identified during tasks. These ?intrinsic networks? are altered in PD and many other diseases, providing an important physiological connection between brain structure and cognitive function. We have developed fMRI-based methods for sensitively quantifying differences in intrinsic networks and shown that networks differ in people with PD and controls. Although fMRI has good spatial resolution, because of hemodynamic delay it lacks temporal resolution. Therefore, differences in networks observed in PD may reflect differences in timing, or dynamics, that we cannot measure at the temporal resolution of fMRI. We want to integrate our innovative framework with a complementary modality, electroencephalography (EEG), which helps us to distinguish differences in spatial extent and timing of networks. Recently, we have shown a systematic relationship between intrinsic network activity and the time course of an attention network task that is different in PD and controls. This link between intrinsic networks and task-related activity allows us to ask how intrinsic network activity relates to cognition in PD. We hypothesize that alterations to networks that support attention and memory are specifically related to cognitive performance in these domains in PD, and that temporal information from EEG will help to resolve this. We will test this hypothesis by simultaneously acquiring fMRI data (for high spatial localization of network structure) and electroencephalography (EEG) data (for high temporal resolution) in subjects with PD and controls, as we pursue the following specific aims: (1) Analyze and compare intrinsic activity from PD and controls obtained at rest. (2) Analyze and compare intrinsic activity from PD and controls during a covert visuospatial attention task with and without a memory load. (3) Analyze trajectories of longitudinal change.

Abstract The Imaging and Biomarker (IB) Core will characterize participants in the Clinical Core through neuroimaging and fluid biomarker analysis, in conformity with prevailing standards. A further focus is to rigorously describe topographic phenotypes of the participants and to link this information to cognitive, fluid biomarker, genetic, and neuropathologic data generated by the Center. The Core will also provide an information architecture and consulting expertise to represent the imaging data to ADRC-affiliated studies and investigators. Many UW ADRC-affiliated studies require human subjects who are well-characterized with imaging and fluid biomarkers. MRI imaging will be obtained on all normal cognition, MCI, and mild AD participants in the Clinical and Native Research and Resource (NRRC) Cores. We will characterize our Clinical Core cohort with A|T|N classification, primarily with CSF biomarkers (A, T) and MRI (N) imaging. The IB Core will coordinate PET scans in ADRC affiliate projects or co-enroll affiliate subjects in the Clinical Core to ensure Clinical Core subjects have PET scanning performed. We provide expertise in planning and analyzing PET molecular imaging studies. Affiliated studies are investigating specific candidate mechanisms of AD, as well as whether, and why, different pathological mechanisms inherent in AD have differing patterns of impact over the cerebral cortex. For such studies, the brain space is a point of integration of the other biomarkers of AD. We have organized the IB Core and its interactions with the Clinical and Neuropathology Cores such that topographical heterogeneity, determined from imaging data, is incorporated as a phenotypic characteristic, along with cognitive domain, fluid biomarker, and genetic data. We will measure cortical degeneration, as well as cortical sparing, across a set of brain regions that represent the range and variability of involvement in AD. Another important aspect of cognitive variability is the relationship of the degree of cognitive impairment that results from a given degree of neurodegeneration (cognitive resilience). Thus we will also extract measures of cognitive resilience from cognitive and anatomic data, as another phenotypic dimension. We will provide consulting expertise in informatics/machine learning, image analysis and statistics for the description and analysis of these data. We have also structured the Core to support the same multidisciplinary phenotyping in decedents from the Clinical cohort who come to autopsy. We will perform ex vivo MRI in all, and process structural measures as in the in vivo studies. We will sample tissue from the same regions that we target with imaging in living participants. We will calculate analogous resilience measures. Ex vivo MRI will also enable targeted sampling of MRI-apparent abnormalities at autopsy and mapping neuropathologic data into standard anatomical space.

Abstract The UW ADRC's driving scientific focus is investigating the biological heterogeneity of ADRD ? the mechanistic and biological underpinnings of the pathophysiology of disease as well as the factors countering degeneration and dementia. Our Center was one of the first to recognize etiologic heterogeneity in Alzheimer's disease2 and this focus is still urgently needed. New technologies and paradigms have emerged to analyze biological mechanisms of ADRD, and require well characterized human subjects and well-curated biospecimens. The proposed organizing framework for our core research resources is multi-disciplinary ADRD phenotyping. The four key disciplines to integrate are genetic, cognitive, topographic/anatomic, and neuropathologic. In this framework, the brain space is the point of integration of the other biomarkers of AD, as the magnitude and location of the different pathologies are the most tangible and objective manifestation of the outcome of different pathophysiological pathways. Thus a key aspect of our work will include integrating biomarkers extended over the cerebral cortex, as derived from imaging and neuropathology, with fluid biomarkers, cognitive and genetic information. An important goal is to support better stratification of AD phenotypes to advance investigation of candidate AD mechanisms. The UW ADRC is uniquely poised to undertake this work, which incorporates the historical strengths of the Center and research resources of the UW, leverages the collective expertise of the Core Leads and the Director, and benefits from new technical abilities that enable us to implement this program. New components are being proposed to bring expertise dedicated to bridging disciplines by innovations in techniques, methods, and informatics. These include Stem Cell and Precision -omics components in the Precision Neuropathology Core, Psychometrics component in the Clinical Core, Informatics expertise in the new Imaging and Biomarker Core and an Open Neuroscience workshop in the Research Education Component. Our Center's philosophy is to view ADRD not only through the lens of what is lost, but also through what is spared, and the associated retained strengths. This perspective permeates our Center, from motivating our interest in the biological and mechanistic basis of resilience and anatomic sparing, to the outreach efforts of the ADRC and its associated Memory and Brain Wellness Center. Another important theme of our Center is ADRD in American Indians and Alaska Natives. Building on our successful efforts in the last 5 years, we plan to extend our outreach efforts to Native tribes and organizations in Washington State, to improve their readiness for ADRD research, and to make a focused effort to understand and develop models to overcome the barriers to biospecimen collection and data sharing in this population.