Blood–brain barrier leakage increases with small vessel disease in acute ischemic stroke

Arba, Francesco; Leigh, R. John; Inzitari, Domenico; Warach, Steven; Luby, Marie; Lees, Kennedy R.

doi:10.1212/wnl.0000000000004677

Cited by 69 publications

(70 citation statements)

References 32 publications

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“…First, we observed no substantial difference in age, hypertension, diabetes, anticoagulant use, intravenous alteplase treatment, rate of haemorrhagic transformation, WMHv or stroke severity in women. A relationship between NAWM BBB permeability and white matter structural integrity has been reported in individuals with cerebral small-vessel disease 25–27. In our acute cohort, however, we observed no difference in strokes attributed to small-vessel occlusive disease between sexes.…”

Section: Discussioncontrasting

confidence: 47%

Sex-specific differences in white matter microvascular integrity after ischaemic stroke

Etherton

Cougo

et al. 2019

Stroke Vasc Neurol

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Background and purposeFunctional outcomes after ischaemic stroke are worse in women, despite adjusting for differences in comorbidities and treatment approaches. White matter microvascular integrity represents one risk factor for poor long-term functional outcomes after ischaemic stroke. The aim of the study is to characterise sex-specific differences in microvascular integrity in individuals with acute ischaemic stroke.MethodsA retrospective analysis of subjects with acute ischaemic stroke and brain MRI with diffusion-weighted (DWI) and dynamic-susceptibility contrast-enhanced (DSC) perfusion-weighted imaging obtained within 9 hours of last known well was performed. In the hemisphere contralateral to the acute infarct, normal-appearing white matter (NAWM) microvascular integrity was measured using the K2 coefficient and apparent diffusion coefficient (ADC) values. Regression analyses for predictors of K2 coefficient, DWI volume and good outcome (90-day modified Rankin scale (mRS) score <2) were performed.Results105 men and 79 women met inclusion criteria for analysis. Despite no difference in age, women had increased NAWM K2 coefficient (1027.4 vs 692.7×10–6/s; p=0.006). In women, atrial fibrillation (β=583.6; p=0.04) and increasing NAWM ADC (β=4.4; p=0.02) were associated with increased NAWM K2 coefficient. In multivariable regression analysis, the K2 coefficient was an independent predictor of DWI volume in women (β=0.007; p=0.01) but not men.ConclusionsIn women with acute ischaemic stroke, increased NAWM K2 coefficient is associated with increased infarct volume and chronic white matter structural integrity. Prospective studies investigating sex-specific differences in white matter microvascular integrity are needed.

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Section: Discussioncontrasting

confidence: 47%

Sex-specific differences in white matter microvascular integrity after ischaemic stroke

Etherton

Cougo

et al. 2019

Stroke Vasc Neurol

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“…Thus, in identifying a link between post-stroke BBB disruption and functional outcome, a biomarker for identification of patients who may benefit from a therapeutic intervention may also have been identified. We previously reported increased BBB permeability in patients with chronic small vessel disease [11]. This form of BBB disruption is also thought to be inflammatory in nature [1].…”

Section: Discussionmentioning

confidence: 95%

“…Image processing was done using an automated pipeline with minimal user interaction. The BBB calculations were completely automated and thus not influenced by an operator or other variables as described previously [11].…”

Section: Mri Parametersmentioning

confidence: 99%

Post-Stroke Blood-Brain Barrier Disruption and Poor Functional Outcome in Patients Receiving Thrombolytic Therapy

et al. 2019

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Background and Purpose: The role played by post-stroke inflammation after an ischemic event in limiting functional recovery remains unclear. One component of post-stroke inflammation is disruption of the blood-brain barrier (BBB). This study examines the relationship between post-stroke BBB disruption and functional outcome. Methods: Acute stroke patients treated with thrombolysis underwent magnetic resonance imaging scanning 24 h and 5 days after their initial event. BBB permeability maps were generated from perfusion weighted imaging. Average permeability was calculated in the affected hemisphere. Good functional outcome, defined as a modified Rankin score of 0 or 1, was compared with average permeability using logistic regression. Results: Of the 131 patients enrolled, 76 patients had the necessary data to perform the analysis at 24 h, and 58 patients had data for the 5-day assessment. Higher BBB permeability measured at 24 h (OR 0.57; 95% CI 0.33–0.99, p = 0.045) and at 5 days (OR 0.24; 95% CI 0.09–0.66, p = 0.005) was associated with worse functional outcome 1–3 months after the acute ischemic stroke. For every percentage increase in BBB disruption at 5 days, there was a 76% decrease in the chance of achieving a good functional outcome after stroke. Multivariate analysis found this to be independent of age, stroke volume, or clinical stroke severity. Conclusions: Post-stroke BBB disruption appears to be predictive of functional outcome irrespective of stroke size.

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“…While the pericytes found here were located outside the vascular bags, these cells and their processes are enclosed by two layers of the basement membrane [ 67 ], and therefore their degeneration might contribute to splitting of the basement membrane. The disruption of the BBB in SVD is also supported by in vivo perfusion-weighted MR imaging performed living patients [ 4 ].…”

Section: Discussionmentioning

confidence: 99%

Endothelial damage, vascular bagging and remodeling of the microvascular bed in human microangiopathy with deep white matter lesions

Forsberg

Zhang

Reiners

et al. 2018

acta neuropathol commun

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White matter lesions (WMLs) are a common manifestation of small vessel disease (SVD) in the elderly population. They are associated with an enhanced risk of developing gait abnormalities, poor executive function, dementia, and stroke with high mortality. Hypoperfusion and the resulting endothelial damage are thought to contribute to the development of WMLs. The focus of the present study was the analysis of the microvascular bed in SVD patients with deep WMLs (DWMLs) by using double- and triple-label immunohistochemistry and immunofluorescence. Simultaneous visualization of collagen IV (COLL4)-positive membranes and the endothelial glycocalyx in thick sections allowed us to identify endothelial recession in different types of string vessels, and two new forms of small vessel/capillary pathology, which we called vascular bagging and ghost string vessels. Vascular bags were pouches and tubes that were attached to vessel walls and were formed by multiple layers of COLL4-positive membranes. Vascular bagging was most severe in the DWMLs of cases with pure SVD (no additional vascular brain injury, VBI). Quantification of vascular bagging, string vessels, and the density/size of CD68-positive cells further showed widespread pathological changes in the frontoparietal and/or temporal white matter in SVD, including pure SVD and SVD with VBI, as well as a significant effect of the covariate age. Plasma protein leakage into vascular bags and the white matter parenchyma pointed to endothelial damage and basement membrane permeability. Hypertrophic IBA1-positive microglial cells and CD68-positive macrophages were found in white matter areas covered with networks of ghost vessels in SVD, suggesting phagocytosis of remnants of string vessels. However, the overall vessel density was not altered in our SVD cohort, which might result from continuous replacement of vessels. Our findings support the view that SVD is a progressive and generalized disease process, in which endothelial damage and vascular bagging drive remodeling of the microvasculature.Electronic supplementary materialThe online version of this article (10.1186/s40478-018-0632-z) contains supplementary material, which is available to authorized users.

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Blood–brain barrier leakage increases with small vessel disease in acute ischemic stroke

Abstract: Global SVD burden is associated with increased BBB leakage in both acutely ischemic and nonischemic area. Our results support that SVD score has construct validity, and confirm a relation between SVD and BBB disruption also in patients with acute stroke.

Cited by 69 publications

References 32 publications

Sex-specific differences in white matter microvascular integrity after ischaemic stroke

Sex-specific differences in white matter microvascular integrity after ischaemic stroke

Post-Stroke Blood-Brain Barrier Disruption and Poor Functional Outcome in Patients Receiving Thrombolytic Therapy

Endothelial damage, vascular bagging and remodeling of the microvascular bed in human microangiopathy with deep white matter lesions

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