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 normalappearing 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 ¼ 0.02 signal enhancement slope), but only signal enhancement slope increased with hypertension (P ¼ 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.

Structural Integrity of Normal Appearing White Matter and Sex-Specific Outcomes After Acute Ischemic Stroke

“…While the tissue integrity of NAWM is negatively impacted by age and hypertension, no sex-specific differences have been reported to date. 13 Thus, our data suggest that white matter structural integrity may be a contributing variable on AIS functional outcomes in women.…”

Ageing and brain white matter structure in 3,513 UK Biobank participants

“…Whereas there is evidence that MD is also more sensitive to age than FA among those with mild stroke48, our sample composition has implications for another aspect of our results. Whereas hippocampal volume and ICVF did not appear to provide unique information about age in this sample, both ICVF (rather than FA)49 and hippocampal volume50 are important dementia biomarkers, emphasizing that our findings, which focus on normal ageing, cannot necessarily be generalized to clinical populations.…”

Integrity of normal-appearing white matter and functional outcomes after acute ischemic stroke

“…6,28 A recent study of patients with mild ischemic stroke demonstrated that MD was the most sensitive metric for distinguishing WMH from NAWM and that the accumulation of interstitial fluid is involved in WMH pathogenesis. 17 Therefore, it is reasonable to assume that DTI-based anisotropy metrics of NAWM provide insights into WM composition and, as a result, are informative of functional connectivity and overall cognitive performance. 7,27,[29][30][31] Thus, it seems intuitive that WM integrity would influence poststroke recovery.…”

“…17 Because WM was defined on the basis of probability masks, no threshold values were used for extraction of the diffusivity anisotropy metrics in this analysis. Statistical analysis.…”