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ABCD1 dysfunction alters white matter microvascular perfusion

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  • Arne Lauer, Germany
  • Xiao Da, United States
  • Mikkel Bo Hansen
  • Gregoire Boulouis, United States
  • Yangming Ou, United States
  • Xuezhu Cai, United States
  • Afonso Liberato Celso Pedrotti
  • ,
  • jayashree kalpathy-Cramer, United States
  • Paul Caruso
  • ,
  • Douglas L. Hayden
  • ,
  • Natalia Rost
  • ,
  • Kim Mouridsen
  • Florian S. Eichler
  • ,
  • Bruce Rosen
  • ,
  • Patricia L. Musolino
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 reson- ance perfusion imaging, we demonstrate that lack of ABCD1 function causes increased capillary flow heterogeneity in asymptom- atic 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 hetero- geneity 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 transplant- ation. 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.
Original languageEnglish
Pages (from-to)3139–3152
Number of pages14
Publication statusPublished - 1 Dec 2017

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