Multicenter ALS Imaging Study

Recruiting

• Conditions: Amyotrophic Lateral Sclerosis; ALS

• Registration Number: NCT06735014
• Lead Sponsor: University of Minnesota

Brief Summary

This is a multi-site study of ALS participants and healthy controls who will undergo brain and cervical spine MRIs and NfL blood testing at up-to 4 time points over the course of a year. The primary goal is to identify objective biomarkers of disease progression that are biologically relevant, linearly progressive, and sensitive to change.

Detailed Description

Recent developments in Magnetic Resonance Imaging (MRI), biophysical modeling, and computing have improved the sensitivity of imaging metrics to detect disease-related changes in the central nervous system in neurological disorders. This improved sensitivity has paved the way for utilizing these metrics as potential biomarkers of disease, in particular, to measure disease progression over short durations.

The investigators hypothesize that the multimodal analysis of MRI biomarkers (microstructure and morphology) from the brain and spine will improve sensitivity to detect disease-related changes over durations as short as 3 to 6 months. The hypothesis is based on prior work detecting longitudinal changes in brain microstructure over 6 months in an ALS cohort with modest change in functional measures over that time, and that a multimodal analysis combining brain and spine MRI measures can improve disease diagnosis accuracy.

In this project, the investigators will establish the scalability, sensitivity over shorter durations, and overall clinical trial readiness of these metrics through a three-site study. The investigators also propose to improve the sensitivity of imaging metrics by combining multiple complementary measures from the brain and spine in a longitudinal multimodal statistical framework. Additionally, the investigators will demonstrate how these imaging metrics correlate with fluid biomarkers and functional progression measures.

Upon completion of the project, the investigators anticipate that the enhanced sensitivity of our proposed longitudinal MRI biomarkers will have an impact on ALS treatment by providing novel surrogate markers as potential outcome measures for clinical trials. The expected increased effect size will also reduce the cohort size needed to conduct trials, thereby increasing their feasibility. Beyond the scope of clinical trials, these multimodal MRI biomarkers will serve as an objective measure of upper motor neuron degeneration at the single patient level. The MRI measures will also be cross validated with fluid biomarkers and will contribute to efforts to stratify ALS patients into clinically homogeneous cohorts.

Participants will be asked to complete 4 study visits over a 12-month period, with visits at baseline, 3 months, 6 months, and 12 months. Participants will receive an exam by a neurologist, blood draw, and MRI scan and will be asked to answer surveys about their medical history and ALS symptoms. Participants will be compensated for each visit via a prepaid card. Non-local participants living ≥100 miles from the research facility will be partially compensated for travel.

Study Timeline

• Study Start: 2024-09-15
• Study First Submitted: 2024-11-22
• Study First Submitted QC: 2024-12-10
• Study First Posted: 2024-12-16
• Status Verified: 2025-04
• Last Update Submitted: 2025-04-06
• Last Update Posted: 2025-04-09
• Primary Completion: 2027-08-31
• Study Completion: 2028-08-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 90

Inclusion Criteria

• < 24 months since onset of symptoms
• Definite, probable, laboratory-supported probable, or possible ALS by El Escorial criteria OR definite, probable, or possible ALS by Awaji-Shima Criteria
• Forced vital capacity within the last 90 days ≥ 60% of the predicted value
• Able to consent for themselves
• Able to read and speak English
• Clear of any contraindications for MRI

Exclusion Criteria

• Individuals will be excluded if they have any condition that makes MRI unsafe or if they are unable to comply with instructions.
• All participants will undergo a neurologic examination at enrollment. Control participants with clinically significant abnormal findings on neurological examination will be excluded from the study.

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Fiber Density	Baseline, 3 months, 6 months, 12 months	This measure comes from the biophysical model used in brain imaging and is collected using MRI. It refers to the volume of the intra-axonal compartment per unit volume of the tissue. As this is a fraction it does not have a unit.
Fiber Cross-Section	Baseline, 3 months, 6 months, 12 months	This measure comes from the biophysical model used in brain imaging and is collected using MRI. It refers to the change it fiber cross-section at the fiber bundle level when undergoing spatial normalization. This measure does not have a unit.
Orientation Dispersion	Baseline, 3 months, 6 months, 12 months	This measure comes from the biophysical model used in brain imaging and is collected using MRI. Orientation dispersion is a measure of the uncertainty in the estimation of the fiber bundle orientation. It varies from 0 to 1 and does not have a unit. Higher values indicate greater uncertainty in estimation.
Intracellular Volume Fraction	Baseline, 3 months, 6 months, 12 months	This measure comes from the biophysical model used in brain imaging and is collected using MRI. It is the proportion of the imaging voxel occupied by intracellular compartments. This ratio varies from 0 to 1 and does not have a unit. Larger values indicate greater density of intracellular compartments.
Free Water	Baseline, 3 months, 6 months, 12 months	This measure comes from the biophysical model used in brain imaging and is collected using MRI. It represents the fractional volume of the free-water compartment. This is a ratio and it does not have a unit.
Cortical Thickness	Baseline, 3 months, 6 months, 12 months	This measure is collected using MRI. It is the thickness of the cortical gray matter and is measured in millimeters.
Spinal Cord Cross-Sectional Area	Baseline, 3 months, 6 months, 12 months	This measure is collected using MRI. It is the area of the spinal cord cross-section measured in millimeter square.
Spinal Cord Corticospinal Tract (CST) Fractional Anisotropy (FA)	Baseline, 3 months, 6 months, 12 months	This measure is collected using MRI. It is a dimensionless scalar value between 0 and 1, indicating the degree of anisotropy (directionality) of water diffusion in the spinal cord's corticospinal tract. Higher values indicate higher anisotropy.

Secondary Outcome Measures

Name	Time	Method
Plasma neurofilament light (NfL) quantification	Baseline, 3 months, 6 months, 12 months	Plasma NfL quantification will be reported in units of pg/ml.
ALS Functional Rating Scale, Revised (ALSFRS-R)	Baseline, 3 months, 6 months, 12 months	The ALSFRS-R includes 12 questions. Each task is rated on a five-point scale from 0 (can't do) to 4 (normal ability). Individual item scores are summed to produce a reported score of between 0=worst and 48=best.
Edinburgh Cognitive and Behavioural Screen (ECAS)	At 3-month visit (optional)	The ECAS is a 20-minute assessment of language, memory, verbal fluency, executive function, visuospatial function, and social cognition, which produce a number of subscales with a maximum total score of 136. Higher scores indicate better functioning.
Penn Upper Motor Neuron Score	Baseline	The Penn Upper Motor Neuron Score (PUMNS) is a 28-item scale that measures upper motor neuron (UMN) signs in amyotrophic lateral sclerosis (ALS). The scale ranges from 0 (normal) to 32 (for widespread/severe UMN involvement) and evaluates the bulbar region (scores 0-4), upper limbs (scores 0-14), and lower limb (scores 0-14). Higher scores indicate greater disease burden.

Trial Locations

Locations (3)

University of Florida; 🇺🇸 Gainesville, Florida, United States

University of Minnesota; 🇺🇸 Minneapolis, Minnesota, United States

Northwestern University; 🇺🇸 Evanston, Illinois, United States