Multicenter ALS Imaging Study

Multicenter Longitudinal Imaging in ALS for Disease Biomarker Development

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.

Study Overview

• Status: Recruiting
• Conditions: Amyotrophic Lateral Sclerosis; ALS
• Intervention / Treatment: Diagnostic test: Magnetic Resonance Imaging; Diagnostic test: Plasma neurofilament light chain (NfL) quantification

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 Type: Observational
• Enrollment (Estimated): 90

Contacts and Locations

• Study Contact: Name: Melisa Bailey, MS; Phone Number: 612-624-4911; Email: baile807@umn.edu

Study Locations

• United States
  • Florida
    • Gainesville, Florida, United States, 32608
      • Recruiting
      • University of Florida
      • Contact: Jennifer Steshyn, MABMH, CCRP
      • Principal Investigator: James Wymer, MD, FAAN
  • Illinois
    • Evanston, Illinois, United States, 60208
      • Recruiting
      • Northwestern University
      • Principal Investigator: Senda Ajroud-Driss, MD
      • Contact: Emma Schmidt
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Recruiting
      • University of Minnesota
      • Principal Investigator: David Walk, MD
      • Contact: Melisa Bailey, MS; Email: baile807@umn.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Adults with early-stage ALS

Description

For participants with ALS:

• < 36 months since onset of symptoms
• Definite, probable, lab supported-probable or possible ALS by El Escorial criteria OR definite, probable or possible ALS per 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 Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Participants with ALS; Adults with early stage ALS	Diagnostic test: Magnetic Resonance Imaging; Participants will undergo 3T MRI scanning of the brain and cervical spine MRIs; Diagnostic test: Plasma neurofilament light chain (NfL) quantification; Participants will undergo a blood draw for the quantification of plasma neurofilament light chain
Participants without ALS; Control participants free from neurological disease	Diagnostic test: Magnetic Resonance Imaging; Participants will undergo 3T MRI scanning of the brain and cervical spine MRIs; Diagnostic test: Plasma neurofilament light chain (NfL) quantification; Participants will undergo a blood draw for the quantification of plasma neurofilament light chain

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fiber Density	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.	Baseline, 3 months, 6 months, 12 months
Fiber Cross-Section	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.	Baseline, 3 months, 6 months, 12 months
Orientation Dispersion	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.	Baseline, 3 months, 6 months, 12 months
Intracellular Volume Fraction	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.	Baseline, 3 months, 6 months, 12 months
Free Water	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.	Baseline, 3 months, 6 months, 12 months
Cortical Thickness	This measure is collected using MRI. It is the thickness of the cortical gray matter and is measured in millimeters.	Baseline, 3 months, 6 months, 12 months
Spinal Cord Cross-Sectional Area	This measure is collected using MRI. It is the area of the spinal cord cross-section measured in millimeter square.	Baseline, 3 months, 6 months, 12 months
Spinal Cord Corticospinal Tract (CST) Fractional Anisotropy (FA)	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.	Baseline, 3 months, 6 months, 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma neurofilament light (NfL) quantification	Plasma NfL quantification will be reported in units of pg/ml.	Baseline, 3 months, 6 months, 12 months
ALS Functional Rating Scale, Revised (ALSFRS-R)	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.	Baseline, 3 months, 6 months, 12 months
Edinburgh Cognitive and Behavioural Screen (ECAS)	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.	At 3-month visit (optional)
Penn Upper Motor Neuron Score	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.	Baseline

Collaborators and Investigators

• Sponsor: University of Minnesota
• Collaborators: Food and Drug Administration (FDA); Minnesota Office of Higher Education
• Investigators: Principal Investigator: Pramod Pisharady, PhD, University of Minnesota

Study record dates

Study Major Dates

• Study Start (Actual): September 15, 2024
• Primary Completion (Estimated): August 31, 2027
• Study Completion (Estimated): August 31, 2028

Study Registration Dates

• First Submitted: November 22, 2024
• First Submitted That Met QC Criteria: December 10, 2024
• First Posted (Actual): December 16, 2024

Study Record Updates

• Last Update Posted (Actual): May 12, 2026
• Last Update Submitted That Met QC Criteria: May 7, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: MRI; Magnetic Resonance Imaging; ALSFRS-R; NfL; ECAS; plasma neurofilament light
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Neuromuscular Diseases; Metabolic Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Motor Neuron Disease; Nutritional and Metabolic Diseases; Amyotrophic Lateral Sclerosis; Diagnostic Techniques and Procedures; Diagnosis; Tomography; Diagnostic Imaging; Magnetic Resonance Imaging
• Other Study ID Numbers: CMRR-2024-32796

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: We plan to publish deidentified and preprocessed data from this study through public neuroimaging repositories. To facilitate the reproduction of our findings, we will also publish the deidentified data used to produce the figures and tables in our publications. We will keep the names and other identifying information of participants confidential.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No