Quantitative MR neurography biomarkers in 5q-linked spinal muscular atrophy

Kollmer, Jennifer; Hilgenfeld, Tim; Ziegler, Andreas; Saffari, Afshin; Sam, Georges; Hayes, John M.; Pietsch, Adriana; Jost, Marie; Heiland, Sabine; Bendszus, Martin; Wick, Wolfgang; Weiler, Markus

doi:10.1212/wnl.0000000000007945

Cited by 29 publications

(49 citation statements)

References 41 publications

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“…Importantly, treatment response should not be based on the improvement of motor function alone, but focus on preventing all aspects of disease progression. This may include additional objective measurements of disease progression, like quantitative high-resolution muscle ultrasound or MRI of muscle and peripheral nerve to indicate early nerve tissue changes and to detect and measure the progression of muscular atrophy and nerve tissue changes in response to the treatment [34][35][36]. In addition, suitable questionnaires for patient-related outcomes have to be developed to assess the efficacy of future treatments.…”

Section: Discussionmentioning

confidence: 99%

Safety and Treatment Effects of Nusinersen in Longstanding Adult 5q-SMA Type 3 – A Prospective Observational Study

Walter¹,

Wenninger²,

Thiele³

et al. 2019

Journal of Neuromuscular Diseases

155

167

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Objective: Spinal muscular atrophy (SMA) is a progressive autosomal recessive motor neuron disease caused by loss of the SMN1 gene. Based on randomized clinical trials in children with SMA type 1 and 2, Nusinersen has been approved as the first treatment for all types of SMA, including adults with SMA type 3. Methods: We evaluated the safety and treatment effects of Nusinersen in longstanding adult 5q-SMA type 3. Patients were treated with intrathecal loading doses at day 1, 14, 28 and 63, followed by maintenance dose every four months up to 300 days. We monitored the patients within SMArtCARE, a prospective open-label outcome study for disease progression, side effects and treatment efficacy, encompassing clinical examination including MRC sum score, vital capacity in sitting position (VC, VC %pred.), ALS Functional Rating Scale (ALS-FRS), 6-Minute-Walk-Test (6MWT), Revised Upper Limb Module (RULM), and Hammersmith Functional Rating Scale (HFMSE). We also measured biomarkers in the spinal fluid (phosphorylated neurofilament heavy chain pNFH, neuron-specific enolase NSE, proteins, ß-Amyloid 1-40, ß-Amyloid 1-42, tau and phospho-tau) and creatine kinase (CK). Assessments were performed at baseline, day 63 (V4), day 180 (V5) and day 300 (V6). For statistical analysis, we compared baseline to V4, V5 and V6, using the paired sample t-test. When there were significant differences, we added cohen´s d and effect size r for evaluation of clinical meaningfulness. 1 Equal contribution.

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Section: Discussionmentioning

confidence: 99%

Safety and Treatment Effects of Nusinersen in Longstanding Adult 5q-SMA Type 3 – A Prospective Observational Study

Walter¹,

Wenninger²,

Thiele³

et al. 2019

Journal of Neuromuscular Diseases

155

167

View full text Add to dashboard Cite

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“…Alternatively, SMN-driving pharmacotherapies could be administered to SMA patients irrespective of their SMN2 copy number, with decisionmaking on the continuation of further treatment depending on individual clinical and biomarker responses [44]. In this context, quantitative imaging biomarkers such as MTR, T2 app or q [13] could be a valuable contribution. The relatively low number of patients in the present study limited our ability to significantly delineate differences in MTR (and/or CSA) between SMA 3a and 3b, even though a tendency towards lower MTR values was observed in the more severely affected SMA 3a patients.…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Recently, we reported that high-resolution magnetic resonance neurography (MRN) [8][9][10][11][12] detects and quantifies peripheral nerve involvement in adults with SMA with high sensitivity [13]. We concluded that the two quantitative MRN markers apparent T2-relaxation time (T2 app ) and proton spin density (q) might serve as novel imaging biomarkers in SMA [13], but the macromolecular changes underlying alterations in T2 app and q are still not fully understood. Magnetization transfer contrast (MTC) imaging can provide valuable information on the concentration of protons bound to macromolecules and their interaction with free water molecules that cannot be measured directly by conventional magnetic resonance imaging (MRI) sequences [14][15][16].…”

Section: Introductionmentioning

confidence: 99%

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Magnetization transfer ratio: a quantitative imaging biomarker for 5q spinal muscular atrophy

Kollmer

Keßler

Sam

et al. 2020

Euro J of Neurology

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Background and purpose: We quantified peripheral nerve lesions in adults with 5q-linked spinal muscular atrophy (SMA) type 3 by analysing the magnetization transfer ratio (MTR) of the sciatic nerve, and tested its potential as a novel biomarker for macromolecular changes. Methods: Eighteen adults with SMA 3 (50% SMA 3a, 50% SMA 3b) and 18 age-/sex-matched healthy controls prospectively underwent magnetization transfer contrast imaging in a 3-Tesla magnetic resonance scanner. Two axial three-dimensional gradient echo sequences, with and without an off-resonance saturation rapid frequency pulse, were performed at the right distal thigh. Sciatic nerve regions of interest were manually traced on 10 consecutive axial slices in the images generated without off-resonance saturation, and then transferred to corresponding slices generated by the sequence with the off-resonance saturation pulse. Subsequently, MTR and cross-sectional areas (CSAs) of the sciatic nerve were analysed. In addition, detailed neurologic, physiotherapeutic and electrophysiologic examinations were conducted in all patients. Results: Sciatic nerve MTR and CSA reliably differentiated between healthy controls and SMA 3, 3a or 3b. MTR was lower in the SMA 3 (P < 0.0001), SMA 3a (P < 0.0001) and SMA 3b groups (P = 0.0020) than in respective controls. In patients with SMA 3, MTR correlated with all clinical scores, and arm nerve compound motor action potentials (CMAPs). CSA was lower in the SMA 3 (P < 0.0001), SMA 3a (P < 0.0001) and SMA 3b groups (P = 0.0006) than in controls, but did not correlate with clinical scores or electrophysiologic results. Conclusions: Magnetization transfer ratio is a novel imaging marker that quantifies macromolecular nerve changes in SMA 3, and positively correlates with clinical scores and CMAPs.

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“…9 Most imaging studies in SMA have focused on a qualitative appreciation of muscle, grading fat infiltration visually. [10][11][12][13][14][15][16][17][18][19][20] Quantitative MRI (qMRI) can complement qualitative evaluation of muscles and has shown promising results in other neuromuscular disorders, such as Duchenne muscular dystrophy (DMD) and limb girdle muscular dystrophies (LGMD). 21,22 Quantitative MRI in SMA has not been studied in detail.…”

Section: Introductionmentioning

confidence: 99%

Quantitative MRI of skeletal muscle in a cross‐sectional cohort of patients with spinal muscular atrophy types 2 and 3

et al. 2020

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The aim of this study was to document upper leg involvement in spinal muscular atrophy (SMA) with quantitative MRI (qMRI) in a cross‐sectional cohort of patients of varying type, disease severity and age. Thirty‐one patients with SMA types 2 and 3 (aged 29.6 [7.6‐73.9] years) and 20 healthy controls (aged 37.9 [17.7‐71.6] years) were evaluated in a 3 T MRI with a protocol consisting of DIXON, T2 mapping and diffusion tensor imaging (DTI). qMRI measures were compared with clinical scores of motor function (Hammersmith Functional Motor Scale Expanded [HFMSE]) and muscle strength. Patients exhibited an increased fat fraction and fractional anisotropy (FA), and decreased mean diffusivity (MD) and T2 compared with controls (all P < .001). DTI parameters FA and MD manifest stronger effects than can be accounted for the effect of fatty replacement. Fat fraction, FA and MD show moderate correlation with muscle strength and motor function: FA is negatively associated with HFMSE and Medical Research Council sum score (τ = −0.56 and −0.59; both P < .001) whereas for fat fraction values are τ = −0.50 and −0.58, respectively (both P < .001). This study shows that DTI parameters correlate with muscle strength and motor function. DTI findings indirectly indicate cell atrophy and act as a measure independently of fat fraction. Combined these data suggest the potential of muscle DTI in monitoring disease progression and to study SMA pathogenesis in muscle.

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Quantitative MR neurography biomarkers in 5q-linked spinal muscular atrophy

Cited by 29 publications

References 41 publications

Safety and Treatment Effects of Nusinersen in Longstanding Adult 5q-SMA Type 3 – A Prospective Observational Study

Safety and Treatment Effects of Nusinersen in Longstanding Adult 5q-SMA Type 3 – A Prospective Observational Study

Magnetization transfer ratio: a quantitative imaging biomarker for 5q spinal muscular atrophy

Quantitative MRI of skeletal muscle in a cross‐sectional cohort of patients with spinal muscular atrophy types 2 and 3

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