Multicenter ALS Imaging Study

University of Minnesota90 enrolled

Overview

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.

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

Conditions

Amyotrophic Lateral Sclerosis ALS

Interventions

Magnetic Resonance ImagingDIAGNOSTIC_TEST

Participants will undergo 3T MRI scanning of the brain and cervical spine MRIs

Plasma neurofilament light chain (NfL) quantificationDIAGNOSTIC_TEST

Participants will undergo a blood draw for the quantification of plasma neurofilament light chain

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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 OR meets Gold Coast 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.

Locations (3)

University of Florida

Gainesville, Florida, United States

RECRUITING

Northwestern University

Evanston, Illinois, United States

RECRUITING

University of Minnesota

Minneapolis, Minnesota, United States

RECRUITING

Outcomes

Primary Outcomes

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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Central Contacts

Melisa Bailey, MS

CONTACT

612-624-4911 baile807@umn.edu

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

Secondary Outcomes

Plasma neurofilament light (NfL) quantification

Plasma NfL quantification will be reported in units of pg/ml.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Baseline