Glial-mediated Inflammation and Iron Accumulation in Frontotemporal Dementia

University Of Pennsylvania, Philadelphia PA

Investigators

Abstract

ABSTRACT Our overall objective is to model and contrast the microscopic, mesoscopic and macroscopic regional progression of neuroinflammation, abnormal iron accumulation and neurodegeneration in human brain tissue from patients with frontotemporal lobar degeneration (FTLD) with tau (FTLD-TDP) vs. TDP-43 (FTLD-TDP) pathology. Frontotemporal dementia (FTD) is a spectrum of clinical dementia syndromes that comprise progressive changes in behavior and social cognition, language and executive functioning. FTD is understudied, yet FTD is as common as Alzheimer’s disease in individuals < 65 years of age. FTD is an incurable condition with no FDA-approved therapies and treatment relies on supportive care. Currently, a major obstacle to the study of the underlying biology of FTLD proteinopathies and the development of disease-mechanism targeted therapies in FTLD is the inability to reliably diagnose underlying FTLD-Tau vs FTLD-TDP pathology in a living FTD patient, necessitating neuropathological examination of human brain tissue. Moreover, the majority of postmortem studies in FTLD to date have focused on the proteinaceous inclusions that define FTLD, while detailed studies of glia and non-cell-autonomous mechanisms of neurodegeneration in FTLD are understudied. We recently discovered distinct microscopic cellular patterns of iron-rich gliosis in FTLD-Tau and FTLD-TDP using histopathologic sampling guided by iron-sensitive 7T-guided ex vivo MRI. To address these gaps and build on our previous work, we propose a unique multidisciplinary approach to comprehensively study glial activation and iron-dysregulation in the extensive Penn FTLD brain bank and translate these findings by integrating our digital histology data with antemortem imaging and detailed clinical data. Our central hypothesis is that FTLD- Tau and FTLD-TDP have distinct cellular laminar and regional patterns of iron-rich gliosis postmortem that relate to antemortem clinical and radiographic progression of disease. We leverage the complementary expertise of our investigator team and our infrastructure of productive collaboration to perform complex statistical modeling from deep spatially-resolved cellular data from multiplexed immunofluorescence imaging methods in human brain tissue. Moreover, using our established ex vivo 7T MRI guided digital histology approach, we will test for cellular patterns of iron dysregulation on the mesoscopic scale and relate these to antemortem clinical data on cognitive and behavioral functioning. Finally, we will integrate multiple digital measures of gliosis and iron- overload with longitudinal antemortem MRI using network science. Thus, our work will provide a fresh examination of the role of glia and iron-homeostasis in progressive spread of Tau vs TDP-43 proteinopathies and provide critical ground-truth human histopathology data to guide MRI biomarker development thereby addressing several key recommendations from the 2022 NIH ADRD summit for FTD research priorities.