Multiparametric in vivo analyses of the brain and spine identify structural and metabolic biomarkers in men with adrenomyeloneuropathy

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.

Automated summary

Progressive myelopathy in men with adrenomyeloneuropathy (AMN) causes severe disability, with treatments being symptomatic and disease-modifying therapies under evaluation. This study used high-resolution MRI techniques to identify non-invasive biomarkers of the brain and spine with high effect sizes, showing macrostructural, microstructural, and metabolic alterations in AMN patients. Further longitudinal and clinical trials are warranted to validate these findings.