# Defining trajectories of dynamic biomarkers for C9ORF72 repeat expansion carriers

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $682,690

## Abstract

PROJECT SUMMARY/ABSTRACT
In 2011, the discovery that a hexanucleotide expansion in C9ORF72 is the most common genetic cause of
frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), revealed a common mechanism for
these two fatal diseases that have no cure. Since then, intensive research on C9ORF72 has culminated in the
identification of its possible pathophysiological mechanisms and excitingly, new drug treatments. Promising
drugs that target the effects of the repeat expansion reduce pathological changes in C9ORF72 mouse models
and patient-derived cell models. Although these drugs are now ready for human clinical trials, the absence of
established biomarkers for detecting disease and monitoring treatment is a major obstacle to the success of
these trials. Thus, this proposal aims to advance the diagnosis and care of C9ORF72 expansion carriers by
analyzing the trajectories of promising biomarkers throughout the natural history of the C9ORF72 lifespan. We
will study 120 C9ORF72 expansion carriers (60 presymptomatic, 60 symptomatic) and 60 gene negative non-
carrier family members for 3 longitudinal time points. All subject data will come from two NIH-funded parent
projects for frontotemporal lobar degeneration: 1) Longitudinal Evaluation of Familial Frontotemporal Dementia
Subjects (LEFFTDS, 1U01AG045390) and 2) Advancing the Research and Treatment of Frontotemporal Lobar
Degeneration (ARTFL, U54NS092089). LEFFTDS and ARTFL employ fully harmonized data protocols to
collect comprehensive longitudinal clinical, imaging and biospecimen data across 16 centers. We will model
C9ORF72 disease trajectories by analyzing multimodal neuroimaging measures and fluid biomarkers to
identify the earliest disease manifestations in C9ORF72 and how they track the natural history of disease. Aim
1 will identify longitudinal changes in brain structure and neural network dysfunction in C9ORF72 carriers. Aim
2 will model trajectories of candidate fluid biomarkers. Aim 3 will determine associations between fluid
biomarkers and brain structure and function. This study will be innovative as a comprehensive, longitudinal
analysis of promising biomarkers to capture C9ORF72 disease trajectories. Upon completion of this study, we
expect to lay the foundation for an integrated framework of biomarkers to monitor treatment response both at
the biochemical level and at the brain-systems level.

## Key facts

- **NIH application ID:** 10146261
- **Project number:** 5R01AG058233-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** SUZEE EURIE LEE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $682,690
- **Award type:** 5
- **Project period:** 2018-08-15 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10146261

## Citation

> US National Institutes of Health, RePORTER application 10146261, Defining trajectories of dynamic biomarkers for C9ORF72 repeat expansion carriers (5R01AG058233-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10146261. Licensed CC0.

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