Lack of Association of White Matter Lesions with Ipsilateral Carotid Artery Stenosis

Abstract

Background: White matter lesions (WML) are commonly seen on brain MRI and are generally considered a marker of tissue damage from cerebral small vessel disease. WML are associated with increasing age and vascular risk factors, but their precise cause is unknown. A role for carotid artery atherothromboemboli has been suggested. If this is the case, more WML would be expected ipsilateral to increasing degrees of carotid stenosis. Methods: We recruited patients with ischaemic stroke from two large, separate prospective stroke studies, assessed with brain MRI and carotid Doppler ultrasound. We scored hemispheric WML visually in periventricular and deep locations. We assessed the association between carotid stenosis asymmetry and WML asymmetry, and vice versa. Further, we assessed the association between carotid stenosis and ipsilateral WML, before and after adjusting for vascular risk factors, and tested associations between ipsilateral and contralateral stenoses and WML. Results: We recruited 247 (Study 1) and 253 (Study 2) patients. In Study 1 and Study 2, 36 (15%) and 29 (11%) patients had ≥50% carotid stenosis, and 27 (11%) and 15 (6%) had ≥70% stenosis, respectively. Carotid stenosis was asymmetric in 28 (11%) and 26 (10%) patients and WML were asymmetric in 22 (9%) and 11 (4%) patients in Study 1 and Study 2, respectively. We found no association between carotid stenosis and ipsilateral WML score, before or after adjusting for vascular risk factors or sidedness, but WML were strongly associated with increasing age (p < 0.001). Conclusion: In two large cohorts of ischaemic stroke patients, we found no association between carotid stenosis and ipsi- or contralateral WML. There is now substantial evidence that atherothromboemboli are unlikely to cause most WML or other forms of cerebral small vessel lesions. Future studies should focus on determining what causes the intrinsic small vessel pathological changes that appear to underlie most WML.

Population-Based Case–Control Study of White Matter Changes on Brain Imaging in Transient Ischemic Attack and Ischemic Stroke

“…First, in the casecase comparison within the OXVASC Study, we did not find any independent association between WMC and unilateral or bilateral carotid stenosis (≥50%) or atrial fibrillation (Table 2). Second, previous studies have also shown that there seems to be no association between WMC and side or severity of atherosclerotic carotid stenosis 39 or atrial fibrillation. 34 WMC are clearly related strongly to age, irrespective of any major role of vascular risk factors.…”

Emerging Evidence for Pathogenesis of Sporadic Cerebral Small Vessel Disease

“…64 Although the bilateral common carotid artery stenosis model cannot replicate small vessel vasculopathy or lacunar infarcts or model SVD, it possesses advantages in terms of reproducibility of WM pathology, characterized by BBB disruption, glial activation, oxidative stress, and oligodendrocyte loss. [65][66][67][68][69] Although clinically there is no direct evidence of an association between carotid stenosis and SVD or cognitive decline, once confounding risk factors are corrected for, 13,70,71 altered hemodynamics following bilateral common carotid artery stenosis results in opening of the endothelial tight junction only 2 hours after manipulation, which can be suppressed by matrix metalloproteinase 2 (MMP2) inhibitors. 66,68 MMP2, an extracellular matrix degradation enzyme, is also known to degrade the tight junction proteins ZO-1, claudin-5, and occludin, as well as induce BBB breakdown.…”

“…Несмотря на то что модель двустороннего стеноза общей сонной артерии не позволяет воспроизвести васкулопатию мелких сосудов, лакунарные инфаркты или поражения, характерные для БМЦС, она обладает преимуществами с точки зрения воспроизводимости патологии БВГМ, характеризующей-ся нарушением ГЭБ, активацией глии, оксидантным стрессом и гибелью олигодендроцитов [65][66][67][68][69]. Несмотря на отсутствие прямых клинических доказательств связи стеноза и БМЦС или развития когнитивных нарушений, при внесении поправок на вмешивающиеся факторы [13,70,71] нарушение гемодинамики в результате двусто-роннего стеноза приводит к открытию эндотелиальных плотных контактов только через 2 часа после манипуля-ций, которое можно подавить с помощью ингибиторов матричной металлопротеиназы-2 (MMP2) [66,68]. Также известно, что MMP2, фермент деградации внеклеточного матрикса, также разрушает белки плотных контактов ZO-1, клаудин-5 и окклюдин и индуцирует разрушение ГЭБ [72].…”

Gliovascular Disruption and Cognitive Deficits in a Mouse Model with Features of Small Vessel Disease

“…Although there is no association between carotid stenosis and SVD in humans, 25 small vessel changes have been linked to histologic features that have been interpreted as representing local hypoperfusion of as yet unknown cause. 26 We therefore hypothesized that sustained hypoperfusion would produce progressive pathologic and cognitive features similar to those seen in SVD.…”