# Clinical Research in ALS and related disorders for Therapeutic Development (CReATe)

> **NIH NIH U54** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2021 · $194,584

## Abstract

PROJECT SUMMARY / ABSTRACT
The biology of ALS is difficult to study, in part because of a paucity of suitable tools, and in part because of the
relatively late stage in the course of the disease when the diagnosis is made. In this supplement to the parent
U54 award that supports the Clinical Research in ALS and Related Disorders for Therapeutic Development,
(CReATe) Consortium, we propose an analytic plan that will help to address both of these issues. Here we
introduce whole-brain proton magnetic resonance spectroscopic imaging (1H MRSI) as an innovative tool to
shed light on the biochemical (neurometabolite) changes in the brain associated with ALS within the context of
Pre-Symptomatic Familial ALS (Pre-fALS), a longitudinal natural history, and biomarker study of individuals at
genetic risk for ALS. Pre-fALS has been ongoing for ~15 years, with ~20 individuals phenoconverting to clinically
manifest ALS. In a subset of these individuals, we have been able to collect multi-modal brain MRI data both
before and following phenoconversion. This valuable resource offers a unique opportunity to explore the early
biochemical changes in the brains of patients with ALS, with potential relevance to the future development of
diagnostic biomarkers. Project-3 of our parent U54 award proposed to characterize the anatomic distribution and
temporal course of structural and functional changes in pre-symptomatic C9ORF72 and SOD1 mutation carriers
using structural, diffusion, perfusion, and resting-state functional MRI but did not include whole-brain proton
magnetic resonance spectroscopy data. This supplemental application aims to fill this gap, with an exclusive
focus on the analysis of whole-brain MRS data. Utilizing already collected MRSI data from the Pre-fALS study,
this supplement will allow us to characterize the anatomic distribution of neurometabolite changes in the brains
of pre-symptomatic SOD1 and C9ORF72 mutation carriers (Aim 1a). Additionally, through the planned pseudo-
longitudinal analysis we aim to identify temporal patterns of changes in neurodegeneration by studying changes
in metabolites in pre-symptomatic carriers across advancing age (Aim 1b). Finally, an exploratory longitudinal
study in phenoconvertors will allow mapping changes in brain metabolites that could provide insights into
neurodegenerative patterns that lead to ALS (Aim 2). The evaluation of MRSI data acquired as part Pre-fALS
will generate for the first time detailed whole-brain maps of neurodegeneration in pre-symptomatic individuals
with the potential to identify early MRSI biomarkers that might have future diagnostic utility. This supplement,
which does not entail any new MRI data collection given its relatively short timeframe (12 months), will strengthen
the nascent collaboration between Michael Benatar, MD, PhD (neurologist), and Mohammed Goryawala, PhD
(radiologist), who is new to the field of ALS. The knowledge gained through this supplement will enable improved
neurom...

## Key facts

- **NIH application ID:** 10381056
- **Project number:** 3U54NS092091-07S1
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Michael Benatar
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $194,584
- **Award type:** 3
- **Project period:** 2014-09-30 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10381056

## Citation

> US National Institutes of Health, RePORTER application 10381056, Clinical Research in ALS and related disorders for Therapeutic Development (CReATe) (3U54NS092091-07S1). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10381056. Licensed CC0.

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