Decreased water exchange rate across blood-brain barrier in hereditary cerebral small vessel disease.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and heterozygous HTRA1 mutation related cerebral small vessel disease (CSVD) are the two types of dominant hereditary CSVD. Blood-brain barrier (BBB) failure has been hypothesized in the pathophysiology of CSVD. However, it is unclear whether there are BBB damage in the two hereditary CSVD, especially in heterozygous HTRA1 mutation related CSVD. In this study, a case control design was used with two disease groups including CADASIL (n = 24), heterozygous HTRA1 mutation related CSVD (n = 9), and healthy control (n = 24) were studied. All participants underwent clinical cognitive assessments and brain MRI. Diffusion-prepared pseudo-continuous arterial spin labeling (DP-pCASL) was used to estimate water exchange rate across the BBB (kw). Correlation and multiple linear regression analysis were used to examine the association between kw and disease burden and neuropsychological performance respectively. Compared with healthy control, kw in the whole brain and multiple brain regions was decreased in both CADASIL and heterozygous HTRA1 mutation related CSVD patients (Bonferroni corrected p < 0.007). In the CADASIL group, decreased kw in the whole brain (β = -0.634, p = 0.001), normal-appearing white matter (NAWM) (β = -0.599, p = 0.002), and temporal lobe (β = -0.654, p = 0.001) was significantly associated with higher CSVD score after adjusting age and sex. Reduced kw in the whole brain was significantly associated with poorer neuropsychological performance after adjusting age, sex, and education in both CADASIL and heterozygous HTRA1 mutation related CSVD group (β = 0.458, p = 0.001; β = 0.884, p = 0.008). This study showed that there was decreased water exchange rate across the BBB in both CADASIL and heterozygous HTRA1 mutation related CSVD patients, suggesting a common pathophysiological mechanism underlying the two hereditary CSVD. These results highlight the potential use of kw for monitoring the course of CADASIL and heterozygous HTRA1 mutation related CSVD, a possibility which should be tested in future research.