Pilot Study on Quantitative Cervical Cord and Muscular MRI in Spinal Muscular Atrophy: Promising Biomarkers of Disease Evolution and Treatment?

Abstract

Introduction: Nusinersen is a recent promising therapy approved for the treatment of spinal muscular atrophy (SMA), a rare disease characterized by the degeneration of alpha motor neurons (αMN) in the spinal cord (SC) leading to progressive muscle atrophy and dysfunction. Muscle and cervical SC quantitative magnetic resonance imaging (qMRI) has never been used to monitor drug treatment in SMA. The aim of this pilot study is to investigate whether qMRI can provide useful biomarkers for monitoring treatment efficacy in SMA.Methods: Three adult SMA 3a patients under treatment with nusinersen underwent longitudinal clinical and qMRI examinations every 4 months from baseline to 21-month follow-up. The qMRI protocol aimed to quantify thigh muscle fat fraction (FF) and water-T2 (w-T2) and to characterize SC volumes and microstructure. Eleven healthy controls underwent the same SC protocol (single time point). We evaluated clinical and imaging outcomes of SMA patients longitudinally and compared SC data between groups transversally.Results: Patient motor function was stable, with only Patient 2 showing moderate improvements. Average muscle FF was already high at baseline (50%) and progressed over time (57%). w-T2 was also slightly higher than previously published data at baseline and slightly decreased over time. Cross-sectional area of the whole SC, gray matter (GM), and ventral horns (VHs) of Patients 1 and 3 were reduced compared to controls and remained stable over time, while GM and VHs areas of Patient 2 slightly increased. We found altered diffusion and magnetization transfer parameters in SC structures of SMA patients compared to controls, thus suggesting changes in tissue microstructure and myelin content.Conclusion: In this pilot study, we found a progression of FF in thigh muscles of SMA 3a patients during nusinersen therapy and a concurrent slight reduction of w-T2 over time. The SC qMRI analysis confirmed previous imaging and histopathological studies suggesting degeneration of αMN of the VHs, resulting in GM atrophy and demyelination. Our longitudinal data suggest that qMRI could represent a feasible technique for capturing microstructural changes induced by SMA in vivo and a candidate methodology for monitoring the effects of treatment, once replicated on a larger cohort.

Degeneration of the Sensorimotor Tract in Degenerative Cervical Myelopathy and Compensatory Structural Changes in the Brain

“…However, it is impossible to evaluate the microstructural changes during the process of neurodegeneration and compensation. Many quantitative magnetic resonance (qMRI) techniques have been used to study the spinal cord (Lommers et al, 2021 ; Savini et al, 2021 ), and diffusion tensor imaging (DTI) is one of the most commonly used research methods (McLachlin et al, 2021 ). DTI is a standard neuroscience technique that is more sensitive than conventional MRI in evaluating spinal cord injuries (Zhang et al, 2018 ), and it provides important information about structural integrity, including myelin formation, axon diameter, and fiber density (Kumar et al, 2021 ), which indirectly reflect the degree of degeneration and pathophysiological structural changes of the spinal cord in vivo .…”

Muscle MRI in motor neuron diseases: a systematic review

“…Among these 28 articles, there were 14 MND/ ALS (18-31), 13 SMA (32-44) and three SBMA (20,29,45) patient groups. There were eight multiple-region (21,(24)(25)(26)28,29,37,45), 13 lower-limb (19,20,(32)(33)(34)(35)(36)38,(40)(41)(42)(43)(44), one paraspinal (30), three bulbar (18,22,23) and three whole-body (27,31,39) studies. These papers are summarized in Tables 1 and 2.…”

“…Studies in motor neuron diseases have applied quantitative (18,19,(22)(23)(24)29,(31)(32)(33)35,39,(42)(43)(44)(45), qualitative (18,20,21,25,26,(28)(29)(30)(32)(33)(34)(36)(37)(38)(39)(40)(41)45), and semi-quantitative (27,31) techniques, often in combination, and imaging protocols vary between studies. Most qualitative studies used the fivepoint Mercuri scale, which grades change from an early moth-eaten appearance to muscle replacement by connective tissue and fat (46).…”

“…No T1 signal changes were observed but DTI demonstrated increased number, length, and organization of muscle fiber tracts at follow-up. The second study assessed thigh FF and quantitative water-T2 signal in three female genetically-confirmed SMA IIIa patients and 11 healthy controls (44). Mean FF in patients increased by 6.7% and the average water-T2 signal decreased by 4.7%.…”