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BACKGROUND

Natural history studies in neuromuscular disorders are vital to understand the disease evolution and to find sensitive outcome measures. We performed a longitudinal assessment of quantitative magnetic resonance imaging (MRI) and phosphorus magnetic resonance spectroscopy ( P MRS) outcome measures and evaluated their relationship with function in lower limb skeletal muscle of dysferlinopathy patients.

METHODS

Quantitative MRI/ P MRS data were obtained at 3 T in two different sites in 54 patients and 12 controls, at baseline, and three annual follow-up visits. Fat fraction (FF), contractile cross-sectional area (cCSA), and muscle water T in both global leg and thigh segments and individual muscles and P MRS indices in the anterior leg compartment were assessed. Analysis included comparisons between patients and controls, assessments of annual changes using a linear mixed model, standardized response means (SRM), and correlations between MRI and P MRS markers and functional markers.

RESULTS

Posterior muscles in thigh and leg showed the highest FF values. FF at baseline was highly heterogeneous across patients. In ambulant patients, median annual increases in global thigh and leg segment FF values were 4.1% and 3.0%, respectively (P < 0.001). After 3 years, global thigh and leg FF increases were 9.6% and 8.4%, respectively (P < 0.001). SRM values for global thigh FF were over 0.8 for all years. Vastus lateralis muscle showed the highest SRM values across all time points. cCSA decreased significantly after 3 years with median values of 11.0% and 12.8% in global thigh and global leg, respectively (P < 0.001). Water T values in ambulant patients were significantly increased, as compared with control values (P < 0.001). The highest water T values were found in the anterior part of thigh and leg. Almost all P MRS indices were significantly different in patients as compared with controls (P < 0.006), except for pH , and remained, similar as to water T , abnormal for the whole study duration. Global thigh water T at baseline was significantly correlated to the change in FF after 3 years (ρ = 0.52, P < 0.001). There was also a significant relationship between the change in functional score and change in FF after 3 years in ambulant patients (ρ = -0.55, P = 0.010).

CONCLUSIONS

This multi-centre study has shown that quantitative MRI/ P MRS measurements in a heterogeneous group of dysferlinopathy patients can measure significant changes over the course of 3 years. These data can be used as reference values in view of future clinical trials in dysferlinopathy or comparisons with quantitative MRI/S data obtained in other limb-girdle muscular dystrophy subtypes.

背景

神经肌肉疾病的自然史研究对于了解疾病的演变和寻找敏感的结局指标至关重要。我们对肌营养不良症患者下肢骨骼肌的定量磁共振成像（MRI）和磷磁共振波谱（P MRS）进行了纵向评估，并评估了它们与功能的关系。

方法

在两个不同的地点，在 54 名患者和 12 名对照者中，在基线时以及 3 次年度随访时，在 3 T 上获得定量 MRI/P MRS 数据。评估了大腿和小腿的全球节段和单个肌肉的脂肪分数（FF）、收缩性横截面积（cCSA）和肌肉水 T，以及前腿部隔间的 P MRS 指数。分析包括患者与对照组之间的比较，使用线性混合模型评估年度变化，标准化反应均值（SRM），以及 MRI 和 P MRS 标志物与功能标志物之间的相关性。

结果

大腿和小腿的后部肌肉显示出最高的 FF 值。基线时，患者之间的 FF 值存在很大的异质性。在可走动的患者中，大腿和小腿全球段 FF 值的中位数每年分别增加 4.1%和 3.0%（P<0.001）。3 年后，大腿和小腿的全球 FF 增加分别为 9.6%和 8.4%（P<0.001）。所有年份的全球大腿 FF 的 SRM 值均大于 0.8。股外侧肌在所有时间点均显示出最高的 SRM 值。3 年后，cCSA 显著下降，大腿和小腿的中位数分别为 11.0%和 12.8%（P<0.001）。与对照组相比，可走动患者的水 T 值显著增加（P<0.001）。大腿和小腿的前半部分水 T 值最高。与对照组相比，几乎所有 P MRS 指数均存在显著差异（P<0.006），除 pH 外，所有指数在整个研究期间均保持异常。基线时的大腿全球水 T 值与 3 年后 FF 的变化显著相关（ρ=0.52，P<0.001）。在可走动的患者中，功能评分的变化与 3 年后 FF 的变化之间也存在显著的关系（ρ=-0.55，P=0.010）。