Thrombogenic microvesicles and white matter hyperintensities in postmenopausal women

Abstract

Objective: To determine the association of conventional cardiovascular risk factors, markers of platelet activation, and thrombogenic blood-borne microvesicles with white matter hyperintensity (WMH) load and progression in recently menopausal women.

Methods: Women (n = 95) enrolled in the Mayo Clinic Kronos Early Estrogen Prevention Study underwent MRI at baseline and at 18, 36, and 48 months after randomization to hormone treatments. Conventional cardiovascular risk factors, carotid intima-medial thickness, coronary arterial calcification, plasma lipids, markers of platelet activation, and thrombogenic microvesicles were measured at baseline. WMH volumes were calculated using a semiautomated segmentation algorithm based on fluid-attenuated inversion recovery MRI. Correlations of those parameters with baseline WMH and longitudinal change in WMH were adjusted for age, months past menopause, and APOE ε4 status in linear regression analysis.

Results: At baseline, WMH were present in all women. The WMH to white matter volume fraction at baseline was 0.88% (0.69%, 1.16%). WMH volume increased by 122.1 mm(3) (95% confidence interval: -164.3, 539.5) at 36 months (p = 0.003) and 155.4 mm(3) (95% confidence interval: -92.13, 599.4) at 48 months (p < 0.001). These increases correlated with numbers of platelet-derived and total thrombogenic microvesicles at baseline (p = 0.03).

Conclusion: Associations of platelet-derived, thrombogenic microvesicles at baseline and increases in WMH suggest that in vivo platelet activation may contribute to a cascade of events leading to development of WMH in recently menopausal women.

Figures

Figure 1. Progression of white matter hyperintensities of a KEEPS-MRI study participant on FLAIR MRI

An example of changes in white matter hyperintensities (WMH) on fluid-attenuated inversion recovery (FLAIR) MRI is shown on the left panel. FLAIR MRI with WMH mask in green is shown on the right panel. The WMH volume was 340 mm3 at baseline and 584 mm3 at 48 months in this Kronos Early Estrogen Prevention Study (KEEPS) participant. The FLAIR images displayed are unprocessed, therefore not corrected for bias field for the comparison of the WMH mask with the unprocessed FLAIR image. However, all MRIs underwent preprocessing corrections for gradient nonlinearity and intensity nonuniformity during the automated WMH segmentation procedure.

Figure 2. Longitudinal changes in white matter hyperintensities in cubic millimeters

Mean white matter hyperintensity (WMH) change (baseline – 18 months, baseline – 36 months, and baseline – 48 months), with 95% bootstrap confidence intervals (CIs). Blue dots represent mean of the change. X-axis shows the total change in WMH from baseline in cubic millimeters. Numbers in the figure show the minimum and maximum confidence intervals from the bootstrap.

Figure 3. Associations between white matter hyperintensity change and platelet-derived microvesicles and carotid intima-medial thickness

Total thrombogenic (annexin V–positive) microvesicles (MV) (A), platelet-derived (CD42a-positive) MV (B), carotid intima-medial thickness (CIMT) (C), and regression coefficients of total white matter hyperintensity (WMH) volume change, in cubic millimeters, at the 95% confidence interval at 36 and 48 months. The dotted line on the left panel is set at 0 and represents the estimated mean of total WMH change. The right panel represents p values at p = 0.05 significance level. Circles represent results from unadjusted and triangles represent results from adjusted (age, time in months past menopause, and APOE ε4 status) linear regression models. B = baseline; m = months.