ABCD1 dysfunction alters white matter microvascular perfusion

Arne Lauer, Xiao Da, Mikkel Bo Hansen, Gregoire Boulouis, Yangming Ou, Xuezhu Cai, Afonso Liberato Celso Pedrotti, Jayashree Kalpathy-Cramer, Paul Caruso, Douglas L. Hayden, Natalia Rost, Kim Mouridsen, Florian S. Eichler, Bruce Rosen, Patricia L. Musolino

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3139-3152
Number of pages14
JournalBrain
Volume140
Issue number12
DOIs
StatePublished - Dec 1 2017
Externally publishedYes

Fingerprint

Perfusion
Demyelinating Diseases
Blood-Brain Barrier
Permeability
Hemizygote
Adrenoleukodystrophy
Magnetic Resonance Angiography
Hematopoietic Stem Cell Transplantation
Neurodegenerative Diseases
Blood Vessels
Disease Progression
Biomarkers
White Matter
Mutation
Brain
Therapeutics
Genes

Keywords

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

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Lauer, A., Da, X., Hansen, M. B., Boulouis, G., Ou, Y., Cai, X., ... Musolino, P. L. (2017). ABCD1 dysfunction alters white matter microvascular perfusion. Brain, 140(12), 3139-3152. https://doi.org/10.1093/brain/awx262

ABCD1 dysfunction alters white matter microvascular perfusion. / Lauer, Arne; Da, Xiao; Hansen, Mikkel Bo; Boulouis, Gregoire; Ou, Yangming; Cai, Xuezhu; Liberato Celso Pedrotti, Afonso; Kalpathy-Cramer, Jayashree; Caruso, Paul; Hayden, Douglas L.; Rost, Natalia; Mouridsen, Kim; Eichler, Florian S.; Rosen, Bruce; Musolino, Patricia L.

In: Brain, Vol. 140, No. 12, 01.12.2017, p. 3139-3152.

Research output: Contribution to journalArticle

Lauer, A, Da, X, Hansen, MB, Boulouis, G, Ou, Y, Cai, X, Liberato Celso Pedrotti, A, Kalpathy-Cramer, J, Caruso, P, Hayden, DL, Rost, N, Mouridsen, K, Eichler, FS, Rosen, B & Musolino, PL 2017, 'ABCD1 dysfunction alters white matter microvascular perfusion', Brain, vol. 140, no. 12, pp. 3139-3152. https://doi.org/10.1093/brain/awx262
Lauer A, Da X, Hansen MB, Boulouis G, Ou Y, Cai X et al. ABCD1 dysfunction alters white matter microvascular perfusion. Brain. 2017 Dec 1;140(12):3139-3152. https://doi.org/10.1093/brain/awx262
Lauer, Arne ; Da, Xiao ; Hansen, Mikkel Bo ; Boulouis, Gregoire ; Ou, Yangming ; Cai, Xuezhu ; Liberato Celso Pedrotti, Afonso ; Kalpathy-Cramer, Jayashree ; Caruso, Paul ; Hayden, Douglas L. ; Rost, Natalia ; Mouridsen, Kim ; Eichler, Florian S. ; Rosen, Bruce ; Musolino, Patricia L. / ABCD1 dysfunction alters white matter microvascular perfusion. In: Brain. 2017 ; Vol. 140, No. 12. pp. 3139-3152.
@article{a72fc9c94b1a44dc9ae0db0a091897bd,
title = "ABCD1 dysfunction alters white matter microvascular perfusion",
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",
author = "Arne Lauer and Xiao Da and Hansen, {Mikkel Bo} and Gregoire Boulouis and Yangming Ou and Xuezhu Cai and {Liberato Celso Pedrotti}, Afonso and Jayashree Kalpathy-Cramer and Paul Caruso and Hayden, {Douglas L.} and Natalia Rost and Kim Mouridsen and Eichler, {Florian S.} and Bruce Rosen and Musolino, {Patricia L.}",
year = "2017",
month = "12",
day = "1",
doi = "10.1093/brain/awx262",
language = "English (US)",
volume = "140",
pages = "3139--3152",
journal = "Brain",
issn = "0006-8950",
publisher = "Oxford University Press",
number = "12",

}

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.

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

UR - http://www.scopus.com/inward/record.url?scp=85038228668&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85038228668&partnerID=8YFLogxK

U2 - 10.1093/brain/awx262

DO - 10.1093/brain/awx262

M3 - Article

C2 - 29136088

AN - SCOPUS:85038228668

VL - 140

SP - 3139

EP - 3152

JO - Brain

JF - Brain

SN - 0006-8950

IS - 12

ER -