Integrated micro-to-macro network models of disease spread in frontotemporal dementia

University Of Pennsylvania, Philadelphia PA

Investigators

Abstract

PROJECT SUMMARY Frontotemporal dementia (FTD) is a clinically heterogenous spectrum of neurodegenerative disorders that is one of the leading sources of early onset dementia in patients. FTD is generally associated with either underlying tau (FTLD-Tau) or TDP-43 (FTLD-TDP) proteinopathies, which are not yet diagnosable prior to autopsy under current clinical criteria. Within each clinical syndrome of FTD, analysis of standard in vivo structural and functional imaging has been confounded by converging patterns of structural and neurocognitive network degeneration that makes it challenging to distinguish between these two disparate pathologies. However, our preliminary findings suggest that observing microscopic pathology burden as covarying connections in a network model can reveal diverging patterns of disease that may inform us on the significance of broader, macroscopic degeneration observed in the brain through in vivo imaging. We hypothesize that a high-dimensional evaluation of neurodegeneration across different modalities and scales can reveal unique characterizations of FTLD-Tau and FTLD-TPD pathology that cannot be observed in isolation. The goal of this proposal is to evaluate this hypothesis through the development of a multi-scale network model that integrates imaging data across different resolution scales and modalities into a single network. To accomplish this goal, we propose two Specific Aims: (1) Integrate microscopic histopathology imaging and macroscopic in vivo magnetic resonance (MR) imaging into a shared multi-scale network framework, which allows us to generate high-dimensional network measures and motifs that can characterize FTLD-Tau and FLTD- TDP pathology relationships across different macroscopic, mesoscopic, and microscopic resolution levels. (2) Develop a novel cellular network model for multiplex immunofluorescent imaging data, which allows us to analyze multi-dimensional, inter-cellular associations with respect to FTLD-Tau and FTLD-TDP pathology. Findings from this study will inform us on the complex interactions between macroscopic degeneration and microscopic spread of pathology. Modeling these key multi-scale relationships between in vivo imaging trends and their underlying pathology provides a new framework that can help identify and quantify potential in vivo imaging markers for therapeutic trials targeting tau or TPD43 in FTD. Lastly, tools developed as part of this proposal to construct and analyze the cellular and multi-scale networks are widely applicable to other neurodegenerative diseases and will be provided as an open resource for the neuroscience community.