Intracranial carotid artery calcification morphology differs in patients with lacunar and nonlacunar acute ischemic strokes.

BACKGROUND AND PURPOSE: Intracranial carotid artery calcifications (ICACs) are a common finding on noncontrast computed tomography (NCCT) and have been associated with an increased risk of ischemic stroke. However, no data are available about the association between ICAC patterns and stroke etiology. We investigated the association between ICAC patterns and etiological subtypes of ischemic stroke. METHODS: We retrospectively analyzed a single center cohort of patients admitted for ischemic stroke with known etiology. Each carotid artery was evaluated separately on NCCT scans to define the ICAC pattern (intimal, medial, mixed). The association between ICAC patterns and stroke etiology was investigated using logistic regression models adjusting for relevant confounders. RESULTS: A total of 485 patients were included (median age = 78 [interquartile range (IQR) = 70-85] years, 243 [50%] female, median National Institutes of Health Stroke Scale = 6 [IQR = 3-12]). Frequencies of ICAC patterns were: intimal, n = 96 (20%); medial, n = 273 (56%); mixed, n = 51 (11%), indistinct/absent, n = 65 (13%) patients. Intimal pattern was more frequent in lacunar compared with nonlacunar (33% vs. 16%, p < 0.001) stroke etiology, whereas medial pattern was less frequent in lacunar compared with nonlacunar stroke (36% vs. 62%, p < 0.001). After adjustment for confounders, intimal ICAC predominant pattern remained associated with lacunar stroke etiology in two multivariate models (Model 1: adjusted odds ratio [aOR] = 2.08, 95% confidence interval [CI] = 1.20-3.56; Model 2: aOR = 2.01, 95% CI = 1.16-3.46). CONCLUSIONS: Our study suggests that intimal ICAC pattern is associated with lacunar stroke and may serve as a marker for lacunar stroke etiology, possibly strengthening the relation between endothelial dysfunction and lacunar stroke.

Characterization of the Involvement of Tumour Necrosis Factor (TNF)-α-Stimulated Gene 6 (TSG-6) in Ischemic Brain Injury Caused by Middle Cerebral Artery Occlusion in Mouse.

The identification of novel targets to modulate the immune response triggered by cerebral ischemia is crucial to promote the development of effective stroke therapeutics. Since tumour necrosis factor (TNF)-α-stimulated gene 6 (TSG-6), a hyaluronate (HA)-binding protein, is involved in the regulation of immune and stromal cell functions in acute neurodegeneration, we aimed to characterize its involvement in ischemic stroke. Transient middle cerebral artery occlusion (1 h MCAo, followed by 6 to 48 of reperfusion) in mice resulted in a significant elevation in cerebral TSG-6 protein levels, mainly localized in neurons and myeloid cells of the lesioned hemisphere. These myeloid cells were clearly infiltrating from the blood, strongly suggesting that brain ischemia also affects TSG-6 in the periphery. Accordingly, TSG-6 mRNA expression was elevated in peripheral blood mononuclear cells (PBMCs) from patients 48 h after ischemic stroke onset, and TSG-6 protein expression was higher in the plasma of mice subjected to 1 h MCAo followed by 48 h of reperfusion. Surprisingly, plasma TSG-6 levels were reduced in the acute phase (i.e., within 24 h of reperfusion) when compared to sham-operated mice, supporting the hypothesis of a detrimental role of TSG-6 in the early reperfusion stage. Accordingly, systemic acute administration of recombinant mouse TSG-6 increased brain levels of the M2 marker Ym1, providing a significant reduction in the brain infarct volume and general neurological deficits in mice subjected to transient MCAo. These findings suggest a pivotal role of TSG-6 in ischemic stroke pathobiology and underscore the clinical relevance of further investigating the mechanisms underlying its immunoregulatory role.

Vessel wall magnetic resonance imaging in COVID-19-associated cryptogenic ischemic stroke.

BACKGROUND AND PURPOSE: Acute ischemic stroke (AIS) is a common complication of coronavirus disease 2019 (COVID-19), but the underlying biological mechanisms remain unclear. We aimed to describe the prevalence of vessel wall alterations in patients with cryptogenic stroke through vessel wall magnetic resonance imaging (vwMRI). METHODS: All consecutive patients admitted for AIS and COVID-19 to a single neuro-COVID unit from 10 November to 31 December 2020 were prospectively evaluated and underwent a complete etiologic workup for AIS. In patients with cryptogenic stroke, the diagnostic workup was completed with vwMRI study. RESULTS: After the exclusion of four patients ineligible for MRI, a total of 10 patients were included (median age = 78 years, 50% males), of whom four (40%) had a cryptogenic stroke. vwMRI showed vascular changes consistent with inflammation of intracranial artery walls in three subjects (75%). Two patients had focal and one multifocal involvement. CONCLUSIONS: vwMRI detected signs of vascular inflammation in the majority of patients with cryptogenic AIS, leading to an etiologic definition with potential therapeutical implications. Our findings are best interpreted as hypothesis-generating, suggesting the possibility of expanding the diagnostic workup of cryptogenic stroke with vessel wall imaging.

Association of the careggi collateral score with radiological outcomes after thrombectomy for stroke with an occlusion of the middle cerebral artery.

We aimed to examine the association between Careggi Collateral Score (CCS) and radiological outcomes in a large multicenter cohort of patients receiving thrombectomy for stroke with occlusion of middle cerebral artery (MCA). We conducted a study on prospectively collected data from 1785 patients enrolled in the Italian Registry of Endovascular Treatment in Acute Stroke. According to the extension of the retrograde reperfusion in the cortical anterior cerebral artery-MCA territories, CCS ranges from 0 (absence of retrograde filling) to 4 (visualization of collaterals until the alar segment of the MCA). Radiological outcomes at 24 h were the presence and severity of infarct growth defined by the absolute change in ASPECTS from baseline to 24 h; presence and severity of cerebral bleeding defined as no ICH, HI-1, HI-2, PH-1, or PH-2; presence and severity of cerebral edema (CED) defined as no CED, CED-1, CED-2, or CED-3. Using CCS = 0 as reference, ORs of CCS grades were significantly associated in the direction of better radiological outcome on infarct growth (0.517 for CCS = 1, 0.413 for CCS = 2, 0.358 for CCS = 3, 0.236 for CCS = 4), cerebral bleeding grading (0.485 for CCS = 1, 0.445 for CCS = 2, 0.400 for CCS = 3, 0.379 for CCS = 4), and CED grading (0.734 for CCS = 1, 0.301 for CCS = 2, 0.295 for CCS = 3, 0.255 for CSS = 4) shift in ordinal regression analysis after adjustment for pre-defined variables (age, NIHSS score, ASPECTS, occlusion site, onset-to-groin puncture time, procedure time, and TICI score). Using CCS = 4 as reference, ORs of CCS grades were significantly associated in the direction of worse radiological outcome on infarct growth (1.521 for CCS = 3, 1.754 for CCS = 2, 2.193 for CCS = 1, 4.244 for CCS = 0), cerebral bleeding grading (2.498 for CCS = 0), and CED grading (1.365 for CCS = 2, 2.876 for CCS = 1, 3.916 for CCS = 0) shift. The CCS could improve the prognostic estimate of radiological outcomes in patients receiving thrombectomy for stroke with MCA occlusion.

CD163 as a Potential Biomarker of Monocyte Activation in Ischemic Stroke Patients.

In ischemic stroke patients, a higher monocyte count is associated with disease severity and worse prognosis. The complex correlation between subset phenotypes and functions underscores the importance of clarifying the role of monocyte subpopulations. We examined the subtype-specific distribution of the CD163+ and CD80+ circulating monocytes and evaluated their association with the inflammatory status in 26 ischemic stroke patients and 16 healthy controls. An increased percentage of CD163+/CD16+ and CD163+/CD14++ events occurred 24 and 48 h after a stroke compared to the controls. CD163+ expression was more pronounced in CD16+ non-classical and intermediate monocytes, as compared to CD14+ classical subtype, 24 h after stroke. Conversely, the percentage of CD80+/CD16+ events was unaffected in patients; meanwhile, the percentage of CD80+/CD14+ events significantly increased only 24 h after stroke. Interleukin (IL)-1beta, TNF-alpha, and IL-4 mRNA levels were higher, while IL-10 mRNA levels were reduced in total monocytes from patients versus controls, at either 24 h or 48 h after stroke. The percentage of CD163+/CD16+ events 24 h after stroke was positively associated with NIHSS score and mRS at admission, suggesting that stroke severity and disability are relevant triggers for CD163+ expression in circulating CD16+ monocytes.

Validation and Comparison of Noncontrast CT Scores to Predict Intracerebral Hemorrhage Expansion.

BACKGROUND AND PURPOSE: The BAT, BRAIN, and HEP scores have been proposed to predict hematoma expansion (HE) with noncontrast computed tomography (NCCT). We sought to validate these tools and compare their diagnostic performance. METHODS: We retrospectively analyzed two cohorts of patients with primary intracerebral hemorrhage. HE expansion was defined as volume growth > 33% or > 6 mL. Two raters analyzed NCCT scans and calculated the scores, blinded to clinical and imaging data. The inter-rater reliability was assessed with the interclass correlation statistic. Discrimination and calibration were calculated with area under the curve (AUC) and Hosmer-Lemeshow χ2 statistic, respectively. AUC comparison between different scores was explored with DeLong test. We also calculated the sensitivity, specificity, positive, and negative predictive values of the dichotomized scores with cutoffs identified with the Youden's index. RESULTS: A total of 230 subjects were included, of whom 86 (37.4%) experienced HE. The observed AUC for HE were 0.696 for BAT, 0.700 for BRAIN, and 0.648 for HEP. None of the scores had a significantly superior AUC compared with the others (all p > 0.4). All the scores had good calibration (all p > 0.3) and good-to-excellent inter-rater reliability (interclass correlation > 0.8). BAT ≥ 3 showed the highest specificity (0.81), whereas BRAIN ≥ 6 had the highest sensitivity (0.76). CONCLUSIONS: The BAT, BRAIN, and HEP scores can predict HE with acceptable discrimination and require just a baseline NCCT scan. These tools may be used to stratify the risk of HE in clinical practice or randomized controlled trials.

Next generation sequencing for systematic assessment of genetics of small-vessel disease and lacunar stroke.

BACKGROUND: The pathogenesis of cerebral small-vessel disease (SVD) is still incompletely understood, although evidence from family and twin studies supports the hypothesis that genetic factors may contribute to SVD pathogenesis. Identification of genetic susceptibility factors for SVD may improve our knowledge on SVD pathogenesis. SVE-LA (Small Vessel and Lacunar) project is a multicenter prospective Lombardia region study aimed at applying innovative genetic technologies and accurate patient phenotyping to discover the genetic basis of SVD. METHODS: A continuous series of subjects (aged 15-80 years) with a clinically and radiologically defined lacunar stroke referring to the participating Lombardia region stroke centers and an adequate number of age- and sex-matched controls are being included into the study. For each patient, clinical, demographic, instrumental, and familial data are collected applying standardized forms. After informed consent, a DNA sample for genetic analysis from patients and controls has been collected. The next generation sequencing (NGS) technology was applied to systematically screen patients for the most important genetic factors both monogenic and polygenic associated with SVD. The study includes also a centralized quantitative and qualitative analysis of neuroimaging studies. RESULTS: Between March 2011 and October 2013, 212 lacunar stroke patients and 78 controls have been collected. Mean age of cases was 65.8 ± 11.1 years and 67% were men. CONCLUSIONS: This is the first study applying systematically NGS technology on a wide series of lacunar stroke patients. A translational approach combining a systematic genetic screening with a detailed phenotyping may facilitate the discovery of genetic basis and improve our knowledge in the pathogenesis of SVD.

Association between procedural time and outcome in unsuccessful mechanical thrombectomy for acute ischemic stroke: analysis from the Italian Registry of Endovascular Treatment in Acute Stroke.

BACKGROUND: We aim to assess the association between procedural time and outcomes in patients in unsuccessful mechanical thrombectomy (MT) for anterior circulation acute stroke. METHODS: We conducted a cohort study on prospectively collected data from patients with M1 and/or M2 segment of middle cerebral artery occlusion with a thrombolysis in cerebral infarction 0-1 at the end of procedure. Primary outcome was 90-day poor outcome. Secondary outcomes were early neurological deterioration (END), symptomatic intracranial hemorrhage (sICH) according to ECASS II and sICH according to SITS-MOST. RESULTS: Among 852 patients, after comparing characteristics of favourable and poor outcome groups, logistic regression analysis showed age (OR: 1.04; 95%CI: 1.02-1.05; p < 0.001), previous TIA/stroke (OR: 0.23; 95%CI: 0.12-0.74; p = 0.009), M1 occlusion (OR: 1.69; 95%CI: 1.13-2.50; p = 0.01), baseline NIHSS (OR: 1.01; 95%CI: 1.06-1.13; p < 0.001) and procedural time (OR:1.00; 95% CI: 1.00-1.01; p = 0.003) as independent predictors poor outcome at 90 days. Concerning secondary outcomes, logistic regression analysis showed NIHSS (OR:0.96; 95%CI: 0.93-0.99; p = 0.008), general anaesthesia (OR:2.59; 95%CI: 1.52-4.40; p < 0.001), procedural time (OR: 1.00; 95% CI: 1.00-1.01; p = 0.002) and intraprocedural complications (OR: 1.89; 95%CI: 1.02-3.52; p = 0.04) as independent predictors of END. Bridging therapy (OR:2.93; 95%CI: 1.21-7.09; p = 0.017) was associated with sICH per SITS-MOST criteria whereas M1 occlusion (OR: 0.35; 95%CI: 0.18-0.69; p = 0.002), bridging therapy (OR: 2.02; 95%CI: 1.07-3.82; p = 0.03) and intraprocedural complications (OR: 5.55; 95%CI: 2.72-11.31; p < 0.001) were independently associated with sICH per ECASS II criteria. No significant association was found between the number of MT attempts and analyzed outcomes. CONCLUSIONS: Regardless of the number of MT attempts and intraprocedural complications, procedural time was associated with poor outcome and END. We suggest a deeper consideration of procedural time when treating anterior circulation occlusions refractory to MT.

Characterization of CB2 Receptor Expression in Peripheral Blood Monocytes of Acute Ischemic Stroke Patients.

Both preclinical and clinical evidence supports the involvement of the endocannabinoid system in the pathobiology of cerebral ischemia. Selective cannabinoid-2 (CB2) receptor agonists exert significant neuroprotection in animal models of focal brain ischemia through a robust anti-inflammatory effect, involving both resident and peripheral immune cells. Nevertheless, no definitive studies demonstrating the relevance of CB2 receptors in human stroke exist.Using rtPCR and flow cytometry assays, we investigated CB2 receptor expression in circulating monocytes from 26 acute ischemic stroke patients and 16 age-matched healthy controls (CT). We also evaluated miR-665 expression, as potential CB2 receptor regulator. The median mRNA levels of CB2 were significantly (p < 0.0001) increased in total monocytes 24 h and 48 h after stroke as compared with CT. This was paralleled by elevation of miR-665 levels in monocytes collected from patients 24 h (p < 0.05 vs CT) and 48 h (p < 0.05 vs CT and p < 0.0001 vs 24 h) after ischemic stroke. Furthermore, an increased percentage of CB2+/CD16+ events, but not CB2+/CD14+ events, was found 24 h [20.17% (IQR, 17.22-23.58)] and 48 h [18.61% (IQR, 15.44-22.06)] after ischemic stroke when compared with CT [10.96% (IQR, 9.185-13.32)]. The percentage of CB2+/CD16+ events in monocytes was positively correlated with NIHSS score at entrance (r = 0.4327, p = 0.027). The potential beneficial functions of CD16+ intermediate and nonclassical monocytes in stroke and the elevated expression of CB2 receptor in these subsets strongly suggest that CB2 receptor agonists can be exploited for the treatment of ischemic stroke patients.

An automated voice response system for anticoagulant therapy management.

The system described in this paper is aimed at improving the clinical workflow of post-stroke patients under oral anticoagulant therapy (OAT). The system helps both physicians and patients during the periodic control visits necessary to assess the anticoagulation status and the next therapeutic plan. Controls represent a burden for both patients, which after blood drawing must wait for the result, and for physicians, that, after assessing the therapy plan, must communicate it to patients, face-to-face or by telephone. A system is proposed, which embeds an algorithm for the patient-tailored calculation of the drug dosage and scheduling, and an automatic telephone dialogue for the communication of the therapy plan, once it has been validated or adjusted by the physician.

Transient global amnesia: hippocampal magnetic resonance imaging abnormalities.

Transient global amnesia (TGA) is an episodic dysfunction of declarative memory that usually resolves within 12 hours and whose underlying pathophysiological mechanisms are still unclear. Recent studies, on the basis of transient focal high-signal abnormalities in the hippocampus on diffusion-weighted imaging (DWI), suggest involvement of memory circuits in the temporo-mesial region. Out of a total of 65 patients presenting with acute or subacute TGA between May 2004 and May 2008, we retrospectively analysed 21 in whom a DWI sequence was performed. Five patients showed a focal hippocampal signal alteration both on DWI and on conventional T2; this alteration was no longer detectable on follow-up MRI two months later. The presence of transient DWI and T2 alterations in the hippocampal formation suggests that TGA could have a multifactorial, non-vascular aetiology. The presence of local susceptibility to neuronal metabolic stress emerges as a likely hypothesis.

Longitudinal Study on Low-Dose Aspirin versus Placebo Administration in Silent Brain Infarcts: The Silence Study.

BACKGROUND: We investigated low-dose aspirin (ASA) efficacy and safety in subjects with silent brain infarcts (SBIs) in preventing new cerebrovascular (CVD) events as well as cognitive impairment. METHODS: We included subjects aged ≥45 years, with at least one SBI and no previous CVD. Subjects were followed up to 4 years assessing CVD and SBI incidence as primary endpoint and as secondary endpoints: (a) cardiovascular and adverse events and (b) cognitive impairment. RESULTS: Thirty-six subjects received ASA while 47 were untreated. Primary endpoint occurred in 9 controls (19.1%) versus 2 (5.6%) in the ASA group (p=0.10). Secondary endpoints did not differ in the two groups. Only baseline leukoaraiosis predicts primary [OR 5.4 (95%CI 1.3-22.9, p=0.022)] and secondary endpoint-a [3.2 (95%CI 1.1-9.6, p=0.040)] occurrence. CONCLUSIONS: These data show an increase of new CVD events in the untreated group. Despite the study limitations, SBI seems to be a negative prognostic factor and ASA preventive treatment might improve SBI prognosis. EU Clinical trial is registered with EudraCT Number: 2005-000996-16; Sponsor Protocol Number: 694/30.06.04.

Warfarin-associated intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is the most serious complication of oral anticoagulant therapy (OAT), with mortality in excess of 50%. Major risk factors are advanced patient age, elevated systolic blood pressure, intensity of anticoagulation, and previous cerebral ischemia. A number of acute treatments are available, but all have significant side effects and no randomized clinical trials assessing clinical outcome have been performed. Future trials will have to address choice and dose of agent, the timing of its administration, and the risk of side effects.