David Wolk - US grants

DESCRIPTION (provided by applicant): The goal of this project is to better define the specific nature of memory loss in patients with Amnestic Mild Cognitive Impairment (a-MCI), a group enriched in patients with early Alzheimer's disease (AD) pathology. This work will aid in discrimination of memory loss due to AD pathology versus that of aging. Dual-process models of memory argue that recognition is subserved by recollection and familiarity. Both are impaired with early AD while only recollection is affected by aging. Little is known about the integrity of these processes in a-MCI. Therefore, recollection and familiarity will be measured by behavioral means in healthy elderly subjects and patients with a-MCI and mild AD. These estimates will then be related to (1) event-related potential (ERP) correlates of these processes and (2) medial temporal and cortical volumes using quantitative MRI techniques. As the earliest pathology of AD involves medial temporal structures, it is hypothesized that behavioral, ERP, and MRI measures will reflect involvement of this region in a-MCI and predict conversion to AD in longitudinal assessment. Specifically, familiarity, a form of memory thought dependent on perirhinal cortex, is expected to be impaired in a-MCI relative to elderly controls. Further, ERP correlates of recollection will differ between healthy aging and a-MCI/AD, reflecting prefrontal dysfunction in the former and hippocampal/entorhinal pathology in the latter. Relation of behavioral estimates of recollection and familiarity with volumetric MRI and ERP will provide further understanding of the anatomic and electrophysiologic bases of these processes and the impact of early AD pathology on them. The training plan for this Career Development Award application will build upon a foundation produced by the candidate's prior work in the study of memory in AD using behavioral and ERP techniques. In addition to enhancing these skills, the candidate will learn a new modality of inquiry, quantitative structural MRI. Training in such a multi-modality approach will allow for the candidate to address scientific questions in a novel and flexible manner as he becomes an independent investigator. Alzheimer's disease is already a tremendous public health burden which is expected to grow dramatically in the next 30 to 40 years. Patients with minimal impairment may benefit the most from potential disease modifying interventions. Thus, the pursuit of tools for early diagnosis, as proposed here, is critical.

DESCRIPTION (provided by applicant): A major goal in Alzheimer's disease (AD) research is to develop biomarkers that are sensitive to early disease, predict decline in those with mild symptoms (e.g. Mild Cognitive Impairment, or MCI), and reflect disease progression. Over the last two decades, a number of candidate neuroimaging, molecular,and psychometric measures have demonstrated variable success in accomplishing these goals. While significant advances have been made with molecular markers (e.g. CSF A?1-42) that are sensitive to specific pathology, these techniques appear relatively insensitive to clinical status or disease progression. On both empirical and theoretical grounds, brain measures that reflect synaptic function are thought to be the most sensitive to the consequences of early AD pathology and predictive of future decline. Fluorodeoyglucose (FDG) PET, a measure of glucose metabolism (CMRGlu), has demonstrated considerable promise in this regard. Arterial spin labeling (ASL) MRI, which is sensitive to cerebral blood flow (CBF) reflective of metabolic activity, may provide overlapping information with FDG-PET, but has several potential advantages: 1) ASL can be acquired in several minutes during routine MR imaging that most patients will obtain as part of their clinical evaluation, and, thus, is less expensive and burdensome~ 2) ASL does not require IV contrast or radiation exposure~ 3) ASL is potentially more accessible than PET~ 4) Short activation or task-related sequences can more easily be implemented with potential for increased sensitivity to early functional change. Further, since ASL is acquired along with other MRI sequences, one can potentially take advantage of orthogonal measures of brain structure and function, the combination of which may offer the fullest characterization of disease state. The central goal of this proposal is to demonstrate that 'state-of-the art' ASL-MRI produces largely equivalent information to FDG-PET in a cohort of amnestic MCI patients. In particular, we will determine the relative capacity of these modalities to determine clinical status [MCI vs healthy control (HC)], disease state (presence/absence of AD CSF profile), and predict future progression. 'Optimized' ASL sequences, leveraging numerous advancements in data acquisition and analysis, will also be compared to a commercially available ASL measure being implemented in the Alzheimer's disease Neuroimaging Initiative renewal (ADNI 2), to determine the relative value of these ASL variants. Additionally, task-related ASL will be explored for its potential to further enhance the predictive value of rest ASL alone. To achieve these aims, MCI patients and HC will undergo a baseline ASL-MRI and FDG-PET scan~ we will also obtain CSF molecular markers (tau/A?). Longitudinal clinical follow-up and a 1-year repeat MRI will allow for assessment of disease progression and determination of the relative predictive value of these imaging biomarkers. Finally, we will utilize the analytic pipeline developed in this project o analyze ASL data from ADNI 2, which will potentially enhance power to address some of the above questions and serve as a replication dataset.

Core B: Clinical Core Core Leader: David A. Wolk, M.D.; Co-Core Leader: Jason Karlawish, M.D. Project Summary/Abstract The mission of the Penn ADCC Clinical Core is to provide patient data (cognitive, neuroimaging, biofluid, genetic, autopsy) to support the thematic goals of the ADCC and the broader AD research community. A major challenge to developing effective therapeutic interventions for disease modification or symptomatic treatment is the growing understanding that AD is a heterogeneous condition. At least two features characterize this heterogeneity: mixed and multiple pathologies and differential involvement of brain regions or networks. The Penn ADCC views this heterogeneity, as well as the potential shared mechanisms of different proteinopathies and the realization that the antecedents of AD and related disorders occur in preclinical and prodromal stages, as opportunities to enhance precision in prognostication, disease monitoring, and targeting of underlying pathophysiology. As such, the major themes of our ADCC in this renewal are to increase the understanding of (1) the interplay of AD and related disorders pathology in the clinical spectrum of AD, (2) the factors which result in clinical and network level heterogeneity in AD, and (3) the relationship of these phenomena to models of transmissibility. The result will be to increase insight into different AD phenotypes and disease mechanisms through the spectrum of preclinical AD through symptomatic stages. These goals are related to and dependent on our strong tradition of biomarker studies which continue to be a focus for both Core B and the overall ADCC, including development and refinement of these measures and investigation into approaches for their implementation and disclosure in clinical settings. The Clinical Core is highly integrated with the other Penn ADCC Cores and it will work towards achieving the following aims to advance the scientific mission of the Center: (1) To identify and longitudinally evaluate individuals across the continuum of AD and ?normal? cognitive aging, gathering clinical, neuroimaging, and biosample data with an emphasis on heterogeneity in clinical expression, further enhanced by inclusion of the FTLD Module. (2) To collaborate with the Outreach and Recruitment Core to facilitate participation of individuals, with an emphasis on African Americans, in Clinical Core research activities, which will add diversity critical to understanding the influence of comorbid risk factors and genetics on disease expression. (3) To foster integration of Core B activities with the other ADCC Cores, including with the Research Education Component (Core F) to train the next generation of investigators in AD research and with the Data Management, Biostatistics & Bioinformatics Core (Core C) and the Neuropathology, Genetics & Biomarker Core (Core D) to collect and manage clinical data, biomarker studies, and biological samples in a manner that facilitates local, national, and international collaborative studies and sample sharing among NIA-funded ADCs and other qualified investigators through the Administrative Core (Core A). Accomplishment of these goals will catalyze achievement of our broader mission to improve diagnosis and treatment of AD.

Project Summary Mild cognitive impairment (MCI) can be a transitional stage between normal aging and Alzheimer's Disease (AD). Obstructive sleep apnea (OSA), a condition in which there is recurrent upper airway obstruction during sleep leading to nocturnal hypoxia and cognitive dysfunction, is present in 58.7% of MCI patients, yet it is rarely diagnosed or treated. OSA can be effectively managed with continuous positive airway pressure (CPAP), a pressurized nasal mask worn during sleep, but there is little information on its efficacy in this population, thus limiting adoption. The primary goal of this proposal is therefore to evaluate whether treatment of OSA in amnestic MCI (aMCI) with CPAP delays cognitive decline and preserves everyday function. The study investigators have successfully completed an NIA Alzheimer's Disease Pilot R01 Clinical Trial (?Memories?) using a quasi-experimental design that provided valuable preliminary and feasibility data (one- year follow-up, two sites, n=68). It consisted of three aMCI groups: 1) CPAP adherent intervention group; and two control groups 2a) CPAP non-adherent and 2b) No OSA. They demonstrated that 1) progression of cognitive impairment was reduced with CPAP; and 2) baseline MRI differences were noted in hippocampal and medial temporal lobe subregions, several of which improved in CPAP adherent patients. While clinically compelling, these findings were not statistically significant (p=0.125 and higher) due to the study sample size. The specific aims of the current proposal are to confirm and expand these findings in a larger four-site study (n=460) using the approach the study team has successfully implemented previously. Aim 1 will evaluate the hypothesis that declines in one-year memory/processing speed (Digit Symbol-Coding test) are attenuated in CPAP adherent (n=200) vs CPAP non-adherent (n=160) aMCI. Aim 2 will evaluate brain MRIs to test the following hypotheses: 1) Right hippocampal hypertrophy noted at baseline in the preliminary study is a hallmark of OSA--the study will compare brain MRIs in OSA+ (n=360) to OSA- (n=100) participants; and 2) At one-year follow-up, CPAP adherent participants will have reductions in atrophy, with partial normalization of the right hippocampal area hypertrophy noted at baseline when compared to CPAP non-adherent participants. Aim 3 will be an exploratory cerebrospinal fluid (CSF) sub-study to evaluate AB42, total tau, phosphorylated tau, as well as pathway biomarkers F2-isoprostane (oxidative stress), hypoxia-inducible factor-1a (OSA-related intermittent hypoxia), and vascular endothelial growth factor (neuroprotective). CPAP adherence can be measured precisely with a sensor that determines hours of use and propensity score analysis will be used to effectively control for confounding variables related to group allocation and outcome. The findings from this large-scale study, adequately powered for clinical and statistical significance based on successful prior trial results, have the potential to change the care of millions of MCI patients as they seek to mitigate the devastating consequences of progressive cognitive decline.

PROJECT SUMMARY/ABSTRACT Older adults are often victims of fraud, raising the question of whether age affects decision-making in such a way that makes people more susceptible to financial exploitation. One potential susceptibility is that older adults can have problems learning and acquiring information for later decision-making. However, significant gaps remain in our understanding of these potential deficits. Previous studies (1) have not examined learning in the social domain, which is most relevant for avoiding fraud; (2) have not examined multiple forms of learning, which may be differentially sensitive to age; and (3) have not examined whether deficits are a general function of age, or rather symptomatic of early pathological changes associated with preclinical Alzheimer's Disease or cerebrovascular disease, which can go undetected in otherwise cognitively normal older adults. This project will test older and middle-aged adults on two tasks using social stimuli that separately isolate hippocampal-mediated episodic learning, which encodes detail-rich associations between items and contexts from single events, and striatal-mediated stimulus-response learning, which encodes less flexible representations of a stimulus's value accrued over many events. Older adults will undergo a comprehensive clinical assessment and be determined to be cognitively normal as part of the Clinical Core longitudinal cohort of Penn's Alzheimer's Disease Core Center (ADCC). Age is expected to be associated with deficits in decisions based on both episodic memory and stimulus-response learning, though these deficits are expected to track with functional changes in different neural regions ? hippocampus and striatum, respectively ? as assessed with functional magnetic resonance imaging (MRI). As part of the ADCC, older adults will also receive positron emission tomography scans to assess amyloid pathology as well as MRI scans to assess white matter hyperintensity burden. Approximately 25% of cognitively normal adults show signs of either preclinical Alzheimer's Disease (amyloid pathology) or cerebrovascular disease (white matter hyperintensities). These data will be used to determine if social decision-making deficits are due to these previously undetected pathological changes, or to other brain structural changes that occur with healthy aging. Social decisions based on episodic memory may be particularly sensitive to preclinical Alzheimer's Disease, given that this targets the hippocampus, whereas social decisions based on stimulus-response learning may be particularly sensitive to cerebrovascular disease, given its impact on frontostriatal circuitry.

Project Summary Alzheimer's Disease (AD) is the major public health crisis of our time. Based on the rationale that treatments are more likely to be effective before significant cognitive impairment has accrued, there is increased focus on intervening in preclinical or early prodromal stages. A major challenge for clinical trials in these populations is development of tools to determine if these interventions are effective. As the earliest neurodegenerative changes of AD are thought linked to the development of pathology within the medial temporal lobe (MTL), measures of episodic memory and imaging of this region may play a critical role in serving as a means for disease monitoring. However, ?normal? aging is also associated with both structural and functional alterations of the MTL, and episodic memory is one of the domains most saliently implicated in age-associated cognitive decline. The major goal of this proposal is to identify MTL-related features that distinguish normal aging from preclinical AD, as well as the factors that influence these differences. In light of structural, functional, and cognitive overlap in normal aging and preclinical AD, a more granular examination is necessary to better distinguish these conditions. Doing so is essential for effective disease monitoring that dissociates age-effects from those of evolving AD. Critically, the MTL consists of a number of inter-related subregions that have been associated with different aspects of memory and may be selectively vulnerable to aging versus preclinical AD. However, despite decades of work focused on the cognitive neuroscience of memory loss with aging, this more granular understanding of specific changes that occur within the MTL and related networks is lacking and the literature conflicting. We will address a number of methodologic issues with the prior literature that may account for this inconsistency. First, we will leverage our extensive experience in development of methods for MTL structural and functional measurement and take advantage of the improved resolution of 7 Tesla (T) MRI imaging over more standard clinical or research MRI scans. Second, we will obtain amyloid imaging to determine the presence preclinical AD, allowing us to isolate aging effects on its own. Third, we will comprehensively account for other factors that may influence MTL changes, including cerebrovascular disease (CVD), presence of neurofibrillary tangle (NFT) pathology independent of preclinical AD, and genetic factors. We will obtain sensitive markers of CVD with 7T MRI, NFT burden with Tau PET imaging, and SNPs associated with AD risk. Fourth, we will examine the cognitive effects of these changes with experimental memory measures. We anticipate that the detailed understanding of the effect of age on MTL structure and function will allow for definition of monitoring targets of preclinical AD and significantly enhance our understanding of mechanisms underlying age-associated memory decline.

Administrative Core Project Summary The primary goal of the Penn ADRC is to increase research and education on Alzheimer?s disease (AD) and its links to related disorders (ADRD) across the continuum of normal aging to dementia with the goal of identifying the causes of and cures for AD/ADRD. To achieve this goal, the Penn ADRC coordinates research programs, stimulates new research, catalyzes academic research training, provides community education and outreach and fosters the development of novel techniques to individualize diagnosis and treatment for the benefit of all elderly persons and their families. It is the role of the Administrative Core to shepherd and facilitate the activities of the ADRC Cores and to serve as a bridge between the ADRC and national and international efforts in pursuit of these goals. Administrative Core will be involved in a number of different activities that are designed to achieve these broad goals, including fiscal and administrative oversight over the ADRC (Aim 1). The leaders of the ADRC and the ADRC Executive Committee, composed of core leaders and co-leaders, will set priorities and develop plans to achieve ADRC goals. The Administrative Core will choose members of an External Advisory Committee that will be charged with the role of evaluating the progress of the Center and providing recommendations (Aim 2). A variety of forums and opportunities for exchange of ideas and dissemination of data will be supported by the Administrative Core through ADRC sponsored retreats and lecture series (Aim 3). These events will include participation of faculty and trainees, providing an opportunity, particularly for the latter, to present data and receive feedback. Critical to the growth and breadth of AD/ADRC research, a unique Developmental Project program linked to topics at annual retreats will foster transdisciplinary work (Aim 4). The Administrative Core will champion participation of the Penn ADRC in numerous state, national, and international efforts to improve care and treatment of ADRD, as well as provide infrastructure to support the sharing of data and biomaterials (Aim 5). Finally, the core will provide oversight on all NIA and local regulatory and reporting procedures and requirements (Aim 6). Critically, the Administrative Core serves to maintain the ?centeredness? of the ADRC by coordinating efforts across the individual cores, by promoting collaborations with other neurodegenerative centers at Penn and beyond, and by promoting activities consistent with our thematic focus around AD heterogeneity. By achieving the above aims, we expect to maintain our highly productive ADRC with the appropriate support to do novel research, to contribute highly and deeply phenotyped individuals to larger data sharing efforts, to grow our diverse and multi-disciplinary faculty by training the next generation of investigators and clinicians, and to educate and empower our region and the nation so as to improve brain health and meet the goals of NAPA.

Clinical Core Project Summary The theme of the Penn ADRC is to better understand both the upstream factors and processes that contribute to Alzheimer?s Disease (AD) heterogeneity and the downstream markers critical to characterizing it. The Clinical Core serves as the central node for this thematic mission by deeply characterizing a clinically and demographically diverse cohort (Aim 1). Given the importance of understanding heterogeneity in the context of the entire AD continuum, we will recruit, assess, and longitudinally follow a cohort, the ADRC UDS Cohort, that spans cognitively normal older adults to those with mild dementia. To capture phenotypic diversity and overlap with other neurodegenerative conditions, the cohort includes frontotemporal dementia (FTD), Lewy Body disease, and atypical and early onset AD presentations. In collaboration with the Outreach, Recruitment, and Engagement Core (ORE), recruitment of African Americans, a group poorly represented in AD research, is also a priority and enhances efforts to examine the diversity of factors that contribute to heterogeneity in expression of disease (Aim 3). In the context of the transformation of AD from being defined as a clinical diagnosis to a disease defined by biomarkers, the Penn ADRC embraces the importance of biomarker acquisition and validation. The Clinical Core facilitates these efforts through acquisition of plasma, cerebrospinal fluid, and MRI and PET imaging (Aim 2). These materials and data are obtained in close collaboration with the Biomarker and Neuroimaging Cores and allow for classification of individuals on the basis of the presence or absence of cerebral b-amyloid plaques (A), tau-based neurofibrillary tangles (T), and neurodegeneration (N). Thus, in as many participants as possible, we will obtain biofluid (CSF and plasma) and/or neuroimaging A/T/(N) designation. To capture the role of cerebrovascular disease (CVD) in AD heterogeneity, we will obtain clinical, biofluid, and neuroimaging measures of risk or downstream manifestations of CVD (e.g. white matter hyperintensities). The Clinical Core will also be a source of genetic material and brain tissue obtained in conjunction with the Genomics and Neuropathology Cores, which will be linked to the above biomarker and clinical data. In light of the potential modulating effect on disease risk, phenotype, and resilience versus vulnerability, we will also obtain measures of social determinants of health (SDoH; Aim 4), which potentially will provide a deeper understanding of the role of ethnoracial differences in disease risk and presentation. In addition to the sharing of this rich and diverse dataset and materials with the National Alzheimer?s Coordinating Center (NACC) and with other ADRCs and institutions, the Clinical Core participates in numerous multi-site collaborative clinical research and intervention studies with the goal of advancing care of people with AD/ADRD (Aim 5). Finally, the Clinical Core serves as an important base for training efforts with the Research Education Component to develop the next generation of investigators and clinicians.

Penn ADRC Overall Project Summary The mission of the University of Pennsylvania?s Alzheimer?s Disease Research Center (Penn ADRC) is to increase research and education on Alzheimer?s disease (AD) and its links to related dementias (ADRD) with the goal of identifying the causes of and cures for AD/ADRD. To do so, the Penn ADRC will address one of the fundamental barriers to effective treatment or prevention, which is the significant phenotypic, pathological, and sociodemographic heterogeneity of AD. We will embrace and seek to characterize and understand this heterogeneity to ultimately achieve a precision medicine approach leading to targeted interventions that will facilitate realization of the National Alzheimer?s Project Act?s (NAPA) ambitious goal of effective prevention or treatment by 2025. Indeed, the Penn ADRC is constructed to directly contribute to a number of the milestones of NAPA necessary to achieve this goal. Emerging from the 30-year history of the Penn Alzheimer?s Disease Core Center (ADCC), the Penn ADRC benefits from a rich scientific milieu in which there is significant integration and collaboration across Penn?s neurodegenerative disease centers. This construction is critical to the understanding of AD heterogeneity which is driven, in part, by overlapping pathologies and mechanisms, such that cross-degenerative disease studies are of increasing importance in capturing the full spectrum of disease. This environment has led to a history of transformative research that has influenced understanding of disease definition and mechanisms, diagnostic approaches and biomarker development, statistical and bioinformatics methodology, and ethical, social and legal perspectives of those suffering from this condition and their care partners. It has also created an intellectual, cultural, and physical setting dedicated to training the next generation of investigators and clinicians, as well as partnering and educating the community. To achieve our mission, the Penn ADRC will bring together eight cores (Administrative; Biomarker; Clinical; Data Management and Statistical; Genomics; Neuroimaging; Neuropathology; Outreach, Recruitment, and Engagement) and the Research Education Component (REC). These highly integrated cores will support development of a phenotypically, pathologically, and ethno-racially diverse cohort which will be deeply characterized through cognitive assessments, measures of social determinants of health, genetics, biofluid and neuroimaging biomarkers, and autopsy. All these data will be stored within the Integrated Neurodegenerative Disease Database (INDD), which is linked to the other neurodegenerative centers at Penn and will contribute to our understanding of the upstream factors and processes that lead to AD heterogeneity and its downstream manifestations. Further, the ADRC supports robust sharing of these data and participation in larger NIA and national programs. The REC leverages these cores and their research programs for training new investigators. Together, the Penn ADRC will advance our ultimate mission to reduce the tremendous burden of AD.