Venous disruption affects white matter integrity through increased interstitial fluid in cerebral small vessel disease

Abstract

Deep medullary veins (DMVs) participate in the drainage of surrounding white matter. In cerebral small vessel disease (CSVD), disrupted DMVs were often observed together with damaged white matter, but the phenomenon lacked validation and explanation. We hypothesized that venous disruption might cause white matter damage through increased interstitial fluid resulting from hemodynamic alteration, and we designed a comprehensive multi-modality MRI study to testify our hypothesis. Susceptibility-weighted imaging was used to investigate the characteristics of DMVs and derive DMVs scores. Free water elimination diffusion tensor imaging model was used to analyze interstitial fluid fraction (fraction of free water, fFW) and white matter integrity (tissue fractional anisotropy, FAt). Totally, 104 CSVD patients were included. Total DMVs score was associated with FAt of DMVs drainage area. The effect of total DMVs score on FAt was mediated by fFW, after controlling for age, sex, hypertension, regional cerebral blood flow and lacune numbers. The relationships between DMVs score, fFW and FAt were also significant in most DMVs drainage subregions. Therefore, we discovered the DMVs disruption – increased interstitial fluid – white matter damage link in CSVD patients, which was independent of arterial perfusion variations.

Increased extracellular fluid is associated with white matter fiber degeneration in CADASIL: in vivo evidence from diffusion magnetic resonance imaging

“…For example, increased aortic stiffness could promote an increase in extracellular water content in WM, eventually leading to the development of WMHs [ 30 ]. While the strong relationship between collagenosis of the deep medullary veins and periventricular WMHs has been confirmed in radiological-pathological correlation studies [ 29 , 31 , 32 ], our recent study further suggests that their association is mediated by increased ECF [ 33 ]. Moreover, enlarged PVS is hypothesized to represent impaired drainage of ISF from the brain [ 34 ] and the fact that WMHs may grow from dilated PVS also suggests significant contribution of ECF accumulation [ 35 ].…”

Impaired dynamic cerebral autoregulation is associated with the severity of neuroimaging features of cerebral small vessel disease

“… 25 , 26 Until recently, the specific pathological mechanisms underlying CSVD still remained largely unknown, in part because of the lack of effective methods that can technically visualize or image small vessels in vivo. 4 , 25 Although the advances in neuroimaging have provided novel information in CSVD including detailed evaluation of the vessel wall, atherosclerotic plaques within intracranial arteries, 27 , 28 white matter integrity, WMH shape, and the fraction of free water in the drainage area, 29 , 30 , 31 there have been few researches investigating the dynamic vasculature's function of small vessels, such as dCA.…”

Deep medullary veins are associated with widespread brain structural abnormalities

“…8 A potential explanation for this is that the pathological changes in venules, such as VC, cause the dysfunction of interstitial fluid drainage and edema in deep WM areas. 2,3,15,16 As a result, the accumulation of interstitial fluid is likely accompanied by an accumulation of toxic wastes, which might provoke an inflammatory response toward myelin. 17 Additionally, the stenosis or occlusion of venules might increase vascular resistance and exacerbate the hypoperfusion of WM.…”