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

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.

Grant Number: 1R21AG089706-01A1
NIH Institute/Center: NIH
Principal Investigator: Min Chen