Objective

Progressive myelopathy causes severe handicap in men with adrenomyeloneuropathy (AMN), an X-linked disorder due to ABCD1 pathogenic variants. At present, treatments are symptomatic but disease-modifying therapies are under evaluation. Given the small effect size of clinical scales in AMN, biomarkers with higher effect size are needed. Here we used high-resolution magnetic resonance techniques to identify non-invasive in vivo biomarkers of the brain and spine with high effect sizes.

Methods

We performed a multiparametric imaging and spectroscopy study in 23 male patients with AMN (age: 44 ± 11) and 23 male controls (age: 43 ± 11) of similar age and body-mass index. We combined (i) macrostructural analyses of the spine, using cross-sectional area (CSA) and magnetization transfer ratio (MTR), (ii) microstructural analyses of the spine and the brain, using diffusion tensor and the newly developed fixel-based analysis, and (iii) advanced metabolic analyses of the spine using metabolite cycling coupled to a semi-LASER sequences.

Results

Macrostructural alterations (decrease in CSA and MTR) were observed in patients at all spinal cord levels studied (C1-T2 for CSA and C1-C5 for MTR) (p < 0.001). Microstructural alterations were observed in the spine and brain on diffusion tensor and fixel-based metrics though the latter showed higher effect sizes. Metabolic alterations were observed in patients as a decreased total N-acetylaspartate/myo-inositol ratio (p < 0.001). Overall, MTR showed the highest effect size.

Conclusion

This cross-sectional study supports the use of multiparametric techniques that elucidate the structural, microstructural and metabolic alterations in AMN. These outcome measures should be tested longitudinally and in clinical trials.

中文翻译：

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大脑和脊柱的多参数体内分析可确定男性肾上腺脊髓神经病的结构和代谢生物标志物

目的

进行性脊髓病会导致患有肾上腺髓质神经病（AMN）的男性严重残疾，这是一种由ABCD1致病性变异引起的X连锁疾病。目前，治疗是对症治疗，但正在评估缓解疾病的疗法。鉴于AMN中临床量表的效应量较小，因此需要具有较高效应量的生物标志物。在这里，我们使用高分辨率磁共振技术来鉴定具有高效应大小的大脑和脊柱的非侵入性体内生物标记。

方法

我们对23名年龄和体质指数相似的男性AMN（年龄：44±11）和23名男性对照组（年龄：43±11）进行了多参数成像和光谱学研究。我们结合（i）使用横截面积（CSA）和磁化传递比（MTR）对脊柱进行宏观结构分析，（ii）使用扩散张量和新开发的基于Fixel的分析对脊柱和大脑进行显微结构分析；以及（iii）使用与半LASER序列耦合的代谢物循环对脊柱进行高级代谢分析。

结果

在所有研究的脊髓水平（CSA为C1-T2，MTR为C1-C5）的患者中均观察到宏观结构改变（CSA和MTR降低）（p <0.001）。在弥散张量和基于fixel的指标上，在脊柱和大脑中观察到微结构改变，尽管后者显示出更高的效应大小。在患者中观察到代谢改变，其总N-乙酰天门冬氨酸/肌醇比例降低（p <0.001）。总体而言，MTR展示了最高的效果大小。

结论

这项横断面研究支持阐明AMN中的结构，微结构和代谢变化的多参数技术的使用。这些结果指标应在纵向和临床试验中进行测试。