TY - JOUR
T1 - ABCD1 dysfunction alters white matter microvascular perfusion
AU - Lauer, Arne
AU - Da, Xiao
AU - Hansen, Mikkel Bo
AU - Boulouis, Gregoire
AU - Ou, Yangming
AU - Cai, Xuezhu
AU - Liberato Celso Pedrotti, Afonso
AU - Kalpathy-Cramer, Jayashree
AU - Caruso, Paul
AU - Hayden, Douglas L.
AU - Rost, Natalia
AU - Mouridsen, Kim
AU - Eichler, Florian S.
AU - Rosen, Bruce
AU - Musolino, Patricia L.
N1 - Publisher Copyright:
© 2017 The Author. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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.
KW - ABCD1
KW - ALD
KW - cerebral X-linked adrenoleukodystrophy
KW - inflammatory demyelination
KW - microvascular perfusion
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U2 - 10.1093/brain/awx262
DO - 10.1093/brain/awx262
M3 - Article
C2 - 29136088
AN - SCOPUS:85038228668
SN - 0006-8950
VL - 140
SP - 3139
EP - 3152
JO - Brain
JF - Brain
IS - 12
ER -