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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 is BBB damage in the two types of 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 controls (n = 24). All participants underwent clinical cognitive assessments and brain MRI. Diffusion-prepared pseudo-continuous arterial spin labelling was used to estimate the water exchange rate across the BBB (kw). Correlation and multiple linear regression analyses were used to examine the association between kw and disease burden and neuropsychological performance, respectively. Compared with the healthy controls, 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 (β = −0.599, P = 0.002) and temporal lobe (β = −0.654, P = 0.001) was significantly associated with higher CSVD score after adjusting for age and sex. Reduced kw in the whole brain was significantly associated with poorer neuropsychological performance after adjusting for age, sex and education in both CADASIL and heterozygous HTRA1 mutation-related CSVD groups (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 types of 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.

White matter hyperintensities (WMH) are common in elderly individuals and cause brain network deficits. However, it is still unclear how the global brain network is affected by the focal WMH. We aimed to investigate the diffusion of WMH‐related deficits along the connecting white matters (WM). Brain magnetic resonance imaging data and neuropsychological evaluations of 174 participants (aged 74 ± 5 years) were collected and analyzed. For each participant, WMH lesions were segmented using a deep learning method, and 18 major WM tracts were reconstructed using automated quantitative tractography. The diffusion characteristics of distal WM tracts (with the WMH penumbra excluded) were calculated. Multivariable linear regression analysis was performed. We found that a high burden of tract‐specific WMH was related to worse diffusion characteristics of distal WM tracts in a wide range of WM tracts, including the forceps major (FMA), forceps minor (FMI), anterior thalamic radiation (ATR), cingulum cingulate gyrus (CCG), corticospinal tract (CST), inferior longitudinal fasciculus (ILF), superior longitudinal fasciculus‐parietal (SLFP), superior longitudinal fasciculus‐temporal (SLFT), and uncinate fasciculus (UNC). Furthermore, a higher mean diffusivity (MD) of distal tracts was linked to worse attention and executive function in the FMI, right CCG, left ILF, SLFP, SLFT, and UNC. The effect of WMH on the microstructural integrity of WM tracts may propagate along tracts to distal regions beyond the penumbra and might eventually affect attention and executive function., A high burden of tract‐specific WMH was related to an increased MD of distal WM tracts. A higher MD of distal tracts was linked to worse attention and executive function. The microstructural changes caused by WMH may propagate along tracts to distal regions beyond the penumbra.

Background and purpose: White matter hyperintensities (WMH) are common in elderly individuals and contribute to age-related cognitive dysfunction. Converging evidence indicates that WMH affect white matter (WM) microstructural integrity in WMH and their penumbra. We aimed to investigate whether this effect extends to the distal WM tracts, and to examine the association between distal WM microstructural integrity and cognitive dysfunction in community-dwelling elderly people. Methods: Brain MRI data including FLAIR and DTI sequences of 174 participants (74 ± 5 years) of the Shanghai Aging Study (SAS) were collected and analyzed. For each participant, WMH lesions were segmented automatically. Eighteen major WM tracts were reconstructed using automated quantitative tractography, and the mean diffusivity (MD) of distal WM tracts (excluding an area of 12 mm around the WMH) was calculated. Multivariable linear regression was performed. Results: A high burden of tract-specific WMH was related to a high MD of distal WM tracts in the forceps major (FMA), anterior thalamic radiations (ATR), cingulum cingulate gyrus (CCG), corticospinal tract (CST), superior longitudinal fasciculus-parietal (SLFP), superior longitudinal fasciculus-temporal (SLFT), and uncinate fasciculus (UNC). Furthermore, a high MD of distal tracts was linked to worse attention and executive function in the forceps minor (FMI), right CCG, left inferior longitudinal fasciculus (ILF), SLFP, SLFT and UNC. Conclusions: The effect of WMH on the microstructural integrity of WM tracts may propagate along tracts to distal regions farther than the penumbra and eventually might affect attention and executive function.