title: Integrity of normal-appearing white matter: Influence of age, visible lesion burden and hypertension in patients with small-vessel disease.
abstract: White matter hyperintensities accumulate with age and occur in patients with stroke, but their pathogenesis is poorly understood. We measured multiple magnetic resonance imaging biomarkers of tissue integrity in normal-appearing white matter and white matter hyperintensities in patients with mild stroke, to improve understanding of white matter hyperintensities origins. We classified white matter into white matter hyperintensities and normal-appearing white matter and measured fractional anisotropy, mean diffusivity, water content (T1-relaxation time) and blood-brain barrier leakage (signal enhancement slope from dynamic contrast-enhanced magnetic resonance imaging). We studied the effects of age, white matter hyperintensities burden (Fazekas score) and vascular risk factors on each biomarker, in normal-appearing white matter and white matter hyperintensities, and performed receiver-operator characteristic curve analysis. Amongst 204 patients (34.3-90.9 years), all biomarkers differed between normal-appearing white matter and white matter hyperintensities ( P < 0.001). In normal-appearing white matter and white matter hyperintensities, mean diffusivity and T1 increased with age ( P < 0.001), all biomarkers varied with white matter hyperintensities burden ( P < 0.001; P = 0.02 signal enhancement slope), but only signal enhancement slope increased with hypertension ( P = 0.028). Fractional anisotropy showed complex age-white matter hyperintensities-tissue interactions; enhancement slope showed white matter hyperintensities-tissue interactions. Mean diffusivity distinguished white matter hyperintensities from normal-appearing white matter best at all ages. Blood-brain barrier leakage increases with hypertension and white matter hyperintensities burden at all ages in normal-appearing white matter and white matter hyperintensities, whereas water mobility and content increase as tissue damage accrues, suggesting that blood-brain barrier leakage mediates small vessel disease-related brain damage.
authors.affiliation: 1 Division of Neuroimaging Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: Susana
authors.initials: S
authors.lastname: Muñoz Maniega
authors.affiliation: 1 Division of Neuroimaging Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: Francesca M
authors.initials: FM
authors.lastname: Chappell
authors.affiliation: 1 Division of Neuroimaging Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Valdés Hernández
authors.affiliation: 2 Department of Cardiovascular Science, University of Sheffield, Sheffield, UK.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Armitage
authors.affiliation: 1 Division of Neuroimaging Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Makin
authors.affiliation: 1 Division of Neuroimaging Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: Anna K
authors.initials: AK
authors.lastname: Heye
authors.affiliation: 1 Division of Neuroimaging Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Thrippleton
authors.affiliation: 1 Division of Neuroimaging Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: Eleni
authors.initials: E
authors.lastname: Sakka
authors.affiliation: 1 Division of Neuroimaging Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Shuler
authors.affiliation: 1 Division of Neuroimaging Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: Martin S
authors.initials: MS
authors.lastname: Dennis
authors.affiliation: 1 Division of Neuroimaging Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Wardlaw
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging; D016880:Anisotropy; D001812:Blood-Brain Barrier / Q000000981:diagnostic imaging / Q000473:pathology; D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology; D056324:Diffusion Tensor Imaging / Q000379:methods; D005260:Female; D006801:Humans; D006973:Hypertension / Q000000981:diagnostic imaging / Q000473:pathology*; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D020521:Stroke / Q000000981:diagnostic imaging / Q000473:pathology; D014652:Vascular Diseases / Q000000981:diagnostic imaging / Q000473:pathology*; D066127:White Matter / Q000000981:diagnostic imaging / Q000473:pathology*
keywords: Magnetic resonance imaging; ageing; blood–brain barrier; cerebrovascular disease; diffusion tensor imaging