Vascular permeability in cerebral cavernous malformations

Abdul G Mikati; Omaditya Khanna; Lingjiao Zhang; Romuald Girard; Robert Shenkar; Xiaodong Guo; Akash Shah; Henrik B W Larsson; Huan Tan; Luying Li; Matthew S Wishnoff; Changbin Shi; Gregory A Christoforidis; Issam A Awad

doi:10.1038/jcbfm.2015.98

Vascular permeability in cerebral cavernous malformations

Abdul G Mikati, Omaditya Khanna, Lingjiao Zhang, Romuald Girard, Robert Shenkar, Xiaodong Guo, Akash Shah, Henrik B W Larsson, Huan Tan, Luying Li, Matthew S Wishnoff, Changbin Shi, Gregory A Christoforidis, Issam A Awad

Department of Clinical Medicine

36 Citations (Scopus)

Abstract

Patients with the familial form of cerebral cavernous malformations (CCMs) are haploinsufficient for the CCM1, CCM2, or CCM3 gene. Loss of corresponding CCM proteins increases RhoA kinase-mediated endothelial permeability in vitro, and in mouse brains in vivo. A prospective case-controlled observational study investigated whether the brains of human subjects with familial CCM show vascular hyperpermeability by dynamic contrast-enhanced quantitative perfusion magnetic resonance imaging, in comparison with CCM cases without familial disease, and whether lesional or brain vascular permeability correlates with CCM disease activity. Permeability in white matter far (WMF) from lesions was significantly greater in familial than in sporadic cases, but was similar in CCM lesions. Permeability in WMF increased with age in sporadic patients, but not in familial cases. Patients with more aggressive familial CCM disease had greater WMF permeability compared to those with milder disease phenotype, but similar lesion permeability. Subjects receiving statin medications for routine cardiovascular indications had a trend of lower WMF, but not lesion, permeability. This is the first demonstration of brain vascular hyperpermeability in humans with an autosomal dominant disease, as predicted mechanistically. Brain permeability, more than lesion permeability, may serve as a biomarker of CCM disease activity, and help calibrate potential drug therapy.

Original language	English
Journal	Journal of Cerebral Blood Flow and Metabolism
Volume	35
Issue number	10
Pages (from-to)	1632-9
Number of pages	8
ISSN	0271-678X
DOIs	https://doi.org/10.1038/jcbfm.2015.98
Publication status	Published - 3 Oct 2015

Keywords

Adolescent
Adult
Aged
Aging
Biomarkers
Brain Ischemia
Capillary Permeability
Cerebrovascular Circulation
Child
Child, Preschool
Female
Genotype
Hemangioma, Cavernous, Central Nervous System
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Image Processing, Computer-Assisted
Magnetic Resonance Imaging
Male
Middle Aged
Observer Variation
Pilot Projects
Young Adult

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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title = "Vascular permeability in cerebral cavernous malformations",

abstract = "Patients with the familial form of cerebral cavernous malformations (CCMs) are haploinsufficient for the CCM1, CCM2, or CCM3 gene. Loss of corresponding CCM proteins increases RhoA kinase-mediated endothelial permeability in vitro, and in mouse brains in vivo. A prospective case-controlled observational study investigated whether the brains of human subjects with familial CCM show vascular hyperpermeability by dynamic contrast-enhanced quantitative perfusion magnetic resonance imaging, in comparison with CCM cases without familial disease, and whether lesional or brain vascular permeability correlates with CCM disease activity. Permeability in white matter far (WMF) from lesions was significantly greater in familial than in sporadic cases, but was similar in CCM lesions. Permeability in WMF increased with age in sporadic patients, but not in familial cases. Patients with more aggressive familial CCM disease had greater WMF permeability compared to those with milder disease phenotype, but similar lesion permeability. Subjects receiving statin medications for routine cardiovascular indications had a trend of lower WMF, but not lesion, permeability. This is the first demonstration of brain vascular hyperpermeability in humans with an autosomal dominant disease, as predicted mechanistically. Brain permeability, more than lesion permeability, may serve as a biomarker of CCM disease activity, and help calibrate potential drug therapy.",

keywords = "Adolescent, Adult, Aged, Aging, Biomarkers, Brain Ischemia, Capillary Permeability, Cerebrovascular Circulation, Child, Child, Preschool, Female, Genotype, Hemangioma, Cavernous, Central Nervous System, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Middle Aged, Observer Variation, Pilot Projects, Young Adult",

author = "Mikati, {Abdul G} and Omaditya Khanna and Lingjiao Zhang and Romuald Girard and Robert Shenkar and Xiaodong Guo and Akash Shah and Larsson, {Henrik B W} and Huan Tan and Luying Li and Wishnoff, {Matthew S} and Changbin Shi and Christoforidis, {Gregory A} and Awad, {Issam A}",

year = "2015",

month = oct,

day = "3",

doi = "10.1038/jcbfm.2015.98",

language = "English",

volume = "35",

pages = "1632--9",

journal = "Journal of Cerebral Blood Flow and Metabolism",

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TY - JOUR

T1 - Vascular permeability in cerebral cavernous malformations

AU - Mikati, Abdul G

AU - Khanna, Omaditya

AU - Zhang, Lingjiao

AU - Girard, Romuald

AU - Shenkar, Robert

AU - Guo, Xiaodong

AU - Shah, Akash

AU - Larsson, Henrik B W

AU - Tan, Huan

AU - Li, Luying

AU - Wishnoff, Matthew S

AU - Shi, Changbin

AU - Christoforidis, Gregory A

AU - Awad, Issam A

PY - 2015/10/3

Y1 - 2015/10/3

N2 - Patients with the familial form of cerebral cavernous malformations (CCMs) are haploinsufficient for the CCM1, CCM2, or CCM3 gene. Loss of corresponding CCM proteins increases RhoA kinase-mediated endothelial permeability in vitro, and in mouse brains in vivo. A prospective case-controlled observational study investigated whether the brains of human subjects with familial CCM show vascular hyperpermeability by dynamic contrast-enhanced quantitative perfusion magnetic resonance imaging, in comparison with CCM cases without familial disease, and whether lesional or brain vascular permeability correlates with CCM disease activity. Permeability in white matter far (WMF) from lesions was significantly greater in familial than in sporadic cases, but was similar in CCM lesions. Permeability in WMF increased with age in sporadic patients, but not in familial cases. Patients with more aggressive familial CCM disease had greater WMF permeability compared to those with milder disease phenotype, but similar lesion permeability. Subjects receiving statin medications for routine cardiovascular indications had a trend of lower WMF, but not lesion, permeability. This is the first demonstration of brain vascular hyperpermeability in humans with an autosomal dominant disease, as predicted mechanistically. Brain permeability, more than lesion permeability, may serve as a biomarker of CCM disease activity, and help calibrate potential drug therapy.

AB - Patients with the familial form of cerebral cavernous malformations (CCMs) are haploinsufficient for the CCM1, CCM2, or CCM3 gene. Loss of corresponding CCM proteins increases RhoA kinase-mediated endothelial permeability in vitro, and in mouse brains in vivo. A prospective case-controlled observational study investigated whether the brains of human subjects with familial CCM show vascular hyperpermeability by dynamic contrast-enhanced quantitative perfusion magnetic resonance imaging, in comparison with CCM cases without familial disease, and whether lesional or brain vascular permeability correlates with CCM disease activity. Permeability in white matter far (WMF) from lesions was significantly greater in familial than in sporadic cases, but was similar in CCM lesions. Permeability in WMF increased with age in sporadic patients, but not in familial cases. Patients with more aggressive familial CCM disease had greater WMF permeability compared to those with milder disease phenotype, but similar lesion permeability. Subjects receiving statin medications for routine cardiovascular indications had a trend of lower WMF, but not lesion, permeability. This is the first demonstration of brain vascular hyperpermeability in humans with an autosomal dominant disease, as predicted mechanistically. Brain permeability, more than lesion permeability, may serve as a biomarker of CCM disease activity, and help calibrate potential drug therapy.

KW - Adolescent

KW - Adult

KW - Aged

KW - Aging

KW - Biomarkers

KW - Brain Ischemia

KW - Capillary Permeability

KW - Cerebrovascular Circulation

KW - Child

KW - Child, Preschool

KW - Female

KW - Genotype

KW - Hemangioma, Cavernous, Central Nervous System

KW - Humans

KW - Hydroxymethylglutaryl-CoA Reductase Inhibitors

KW - Image Processing, Computer-Assisted

KW - Magnetic Resonance Imaging

KW - Male

KW - Middle Aged

KW - Observer Variation

KW - Pilot Projects

KW - Young Adult

U2 - 10.1038/jcbfm.2015.98

DO - 10.1038/jcbfm.2015.98

M3 - Journal article

C2 - 25966944

SN - 0271-678X

VL - 35

SP - 1632

EP - 1639

JO - Journal of Cerebral Blood Flow and Metabolism

JF - Journal of Cerebral Blood Flow and Metabolism

IS - 10

ER -

Vascular permeability in cerebral cavernous malformations

Abstract

Keywords

UN SDGs

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