Overall intact cognitive function in male X-linked adrenoleukodystrophy adults with normal MRI

Buermans, Noortje J. M. L.; Sharon J. G. van den Bosch; Huffnagel, Irene C.; Steenweg, Marjan E.; Engelen, Marc; Oostrom, Kim J.; Geurtsen, Gert J. · 2019 · DOAJ

DOI: 10.1186/s13023-019-1184-4

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Summary

This cross-sectional study investigated the cognitive functioning of adult men with X-linked adrenoleukodystrophy (ALD) who exhibit normal or minimal abnormalities on magnetic resonance imaging (MRI). While inflammatory demyelinating lesions in the brain are known to cause severe disability in ALD, it has been unclear whether patients without such lesions possess entirely intact cognitive function or if subtle deficits exist. The research aimed to characterize cognitive performance in this specific patient subgroup to define the natural history of the disease and determine neuropsychological monitoring requirements. The study recruited 33 adult male ALD patients (median age 44 years) from a Dutch natural history cohort, excluding those with extensive MRI lesions (Loes score > 3) or post-contrast enhancement. Participants underwent a comprehensive neuropsychological assessment covering language, verbal and non-verbal memory, visuoconstruction, executive functioning, and psychomotor speed. Test results were converted to standardized T scores and compared against age-, education-, and gender-corrected Dutch normative data. Borderline performance was defined as T scores between 30 and 36, while impairment was defined as T scores ≤29. Statistical analyses included comparisons of mean scores and proportions of borderline/impaired scores, as well as subgroup analyses based on MRI findings. Overall cognitive functioning was largely intact, but specific subtle deficits were identified. Patients performed significantly worse than the norm group on verbal fluency (mean T score 45.70 vs. 50, p = 0.009). The proportion of patients with borderline or impaired scores was significantly higher than the 8% expected in the norm group for visuoconstruction tasks (Beery VMI: 19%, p = 0.02; RCFT copy: 81%, p < 0.0005) and mental reaction time during complex decision tasks (18%, p = 0.055). A case-by-case analysis revealed that 27.3% of patients had borderline or impaired scores in two or more cognitive domains, with psychomotor speed and executive functioning being the most frequently affected areas. Only 3% of patients showed severe impairment. Neither age nor the presence of minor MRI abnormalities significantly predicted these multi-domain deficits. The findings suggest that while the vast majority of adult ALD males with normal or minimal MRI abnormalities maintain intact cognitive function, a significant minority (27.3%) exhibit heterogeneous, mostly borderline cognitive dysfunction. These deficits, particularly in visuoconstruction and complex psychomotor speed, may reflect functional white matter abnormalities caused by the underlying *ABCD1* mutation or very early inflammatory changes below the detection limit of structural MRI. The study highlights the need for longitudinal research to determine if these borderline scores represent a risk profile for the development of cerebral ALD.

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• cognitive impairment