Quantitative Proton Magnetic Resonance Spectroscopy of Children with Adrenoleukodystrophy Before and After Hematopoietic Stem Cell Transplantation

Abstract

About 35 - 40 % of boys with X-linked adrenoleukodystrophy (ALD) develop a rapidly progressive cerebral form which leads to severe neurologic disability and death within 3 - 5 years after onset of clinical symptoms. Because previous proton magnetic resonance spectroscopy (MRS) studies of ALD identified metabolite patterns characteristic of demyelination, gliosis, and neuroaxonal loss, this work tested the hypothesis that MRS - apart from indicating disease progression - provides criteria for the outcome after hematopoietic stem cell transplantation (HSCT) which has been promising at an early stage of the active disease. Follow-up quantitative proton MRS was performed in frontal and occipital white matter of ALD patients (n = 12) before and up to 5 years after HSCT. The observed metabolite alterations were retrospectively correlated with the clinical outcome representing either a stable condition (n = 5), a further deterioration (n = 5), or death (n = 2). While disease progression of patients before HSCT was mainly characterized by a further increase of elevated choline-containing compounds (Cho) as an indicator of active demyelination, a positive outcome after HSCT was correlated with high N-acetylaspartate (tNAA) levels in affected white matter before HSCT yielding positive and negative predictive values for tNAA of 80 %. Although to be confirmed in a larger cohort of patients, the present findings suggest the preservation of neuroaxonal integrity as a prerequisite for an arrested course. Conversely, the combination of increased Cho with markedly reduced tNAA before HSCT apparently reflects a degree of tissue degeneration which precludes a successful therapeutic intervention.