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.
Highlights
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 in the spinal cord (SC) leading to progressive muscle atrophy and dysfunction
In gray matter (GM), we report a reduction in radial diffusivity (RD) and an increase in fractional anisotropy (FA) in SMA patients with respect to healthy controls (HC), while no differences can be observed for axial diffusivity (AD) and mean diffusivity (MD) values
In the SC, we observed reduced cross-sectional area (CSA), GM, and ventral horns (VHs) CSA of SMA patients transversally compared to HCs at TP3; these values remained generally stable over time, Patient 2 exhibited a trend of increasing GM and VHs area over time
Summary
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. Spinal muscular atrophy (SMA) refers to a spectrum of genetic neuromuscular disorders characterized by the degeneration of alpha motor neurons (αMNs) in the spinal cord (SC) [1] that leads to progressive muscle atrophy, consequent loss of muscular strength and paralysis. Within this group of disorders, the socalled 5q SMA is a rare condition (estimated incidence: from 1/6,000 to 1/10,000 live births) [2] caused by homozygous loss of function of SMN1 gene (survival motor neuron gene 1—telomeric form) (5q11.2-q11.3), with consequent SMN protein deficiency in lower motor neurons. The SMN2 copy number inversely correlates with disease severity [4, 5]
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