Emily J. Rogalski, Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): This application proposes to study individuals with Primary Progressive Aphasia (PPA), a unique neurodegenerative disease that primarily affects the language network, to identify limitations in memory performance due to aphasia by manipulating standard implicit and explicit memory paradigms. More specifically, the studies will 1) measure interference caused by semantic relatedness, 2) compare verbal and nonverbal memory performance, and 3) vary stimulus presentation order (word-to-picture or picture-to- word) priming to determine vulnerabilities in PPA patient's memory performance. Results from the studies will provide behavioral information about the influence of aphasia on memory in a model where the lesions are not as arbitrary as they are in stroke related aphasia. Currently, evidence for preserved memory in PPA comes mainly from caregivers' observations of behavior in daily life, since it is difficult to assess memory clinically due to the language dependence of most neuropsychological tests. Thus, this proposal may have translational value clinically, since it may identify differences in the aphasic patients' memory that would result in a more comprehensive clinical characterization and, ultimately, better care. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Primary progressive aphasia (PPA) is a clinical dementia syndrome caused by neurodegenerative brain disease, with language impairment as the primary feature. Although functional decline invariably occurs, the factors influencing the time course of decline and severity of symptoms in PPA have not been fully elucidated. Furthermore, PPA is associated with two main classes of underlying pathology: Alzheimer pathology (PPA-AD) and frontotemporal lobar degeneration (PPA-FTLD) pathology, but there is currently no reliable in vivo method for identifying the nature of the pathology. Numerous autopsy series, including one from our Center, indicate that approximately 30% of cases with the PPA phenotype have PPA-AD pathology while the other 70% show PPA-FTLD pathology. However, the reliable identification of clinical and anatomical features of underlying pathology in living patients remains an ongoing challenge. The proposed studies are directed at establishing potential markers for disease etiology and progression. The Specific Aims include: 1) To follow 40 patients with the PPA syndrome using MR imaging at 6-month intervals over an 18-month time period to quantify and characterize how brain atrophy changes over time; 2) to determine the temporal relationship between cognitive change and the quantity and location of atrophy; and 3) to use the new [18F]-AV-45 PET imaging compound to identify amyloid burden in PPA patients as a marker of AD pathology and to identify its relationship to atrophy. Longitudinal rates of regional (i.e., medial temporal) atrophy have been useful in predicting cognitive decline in the amnestic dementia of the Alzheimer's type. Therefore, we predict that atrophy rates in language related brain areas will be useful in differential diagnosis and monitoring of disease progression in PPA, potentially pointing the way to an outcome measure for clinical trials. The clinical, cognitive and anatomical features associated with amyloid burden will be identified. Data from this project will determine whether the temporal progression of atrophy is related to cognitive decline, anatomical site of primary atrophy, or putative underlying pathology based on amyloid burden. This project represents the first multidimensional study of longitudinal course using the new antemortem amyloid biomarker [18F]-AV-45 in PPA. In addition to their theoretical interest, the results from this study are of crucial importance for defining objective biomarkers of disease type and progression, which will inform therapeutic treatment strategies for this relatively underserved dementia population. Results from this project will also fill gaps n our knowledge of the relationship between atrophy patterns and both clinical progression and underlying pathology in patients with PPA. The approach in Aim 1 is driven by atrophy patterns and free of clinical bias, while Aims 2 and 3 consider the relationship with cognitive performance and amyloid positivity, respectively. This is of considerable importance for increasing the accuracy with which we assign patients to therapeutic trials.

DESCRIPTION (provided by applicant): Memory complaints are widespread among the elderly, leading to the belief that a gradual loss of intellectual ability is an inevitable part of normal aging. However, recent pilot data from our cohort of SuperAgers in their 80s and 90s suggest that it is possible to have memory test scores at or above the average range for healthy individuals at least 20 to 30 years their junior. Our preliminary data demonstrate that SuperAgers, the focus of the current application, have larger cortical volumes (especially in the cingulate cortex), less prevalence of ApoE4, more von Economo neurons, and fewer markers of Alzheimer neuropathology than their cognitively average age peers. Longitudinal study of larger subject groups and additional neuropathologic analysis is needed to build on these findings and to disentangle cause from effect as we identify factors that promote unusually successful cognitive aging. This application will study a group of octo- and nona-genarians who have memory performance at least at an average level for individuals in their 50s and 60s in order to differentiate the inevitable consequences of time from the cumulative but preventable impact of stochastic phenomena embedded within time. Thus far, 34 SuperAgers and 10 normal agers have completed initial visits (including blood samples), >50% of these subjects have longitudinal data, 100% have agreed to or are considering brain donation, and two individuals have expired and donated their brains, demonstrating the feasibility of following this unusual cognitive aging cohort. This multidisciplinary study will take place in a setting ideally suited for this project, ith an established team of investigators with expertise in cognitive neuroscience and neuroimaging, behavioral neurology, neuropathology and neuroscience, neuropsychology, biostatistics and MR physics. The Northwestern AD Center, funded by the NIA, will support recruitment and collection of additional data. The Specific Aims of the proposed research will: 1) Establish the longitudinal phenotype of SuperAgers through neuropsychological performance as well as MR and amyloid PET imaging. 2) Investigate the prevalence and density of age-related plaque and tangle accumulation, status of basal forebrain cholinergic system and neuronal number in SuperAgers. 3) Establish a resource of behavioral and biological data for further resource sharing and collaborative investigations of SuperAgers. By identifying neurobiologic features that contribute to high memory performance in SuperAgers, it may be possible to help elderly avoid disease and disability, improve quality of life and alleviate a looming public health crisis.

Language impairment (aphasia) is the defining feature of the clinical dementia syndrome primary progressive aphasia (PPA) and significantly compromises the diagnosed individual?s independence and activities of daily living. There are currently no treatments to reverse the degenerative process responsible for PPA, which is caused by Alzheimer?s disease or a form of frontotemporal lobar degeneration. Nonpharmacological interventions including speech-language treatment may offer significant benefit to the diagnosed individual?s quality of life, but there are few efficacy studies and no guidelines to direct best clinical care practices. There are also several barriers to accessing care. Individuals with PPA are under-referred for nonpharmacological services, making it challenging for families to find care unless the individual with PPA lives near an informed specialist. Evidence-based research outcomes from speech-language therapy studies are promising but have been limited to case reports or small groups of local patients and often lack a control group. This project will circumvent both geographic limitations and poor access to care by using a previously validated telepractice model to deliver speech-language treatments to adults with PPA. The proposed study will use a randomized controlled trial design (RCT) to evaluate whether a person-centered treatment (Experimental) for adults with mild PPA maximizes functional communication participation as compared to a dose-matched impairment-only treatment (Control). Ninety individuals with a diagnosis of PPA and their actively-engaged care partners will be enrolled into the study. Both the Experimental and Control arms of the study will receive treatment and evaluations over the course of 12 months. The trial will be supported by a custom web-application, which has an aphasia-friendly design and provides a place for participants to connect to evaluation and treatment sessions. Participants will also use the web-application to receive weekly To-Do lists of home exercises, which are provided to reinforce evidence-based strategies learned during treatment sessions and to facilitate implementation into the context of daily life. Aim 1 will determine the within-group response of the Experimental and Control treatments for individuals with PPA. Aim 2 will determine between group differences in treatment outcomes. In the absence of a cure for dementia, it is important to identify and evaluate strategies that help individuals maximize their quality of life, and this study will help fulfill this need.

PROJECT SUMMARY/ABSTRACT: Primary progressive aphasia (PPA) is a clinical dementia syndrome caused by neurodegenerative brain disease, with language impairment as the primary feature. PPA is associated with two main classes of underlying neuropathology: Alzheimer's disease (AD) neuropathology and frontotemporal lobar degeneration (FTLD) neuropathology. Research advances, knowledge and interest in dementias due to FTLD have flourished over the past few years allowing for new dedicated resources (e.g., Advancing Research and Treatment for Frontotemporal Degeneration [ARTFL]), which promise exciting new opportunities for advancing our understanding the disease and for developing therapeutics. Unfortunately, individuals with PPA due to AD have been largely orphaned during this process; failing to meet pathologic inclusion criteria for FTLD studies and failing to meet clinical criteria for AD clinical trials, which tend to focus on individuals with the more typical amnestic phenotype. This is unfortunate because individuals with PPA due to AD represent up to 45% of all PPA cases and these individuals are potentially viable candidates for AD-related therapeutics. The proposed study will longitudinally and quantitatively characterize the clinical, cognitive, functional, neuroanatomic and molecular features of individuals with PPA who have biomarker findings consistent with AD (termed PPA-ADbio+ for this project). Aim 1a will quantitatively characterize longitudinal changes in morphometry (using structural MRI), functional connectivity (using resting state MRI), tau accumulation (with [18F]-AV-1451 Tau- PET) and clinical profiles (using detailed neuropsychological testing) of 50 PPA-ADbio+ participants at 3 consecutive annual visits. Aim 1b will characterize the temporal relationship among the variables measured in Aim 1a. This project represents one of the first prospective multidimensional studies of longitudinal course using the relatively new tau biomarker [18F]-AV-1451 in PPA-ADbio+ individuals. In addition to their theoretical interest, the results from this study are relevant for defining objective biomarkers of disease type and progression, which will inform therapeutic treatment strategies for this relatively underserved dementia population.

ABSTRACT: The purpose of this application is to establish an Imaging Core for the Northwestern Alzheimer?s Disease Center (ADC) to enhance research activities on aging and dementia within and outside of Northwestern University. The Aims of this proposal are to: 1) Initiate a Imaging Core in our current cycle focusing on the spectrum from healthy cognitive aging to dementia, including the FTLD-spectrum of disorders using imaging modalities that will yield optimal quantitative information on brain structure (MP-RAGE), white matter integrity (FLAIR), axonal pathways (dMRI), resting state hemodynamic fluctuations for establishing functional connectivity (rs-fMRI), blood flow (ASL) as well as amyloid and tau binding (amyloid-PET, tau-PET). 2) Establish a secure database, automated pipelines for processing imaging files, and tools for exploring and accessing the data to facilitate data analysis in order to leverage projects of our collaborators and to contribute to multi-center data repositories such as the National Alzheimer?s Coordinating Center (NACC). 3) Integrate imaging parameters with clinical and post-mortem information on Clinical Core subjects in a unified database so that control subjects can be more fully characterized, patient groups have more solid diagnostic information and clinico- pathologic correlations can be guided by pre-mortem imaging biomarkers. Nearly all aspects of the Northwestern ADC will be enhanced by the availability of the Imaging Core. For example, the diagnostic, anatomical and physiological characterization of Clinical Core subjects who participate in collaborative studies will be improved and all clinical investigations at the Northwestern ADC will be able to access more sophisticated tools for correlating imaging markers with behavioral and clinical parameters. The Imaging Core will unburden researchers using Clinical Core subjects from the need to gather ad hoc imaging data and will add a new dimension to clinicopathologic investigations of autopsy specimens. Thus, the range of hypotheses that can be addressed by collaborative projects relying on Northwestern ADC resources will be increased. An additional and consequential benefit will be to create new training and research opportunities for young investigators and clinicians at the Northwestern ADC. The imaging data generated by this proposal will also improve the amount of available multimodal data available in NACC, which will benefit extramural research.

PROJECT SUMMARY/ABSTRACT: Language impairment (aphasia) is the defining feature of the clinical dementia syndrome primary progressive aphasia (PPA) and significantly compromises the diagnosed individual's independence and activities of daily living. There are currently no treatments to reverse the degenerative process responsible for PPA, which is caused by Alzheimer's disease or a form of frontotemporal lobar degeneration. Nonpharmacological interventions including speech-language treatment may offer significant benefit to the diagnosed individual's quality of life, but there are few efficacy studies and no guidelines to direct best clinical care practices. There are also several barriers to accessing care. Individuals with PPA are under-referred for nonpharmacological services, making it challenging for families to find care unless the individual with PPA lives near an informed specialist. Evidence-based research outcomes from speech-language therapy studies are promising but have been limited to case reports or small groups of local patients and often lack a control group. This project will circumvent both geographic limitations and poor access to care by using a previously validated telepractice model to deliver speech-language treatments to adults with PPA. The proposed study will use a randomized controlled trial design (RCT) to evaluate whether a person-centered treatment (Experimental) for adults with mild PPA maximizes functional communication participation as compared to a dose-matched impairment-only treatment (Control). Ninety individuals with a diagnosis of PPA and their actively-engaged care partners will be enrolled into the study. Both the Experimental and Control arms of the study will receive treatment and evaluations over the course of 12 months. The trial will be supported by a custom web-application, which has an aphasia-friendly design and provides a place for participants to connect to evaluation and treatment sessions. Participants will also use the web-application to receive weekly To-Do lists of home exercises, which are provided to reinforce evidence-based strategies learned during treatment sessions and to facilitate implementation into the context of daily life. Aim 1 will determine the within-group response of the Experimental and Control treatments for individuals with PPA. Aim 2 will determine between group differences in treatment outcomes. In the absence of a cure for dementia, it is important to identify and evaluate strategies that help individuals maximize their quality of life, and this study will help fulfill this need.

PROJECT SUMMARY/ABSTRACT: Memory complaints are widespread among the elderly and aging is a major risk factor for Alzheimer's disease (AD), leading to the impression that a gradual loss of memory ability, eventually culminating in dementia, may be a nearly universal consequence of getting old. Our studies explore an alternative aging trajectory by studying 80+ year olds, who have episodic memory performance that appears to have escaped age-related decline and that remains in the range that is at least normal for 50-60 year-olds and we have labelled `SuperAgers'. We enrolled a dedicated and unique cohort of SuperAgers and Controls committed to longitudinal assessment and brain donation at death. Our initial studies identified domain-specific biologic, psychosocial, and genetic features of the SuperAgers, including maintenance of cortical integrity (especially in the anterior cingulate), an abundance of anterior cingulate Von Economo neurons and sparse cortical Alzheimer pathology compared to their cognitively average peers. These features may contribute in part to maintenance of superior memory performance past the 8th decade of life. This Project plans to extend the characterization of the SuperAging phenotype through hypothesis-driven novel evaluations of functional brain network connectivity, regional distribution of gene expression, and integrity of dendritic, synaptic and axonal markers. The proposed project will allow us to expand our unique group of SuperAgers and cognitively average peers and address important questions related to the neurobiology of resilience and cognitive reserve. By identifying neurobiologic features that contribute to superior memory performance in old age, outcomes from this project will help isolate factors that promote successful cognitive aging and perhaps also prevent age- related brain diseases such as AD. The project's reliance on a cohort that has already been partially recruited, its longitudinal design, multidisciplinary structure, and collaboration-friendly organization increases the likelihood that consequential progress will be achieved.

PROJECT SUMMARY - IMAGING BIOMARKER CORE The Northwestern ADRC Imaging Biomarker Core has the long-term goal to characterize all eligible Clinical Core participants with state-of-the-art structural, functional, and molecular imaging and curate these data for use in future projects. The Northwestern ADRC Clinical Core currently maintains a cohort of over 500 participants. Approximately half of the Clinical Core Participants receive systematic MR imaging funded by R01s from NIA, NINDS, and NIDCD. During the last cycle, the Imaging Biomarker Core increased imaging coverage from approximately 50% of the Clinical Core cohort to nearly 70%. For the next cycle, it will acquire and process structural, functional, and molecular imaging on additional Clinical Core participants who are not covered by other research grants and who are targeted for relevant collaborative studies. We will use advanced acquisition and analysis methods and ensure these data are integrated with other variables within an infrastructure that supports intramural and extramural collaborations and provides rich opportunities for training. The Imaging Biomarker Core is highly interconnected with the other Northwestern ADRC Cores in a manner that enhances the missions of NAPA and the NIA. It will be guided by the following goals: 1) Acquire systematic and multimodal neuroimaging (MR, PET) on Clinical Core participants who lack these biomarkers and who are eligible/recruited for collaborative studies we support. To this end, Clinical Core participants including cognitively healthy controls, individuals with amnestic mild cognitive impairment (aMCI), and individuals with AD/ADRD will be scanned with advanced PET and MR imaging modalities. 2) Curate and share integrated imaging datasets on Clinical Core participants, which will serve intramural and extramural collaborations including REC trainee projects. This aim will draw upon a mature institutional computing structure to run pipelines for quality assurance, processing, and analysis of imaging data. The resulting imaging outputs will be incorporated with clinical and post-mortem data in our unified ADRC NeuroFiles database developed in collaboration with the Data Management and Statistics Core. The infrastructure of the Imaging Biomarker Core includes two research-dedicated 3T Siemens MR magnets at Northwestern?s Center for Translational Imaging (CTI) and a PET/CT scanner at Northwestern Memorial Hospital. Data are directly routed from the scan console to the Northwestern University Neuroimaging Data Archive (NUNDA), where quality assurance and analysis tools are launched with the support of a high- performance computing cluster called QUEST. Collectively, these data will enhance the clinical and diagnostic characterization of each Clinical Core participant and will be made available to approved intramural and national collaborators including NACC. All phases of this proposal will offer unique opportunities for the training of junior investigators in areas related to imaging and translational research.

PROJECT SUMMARY (Overall): The primary goal is to establish a multicenter SuperAging Consortium to identify behavioral, health, biologic, genetic, environmental, socioeconomic, psychosocial, anatomic and neuropathologic factors associated with SuperAging. These goals will be achieved through an organizational structure with 3 Cores (Administrative/Biostatistics, Clinical/Imaging, and Biospecimen/Neuropathology) and 2 Research Projects. The Consortium will enroll 500 participants across 4 US Sites located in Illinois, Wisconsin, Michigan and Georgia, and the Canadian Site in Southwest, Ontario, with a focus on the enrollment of Black SuperAgers and Cognitively Average Elderly Controls with similar demographics (Controls). The Administrative/Biostatistics Core will provide governance and fiscal oversight, maintain scientific integrity, and create a centralized biostatistics and database infrastructure to harmonize the goals and activities of the Cores, Sites, and Projects, with each other, with the NIA and with extramural collaborators. The Clinical/Imaging Core will standardize criteria for the uniform cross-site and multidisciplinary characterization of SuperAgers, streamline recruitment including that of Black participants, enter relevant information in the comprehensive database, support co-enrollment into Project 1, and encourage collaborative ventures aiming to understand the factors that promote SuperAging. The Biospecimen/Neuropathology Core will collect and bank brain tissue and blood products from SuperAging and Control cases, according to optimized procedures. It will render pathological diagnoses, quantitate selected markers of neurodegeneration and neuronal structure, coordinate the analyses of plasma biomarkers for Alzheimer's disease, and make specimens available for collaborative investigations. Project 1 will use state-of- the-art wearable technology to obtain real-time measurements in the course of everyday life to characterize quantitative parameters related to sleep, physical activity, autonomic responsivity, and social engagement to determine whether SuperAgers have relatively preserved and quantitatively determined physiologic and behavioral `complexity' compared to Controls. Project 2 will use transcriptomic, genetic, and protein profiling approaches to test the hypothesis that SuperAgers will demonstrate significant molecular differences in their central and peripheral immune and inflammatory system parameters compared to matched Control and Alzheimer's disease participants. By identifying neurobiologic features that contribute to superior memory performance in old age, outcomes from this Consortium will help isolate factors that promote successful cognitive aging and perhaps also prevent age-related brain diseases such as Alzheimer's disease.