# Anatomic mechanisms of resilience and genetic susceptibility in TDP-related disorders

> **NIH NIH P01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $278,318

## Abstract

Project Summary
Behavioral variant frontotemporal degeneration (bvFTD) is a common cause of young-onset
neurodegenerative disease and life expectancy is approximately 7 years, but this is highly variable. Recent
work associates change in cognitive and MRI imaging with pathologic phases of accumulating FTLD-TDP and
FTLD-Tau pathology. However, major gaps in knowledge concern the tremendous variability in the rate of
clinical progression in bvFTD, and the factors contributing to this variability. Studies have demonstrated that
lifestyle factors moderate the rate of clinical progression in neurodegenerative disease. This is attributed to
cognitive reserve, a form of resilience where cognitive strategies help support brain functioning in the face of
relentlessly accumulating pathology and thus modulate the rate of longitudinal decline. For example,
neuroanatomic factors may also play a role in neural implementation of compensatory function, such as
supporting alternate brain networks for optimal performance. Genetic factors associated with single nucleotide
polymorphisms (SNPs) also may impact the variable rate of decline in bvFTD by selectively increasing
anatomic network vulnerability to disease burden. The overall aim of this proposal is to better understand how
lifestyle and genetic factors impact neural networks to influence the rate of longitudinal decline. In Aim 1, we
will examine education, occupation and leisure activities that moderate the rate of longitudinal decline on
cognitive and functional measures. We will relate this to MRI of gray matter (GM) and white matter (WM) using
powerful graph theoretic analyses that examine key metrics of network connectivity and elucidate the
neuroanatomic basis of resilience. Aim 2 will use arterial spin labeling to enhance models of network
connectivity that predict the rate of longitudinal clinical decline, and expect to find key connectomic properties
of frontal networks related to cerebral blood flow that contribute to resilience in bvFTD. In Aim 3, we will
examine hypothesis-driven SNPs that may moderate the rate of clinical decline and relate SNP variation to
anatomic regions in connectomic networks. This unique combination of lifestyle, genetic and imaging factors
will lead to novel predictive models of clinical disease progression that are critical for clinical management and
clinical trial endpoints, while providing important prognostic data for patients and families.
!

## Key facts

- **NIH application ID:** 10889944
- **Project number:** 5P01AG066597-05
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Lauren M Massimo
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $278,318
- **Award type:** 5
- **Project period:** 2020-09-15 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10889944

## Citation

> US National Institutes of Health, RePORTER application 10889944, Anatomic mechanisms of resilience and genetic susceptibility in TDP-related disorders (5P01AG066597-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10889944. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*