Margaret E. Flanagan - US grants

According to the World Health Organization approximately 50 million people worldwide suffer from cognitive disorders. The incidence of dementia increases with age, especially for those over 65. CNS white matter lesions are also known to increase with age and to increase the risk of developing dementia. Vascular dementia (VD) is the second most common cause of cognitive abnormalities in the elderly behind Alzheimer?s disease (AD). VD has been associated with various cardiovascular maladies, which are thought to contribute to diffuse white matter disease leading to dementia. The underlying hypothesis of this proposal is that the impact of the cytotoxic environment created by disruptions to the CNS vasculature associated with aging and diverse cardiovascular disorders are particularly detrimental to oligodendrocyte viability and function. We posit that the heightened sensitivity to cellular stress that oligodendrocytes display due to their unique metabolic demands makes them particularly vulnerable to the changing extracellular environment that develops with advancing age and in response an altered cerebral circulation. The white matter abnormalities that occur as a consequence of oligodendrocyte perturbation are likely critical to the development of neurodegenerative, cognitive and behavioral changes. The goal of the current proposal is to a gain a mechanistic understanding of the impact of ageing and cerebrovascular abnormalities on oligodendrocytes, both in humans and in mouse models. Our focus will be on examining the role that intrinsic cytoprotective pathways play in the response of oligodendrocytes to the adverse cytotoxic environment created by these conditions. We will focus on three cytoprotective pathways: the integrated stress response (ISR) pathway is initiated by a variety of stresses including oxidative stress, hypoxia and inflammation; the nuclear factor erythroid 2-related factor 2 (NRF2) pathway is activated in response to oxidative stress; and the hypoxia-inducible factor 1 (HIF-1) pathway is the master transcriptional regulator of the cellular response to hypoxia. We will examine human postmortem samples from individuals with vascular dementia for activation of these pathways in oligodendrocyte lineage cells, and we will similarly assess their activation in ageing mice, which are known to display oligodendrocyte and myelin deficiencies. We will also examine a mouse model of heart failure with preserved ejection fraction (HFpEF) for oligodendrocyte and myelin abnormalities linked to ISR, NRF2 and HIF activation. HFpEF is a common cardiovascular abnormality associated with dementia. We will also use a genetic approach to further examine the response of these cytoprotective pathways to the adverse CNS environment created by ageing and cerebrovascular abnormalities. Together, these efforts will substantially increase our understanding of the response of oligodendrocytes to the cytotoxic CNS environment created by ageing and cerebrovascular dysfunction. A better appreciation of the contribution of myelinating glia dysfunction to the pathogenesis of dementia is essential to our understanding of this growing health concern and may serve as the basis for the design of neuroprotective therapeutic strategies.

PROJECT SUMMARY This NIH Career Development Award proposal describes a five-year career development and training plan for Dr. Margaret Flanagan, a physician-scientist in the Division of Neuropathology in the Department of Laboratory Medicine and Pathology at the University of Minnesota. Her long-term goal is to become an independent, physician-scientist leader who will make significant contributions in the field of dementia research. Her career development training plan includes the following: protected research time, focused formal graduate coursework targeted to advance her knowledge and skills in Epidemiology, a structured mentoring program with a multidisciplinary team of experienced senior scientists, and focused research experience investigating the role of neuroinflammation in Limbic predominant age-related TDP43 encephalopathy (LATE). This training plan will culminate in a successful application for independent research funding by an investigator who is prepared to take an active leadership role in transformative change leading to improved health care outcomes in dementias associated with transactive response binding protein-43 (TDP43) associated inflammation, including Alzheimer Disease (AD), hippocampal sclerosis of aging and frontotemporal dementia. TDP43 is a highly conserved nuclear riboprotein that plays a role in a variety of cellular functions including RNA processing. More recently, it has been shown that age-related increases in dementia risk are attributed to the accumulation of multiple co-existing brain lesions, each of which contributes significantly to dementia risk. Because there are no reliable biomarkers for TDP43 or ?-synuclein, it is currently impossible to accurately detect all co-existing lesions in vivo, limiting these comprehensive assessments to postmortem studies of the brain. The objective of this proposed research is to clarify the role of neuroinflammation in LATE clinical disease progression. Dr. Flanagan will investigate TDP43 associated inflammatory markers relevant to pathways of interest, co-existing neuropathologic lesions, LATE genetic risk variants and cognitive performance data in well-characterized samples from Mayo Clinic. This work will inform on the role of TDP43-associated neuroinflammation in the development of cognitive impairment and dementia in late life and ultimately, enable the development of future preventative and therapeutic interventions. This research will provide some of the first information about neuroinflammation in LATE. In summary, a comprehensive career development plan in the context of a well-defined training, research and mentorship structure will allow Dr. Flanagan to become a successful, independent physician-scientist.

PROJECT SUMMARY -NEUROPATHOLOGY CORE Autopsy remains the gold standard for the diagnosis of diseases that cause dementia. It provides knowledge essential for developing biomarkers, understanding cellular pathology responsible for the dementia, and retrospectively identifying features most reliable for early diagnosis. Without this information rational discovery of disease-modifying drugs for dementia syndromes would not be possible. The Neuropathology Core will pursue the dual goals of fulfilling national priorities set by NIA and NAPA while also fostering the ?Heterogeneity in Aging and Dementia? theme of the Northwestern ADRC. These goals will be achieved through the following interactive aims: 1) Provide state-of-the-art postmortem diagnosis on Clinical Core participants and make the results available in a timely fashion to family, clinicians, qualified researchers, and NACC. 2) Collect, curate, and distribute biospecimens to qualified research projects, both within Northwestern University and for multi-center collaborations including NCRAD and ADGC. 3) Support the specialized research interests within Northwestern University on unusually successful cognitive aging (SuperAgers), non-amnestic dementias such as primary progressive aphasia (PPA), frontotemporal lobar degenerations (FTLD), neuroinflammation, and mid-life onset AD (MOAD). 4) Support local research on clinicopathologic correlation through a banking protocol that emphasizes bilateral tissue sampling for detection of hemispheric asymmetry and through stereology and densitometry for quantitative comparisons of cellular pathology with in vivo clinical and imaging data. 5) Train the next generation of neuropathologists in a multidisciplinary setting that includes close interaction with clinicians, imagers and neuroanatomists and in a manner that serves the goals of the Research Education Component. Integrating the cellular basis of the disease with its clinical manisfestations requires close interaction among neuropathologist, neuroanatomist, imager and clinician to link the nature and distribution of the neuropathology to the clinical phenotype and its trajectory. To this end, monthly CPC meetings provide an interactive setting for superb training of fellows in rigorous diagnosis, clinicopathologic correlation and potential collaborative research. The ADRC Brain Bank and Neuropathology and Imaging Biomarker Core laboratories, as well as Core Leader and Director offices and other resources, are located in contiguous space on the same floor. This infrastructure offers a dynamic incubator for multidisciplinary interactions between the Neuropathology Core and other components of the ADRC.