Vascular Risk and White Matter Burden Differ by Stroke Classification Subtype

June 11, 2020

Effectively addressing vascular risk factors could provide an important avenue for modifying white matter hyperintensity disease burden.

Anne-Katrin Giese, MD

Results from the MRI Genetics Interface Exploration (MRI-GENIE) international multicenter trial suggest vascular risk factor profiles and extent of white matter hyperintensity (WMH) burden differ by Causative Classification of Ischemic Stroke (CCS) subtype, with the highest lesion burden detected in patients with small artery occlusion (SAO).

Led by Anne-Katrin Giese, MD, department of neurology, University of Utah, and colleagues, MRI-GENIE assembled brain imaging and phenotype data using standardized web tool-based stroke subtyping with CCS for 3301 patients with acute ischemic stroke (AIS). After successfully extracting WMH volume (WMHv) from clinical axial fluid-attenuated inversion recovery (FLAIR) images, the MRI-GENIE cohort was left with 2529 patients.

At the end of the study, patients with AIS with larger artery atherosclerosis (LAA; n = 545), major cardioembolic stroke (n = 394), SAO (n = 387), other (n = 181), and undetermined causes (n = 1,022) of AIS differed significantly in their vascular risk profile (all P <.001).

Using a fully automated deep-learning trained algorithm to measure WMHv on T2 brain MRI scans, researchers found that median WMHv in all patients with AIS was 5.86 cm3 (interquartile range [IQR], 2.18—14.61 cm3) and differed significantly across CCS subtypes (P <.0001).

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When using a multivariate analysis, age, hypertension, prior smoke, smoking (all P <.001), and diabetes mellitus (P = .041) were independent predictors of WMHv. More specifically, age was the strongest predictor of WMHv of them all (β = 0.05; 95% CI, 0.05—0.05; P <.001).

WMHv for the 5-item CCS subtypes was reassessed when adjusted for the identified multivariable predictors of WMHv, as well as for site in random variable, by comparing the residuals of the multivariate linear mixed-effects model by CCS subtype. In the Bonferroni-adjusted group-wise comparison of CCS subtypes, cases classified as SAO demonstrated the highest adjusted residual WMHv (1.47 cm3 [IQR, —1.52 to 3.15]).

“Furthermore, in multivariable modeling, we show that in LAA, only age and prior stroke were independently associated with WMHv, while in CE major, only age independently contributed to WMH burden. Such specific CCS subtype findings support the concept of a different underlying etiologic disease processes,” Giese and colleagues concluded.

When delving into the CCS-subtype specific associations with WMHv, researchers found that age (β = 0.04; 95% CI, 0.03—0.05; P <.001), hypertension (β = 0.43; 95% CI, 0.16—0.70; P =.002), and prior stroke (β = 0.52; 95% CI, 0.11—0.93) emerged as independent predictors of WMHv in SAO. In comparison, in cases with Other stroke subtype, age (β = 0.04; 95% CI, 0.03–0.06; P <.001) and prior stroke (β = 0.90; 95% CI, 0.13—1.66; P = .021) were associated with higher WMHv, and female sex (β = −0.37; 95% CI, −0.72 to −0.02; P = .040) was associated with lower WMHv.

The overall demographics of the patient population were a mean age of 63.4 years (standard deviation [SD], 14.6), 39.3% (n = 993) female, and a majority of the patients were white (n = 2141; 84.7%). A medical history of hypertension was found in 1,668 patients (66.4%), and either current or former tobacco smokers accounted for 1323 of the population (54.1%).

Giese and colleagues went on to say, “Our findings in part reconcile the previously described differences in risk factor profiles for WMH in stroke-free and AIS populations. Effectively addressing these vascular risk factors could provide an important avenue for modifying WMH disease burden and thus potentially preventing the detrimental downstream effects of high WMH burden in patients with AIS.”


Giese AK, Schirmer MD, Dalca AV, et al. White matter hyperintensity burden in acute stroke patients differs by ischemic stroke subtype. Neurology. Published online June 3, 2020. doi: 10.1212/WNL.0000000000009728