Understanding the Importance of Blood-Brain Barrier Alterations in Brain Arteriovenous Malformations and Implications for Treatment: A Dynamic Contrast-Enhanced-MRI-Based Prospective Study.

BACKGROUND AND OBJECTIVES: The major clinical implication of brain arteriovenous malformations (bAVMs) is spontaneous intracranial hemorrhage. There is a growing body of experimental evidence proving that inflammation and blood-brain barrier (BBB) dysfunction are involved in both the clinical course of the disease and the risk of bleeding. However, how bAVM treatment affects perilesional BBB disturbances is yet unclear. METHODS: We assessed the permeability changes of the BBB using dynamic contrast-enhanced MRI (DCE-MRI) in a series of bAVMs (n = 35), before and at a mean of 5 (±2) days after treatment. A set of cerebral cavernous malformations (CCMs) (n = 16) was used as a control group for the assessment of the surgical-related collateral changes. The extended Tofts pharmacokinetic model was used to extract permeability (Ktrans) values in the lesional, perilesional, and normal brain tissues. RESULTS: In patients with bAVM, the permeability of BBB was higher in the perilesional of bAVM tissue compared with the rest of the brain parenchyma (mean Ktrans 0.145 ± 0.104 vs 0.084 ± 0.035, P = .004). Meanwhile, no significant changes were seen in the perilesional brain of CCM cases (mean Ktrans 0.055 ± 0.056 vs 0.061 ± 0.026, P = .96). A significant decrease in BBB permeability was evident in the perilesional area of bAVM after surgical resection (mean Ktrans 0.145 ± 0.104 vs 0.096 ± 0.059, P = .037). This benefit in BBB permeability reduction after surgery seemed to surpass the relative increase in permeability inherent to the surgical manipulation. CONCLUSION: In contrast to CCMs, BBB permeability in patients with bAVM is increased in the perilesional parenchyma, as assessed using DCE-MRI. However, bAVM surgical resection seems to reduce BBB permeability in the perilesional tissue. No evidence of the so-called breakthrough phenomenon was detected in our series. DCE-MRI could become a valuable tool to follow the longitudinal course of BBB damage throughout the natural history and clinical course of bAVMs.

Wall enhancement as a biomarker of intracranial aneurysm instability: a histo-radiological study.

BACKGROUND: The aim of this is to explore the histological basis of vessel wall enhancement (WE) on magnetic resonance imaging (MRI), which is a strong radiological biomarker of aneurysmal prone to rupture compared to other classical risk predictors (e.g., PHASES score, size, morphology). METHODS: A prospective observational study was performed including all consecutive patients presenting with a saccular intracranial aneurysm at Vall d'Hebron University Hospital between October 2017 and May 2019. The patients underwent high-resolution 3 T MRI, and their aneurysms were classified into asymptomatic, symptomatic, and ruptured. A histological and immunohistochemical study was performed in a subgroup of patients (n = 20, of which 15 presented with WE). Multiple regression analyses were performed to identify predictors of rupture and aneurysm symptoms. RESULTS: A total of 132 patients were enrolled in the study. WE was present in 36.5% of aneurysms: 22.9% asymptomatic, 76.9% symptomatic, and 100% ruptured. Immunohistochemical markers associated with WE were CD3 T cell receptor (p = 0.05) and CD45 leukocyte common antigen (p = 0.05). Moreover, WE is an independent predictor of symptomatic and ruptured aneurysms (p < 0.001). CONCLUSIONS: Aneurysms with WE present multiple histopathological changes that may contribute to wall disruption and represent the pathophysiological basis of radiological WE. Moreover, WE is an independent diagnostic predictor of aneurysm symptoms and rupture.

Association of candidate genetic variants and circulating levels of ApoE/ApoJ with common neuroimaging features of cerebral amyloid angiopathy.

Introduction: Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of amyloid-ß (Aß) in brain vessels and is a main cause of lobar intracerebral hemorrhage (ICH) in the elderly. CAA is associated with magnetic resonance imaging (MRI) markers of small vessel disease (SVD). Since Aß is also accumulated in Alzheimer's disease (AD) in the brain parenchyma, we aimed to study if several single nucleotide polymorphisms (SNPs) previously associated with AD were also associated with CAA pathology. Furthermore, we also studied the influence of APOE and CLU genetic variants in apolipoprotein E (ApoE) and clusterin/apolipoprotein J (ApoJ) circulating levels and their distribution among lipoproteins. Methods: The study was carried out in a multicentric cohort of 126 patients with lobar ICH and clinical suspicion of CAA. Results: We observed several SNPs associated with CAA neuroimaging MRI markers [cortical superficial siderosis (cSS), enlarged perivascular spaces in the centrum semiovale (CSO-EPVS), lobar cerebral microbleeds (CMB), white matter hyperintensities (WMH), corticosubcortical atrophy and CAA-SVD burden score]. Concretely, ABCA7 (rs3764650), CLU (rs9331896 and rs933188), EPHA1 (rs11767557), and TREML2 (rs3747742) were significantly associated with a CAA-SVD burden score. Regarding circulating levels of apolipoproteins, protective AD SNPs of CLU [rs11136000 (T) and rs9331896 (C)] were significantly associated with higher HDL ApoJ content in the lobar ICH cohort. APOEε2 carriers presented higher plasma and LDL-associated ApoE levels whereas APOEε4 carriers presented lower plasma ApoE levels. Additionally, we observed that lower circulating ApoJ and ApoE levels were significantly associated with CAA-related MRI markers. More specifically, lower LDL-associated ApoJ and plasma and HDL-associated ApoE levels were significantly associated with CSO-EPVS, lower ApoJ content in HDL with brain atrophy and lower ApoE content in LDL with the extent of cSS. Discussion: This study reinforces the relevance of lipid metabolism in CAA and cerebrovascular functionality. We propose that ApoJ and ApoE distribution among lipoproteins may be associated with pathological features related to CAA with higher ApoE and ApoJ levels in HDL possibly enhancing atheroprotective, antioxidative, and anti-inflammatory responses in cerebral ß-amyloidosis.

Intracranial atherosclerotic plaque enhancement and long-term risk of future strokes: A prospective, longitudinal study.

BACKGROUND AND PURPOSE: The prognostic significance of postcontrast enhancement of intracranial atheromatous plaque is uncertain. Prospective, long-term follow-up studies in Caucasians, using a multicenter design, are lacking. We aimed to evaluate whether this radiological sign predicts long-term new stroke in symptomatic and asymptomatic intracranial atherosclerotic disease (ICAD) patients. METHODS: This was a prospective, observational, longitudinal, multicenter study. We included a symptomatic and an asymptomatic cohort of ICAD patients that underwent 3T MRI including high-resolution sequences focused on the atheromatous plaque. We evaluated grade of stenosis, plaque characteristics, and gadolinium enhancement ratio (postcontrast plaque signal/postcontrast corpus callosum signal). The occurrence of new events was evaluated at 3, 6, 9, and 12 months and annually thereafter. The association between plaque characteristics and new stroke was studied using Cox multiple regression survival analysis and Kaplan-Meier curves. RESULTS: Forty-eight symptomatic and 13 asymptomatic patients were included. During 56.3 ± 16.9 months, 11 patients (18%) suffered a new event (seven ischemic, two hemorrhagic, and two transient ischemic attacks). A receiver operating characteristic curve identified an enhancement ratio of >1.77 to predict a new event. In a multivariable Cox regression, postcontrast enhancement ratio >1.77 (hazard ratio [HR]= 3.632; 95% confidence interval [CI], 1.082-12.101) and cerebral microbleeds (HR = 5.244; 95% CI, 1.476-18.629) were independent predictors of future strokes. Patients with a plaque enhancement ratio >1.77 had a lower survival free of events (p < .05). CONCLUSIONS: High intracranial postcontrast enhancement is a long-term predictor of new stroke in ICAD patients. Further studies are needed to elucidate whether postcontrast enhancement reflects inflammatory activity of intracranial atheromatous plaque.

Circulating AQP4 Levels in Patients with Cerebral Amyloid Angiopathy-Associated Intracerebral Hemorrhage.

Cerebral amyloid angiopathy (CAA) is a major cause of lobar intracerebral hemorrhage (ICH) in elderly patients. Growing evidence suggests a potential role of aquaporin 4 (AQP4) in amyloid-beta-associated diseases, including CAA pathology. Our aim was to investigate the circulating levels of AQP4 in a cohort of patients who had suffered a lobar ICH with a clinical diagnosis of CAA. AQP4 levels were analyzed in the serum of 60 CAA-related ICH patients and 19 non-stroke subjects by enzyme-linked immunosorbent assay (ELISA). The CAA-ICH cohort was divided according to the time point of the functional outcome evaluation: mid-term (12 ± 18.6 months) and long-term (38.5 ± 32.9 months) after the last ICH. Although no differences were found in AQP4 serum levels between cases and controls, lower levels were found in CAA patients presenting specific hemorrhagic features such as ≥2 lobar ICHs and ≥5 lobar microbleeds detected by magnetic resonance imaging (MRI). In addition, CAA-related ICH patients who presented a long-term good functional outcome had higher circulating AQP4 levels than subjects with a poor outcome or controls. Our data suggest that AQP4 could potentially predict a long-term functional outcome and may play a protective role after a lobar ICH.

Computed Tomography Perfusion After Thrombectomy: An Immediate Surrogate Marker of Outcome After Recanalization in Acute Stroke.

Background and Purpose- Despite recanalization, almost 50% of patients undergoing endovascular treatment (EVT) experience poor outcome. We aim to evaluate the value of computed tomography perfusion as immediate outcome predictor postendovascular treatment. Methods- Consecutive patients receiving endovascular treatment who achieved recanalization (modified Thrombolysis in Cerebral Ischemia [mTICI] 2a-3) underwent computed tomography perfusion within 30 minutes from recanalization (CTPpost). Hypoperfusion was defined as the Tmax>6 second volume; hyperperfusion as visually increased cerebral blood flow/cerebral blood volume with reduced Tmax compared with unaffected hemisphere. Dramatic clinical recovery (DCR) was defined as 24-hour National Institutes of Health Stroke Scale score ≤2 or ≥8 points drop. Delayed recovery was defined as no-DCR with favorable outcome (modified Rankin Scale score 0-2) at 3 months. Results- We included 151 patients: median National Institutes of Health Stroke Scale score 16 (interquartile range, 10-21), median admission ASPECTS 9 (interquartile range, 8-10). Final recanalization was the following: mTICI2a 11 (7.3%), mTICI2b 46 (30.5%), and mTICI3 94 (62.3%). On CTPpost, 80 (52.9%) patients showed hypoperfusion (median Tmax>6 seconds: 4 cc [0-25]) and 32 (21.2%) hyperperfusion. There was an association between final TICI and CTPpost hypoperfusion(median Tmax>6: 91 [56-117], 15 [0-37.5], and 0 [0-7] cc, for mTICI 2a, 2b, and 3, respectively, P<0.01). Smaller hypoperfusion volumes on CTPpost were observed in patients with DCR (0 cc [0-13] versus non-DCR 8 cc [0-56]; P<0.01) or favorable outcome (modified Rankin Scale score 0-2: 0 cc [0-13] versus 7 [0-56] cc; P<0.01). No associations were detected with hyperperfusion pattern. An hypoperfusion volume <3.5 cc emerged as independent predictor of DCR (OR, 4.1 [95% CI, 2.0-8.3]; P<0.01) and 3 months favorable outcome (OR, 3.5 [95% CI, 1.6-7.8]; P<0.01). Conclusions- Hypoperfusion on CTPpost constitutes an immediate accurate surrogate marker of success after endovascular treatment and identifies those patients with delayed recovery and favorable outcome.

Predictors of response to endovascular treatment of posterior circulation stroke.

BACKGROUND: Endovascular treatment is considered a reasonable approach for patients with acute posterior circulation stroke, but it remains uncertain which patients will benefit the most from it. OBJECTIVE: To find independent clinical and angiographic predictors of outcome after endovascular treatment for posterior circulation stroke. METHODS: We evaluated consecutive patients with acute posterior circulation stroke who underwent endovascular treatment in our comprehensive stroke center from January 2015 to December 2017. Good outcome was defined as a modified Rankin score of 0-3 at 90 days. Intracranial atheromatous disease was established on focal stenosis recorded during endovascular treatment. Associations were sought between a good outcome and clinical and angiographic factors. Adjusted logistic regression models were used to define independent outcome predictors. RESULTS: Forty-seven consecutive patients were included: mean age 70.9 ± 12.1 years, median admission NIHSS score, 16 (IQR: 8-30). On univariate analysis, age (p = 0.01), smoking (p = 0.04), hypertension (p = 0.03), successful reperfusion (p = 0.04), presence of extracranial atherosclerosis (p = 0.02), and absence of atherosclerosis (p = 0.03) were significantly associated with a good outcome. On multivariate analysis, age <70 years (odds ratio = 6.20, 95%CI 1.52-25.47, p = 0.01) and absence of intracranial atherosclerosis (odds ratio = 6.45, 95% CI 1.09-38.24, p = 0.04) were independently associated with a good outcome. CONCLUSIONS: Pretreatment determination of the presence or absence of intracranial atherosclerosis can aid management of posterior circulation stroke patients. The absence of intracranial atherosclerosis may have value as a positive selection criterion for endovascular treatment in future trials. The presence of intracranial atherosclerosis could be used as a selection tool in future studies investigating new treatment protocols for this population.

MR imaging in hyperacute ischemic stroke.

Brain and vascular imaging are required components of the emergency assessment of patients with suspected stroke. Either CT or MRI may be used as the initial imaging test. MRI is more sensitive to the presence of acute and chronic ischemic lesions, and chronic microbleeds, but CT remains the most practical and used initial brain imaging test. Although, a non-enhanced CT or T2* MRI sequence showing no haemorrhage is sufficient for deciding intravenous treatment eligibility within the first 4.5h after stroke onset, a non-invasive intracranial vascular study is strongly recommended during the initial imaging evaluation of the acute stroke patient, particularly if mechanical thrombectomy is contemplated. Advanced imaging with multimodal MRI may facilitate accurate ischemic stroke diagnosis and characterization, and should be considered as an alternative to CT, especially for the selection of patients for acute reperfusion therapy in extended time windows, and in patients in which time of stroke onset is unknown. However, MRI should only be considered in the acute stroke workflow if centres are able to achieve speed and triaging efficiency similar to that which is currently available with CT-based imaging.

Maximal Admission Core Lesion Compatible With Favorable Outcome in Acute Stroke Patients Undergoing Endovascular Procedures.

BACKGROUND AND PURPOSE: Multiparametric imaging is meant to identify nonreversible lesions and predict on admission the minimum final infarct volume, a strong predictor of outcome. We aimed to confirm this hypothesis and define the maximal admission lesion volume compatible with favorable outcome (MALCOM). METHODS: We studied patients with internal carotid artery/middle cerebral artery occlusion selected with multiparametric computed tomography/magnetic resonance imaging, who underwent endovascular procedures. Admission infarct core was measured on initial cerebral blood volume-computed tomography perfusion or diffusion weighted imaging-magnetic resonance imaging. We defined percentage of lesion growth (final lesion admission core/admission core) and MALCOM: cutoff admission core volume above which probability of modified Rankin Scale 0 to 2 is <10%. RESULTS: Fifty-seven patients were studied (29 magnetic resonance imaging and 28 computed tomography perfusion). Mean core volume was 28±22 mL, and recanalization thrombolysis in cerebral ischemia 2b-3 was 77%. At 24 hours, mean infarct volume was 64±97 mL, and at 3 months modified Rankin Scale 0 to 2 was 45%. Median lesion growth was smaller in recanalizers (16.7% versus 198.3%; P<0.01). MALCOM was 39 mL. When recanalization was achieved, 64% of patients within MALCOM (<39 mL) achieved favorable outcome, whereas despite recanalization only 12% of patients beyond MALCOM (>39 mL) achieved modified Rankin Scale 0 to 2 (P=0.01). A regression model adjusted for age and recanalization showed that the only predictor of favorable outcome was having admission core lesion below MALCOM (OR: 9.3, 95% CI: 1.9-46.4; P<0.01). Analysis according to imaging modality showed that computed tomography-cerebral blood volume allowed larger MALCOM (42 mL) than magnetic resonance-diffusion weighted imaging (29 mL). In octogenarians, MALCOM (15 mL) was lower in younger patients (40 mL). CONCLUSIONS: Admission lesion core is associated with final infarct volume and is a strong predictor of favorable outcome. MALCOM according to imaging modality and patient age could be set and used on admission to select candidates for endovascular procedures.

Cerebral amyloid angiopathy-related inflammation: imaging findings and clinical outcome.

INTRODUCTION: We aim to investigate the clinical onset, computed tomography (CT) and magnetic resonance (MR) imaging findings, and follow-up of patients with cerebral amyloid angiopathy (CAA)-related inflammation, an uncommon but clinically striking presentation of CAA. METHODS: We retrospectively reviewed the clinical manifestations, CT/MR imaging findings, and outcome of ten consecutive patients with CAA-related inflammation. In each patient, a brain CT study was performed at hospital admission, and brain MR imaging was carried out 2 to 4 days later. Clinical and radiologic follow-up findings were evaluated in all patients. RESULTS: The most common clinical onset was rapidly progressive cognitive decline, followed by focal neurological signs. Brain CT/MR showed unenhanced expansive subcortical lesions, corresponding to areas of vasogenic edema, associated with chronic lobar, cortical, or cortical-subcortical micro/macrohemorrhages. Clinical symptoms recovered in a few weeks under treatment in eight patients and spontaneously in the remaining two. MRI follow-up at 2 to 12 months after treatment showed resolution of the lesions. Three patients experienced symptomatic disease recurrence, with new lesions on CT/MR. CONCLUSION: In the absence of histological data, early recognition of the clinical symptoms and typical radiologic features of CAA-related inflammation is essential to enable timely establishment of proper treatment.

3 TESLA MR imaging in adults with focal onset epilepsy.

OBJECTIVE: The finding of cerebral epileptogenic lesions in magnetic resonance (MR) has demonstrated to be a relevant prognostic factor for potential surgical candidates. In a series of consecutive adults with focal onset epilepsy, we investigated the yield of 3T MR imaging for detecting epileptogenic cerebral lesions. MATERIALS AND METHODS: We prospectively recruited 161 adult patients with a diagnosis of focal epilepsy, all of whom underwent standardized MR imaging study performed with a 3T magnet. RESULTS: Lesion-related epilepsy was observed in 48% of patients, and 12% of cryptogenic patients showed subtle or non-specific lesions related to the epileptogenic source. The most common findings were focal cortical dysplasia and vascular lesions, followed by mesial temporal sclerosis, tumors, and scars from previous cerebral injuries. Patients older than 72 years were more likely to have vascular epilepsy. CONCLUSIONS: Diagnostic assessment using a standardized 3T MR imaging protocol for focal-onset epilepsy detects lesions in nearly half the patients. Our results indicate that elders with focal epilepsy should be searched for vascular lesions.