Editorial for “MRI-Based Investigation of Association Between Cerebrovascular Structural Alteration and White Matter Hyperintensity Induced by High Blood Pressure”

Cerebral small vessel disease (CSVD) is a common underlying cause of stroke and vascular dementia.¹ This disease mainly affects small perforating arteries and capillaries, leading to various neuroimaging abnormalities that can be detected with magnetic resonance imaging (MRI) or computed tomography (CT), including white matter hyper-intensities (WMH), superficial siderosis, visible perivascular spaces, lacunes, and microinfarcts. It is known that certain genetic mutations lead to inherited forms of CVSD, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebral autosomal recessive arteriopathy with sub-cortical infarcts and leukoencephalopathy (CARASIL), and hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC).² However, majority of CSVD cases are sporadic, raising from vascular risk factors including hypertension. In this issue of Journal of Magnetic Resonance Imaging, Boyu Zhang and colleagues studied the connection between hypertension, cerebrovascular morphology, and WMH burden.³

In their study, the authors used MRI data from 863 participants (465 had hypertension) from Taizhou Imaging Study and quantified the white matter lesion burden using automated lesion prediction algorithm based on T2-weighted fluid attenuated inversion recovery (FLAIR) images. Brain vascular morphology was studied using time-of-flight MR angiography (TOF MRA) for vessel density, tortuosity (describing the healthy curvature of individual blood vessels), branch numbers, and radius. First, the authors show that high blood pressure correlated with WMH counts and volumes. Higher blood pressure, especially diastolic pressure, correlated with lower cerebrovascular density (and proportion of small vessels), lower tortuosity, lower branch numbers, and increased mean radius. Blood pressure correlated inversely with the proportion of small vessels. Higher WMH lesion volumes were associated with decreased blood vessel density and tortuosity and increased radius. Finally, the authors performed path analyses with mediation models showing that cerebrovascular morphology mediated the association between high blood pressure and WMH.

Taken together, the authors have convincingly shown the association between high blood pressure and WMH. Interestingly, this association was mediated by changes in the cerebrovascular morphology indicating remodeling of brain vascular network by elevated blood pressure. The question remaining is, how altered cerebrovascular morphology can be mechanistically linked to the development of WMH? The current study focused on large caliber vessels (the mean radius of the smallest vessels detected with MRA was 0.82 mm), and the reduced density of arteries/veins could possibly lead to reduction in white matter blood flow increasing the risk for WMH and cognitive decline.⁴ However, it is even more intriguing to speculate what happens to the arterioles/venules and capillary network in these circumstances. Many of the aging and dementia-related pathological changes in the vascular network occur within these small vessels.⁵ These changes include reduction in pericyte coverage, breakdown of blood–brain barrier (BBB), deposition of blood-derived molecules into the brain parenchyma, and reduced capillary length and correlate with cognitive impairment in certain forms of dementia. Moreover, recent studies have shown that BBB breakdown is an independent biomarker of human cognitive dysfunction⁶ and that in individuals with genetic predisposition for dementia and Alzheimer’s disease may predict cognitive decline.⁷ In animal models of hypertension, BBB leakage occurs in arterioles and venules and contributes to white matter damage induced by hypoperfusion.^8,9 Accumulation of blood-derived molecules in the white matter through dysfunctional BBB due to loss of pericyte coverage might ultimately lead to white matter damage and loss.¹⁰

In conclusion, Boyu Zhang and colleagues have demonstrated that hypertension is associated with changes in the vascular morphology in the brain that mediate development of WMH, highlighting the importance of controlling vascular risk factors to prevent brain changes that increase the risk for dementia. Future studies will be needed to further characterize other pathologies including cerebral blood flow (ASL-MRI) and BBB permeability changes (DCE-MRI, T2*/SWI for microbleeds) related to altered vascular (MRA) and perivascular morphology (T2w sequences) in the context of brain white matter diseases. It would also be important to correlate these vascular pathologies to cognitive performance in addition to WMH burden. Possible common vascular pathways that mediate the development of both hereditary and sporadic white matter diseases could represent a potential treatment target for these conditions.