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. 2021:29:102566.
doi: 10.1016/j.nicl.2021.102566. Epub 2021 Jan 19.

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

Isaac M Adanyeguh  1 , Xiaofang Lou  1 , Eavan McGovern  1 , Marie-Pierre Luton  1 , Magali Barbier  1 , Elise Yazbeck  1 , Romain Valabregue  2 , Dinesh Deelchand  3 , Pierre-Gilles Henry  3 , Fanny Mochel  4
Affiliations

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

Isaac M Adanyeguh et al. Neuroimage Clin. 2021.

Abstract

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.

Keywords: Adrenomyeloneuropathy; Fixel-based analysis; Imaging biomarkers; Metabolite cycling; Spinal cord imaging; Spinal cord toolbox.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
Cross-sectional area of the spinal cord. Spine CSA was reduced in all vertebral regions in patients with AMN (A), and the decrease was more evident in the gray matter (B). (*** p < 0.001).
Fig. 2
Fig. 2
Metabolite alterations in the spinal cord. Absolute concentrations showed a significantly reduced tNAA and a trend to increase in myo-Ins in patients with AMN (A). The ratio of tNAA/myo-Ins was significantly decreased in patients compared to controls (B). tNAA, total N-acetylaspartate; tCr, total creatine; tCho, total choline; myo-Ins, myo-Inositol. (*** p < 0.001).
Fig. 3
Fig. 3
Percentage MTR changes in the spinal cord. MTR was markedly reduced in cervical levels C1-C5 in patients with AMN (A) and in the spine gray matter and white matter regions examined (B). (*** p < 0.001).
Fig. 4
Fig. 4
Alterations in DTI and FBA metrics in the spinal cord. FA was reduced in C3-C5 in patients (A), and in the gray matter and white mater regions examined (B). FC, FD and FDC were reduced in the spine of patients compared to controls (C). FC values have been log normalized for normal distribution and to center the mean around zero. FC, fiber cross-section; FD, fiber density; FDC, fiber density and cross-section. (*** p < 0.001).
Fig. 5
Fig. 5
Effect sizes of spinal cord imaging metrics. The spinal cord imaging metrics showed very large to huge effect sizes with the exception of RD that showed a very small effect size. MTR showed the largest effect size among all the metrics. MTR, magnetization transfer ratio; FD, fiber density; FBA, fixel-based analysis; CSA, cross-sectional area; tNAA, total N-acetylaspartate; myo-Ins, myo-Inositol; MRS, magnetic resonance spectroscopy; FC, fiber cross-section; FA, fractional anisotropy; DTI, diffusion tensor imaging; FDC, fiber density and cross-section; RD, radial diffusivity.
Fig. 6
Fig. 6
Brain microstructural alterations between patients and controls. DTI metrics showed significantly increased FA and reduced MD, RD and AD in the brain of patients with AMN compared to controls (A). FBA metrics showed significantly reduced fixel in the corticospinal tract and corpus callosum of patients with AMN compared to controls (B). FA, fractional anisotropy; MD, mean diffusivity; RD, radial diffusivity; AD, axial diffusivity; FD, fiber density; FC, fiber cross-section; FDC, fiber density and cross-section.
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