Cerebral X-linked adrenoleukodystrophy is a devastating neurodegenerative disorder caused by mutations in the ABCD1 gene, which lead to a rapidly progressive cerebral inflammatory demyelination in up to 60% of affected males. Selective brain endothelial dysfunction and increased permeability of the blood–brain barrier suggest that white matter microvascular dysfunction contributes to the conversion to cerebral disease. Applying a vascular model to conventional dynamic susceptibility contrast magnetic resonance perfusion imaging, we demonstrate that lack of ABCD1 function causes increased capillary flow heterogeneity in asymptomatic hemizygotes predominantly in the white matter regions and developmental stages with the highest probability for conversion to cerebral disease. In subjects with ongoing inflammatory demyelination we observed a sequence of increased capillary flow heterogeneity followed by blood–brain barrier permeability changes in the perilesional white matter, which predicts lesion progression. These white matter microvascular alterations normalize within 1 year after treatment with haematopoietic stem cell transplantation. For the first time in vivo, our studies unveil a model to assess how ABCD1 alters white matter microvascular function and explores its potential as an earlier biomarker for monitoring disease progression and response to treatment.

中文翻译：

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ABCD1功能异常改变白质微血管灌注

脑X连锁性肾上腺白质营养不良是由ABCD1突变引起的毁灭性神经退行性疾病基因，可导致多达60％的受影响男性迅速进展性脑炎性脱髓鞘。选择性脑内皮功能障碍和血脑屏障通透性增加表明白质微血管功能障碍有助于转化为脑部疾病。将血管模型应用于常规动态磁化率对比磁共振灌注成像，我们证明缺乏ABCD1功能会导致无症状半合子中毛细血管血流异质性增加，主要发生在白质区域和发育阶段，转化为脑病的可能性最高。在进行性炎症性脱髓鞘的受试者中，我们观察到毛细血管血流异质性增加，随后病灶周围白质中的血脑屏障通透性改变，从而预测了病灶进展。这些白质微血管改变在造血干细胞移植治疗后1年内恢复正常。首次在体内，我们的研究揭示了一种评估ABCD1如何改变白质微血管功能的模型，并探索了其作为监测疾病进展和对治疗反应的早期生物标记物的潜力。