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ABCD1 dysfunction alters white matter microvascular perfusion

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DOI

  • 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
JournalBrain
Volume140
Issue12
Pages (from-to)3139–3152
Number of pages14
ISSN0006-8950
DOIs
Publication statusPublished - 1 Dec 2017

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