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.

Keywords: Magnetic resonance imaging; ageing; blood–brain barrier; cerebrovascular disease; diffusion tensor imaging.

Figure 1.

Example of images from a patient. (a) FLAIR images showing white matter hyperintensities, (b) binary masks of normal-appearing white matter in blue and white matter hyperintensities in red, MRI parametric maps: (c) fractional anisotropy, (d) mean diffusivity, (e) longitudinal relaxation time (T1) and (f) signal enhancement slope.

Figure 2.

Box plots of the imaging markers in white matter hyperintensities (WMH) and normal-appearing white matter (NAWM) for all 204 patients, before adjusting for any other confounds. MD: mean diffusivity; FA: fractional anisotropy; T1: longitudinal relaxation time.

Figure 3.

Box plots of (a) mean diffusivity (MD), (b) fractional anisotropy (FA), (c) T1-relaxation time and (d) signal enhancement slope in white matter hyperintensities (WMH) and normal-appearing white matter (NAWM). Age groups are represented in panels: group 1: 30–55 years; group 2: 56–65 years; group 3: 66–75 years and group 4: 76–100 years. Fazekas groups are represented with different shaded box plots, with light colours for low Fazekas and dark colours for high Fazekas.

Figure 4.

Receiver operating characteristic curves of the imaging parameters. Data were divided by age group with tissue type as outcome (WMH or NAWM). FA: fractional anisotropy; MD: mean diffusivity; T1: longitudinal relaxation time; eht slope: signal enhancement slope; AUC: area under the curve.