ADAMTS13 and von Willebrand Factor in relation to vascular cognitive impairment and cerebral small vessel disease: the heart-brain connection study

BACKGROUND: Reduced activity of a disintegrin-like and metalloprotease with thrombospondin type 1 repeats 13 (ADAMTS13) is associated with an increased risk of dementia, independent of Von Willebrand factor (VWF) levels. Pathways underlying this association remain poorly understood. OBJECTIVES: Investigate the associations of VWF levels and ADAMTS13 activity with vascular cognitive impairment (VCI) and cerebral small vessel disease (CSVD). METHODS: In this cross-sectional study, we included 147 participants with VCI and 120 reference subjects (mean age: 67.5 years, 41% women). Using multivariable logistic regression, we determined the cross-sectional association of ADAMTS13 activity and VWF levels in plasma with VCI. Additionally, across cases and reference subjects combined, we determined the cross-sectional association of VWF and ADAMTS13 with markers of CSVD on 3T brain magnetic resonance imaging (MRI) scan. RESULTS: Participants with lower ADAMTS13 activity had a higher odds of VCI (odds ratio OR per 1-SD decrease: 1.46 95% CI, 1.04-2.04), whereas participants with higher VWF levels did not (OR per 1-SD increase: 1.15 95% CI, 0.85-1.56). Overall, lower ADAMTS13 and higher VWF levels were similarly associated with higher white matter hyperintensity volume (mean difference per 1-SD change in ADAMTS13: 0.12 95% CI, -0.01 to 0.25 and for VWF: 0.13 95% CI, 0.01-0.26). For microbleeds, lacunes, and microinfarcts, low ADAMTS13 and high VWF showed ORs of around 2 for the uppermost quartiles, which were statistically significant only for VWF and lacunes. We found no evidence of synergistic effects of ADAMTS13 and VWF. CONCLUSIONS: Low ADAMTS13 activity is associated with VCI, independent of concurrently measured VWF. Low ADAMTS13 activity and high VWF levels are associated with markers of CSVD.