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

Abstract

Background and Purpose Women have worse post-stroke outcomes than men. We evaluated sex-specific clinical and neuroimaging characteristics of white matter in association with functional recovery after acute ischemic stroke (AIS). Methods We performed a retrospective analysis of AIS patients with admission brain MRI and 3 to 6 month modified Rankin scale score (mRS). White matter hyperintensity (WMH) and acute infarct volume were quantified on fluid attenuated inversion recovery (FLAIR) and diffusion-tensor imaging MRI, respectively. Diffusivity anisotropy metrics were calculated in normal appearing white matter (NAWM) contralateral to the acute ischemia. Results Among 319 AIS patients, women were older (68.0 vs. 62.7 years; p=0.004), had increased incidence of atrial fibrillation (21.4% vs. 12.2%; p=0.04), and lower rate of tobacco use (21.1% vs. 35.9%; p=0.03). There was no sex-specific difference in WMH volume, acute infarct volume, NIHSS, pre-stroke mRS, or NAWM diffusivity anisotropy metrics. However, women were less likely to have an excellent outcome (mRS <2: 49.6% vs. 67.0%; p=0.005). In logistic regression analysis, female sex and the interaction of sex with FA, RD, and AD were independent predictors of functional outcome. Conclusions Female sex is associated with decreased likelihood of excellent outcome following AIS. The correlation between markers of white matter integrity and functional outcomes in women, but not men, suggests a potential sex-specific mechanism.

Sex-specific differences in white matter microvascular integrity after ischaemic stroke

“…Our finding of sex-specific differences in NAWM K 2 coefficient, as a putative measure of BBB dysfunction, is of clinical interest. We have previously reported an association between NAWM structural integrity (fractional anisotropy) and sex-specific functional outcomes 11. Together, these observations offer some insight into the potential factors contributing to the disparity in stroke outcomes between sexes as they suggest that sex-specific differences in NAWM microvascular integrity predispose to worse outcomes in women.…”

“…WMH lesions in the hemisphere contralateral to the acute infarct were outlined in a semi-automated manner using MRIcro software as described previously 11 19. All images were analysed by trained research staff that were blinded to all outcome data.…”

“…Evidence of cerebral microvascular dysfunction can be detected on T2-weighted MRI as white matter hyperintensities (WMH), enhanced BBB permeability on perfusion-weighted imaging (PWI), or measured in normal-appearing white matter (NAWM) as loss of microstructural integrity on diffusion-tensor imaging (DTI), and reflected as an increase in the apparent diffusion coefficient (ADC) values 7 10. Both increased diffusivity and BBB permeability have been linked to poor outcomes after AIS,6–8 with a potential sex-specific contribution 11. We have also reported a novel association between increasing NAWM K 2 coefficient, as a potential surrogate of BBB permeability, and worse functional outcomes after AIS 7.…”

Sex-specific and opposite modulatory aspects revealed by PPI network and pathway analysis of ischemic stroke in humans

“…Sex differences were seen for IS as females had higher incidence and longer life expectancy but worse functional outcomes [3,4], which might be due to different risk factors [5,6,7], anatomic structural Willis incompletion or white integrity [8,9], biologically inherent sex chromosome complemented with gonadal hormones [10,11,12], socialized reasons of in-hospital care [6,13], and therefore, pathology and treatment [14,15]. However, animal-based research has observed decreased infarct size and improved outcomes in female compared to males [16].…”

Sex-Dependent Effects of Bmal1-Deficiency on Mouse Cerebral Cortex Infarction in Response to Photothrombotic Stroke

“…While age-specific stroke rates are higher in men, women have relatively more stroke events because of their longer life expectancy [ 1 ]. In addition women are less likely to show excellent recovery [ 2 ]. There is a time-of-day dependent variation in the vulnerability to ischemia and in the occurrence of ischemic events [ 3 , 4 ], and shift work has been shown to be a risk factor for cardiovascular diseases in women [ 5 ].…”