Markers of endothelial and hemostatic activation and progression of cerebral white matter hyperintensities: longitudinal results of the Austrian Stroke Prevention Study.
OBJECTIVE
The pathogenesis of cerebral small vessel disease (SVD) is poorly understood, but endothelial activation and dysfunction may play a causal role. Cross-sectional studies have found increased circulating markers of endothelial activation, but this study design cannot exclude causality from secondary elevations. Confluent white matter hyperintensities (WMHs) on magnetic resonance imaging (MRI) appear to represent asymptomatic cerebral SVD. In a prospective study, we determined whether circulating markers of endothelial activation predicted progression of WMH.


METHODS
In the community-based Austrian Stroke Prevention Study, MRI was performed at baseline in 296 subjects and repeated at 3 and 6 years. The following were measured on baseline plasma samples: intercellular adhesion molecule (ICAM), thrombomodulin, tissue factor plasma inhibitor, prothrombin fragments 1 and 2, and D-dimers.


RESULTS
ICAM was associated with age- and gender-adjusted WMH lesion progression at both 3 and 6 years, respectively; (odds ratio [OR], 1.007; 95% confidence interval [CI], 1.002 to 1.012; P=0.004; and OR, 1.004; 95% CI, 1.000 to 1.009 per ng/mL; P=0.057). After multivariate analysis controlling for other cardiovascular risk factors and C-reactive protein, 3-year OR was 1.010 (95% CI, 1.004 to 1.017; P=0.001) and 6-year OR was 1.008 (1.002 to 1.014 per ng/mL; P=0.006). Baseline log lesion volume was a strong independent predictor of progression but associations remained after controlling for this (3-year OR, 1.011; 95% CI, 1.002 to 1.020; P=0.013; and 6-year OR, 1.009; 95% CI, 1.000 to 1.017; P=0.039 per ng/mL). There was no association between WMH progression and other markers.


CONCLUSIONS
ICAM levels are related to progression of WMH on MRI. The prospective study design increases the likelihood that this association is causal and supports a role of endothelial cell activation in disease pathogenesis. In contrast, we found no evidence for coagulation activation being important.
Markus
Hugh S
HS
Clinical Neuroscience, St George's Hospital Medical School, Cranmer Terrace, London SW17 0RE, UK. h.markus@sghms.ac.uk
Hunt
Beverley
B
Palmer
Kiran
K
Enzinger
Christian
C
Schmidt
Helena
H
Schmidt
Reinhold
R
D000368:Aged; D001317:Austria; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002319:Cardiovascular System / Q000473:pathology; D018450:Disease Progression; D005260:Female; D005338:Fibrin Fibrinogen Degradation Products / Q000096:biosynthesis; D006487:Hemostasis; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D008074:Lipoproteins / Q000097:blood; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016017:Odds Ratio; D010446:Peptide Fragments / Q000097:blood; D011446:Prospective Studies; D011498:Protein Precursors / Q000097:blood; D011516:Prothrombin; D012307:Risk Factors; D012737:Sex Factors; D020521:Stroke / Q000473:pathology* / Q000517:prevention & control*; D018180:Thrombomodulin / Q000097:blood; D013997:Time Factors
D005338:Fibrin Fibrinogen Degradation Products; D008074:Lipoproteins; D010446:Peptide Fragments; D011498:Protein Precursors; D018180:Thrombomodulin; C036309:fibrin fragment D; C051928:lipoprotein-associated coagulation inhibitor; D018799:Intercellular Adhesion Molecule-1; C029733:prothrombin fragment 1; C044183:prothrombin fragment 2; D011516:Prothrombin