# Clinical Research in ALS & Related Disorders for Therapeutic Development (CReATe) - Project Core #3

> **NIH NIH U54** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2021 · $110,637

## Abstract

PROJECT SUMMARY/ABSTRACT
Despite decades of research and dozens of trials, effective disease-modifying treatments for amyotrophic
lateral sclerosis (ALS) and other neurodegenerative disorders still elude us. A primary source of the litany of
negative trials is the increasing recognition that experimental therapeutics are frequently administered too late
in the course of disease, after irreversible neuronal loss has already occurred. These delays stem in part from
the fact that the degenerative processes in ALS begins prior to overt clinical disease, and in part from delays in
diagnosis (approximately 12 months from symptom onset) and delays between onset and clinical trial
enrollment (approximately 17 months interventional delay). The overall goal of this project is to address the
challenge to ALS drug development that is posed by the relatively late stage in the course of disease when
diagnosis is made and patients are enrolled in clinical trials. The study of pre-symptomatic disease is currently
only possible in (but also most relevant to) those with the genetic forms of ALS, most commonly due to point
mutations in the SOD1 gene or a repeat expansion in C9orf72. But earlier diagnosis of symptomatic disease is
relevant to patients with all forms of ALS (both genetic and non-genetic). In this project, we outline two
strategies for addressing these challenges, with a view to preparing for a future of clinical trials that enroll
patients at significantly earlier stages in the course of their disease. In Aim 1 of this project we propose to use
multimodal neuroimaging (MRI, DTI, and perfusion MRI) combined with pseudo-longitudinal, exploratory
longitudinal, and multivariate network statistical techniques to characterize the anatomic distribution and
temporal course of structural and functional changes in pre-symptomatic C9orf72 and SOD1 mutation carriers.
We hypothesize that this approach will help us better understand how and when anatomic changes occur
across adult aging in pre-symptomatic individuals at risk for ALS (or FTD) relative to age-matched non-
mutation controls. We also hypothesize that network and multivariate approaches will help increase our
biological understanding of C9orf72 and SOD1, as well as how these distinct etiologies of familial ALS may
differ from one another. In Aim 2 of this project we will use a “cohort” approach to evaluate the diagnostic
accuracy (sensitivity, specificity and positive/negative predictive value) of serum and CSF measurement of
neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) for the early diagnosis of ALS. This
approach will fill a critical gap in the current literature about the utility of neurofilaments for the diagnosis, and
particularly in earlier stages of ALS. Since the currently available evidence is based on case-control studies
(i.e. a comparison of patients already known to have ALS vs. patients already known to have some other
disease), current estimates of sensitivity,...

## Key facts

- **NIH application ID:** 10242884
- **Project number:** 5U54NS092091-08
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Corey T McMillan
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $110,637
- **Award type:** 5
- **Project period:** 2014-09-30 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242884

## Citation

> US National Institutes of Health, RePORTER application 10242884, Clinical Research in ALS & Related Disorders for Therapeutic Development (CReATe) - Project Core #3 (5U54NS092091-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10242884. Licensed CC0.

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