Analysis of Interindividual Lesion Progression Variability in Adult Cerebral Adrenoleukodystrophy.

Background

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Objectives

Cerebral adrenoleukodystrophy (cALD), the most severe clinical phenotype of X-linked adrenoleukodystrophy (X-ALD), is characterized by rapidly progressive, inflammatory destruction of the cerebral white matter. In adult patients, therapeutic options are limited to hematopoietic stem cell transplantation, which carries substantial treatment-related risks, necessitating careful and individualized clinical decision-making. Monitoring the progression of characteristic MRI changes provides a promising approach, both for guiding treatment and for serving as an outcome measure in interventional trials. Although the natural history of these MRI changes has been well described in childhood cALD, analogous data in adult patients remain scarce.

Methods

In this multicenter retrospective cohort study, we screened adult men with confirmed X-ALD at leukodystrophy centers in Leipzig, Amsterdam, and Boston between 2000 and 2025. Inclusion criteria required lesion progression on at least 2 high-quality MRI scans during a minimal untreated follow-up of 3 months. Volumes calculated from lesion masks were segmented using a 3D U-Net convolutional neural network followed by manual correction and compared with the disease-specific semiquantitative MRI Loes score. Gadolinium enhancement, primary lesion location, and serum neurofilament light chain (sNfL) levels, alongside demographic data, were evaluated as potential predictors of lesion progression.

Results

Of 578 individuals screened, 48 patients and 338 MRI scans were included in the analysis. Lesion progression followed an overall exponential growth rate of 3.4% per month (95% CI 2.6-4.2), with substantial interindividual variability (range 0.5-7.3). Growth rates were slower in lesions without contrast enhancement (0.9%/month vs 3.4%/month, p = 0.010) and varied depending on the initial lesion location. Increased sNfL concentrations (n = 37), a marker of neuroaxonal damage, were better explained by absolute lesion volume (mL) and lesion volume increase (mL/month; adjusted R2 = 0.669) than by semiquantitative Loes score measures (adjusted R2 = 0.488).

Discussion

In this comprehensive multicenter retrospective study on lesion evolution in adult cALD, we demonstrate that lesion growth follows an exponential trajectory, with considerable interindividual variability. Primary lesion location, contrast enhancement, and NfL levels emerge as potential predictors of lesion progression. This might support personalized treatment strategies for adults with cALD and guide clinical trial design in the future.