Spectroscopic evidence of cerebral axonopathy in patients with "pure" adrenomyeloneuropathy

Background: Adrenomyeloneuropathy (AMN) is the adult variant of X-linked adrenoleukodystrophy. The disease pathology is usually limited to spinal cord and peripheral nerves, and when this is the case, it is referred to as "pure" AMN. Histopathology shows cerebral involvement even in pure AMN; however, not much is known about the nature, extent, and clinical relevance of these findings. Objective: To investigate brain involvement in AMN patients with normal MRI, employing multislice MR spectroscopic imaging. Methods: Twelve men with pure AMN were compared with 19 age-matched healthy volunteers. Metabolite ratios (N-acetylaspartate [NAA]/choline [Cho], NAA/creatine [Cr], and Cho/Cr) were measured from seven brain regions. Global metabolite ratios were generated as an average of these seven regional ratios. The Expanded Disability Status Scale (EDSS) was used for neurologic evaluation. Results: The patients with AMN showed reduced global NAA/Cho (AMN 1.40 ± 0.16 vs controls 1.75 ± 0.34; p = 0.003)) and global NAA/Cr (AMN 2.32 ± 0.13 vs controls 2.62 ± 0.43; p = 0.03). Regionally, NAA/Cho was lowered in the internal capsule (AMN 1.30 ± 0.20 vs controls 1.69 ± 0.37; p = 0.002) and in parieto-occipital white matter (AMN 1.45 ± 0.19 vs controls 1.78 ± 0.55; p = 0.04). NAA/Cr was lowered in parieto-occipital white matter (AMN 2.34 ± 0.31 vs controls 2.83 ± 0.71; p = 0.04). EDSS demonstrated an inverse association with global NAA/Cr (r = -0.65, p = 0.02) and NAA/Cr in centrum semiovale (r = -0.73, p = 0.006) and in parieto-occipital white matter (r = -0.64, p = 0.02). Cho/Cr was not significantly elevated. Conclusions: ¹H-MR spectroscopic imaging is able to detect biochemical abnormalities suggestive of axonal damage even in the brains of patients with pure adrenomyeloneuropathy. The axonopathy is most prominent in internal capsule and parieto-occipital white matter and may contribute to clinical disability.