Metabolic determinants of white matter hyperintensity burden in patients with ischemic stroke

Atherosclerosis. 2015 May;240(1):149-53. doi: 10.1016/j.atherosclerosis.2015.02.052. Epub 2015 Mar 2.


Objective: Increasing white matter hyperintensity (WMH) burden is linked to risk of stroke and poor post-stroke outcomes. While the biology of WMH remains ill-defined, several lines of evidence implicate endothelial dysfunction. In this study, we sought to assess the association between metabolic markers of endothelial dysfunction and WMH severity in patients with acute ischemic stroke (AIS).

Methods: In this retrospective study, consecutive subjects, ≥18 years of age, admitted to our ED with AIS, brain MRI, and blood homocysteine (Hcy) and hemoglobin A1c (HgbA1c) measurements were eligible for this analysis. WMH volume (WMHV) was quantified using a validated semi-automated algorithm and log-transformed for linear regression analyses.

Results: There were 809 AIS subjects included (mean age 65.57±14.7, median WMHV 6.25 cm3 (IQR 2.8-13.1)). In univariate analysis, age, female gender, race, ethnicity, systolic blood pressure, history of hypertension, atrial fibrillation, coronary artery disease, prior stroke, and current alcohol and tobacco use (all p<0.05), as well as Hcy (p<0.0001) and HgbA1c levels (p=0.0005) were associated with WMHV. However, only Hcy (β=0.11, p=0.003) and HgbA1c levels (β=0.1, p=0.008) independently predicted WMHV in the multivariate model, along with age (β=0.03, p<0.0001), race (β=0.39, p=0.01), ethnicity (β=-0.11, p=0.03), and current alcohol use (β=0.26, p=0.002).

Conclusions: Elevated levels of Hcy and HgbA1c have been previously linked to endothelial dysfunction related to oxidative stress. The association between Hcy and HgbA1c and WMH burden in AIS suggests that the degree of endothelial dysfunction may be greater in patients with increased WMHV, and may in part explain the relationship between WMHV and poor post-stroke outcomes.

Keywords: Acute ischemic stroke; Blood biomarkers; Endothelial dysfunction; Hyperglycemia; Hyperhomocysteinemia; Small vessel disease; White matter hyperintensity.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Algorithms
  • Biomarkers / blood
  • Boston
  • Brain Ischemia / blood*
  • Brain Ischemia / diagnosis
  • Brain Ischemia / physiopathology
  • Endothelium, Vascular / metabolism*
  • Endothelium, Vascular / physiopathology
  • Female
  • Glycated Hemoglobin / analysis*
  • Homocysteine / blood
  • Humans
  • Leukoencephalopathies / blood*
  • Leukoencephalopathies / diagnosis
  • Leukoencephalopathies / physiopathology
  • Linear Models
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Multivariate Analysis
  • Predictive Value of Tests
  • Prognosis
  • Retrospective Studies
  • Risk Factors
  • Severity of Illness Index
  • Signal Processing, Computer-Assisted
  • Stroke / blood*
  • Stroke / diagnosis
  • Stroke / physiopathology
  • Up-Regulation


  • Biomarkers
  • Glycated Hemoglobin A
  • hemoglobin A1c protein, human
  • Homocysteine