In the present study, we used BOLD signal based on rs-fMRI to calculate the CVR in different grades of WMH subjects. We firstly found that with the degree of WMH aggravated, the CVR of left frontal and occipital areas decreased, and the cognitive tests score decreased. In all WMH subjects, mediation analysis revealed that impaired CVR in left frontal and occipital areas leaded to cognitive decline in different domains through WMH, suggesting that impaired CVR may be the initial cause of WMH, and then leading to WMH-related cognitive decline. Our results suggested that the CVR based on BOLD data could be used to monitor impaired brain regions in the potential risk of WMH and WMH-related cognitive decline. Additionally, this study provided a comprehensive understanding of the pathophysiology mechanisms regarding WMH progression and WMH-related cognitive decline.
Consistent with previous cross-sectional studies [33, 34], our study revealed that the brain CVR decreased in moderate or severe WMH individuals including gray matter and white matter areas. It remains unknown whether WMH causes reduced CVR due to decreased metabolic demand or whether reductions in CVR lead to the development of WMH. Animal models demonstrated cerebrovascular dysfunction appeared months ahead of the first histological evidence of white matter injury, including oligodendrocyte loss and glial activation [35, 36]. Previous clinical studies followed up moderate-severe WMH patients for one year and found in comparison with contralateral normal appearing white matter (NAWM) that did not progress, NAWM that progressed to WMH had significantly decreased CVR value [30, 31]. This result suggested that impaired dynamic cerebrovascular response to hypercapnia precedes the occurrence of WMH and may result in the development of WMH. It is interesting to note that in our study, decreased CVR wasn’t directly related to cognitive decline, but caused cognitive decline through WMH, which indirectly indicating that the decrease of CVR may precede the occurrence of WMH. In terms of etiology, we can conclude that hemodynamic disorder represented by CVR may be an etiological factor of WMH, as well as WMH related cognitive decline.
Sequential evidences indicated that endothelial dysfunction may result in increased blood-brain barrier permeability with leakage of blood constituents into the vessel wall and white matter, and lead to increased arterial stiffness and persistent vasodilation/reconstruction that impairs vasoreactivity [37], which was crucial driver of CSVD [38–40]. The decrease of CVR represents low perfusion of brain tissue which may be a manifestation of endothelial dysfunction and impaired blood-brain barrier [41]. Therefore, assessment of CVR can provide early warning of the occurrence and development of WMH and WMH-related cognitive decline. Assessment of CVR by breath-holding index of middle cerebral arteries via transcranial doppler ultrasound has found global CVR decreased as the severity of WMH increased and associated with cognitive performance [34]. Findings from BOLD-based CVR studies remain controversial [16]. Some studies reported whole brain CVR was not related to WMH [42, 43], but others showed decreased CVR at baseline can predict the process of WMH lesions [18, 44, 45]. Based on previous studies, the current study confirmed that WMH was associated with decreased CVR again. What’s more, we further explore the relationships among decreased CVR, WMH and cognitive performance in different cognitive domains and found decreased CVR in left frontal and occipital areas was the initial cause of WMH related cognitive decline, suggesting that hemodynamic impairment may contribute to the pathogenesis and progression of WMH related cognitive decline.
Frontal and occipital areas are the main watershed regions bordered by the distal territories of the anterior, middle, and posterior cerebral arteries. In an event of hemodynamic compromise, peripheral circulation and small blood vessels in watershed areas are most susceptible to hypoperfusion, resulting in cerebral ischemia and hypoxia and thus more likely to develop ischemic lesion. A previous study revealed that the magnitude of the CVR decreased significantly with age in frontal white matter regions comprising the ACA-MCA watershed area[46]. Another study found hypertension with diabetes patients had decreased CVR in bilateral occipitoparietal areas [47]. In the present study, we found the CVR decline in left frontal and occipital areas may precede the occurrence of WMH. Therefore, combined with previous research findings and hemodynamic theory, we can conclude that CVR in frontal and occipital areas is more vulnerable to CVR damage and leading to WMH.
The current study is innovative and receivable for some of reasons. Firstly, we used BOLD signal based on rs-fMRI that does not require any specialized cooperation, resulting in higher patient compliance and research accuracy. Secondly, we enrolled patients with relatively homogeneous WMH subjects restricted to CSVD populations. In order to rule out the effects of severe cerebral microbleeds, lacunar and other vascular risk factors, brain /hippocampus volume on cognitive function and cerebral perfusions in comparisons among groups, we used semiquantitative classification to group WMH patients in attempting to match the confounding factors of each group, so that these factors did not influence the conclusion. Additionally, in the regression analysis and mediation analysis, we controlled for all possible potential confounders including age, gender, education, numbers of 、、、cerebral microbleeds and lacunars, and other vascular risk factors.
This is an initial cross-sectional study investigating the effects of decreased CVR on WMH progress and WMH-related cognitive decline using BOLD signal based on re-fMRI .Several limitations should be addressed, Firstly, BOLD signal based on re-fMRI was just validated in large artery disease, Moyamoya disease and healthy individuals, which was not validated by clinically established prospective CO2 targeting CVR method. So that, further studies with CO2 validation should be recommended. Secondly, because our study population came from outpatients and inpatients in department of neurology, no healthy controls were included. A previous study via transcranial doppler ultrasound indicated that no significant difference in CVR between WMH-0 and WMH-I groups [34]. Whatever, future works should recruit healthy controls to verify whether CVR declines have existed in WMH-I subjects compared to healthy controls. Finally, the nature of this study is cross-sectional. No causal inferences, or directionality can be made. We are continuing to follow-up them to validate our findings.