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

Abstract

Background White matter hyperintensities (WMHs) are one of the hallmarks of cerebral small vessel disease (CSVD), but the pathological mechanisms underlying WMHs remain unclear. Recent studies suggest that extracellular fluid (ECF) is increased in brain regions with WMHs. It has been hypothesized that ECF accumulation may have detrimental effects on white matter microstructure. To test this hypothesis, we used cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) as a unique CSVD model to investigate the relationships between ECF and fiber microstructural changes in WMHs. Methods Thirty-eight CADASIL patients underwent 3.0 T MRI with multi-model sequences. Parameters of free water (FW) and apparent fiber density (AFD) obtained from diffusion-weighted imaging (b = 0 and 1000 s/mm2) were respectively used to quantify the ECF and fiber density. WMHs were split into four subregions with four levels of FW using quartiles (FWq1 to FWq4) for each participant. We analyzed the relationships between FW and AFD in each subregion of WMHs. Additionally, we tested whether FW of WMHs were associated with other accompanied CSVD imaging markers including lacunes and microbleeds. Results We found an inverse correlation between FW and AFD in WMHs. Subregions of WMHs with high-level of FW (FWq3 and FWq4) were accompanied with decreased AFD and with changes in FW-corrected diffusion tensor imaging parameters. Furthermore, FW was also independently associated with lacunes and microbleeds. Conclusions Our study demonstrated that increased ECF was associated with WM degeneration and the occurrence of lacunes and microbleeds, providing important new insights into the role of ECF in CADASIL pathology. Improving ECF drainage might become a therapeutic strategy in future.

Perfusion heterogeneity of cerebral small vessel disease revealed via arterial spin labeling MRI and machine learning

“…Zhang et al have reported that an increased pericarotid fat density is associated with the presence of lacunes, and may be linked to CSVD ( Zhang et al, 2021 ). A previous cross-sectional study has provided evidence which linked lacunes and WMHs to a common pathogenesis of CSVD ( Yu et al, 2021 ). In addition, CSVD subtype 2 and subtype 3 also showed higher possibility of PVWMH but not deep WMH (DWMH) compared with subtype 1.…”

Contrast agent‐free state‐of‐the‐art magnetic resonance imaging on cerebral small vessel disease – Part 2: Diffusion tensor imaging and functional magnetic resonance imaging

“…Increased FW also correlated with an IL‐18–centered inflammatory network, 85 was found to mediate the association between deep medullary veins disruption and WM integrity in cSVD, 16 was related to geriatric depressive symptoms 86 and presented a stronger association with cognitive deficits than the conventional DTI method, showing it to be a marker of cSVD‐related degeneration 87 . Extracellular fluid quantified with FW‐related parameters associated positively with microstructural degeneration and the presence of lacunes and CMB in CADASIL patients, suggesting a role for extracellular fluid in cSVD pathology 88 …”

“…87 Extracellular fluid quantified with FW-related parameters associated positively with microstructural degeneration and the presence of lacunes and CMB in CADASIL patients, suggesting a role for extracellular fluid in cSVD pathology. 88 An alternative diffusion tensor decomposition model has been developed to provide isotropic and anisotropic tensor components. Such parameters were significantly correlated with executive functions, IPS, and conversion to dementia in a 3-year longitudinal study.…”

Superficial white matter microstructure affects processing speed in cerebral small vessel disease

“…The present study suggests that FW in the SWM may constitute an early marker of white matter microstructural abnormality in CSVD. Although FW was originally estimated to correct for freely diffusing extracellular water (Pasternak et al, 2009 ), many studies have found that FW is particularly sensitive to disease severity (Duering et al, 2018 ; Gullett et al, 2020 ; Huang, Zhang, Jiaerken, Wang, Hong, et al, 2021 ; Ji et al, 2017 ; Maillard et al, 2019 ; Yu et al, 2021 ). Using FW imaging, increasing evidence suggests a prominent increase in extracellular water in CSVD, with less demyelination and axonal loss than would be suggested by conventional diffusion measures (Duering et al, 2018 ; Wardlaw et al, 2019 ).…”