Perivascular space dilation in white matter mediates a significant relationship between white matter hyperintensity burden and venous collagenosis

Abstract

AbstractBackgroundPeriventricular T2 MRI white matter hyperintensities (WMH) are commonly observed in older individuals and are associated with cognitive and motor decline. While likely vascular in origin, the specific etiology of WMH remains unknown. Vascular insufficiency due to venous collagenosis has been implicated. Collagenosis may also interfere with perivascular fluid flow leading to dilation of perivascular spaces (PVS). PVS are thus an unexplored potential mediating factor between collagenosis and periventricular WMH.MethodBrain tissue from 25 Oregon Alzheimer’s Disease Center subjects was selected based on availability of in vivo 1.5 Tesla MRI (Table 1), which was used to quantify whole brain WMH burden. Three paraffin embedded 6μm thick coronal blocks of tissue per subject from anterior, middle and posterior white matter abutting the ventricle were stained with Masson’s Trichrome and Smooth Muscle Actin (SMA). Slides were scanned and an automated hue based algorithm identified 547 vessels and segmented them into blue collagen vessel walls, lumen holes within them and perivascular spaces outside them (Figure 1). Pearson correlation coefficients were calculated to assess relationships between PVS, periventricular WMH and collagenosis. Coregistered SMA images were used to classify vessels into veins (n=163) and arteries (n=251). Multiple linear regressions accounting for sex, age at death, and MRI to death interval followed by a Sobel test of mediation were calculated to determine the mediating effect of PVS on the relationship between collagenosis and periventricular WMH.ResultPeriventricular WMH volume, collagenosis and PVS were correlated with each other (p<.001) (Figure 1). In separate regression models, PVS and collagenosis in veins were significant predictors of WMH volume (p=.005, p=.007) but not in arteries (p=.256, p=.244). A Sobel test of the mediating effect of PVS on the relationship between collagenosis in veins and WMH burden was significant (p=.027) and the remaining direct effect of collagenosis on WMH was not significant (p=.21) (Figure 2).ConclusionPerivascular space dilation is an under recognized mechanism which may mediate the relationship between the development of venous collagenosis and periventricular WMH in an aged population.