# Microscopic and Large-Scale Networks of Molecular Pathology in Frontotemporal Lobar Degeneration

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $760,446

## Abstract

ABSTRACT
The overall goals and objectives of this proposal are to integrate digital histopathology and structural
neuroimaging data to model patterns of spread of molecular pathology associated with frontotemporal
dementia (FTD). FTD is an incurable progressive neurodegenerative disorder that is a common form of
dementia in patients between the ages of 40-65. FTD clinical syndromes include the behavioral-variant
(bvFTD) and primary progressive aphasia (PPA). The underlying neuropathology associated with FTD clinical
syndromes is classified as frontotemporal lobar degeneration (FTLD) with either tau (FTLD-Tau) or TDP-43
(FTLD-TDP) proteinaceous intracellular incisions in brain cells, which currently can only be detected at
autopsy. These disparate proteinopathies can result in clinically indistinguishable FTD clinical bvFTD and PPA
syndromes during life. Cell-to-cell spread of pathogenic forms of these proteins contributes to disease
pathogenesis and thus, a major obstacle for disease modifying therapies targeting this process is the ability to
detect and track these specific protein aggregations antemortem. A network science approach to neuroimaging
in living patients finds bvFTD and PPA patients have disease in brain regions corresponding to neurocognitive
networks for social/executive and language functioning, respectively, but the patterns of disease progression of
these specific proteinopathies within these neurocognitive networks is unknown. The overarching hypothesis of
this proposal is that FTLD-Tau and FTLD-TDP have partially dissociable patterns of cellular pathology in
microscopic networks of neurons and glia that selectively impact large-scale regional cognitive networks, and
this can be used to differentiate and track these pathologies antemortem. The aims of this study are to first
perform a detailed digital histopathological study to quantify and compare the cellular and regional pattern of
FTLD-Tau and FTLD-TDP pathology in the cerebrum. Next, network-science analytics will be performed to
study the microscopic connectivity patterns of spread of these disparate pathologies in high-density sampling
from multiple frontotemporal regions in each hemisphere. Finally, network analytics will be applied to
longitudinal antemortem structural imaging to define “signatures” of progressive FTLD-Tau and FTLD-TDP
neuropathology networks in clinical bvFTD and PPA. These findings will discover histopathology-validated
markers of progressive disease that inform theories of spreading pathology in humans with FTLD-tau and
FTLD-TDP, and provide pathology-validated clinical and anatomical models of in vivo disease progression that
will be useful for diagnosis, staging and prognosis in FTD-spectrum disorders.

## Key facts

- **NIH application ID:** 10470097
- **Project number:** 5R01NS109260-04
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** David John Irwin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $760,446
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10470097

## Citation

> US National Institutes of Health, RePORTER application 10470097, Microscopic and Large-Scale Networks of Molecular Pathology in Frontotemporal Lobar Degeneration (5R01NS109260-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10470097. Licensed CC0.

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