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Brain. 2017 Dec 1;140(12):3139-3152. doi: 10.1093/brain/awx262.

ABCD1 dysfunction alters white matter microvascular perfusion.

Author information

1
Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
2
Department of Neuroradiology, Goethe University, Frankfurt a.M., Germany.
3
Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, MA, USA.
4
Department of Clinical Medicine, Aarhus University, Denmark.
5
Department of Neuroradiology, Université Paris-Descartes, INSERM UMR 894, Centre Hospitalier Sainte-Anne, Paris, France.
6
Fetal-Neonatal Neuroimaging and Developmental Science Center, Boston Children's Hospital, Boston, MA, USA.
7
Department of Radiology, Massachusetts General Hospital, Boston, MA, USA.
8
Department of Biostatistics, Massachusetts General Hospital, Boston, MA, USA.

Abstract

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.

KEYWORDS:

ABCD1; ALD; cerebral X-linked adrenoleukodystrophy; inflammatory demyelination; microvascular perfusion

PMID:
29136088
PMCID:
PMC5841142
DOI:
10.1093/brain/awx262
[Indexed for MEDLINE]
Free PMC Article

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