Early versus Later Anticoagulation for Stroke with Atrial Fibrillation.

BACKGROUND: The effect of early as compared with later initiation of direct oral anticoagulants (DOACs) in persons with atrial fibrillation who have had an acute ischemic stroke is unclear. METHODS: We performed an investigator-initiated, open-label trial at 103 sites in 15 countries. Participants were randomly assigned in a 1:1 ratio to early anticoagulation (within 48 hours after a minor or moderate stroke or on day 6 or 7 after a major stroke) or later anticoagulation (day 3 or 4 after a minor stroke, day 6 or 7 after a moderate stroke, or day 12, 13, or 14 after a major stroke). Assessors were unaware of the trial-group assignments. The primary outcome was a composite of recurrent ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial hemorrhage, or vascular death within 30 days after randomization. Secondary outcomes included the components of the composite primary outcome at 30 and 90 days. RESULTS: Of 2013 participants (37% with minor stroke, 40% with moderate stroke, and 23% with major stroke), 1006 were assigned to early anticoagulation and 1007 to later anticoagulation. A primary-outcome event occurred in 29 participants (2.9%) in the early-treatment group and 41 participants (4.1%) in the later-treatment group (risk difference, -1.18 percentage points; 95% confidence interval [CI], -2.84 to 0.47) by 30 days. Recurrent ischemic stroke occurred in 14 participants (1.4%) in the early-treatment group and 25 participants (2.5%) in the later-treatment group (odds ratio, 0.57; 95% CI, 0.29 to 1.07) by 30 days and in 18 participants (1.9%) and 30 participants (3.1%), respectively, by 90 days (odds ratio, 0.60; 95% CI, 0.33 to 1.06). Symptomatic intracranial hemorrhage occurred in 2 participants (0.2%) in both groups by 30 days. CONCLUSIONS: In this trial, the incidence of recurrent ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial hemorrhage, or vascular death at 30 days was estimated to range from 2.8 percentage points lower to 0.5 percentage points higher (based on the 95% confidence interval) with early than with later use of DOACs. (Funded by the Swiss National Science Foundation and others; ELAN ClinicalTrials.gov number, NCT03148457.).

Toward Individual Treatment in Cervical Artery Dissection: Subgroup Analysis of the TREAT-CAD Randomized Trial.

OBJECTIVE: Uncertainty remains regarding antithrombotic treatment in cervical artery dissection. This analysis aimed to explore whether certain patient profiles influence the effects of different types of antithrombotic treatment. METHODS: This was a post hoc exploratory analysis based on the per-protocol dataset from TREAT-CAD (NCT02046460), a randomized controlled trial comparing aspirin to anticoagulation in patients with cervical artery dissection. We explored the potential effects of distinct patient profiles on outcomes in participants treated with either aspirin or anticoagulation. Profiles included (1) presenting with ischemia (no/yes), (2) occlusion of the dissected artery (no/yes), (3) early versus delayed treatment start (median), and (4) intracranial extension of the dissection (no/yes). Outcomes included clinical (stroke, major hemorrhage, death) and magnetic resonance imaging outcomes (new ischemic or hemorrhagic brain lesions) and were assessed for each subgroup in separate logistic models without adjustment for multiple testing. RESULTS: All 173 (100%) per-protocol participants were eligible for the analyses. Participants without occlusion had decreased odds of events when treated with anticoagulation (odds ratio [OR] = 0.28, 95% confidence interval [CI] = 0.07-0.86). This effect was more pronounced in participants presenting with cerebral ischemia (n = 118; OR = 0.16, 95% CI = 0.04-0.55). In the latter, those with early treatment (OR = 0.26, 95% CI = 0.07-0.85) or without intracranial extension of the dissection (OR = 0.34, 95% CI = 0.11-0.97) had decreased odds of events when treated with anticoagulation. INTERPRETATION: Anticoagulation might be preferable in patients with cervical artery dissection presenting with ischemia and no occlusion or no intracranial extension of the dissection. These findings need confirmation. ANN NEUROL 2024;95:886-897.

Endovascular Treatment for Acute Ischemic Stroke With or Without General Anesthesia: A Matched Comparison.

BACKGROUND: Endovascular treatment in large artery occlusion stroke reduces disability. However, the impact of anesthesia type on clinical outcomes remains uncertain. METHODS: We compared consecutive patients in the Swiss Stroke Registry with anterior circulation stroke receiving endovascular treatment with or without general anesthesia (GA). The primary outcome was disability on the modified Rankin Scale after 3 months, analyzed with ordered logistic regression. Secondary outcomes included dependency or death (modified Rankin Scale score ≥3), National Institutes of Health Stroke Scale after 24 hours, symptomatic intracranial hemorrhage with ≥4 points worsening on National Institutes of Health Stroke Scale within 7 days, and mortality. Coarsened exact matching and propensity score matching were performed to adjust for indication bias. RESULTS: One thousand two hundred eighty-four patients (GA: n=851, non-GA: n=433) from 8 Stroke Centers were included. Patients treated with GA had higher modified Rankin Scale scores after 3 months than patients treated without GA, in the unmatched (odds ratio [OR], 1.75 [1.42-2.16]; P<0.001), the coarsened exact matching (n=332-524, using multiple imputations of missing values; OR, 1.60 [1.08-2.36]; P=0.020), and the propensity score matching analysis (n=568; OR, 1.61 [1.20-2.15]; P=0.001). In the coarsened exact matching analysis, there were no significant differences in National Institutes of Health Stroke Scale after 1 day (estimated coefficient 2.61 [0.59-4.64]), symptomatic intracranial hemorrhage (OR, 1.06 [0.30-3.75]), dependency or death (OR, 1.42 [0.91-2.23]), or mortality (OR, 1.65 [0.94-2.89]). In the propensity score matching analysis, National Institutes of Health Stroke Scale after 24 hours (estimated coefficient, 3.40 [1.76-5.04]), dependency or death (OR, 1.49 [1.07-2.07]), and mortality (OR, 1.65 [1.11-2.45]) were higher in the GA group, whereas symptomatic intracranial hemorrhage did not differ significantly (OR, 1.77 [0.73-4.29]). CONCLUSIONS: This large study showed worse functional outcome after endovascular treatment of anterior circulation stroke with GA than without GA in a real-world setting. This finding appears to be independent of known differences in patient characteristics between groups.

Prior Anticoagulation in Patients with Ischemic Stroke and Atrial Fibrillation.

OBJECTIVE: The aim was to evaluate, in patients with atrial fibrillation (AF) and acute ischemic stroke, the association of prior anticoagulation with vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs) with stroke severity, utilization of intravenous thrombolysis (IVT), safety of IVT, and 3-month outcomes. METHODS: This was a cohort study of consecutive patients (2014-2019) on anticoagulation versus those without (controls) with regard to stroke severity, rates of IVT/mechanical thrombectomy, symptomatic intracranial hemorrhage (sICH), and favorable outcome (modified Rankin Scale score 0-2) at 3 months. RESULTS: Of 8,179 patients (mean [SD] age, 79.8 [9.6] years; 49% women), 1,486 (18%) were on VKA treatment, 1,634 (20%) on DOAC treatment at stroke onset, and 5,059 controls. Stroke severity was lower in patients on DOACs (median National Institutes of Health Stroke Scale 4, [interquartile range 2-11]) compared with VKA (6, [2-14]) and controls (7, [3-15], p < 0.001; quantile regression: ß -2.1, 95% confidence interval [CI] -2.6 to -1.7). The IVT rate in potentially eligible patients was significantly lower in patients on VKA (156 of 247 [63%]; adjusted odds ratio [aOR] 0.67; 95% CI 0.50-0.90) and particularly in patients on DOACs (69 of 464 [15%]; aOR 0.06; 95% CI 0.05-0.08) compared with controls (1,544 of 2,504 [74%]). sICH after IVT occurred in 3.6% (2.6-4.7%) of controls, 9 of 195 (4.6%; 1.9-9.2%; aOR 0.93; 95% CI 0.46-1.90) patients on VKA and 2 of 65 (3.1%; 0.4-10.8%, aOR 0.56; 95% CI 0.28-1.12) of those on DOACs. After adjustments for prognostic confounders, DOAC pretreatment was associated with a favorable 3-month outcome (aOR 1.24; 1.01-1.51). INTERPRETATION: Prior DOAC therapy in patients with AF was associated with decreased admission stroke severity at onset and a remarkably low rate of IVT. Overall, patients on DOAC might have better functional outcome at 3 months. Further research is needed to overcome potential restrictions for IVT in patients taking DOACs. ANN NEUROL 2021;89:42-53.

Ischemic stroke in COVID-19 patients: Mechanisms, treatment, and outcomes in a consecutive Swiss Stroke Registry analysis.

BACKGROUND: Most case series of patients with ischemic stroke (IS) and COVID-19 are limited to selected centers or lack 3-month outcomes. The aim of this study was to describe the frequency, clinical and radiological features, and 3-month outcomes of patients with IS and COVID-19 in a nationwide stroke registry. METHODS: From the Swiss Stroke Registry (SSR), we included all consecutive IS patients ≥18 years admitted to Swiss Stroke Centers or Stroke Units during the first wave of COVID-19 (25 February to 8 June 2020). We compared baseline features, etiology, and 3-month outcome of SARS-CoV-2 polymerase chain reaction-positive (PCR+) IS patients to SARS-CoV-2 PCR- and/or asymptomatic non-tested IS patients. RESULTS: Of the 2341 IS patients registered in the SSR during the study period, 36 (1.5%) had confirmed COVID-19 infection, of which 33 were within 1 month before or after stroke onset. In multivariate analysis, COVID+ patients had more lesions in multiple vascular territories (OR 2.35, 95% CI 1.08-5.14, p = 0.032) and fewer cryptogenic strokes (OR 0.37, 95% CI 0.14-0.99, p = 0.049). COVID-19 was judged the likely principal cause of stroke in 8 patients (24%), a contributing/triggering factor in 12 (36%), and likely not contributing to stroke in 13 patients (40%). There was a strong trend towards worse functional outcome in COVID+ patients after propensity score (PS) adjustment for age, stroke severity, and revascularization treatments (PS-adjusted common OR for shift towards higher modified Rankin Scale (mRS) = 1.85, 95% CI 0.96-3.58, p = 0.07). CONCLUSIONS: In this nationwide analysis of consecutive ischemic strokes, concomitant COVID-19 was relatively rare. COVID+ patients more often had multi-territory stroke and less often cryptogenic stroke, and their 3-month functional outcome tended to be worse.

Elevated post-ischemic ubiquitination results from suppression of deubiquitinase activity and not proteasome inhibition.

Cerebral ischemia-reperfusion increases intraneuronal levels of ubiquitinated proteins, but the factors driving ubiquitination and whether it results from altered proteostasis remain unclear. To address these questions, we used in vivo and in vitro models of cerebral ischemia-reperfusion, in which hippocampal slices were transiently deprived of oxygen and glucose to simulate ischemia followed by reperfusion, or the middle cerebral artery was temporarily occluded in mice. We found that post-ischemic ubiquitination results from two key steps: restoration of ATP at reperfusion, which allows initiation of protein ubiquitination, and free radical production, which, in the presence of sufficient ATP, increases ubiquitination above pre-ischemic levels. Surprisingly, free radicals did not augment ubiquitination through inhibition of the proteasome as previously believed. Although reduced proteasomal activity was detected after ischemia, this was neither caused by free radicals nor sufficient in magnitude to induce appreciable accumulation of proteasomal target proteins or ubiquitin-proteasome reporters. Instead, we found that ischemia-derived free radicals inhibit deubiquitinases, a class of proteases that cleaves ubiquitin chains from proteins, which was sufficient to elevate ubiquitination after ischemia. Our data provide evidence that free radical-dependent deubiquitinase inactivation rather than proteasomal inhibition drives ubiquitination following ischemia-reperfusion, and as such call for a reevaluation of the mechanisms of post-ischemic ubiquitination, previously attributed to altered proteostasis. Since deubiquitinase inhibition is considered an endogenous neuroprotective mechanism to shield proteins from oxidative damage, modulation of deubiquitinase activity may be of therapeutic value to maintain protein integrity after an ischemic insult.

Lipoprotein(a) is associated with large artery atherosclerosis stroke aetiology and stroke recurrence among patients below the age of 60 years: results from the BIOSIGNAL study.

AIMS: Lipoprotein(a) [Lp(a)] is a recognized causal risk factor for atherosclerotic cardiovascular disease but its role for acute ischaemic stroke (AIS) is controversial. In this study, we evaluated the association of Lp(a) with large artery atherosclerosis (LAA) stroke and risk of recurrent cerebrovascular events in AIS patients. METHODS AND RESULTS: For this analysis of the prospective, observational, multicentre BIOSIGNAL cohort study we measured Lp(a) levels in plasma samples of 1733 primarily Caucasian (98.6%) AIS patients, collected within 24 h after symptom onset. Primary outcomes were LAA stroke aetiology and recurrent cerebrovascular events (ischaemic stroke or transient ischaemic attack) within 1 year. We showed that Lp(a) levels are independently associated with LAA stroke aetiology [adjusted odds ratio 1.48, 95% confidence interval (CI) 1.14-1.90, per unit log10Lp(a) increase] and identified age as a potent effect modifier (Pinteraction =0.031) of this association. The adjusted odds ratio for LAA stroke in patients aged <60 years was 3.64 (95% CI 1.76-7.52) per unit log10Lp(a) increase and 4.04 (95% CI 1.73-9.43) using the established cut-off ≥100 nmol/l. For 152 recurrent cerebrovascular events, we did not find a significant association in the whole cohort. However, Lp(a) levels ≥100 nmol/l were associated with an increased risk for recurrent events among patients who were either <60 years [adjusted hazard ratio (HR) 2.40, 95% CI 1.05-5.47], had evident LAA stroke aetiology (adjusted HR 2.18, 95% CI 1.08-4.40), or had no known atrial fibrillation (adjusted HR 1.60, 95% CI 1.03-2.48). CONCLUSION: Elevated Lp(a) was independently associated with LAA stroke aetiology and risk of recurrent cerebrovascular events among primarily Caucasian individuals aged <60 years or with evident arteriosclerotic disease.

Carotid-cavernous sinus fistula following mechanical thrombectomy in acute ischaemic stroke: a rare complication.

Carotid-cavernous sinus fistulas (CCFs) are abnormal communications between the internal carotid artery (ICA) and the cavernous sinus (CS). Direct CCFs are associated with trauma or are iatrogenic complications of neuroendovascular procedures. Meanwhile, mechanical endovascular thrombectomy (MT) in acute ischaemic stroke (AIS) patients with large vessel occlusion (LVO) has been established as a common treatment approach. However, MT is not without its risks of complications, and only a few reports exist on CCF occurring after MT. Here, we present a case of a 63-year-old patient with iatrogenic high-flow CCF of the right horizontal cavernous ICA segment (C4) following repeated MT due to LVO of the middle cerebral artery, and the recent literature is reviewed.

Angioplasty Using Drug-Coated Balloons in Ostial Vertebral Artery Stenosis.

BACKGROUND: Ostial vertebral artery stenosis (OVAS) is a relevant cause of acute ischemic posterior circulation stroke. Percutaneous trans-luminal angioplasty (PTA) might offer a promising treatment modality, but restenosis rate is high. So far, little is known about recanalization using drug-coated balloons (DCB) in OVAS. We aimed to show feasibility and safety of DCB-PTA in OVAS. METHODS: Retrospective, monocenter case series of 12 patients with ostial vertebral artery stenosis (≥50%) treated with PTA using a drug-coated balloon. RESULTS: Median age was 69.5 years (IQR 57-78.5) with a female rate of 41%. Patients were treated either with a SeQuent Please NEO or Neuro Elutax SV DEB. Median preinterventional stenosis degree was 75% (IQR 70-85) with a median lesion length of 4.5 mm (IQR 4-7.5). Median postinterventional stenosis degree was 40% (IQR 27-50). All treated vessels remained patent. No major complications such as dissection, vessel perforation, hemorrhage, or ischemic events occurred. Moreover, we did not detect any restenosis during a median follow-up period of 6.1 months. The clinical outcome was excellent with median mRS scale of 0 (IQR 0-1). CONCLUSIONS: PTA using drug-coated balloons is feasible and safe in patients with ostial vertebral artery stenosis.

Prediction of post-acute care demand in medical and neurological inpatients: diagnostic assessment of the post-acute discharge score - a prospective cohort study.

BACKGROUND: Early identification of patients requiring transfer to post-acute care (PAC) facilities shortens hospital stays. With a focus on interprofessional assessment of biopsychosocial risk, this study's aim was to assess medical and neurological patients' post-acute care discharge (PACD) scores on days 1 and 3 after hospital admission regarding diagnostic accuracy and effectiveness as an early screening tool. The transfer to PAC facilities served as the outcome ("gold standard"). METHODS: In this prospective cohort study, registered at ClinicalTrial.gov (NCT01768494) on January 2013, 1432 medical and 464 neurological patients (total n = 1896) were included consecutively between February and October 2013. PACD scores and other relevant data were extracted from electronic records of patient admissions, hospital stays, and interviews at day 30 post-hospital admission. To gauge the scores' accuracy, we plotted receiver operating characteristic (ROC) curves, calculated area under the curve (AUC), and determined sensitivity and specificity at various cut-off levels. RESULTS: Medical patients' day 1 and day 3 PACD scores accurately predicted discharge to PAC facilities, with respective discriminating powers (AUC) of 0.77 and 0.82. With a PACD cut-off of ≥8 points, day 1 and 3 sensitivities were respectively 72.6% and 83.6%, with respective specificities of 66.5% and 70.0%. Neurological patients' scores showed lower accuracy both days: using the same cut-off, respective day 1 and day 3 AUCs were 0.68 and 0.78, sensitivities 41.4% and 68.7% and specificities 81.4% and 83.4%. CONCLUSION: PACD scores at days 1 and 3 accurately predicted transfer to PAC facilities, especially in medical patients on day 3. To confirm and refine these results, PACD scores' value to guide discharge planning interventions and subsequent impact on hospital stay warrants further investigation. TRIAL REGISTRATION: ClinialTrials.gov Identifier, NCT01768494 .

[Secondary prevention of ischemic stroke: overview of updated guidelines]. / Sekundärprävention des Schlaganfalls.

Secondary prevention of ischemic stroke: overview of updated guidelines Abstract. It is widely stated that stroke is one of the most common diseases and the leading cause of severe disability in adults. Secondary stroke prevention is based on drug treatment, risk factor control as well as interventional procedures such as carotid artery revascularization or percutaneous device closure of a patent foramen ovale in cryptogenic stroke patients younger than 60 years.

Emergent vs. elective stenting of carotid stenosis with intraluminal carotid thrombus.

BACKGROUND AND PURPOSE: Carotid stenosis (CS) with intraluminal carotid artery thrombus (ICAT) is rare but ominous finding. The optimal treatment modality is unclear. The aim of this study was to analyze the feasibility and outcome of acute endovascular intervention and delayed elective endovascular therapy after initial anticoagulation in these delicate cases. Moreover, both treatment points were compared and several parameters discussed to facilitate the determination of the optimal time modality in future cases. MATERIALS AND METHODS: A series of 11 consecutive cases with acute symptomatic CS with ICAT that received endovascular treatment was retrospectively analyzed. General patient data, pre and post-interventional symptoms and imaging were evaluated in an overall mean follow-up of 84 weeks. RESULTS: Urgent stenting and mechanical thrombectomy was performed in 6 patients. In the remaining 5 cases, elective endovascular treatment was planned after initial anticoagulation therapy with thrombus resolution. One case received secondary urgent treatment due to clinical deterioration. Overall outcome at three months follow-up was excellent (Modified Ranking Scale [mRS] 0-1) in 5 cases, good (mRS 2) in 4 and unfavorable in the remaining 2. Important differences between the two treatment arms were seen in 3 parameters (stenosis degree, thrombus length, and NIHSS score). CONCLUSIONS: This is one of the largest studies analysing endovascular treatment in patients with acute symptomatic CS and additional ICAT only. Both endovascular treatment strategies seem feasible. Parameters such as size of intraluminal thrombus and clinical symptoms should be included in the decision-making process regarding the optimal individual treatment time.

Copeptin for risk stratification in non-traumatic headache in the emergency setting: a prospective multicenter observational cohort study.

BACKGROUND: In the emergency setting, non-traumatic headache is a benign symptom in 80% of cases, but serious underlying conditions need to be ruled out. Copeptin improves risk stratification in several acute diseases. Herein, we investigated the value of copeptin to discriminate between serious secondary headache and benign headache forms in the emergency setting. METHODS: Patients presenting with acute non-traumatic headache were prospectively enrolled into an observational cohort study. Copeptin was measured upon presentation to the emergency department. Primary endpoint was serious secondary headache defined by a neurologic cause requiring immediate treatment of the underlying disease. Secondary endpoint was the combination of mortality and hospitalization within 3 months. Two board-certified neurologist blinded to copeptin levels verified the endpoints after a structured 3-month-telephone interview. RESULTS: Of the 391 patients included, 75 (19%) had a serious secondary headache. Copeptin was associated with serious secondary headache (OR 2.03, 95%CI 1.52-2.70, p < 0.0001). Area under the curve (AUC) for copeptin to identify the primary endpoint was 0.70 (0.63-0.76). After adjusting for age > 50, focal-neurological abnormalities, and thunderclap onset of symptoms, copeptin remained an independent predictive factor for serious secondary headache (OR 1.74, 95%CI 1.26-2.39, p = 0.001). Moreover, copeptin improved the AUC of the multivariate logistic clinical model (p-LR-test < 0.001). Even though copeptin values were higher in patients reaching the secondary endpoint, this association was not significant in multivariate logistic regression. CONCLUSIONS: Copeptin was independently associated with serious secondary headache as compared to benign headaches forms. Copeptin may be a promising novel blood biomarker that should be further validated to rule out serious secondary headache in the emergency department. TRIAL REGISTRATION: Study Registration on 08/02/2010 as NCT01174901 at clinicaltrials.gov.

Repeated Intravenous Thrombolysis for Early Recurrent Stroke: Challenging the Exclusion Criterion.

BACKGROUND AND PURPOSE: Intravenous thrombolysis (IVT) within 4.5 hours from symptom onset improves functional outcome in patients with acute ischemic stroke. Its use in patients with previous stroke within the preceding 3 months is contraindicated because of the assumed higher risk of intracranial hemorrhage. In addition, tissue-type plasminogen activator may itself promote neurotoxicity and blood-brain barrier disruption. However, safety and effectiveness of repeated IVT is essentially unknown in patients with early (<3 months) recurrent stroke (ERS), because they were excluded from thrombolysis trials. This article reports the largest case series of repeated IVT in ERS. METHODS: We reviewed databases of prospectively collected patient data of 8 European stroke centers for the presence of patients with ERS, who received IVT for both the index stroke and ERS. Demographics, clinical and radiological data, bleeding complications, and functional outcome were analyzed. RESULTS: We identified 19 subjects with repeated IVT in ERS. Mean age was 68±12 years, and 37% of them were female. Median interthrombolysis interval was 30 days (interquartile range, 13-50). Functional independence (modified Rankin scale score ≤2) was achieved in 79% of patients after the first and in 47.4% after repeated IV tissue-type plasminogen activator, respectively. There was no symptomatic intracranial hemorrhage. Median final infarct volume after the first IVT was 1.5 cm(3) (interquartile range, 0.5-3.1). CONCLUSIONS: Patients with small infarct volumes and robust clinical improvement might be considered for repeated IVT within 3 months. Studies following strict protocols and larger registries incorporating these patients might serve to identify selection criteria for the safe use of repeated IVT in ERS.

Pharmacological recanalization therapy in acute ischemic stroke - evolution, current state and perspectives of intravenous and intra-arterial thrombolysis.

Stroke ranges third in mortality in industrialized nations and is the leading cause of disability in older people. Ischemic stroke following thrombotic or embolic vessel occlusion accounts for more than 80% of cerebrovascular events. Immediate restoration of cerebral blood flow is crucial in order to salvage brain tissue. Experimental thrombolytic treatment was introduced into the clinical setting in the late 1950s and required more than 30 years of intense research till its breakthrough and subsequent routine clinical use by the presentation of the NINDS trial results in 1995. To date, intravenous thrombolysis with tissue plasminogen activator up to 4.5 h after symptom onset is the only proven reperfusion therapy for acute ischemic stroke. In this review, we summarize the evolution of intravenous and intra-arterial pharmacological recanalization therapies in acute ischemic stroke and present current clinical practice as well as its promising perspectives.

Progranulin deficiency promotes post-ischemic blood-brain barrier disruption.

Loss-of-function mutations of progranulin (PGRN) have been linked to frontotemporal dementia, but little is known about the effects of PGRN deficiency on the brain in health and disease. PGRN has been implicated in neurovascular development, inflammation, and Wnt signaling, a pathway involved in the formation of the blood-brain barrier (BBB). Because BBB alterations and inflammation contribute to ischemic brain injury, we examined the role of PGRN in the brain damage produced by ischemia-reperfusion. PGRN(+/-) and PGRN(-/-) mice underwent middle cerebral artery occlusion (MCAO) with monitoring of cerebral blood flow. Infarct volume and motor deficits were assessed 72 h later. Post-ischemic inflammation was examined by expression of inflammatory genes and flow cytometry. BBB structure and permeability were examined by electron microscopy (EM) and Evans blue (EB) extravasation, respectively. MCAO resulted in ~60% larger infarcts in PGRN(+/-) and PGRN(-/-) mice, an effect independent of hemodynamic factors or post-ischemic inflammation. Rather, massive hemorrhages and post-ischemic BBB disruption were observed, unrelated to degradation of tight junction (TJ) proteins or matrix metalloproteinases (MMPs). By EM, TJ were 30-52% shorter, fewer, and less interlocking, suggesting a weaker seal between endothelial cells. Intracerebral injection of platelet-derived growth factor-CC (PDGF-CC), which increases BBB permeability, resulted in a more severe BBB breakdown in PGRN(+/-) and PGRN(-/-) than wild-type mice. We describe a previously unrecognized involvement of PGRN in the expression of key ultrastructural features of the BBB. Such a novel vasoprotective role of PGRN may contribute to brain dysfunction and damage in conditions associated with reduced PGRN function.

Age and Stroke Severity Matter Most for Clinical Outcome in Acute Arteriosclerotic Tandem Lesions.

Background: Tandem lesions (TLs) cause up to 15-30% of all acute ischemic strokes (AISs). Endovascular treatment (EVT) is regarded as the first-line treatment; however, uncertainties remain with respect to the treatment and predictive outcome parameters. Here, we aimed to identify the clinical and demographic factors associated with functional short- and long-term outcomes in AIS patients with arteriosclerotic TLs undergoing EVT. Methods: This was a retrospective, mono-centric cohort study of 116 consecutive AIS patients with arteriosclerotic TLs who were endovascularly treated at a stroke center, with analysis of the relevant demographic, procedural, and imaging data. Results: A total of 116 patients were included in this study, with a median age of 72 years (IQR 63-80), 31% of whom were female (n = 36). The median NIHSS on admission was 14 (IQR 7-19), with a median ASPECT score of 9 (IQR 8-10) and median NASCET score of 99% (IQR 88-100%). A total of 52% of the patients received intravenous thrombolysis. In 77% (n = 89) of the patients, an antegrade EVT approach was used, with a good recanalization (mTICI2b3) achieved in 83% of patients (n = 96). Symptomatic intracerebral hemorrhage occurred in 12.7% (n = 15) of patients. A favorable outcome (mRS0-2) and mortality at 3 months were obtained for 40% (n = 47) and 28% of patients (n = 32), respectively. Age and NIHSS on admission were strongly associated with outcome parameters. Diabetes mellitus and previous neurological disorders were independently associated with long-term mortality (median 11 months, IQR 0-42). Conclusions: Younger age, lower stroke severity, and good recanalization were found to be independently associated with a favorable outcome. In contrast, older age, higher stroke severity, previous neurological disorders, and diabetes were correlated with mortality. The endovascular treatment of acute arteriosclerotic tandem lesions is feasible and relatively safe.

Natriuretic Peptides to Classify Risk of Atrial Fibrillation Detection After Stroke: Analysis of the BIOSIGNAL and PRECISE Cohort Studies.

BACKGROUND AND OBJECTIVES: Prolonged cardiac monitoring (PCM) increases atrial fibrillation (AF) detection after ischemic stroke, but access is limited, and it is burdensome for patients. Our objective was to assess whether midregional proatrial natriuretic peptide (MR-proANP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) could classify people who are unlikely to have AF after ischemic stroke and allow better targeting of PCM. METHODS: We analyzed people from the Biomarker Signature of Stroke Aetiology (BIOSIGNAL) study with ischemic stroke, no known AF, and ≥3 days cardiac monitoring. External validation was performed in the Preventing Recurrent Cardioembolic Stroke: Right Approach, Right Patient (PRECISE) study of 28 days of cardiac monitoring in people with ischemic stroke or transient ischemic attack and no known AF. The main outcome is no AF detection. We assessed the discriminatory value of MR-proANP and NT-proBNP combined with clinical variables to identify people with no AF. A decision curve analysis was performed with combined data to determine the net reduction in people who would undergo PCM using the models based on a 15% threshold probability for AF detection. RESULTS: We included 621 people from the BIOSIGNAL study. The clinical multivariable prediction model included age, NIH Stroke Scale score, lipid-lowering therapy, creatinine, and smoking status. The area under the receiver-operating characteristic curve (AUROC) for clinical variables was 0.68 (95% CI 0.62-0.74), which improved with the addition of log10MR-proANP (0.72, 0.66-0.78; p = 0.001) or log10NT-proBNP (0.71, 0.65-0.77; p = 0.009). Performance was similar for the models with log10MR-proANP vs log10NT-proBNP (p = 0.28). In 239 people from the PRECISE study, the AUROC for clinical variables was 0.68 (0.59-0.76), which improved with the addition of log10NT-proBNP (0.73, 0.65-0.82; p < 0.001) or log10MR-proANP (0.79, 0.72-0.86; p < 0.001). Performance was better for the model with log10MR-proANP vs log10NT-proBNP (p = 0.03). The models could reduce the number of people who would undergo PCM by 30% (clinical and log10MR-proANP), 27% (clinical and log10NT-proBNP), or 20% (clinical only). DISCUSSION: MR-proANP and NT-proBNP help classify people who are unlikely to have AF after ischemic stroke. Measuring MR-proANP or NT-proBNP could reduce the number of people who need PCM by 30%, without reducing the amount of AF detected. TRIAL REGISTRATION INFORMATION: NCT02274727; clinicaltrials.gov/study/NCT02274727.

Intracerebral haemorrhage in patients taking different types of oral anticoagulants: a pooled individual patient data analysis from two national stroke registries.

BACKGROUND: We investigated outcomes in patients with intracerebral haemorrhage (ICH) according to prior anticoagulation treatment with Vitamin K antagonists (VKAs), direct oral anticoagulants (DOACs) or no anticoagulation. METHODS: This is an individual patient data study combining two prospective national stroke registries from Switzerland and Norway (2013-2019). We included all consecutive patients with ICH from both registries. The main outcomes were favourable functional outcome (modified Rankin Scale 0-2) and mortality at 3 months. RESULTS: Among 11 349 patients with ICH (mean age 73.6 years; 47.6% women), 1491 (13.1%) were taking VKAs and 1205 (10.6%) DOACs (95.2% factor Xa inhibitors). The median percentage of patients on prior anticoagulation was 23.7 (IQR 22.6-25.1) with VKAs decreasing (from 18.3% to 7.6%) and DOACs increasing (from 3.0% to 18.0%) over time. Prior VKA therapy (n=209 (22.3%); adjusted ORs (aOR), 0.64; 95% CI, 0.49 to 0.84) and prior DOAC therapy (n=184 (25.7%); aOR, 0.64; 95% CI, 0.47 to 0.87) were independently associated with lower odds of favourable outcome compared with patients without anticoagulation (n=2037 (38.8%)). Prior VKA therapy (n=720 (49.4%); aOR, 1.71; 95% CI, 1.41 to 2.08) and prior DOAC therapy (n=460 (39.7%); aOR, 1.28; 95% CI, 1.02 to 1.60) were independently associated with higher odds of mortality compared with patients without anticoagulation (n=2512 (30.2%)). CONCLUSIONS: The spectrum of anticoagulation-associated ICH changed over time. Compared with patients without prior anticoagulation, prior VKA treatment and prior DOAC treatment were independently associated with lower odds of favourable outcome and higher odds of mortality at 3 months. Specific reversal agents unavailable during the study period might improve outcomes of DOAC-associated ICH in the future.

Lipoprotein receptor-related protein-6 protects the brain from ischemic injury.

BACKGROUND AND PURPOSE: Loss-of-function mutations of the lipoprotein receptor-related protein-6 (LRP6), a coreceptor in the Wingless-related integration site-ß-catenin prosurvival pathway, have been implicated in myocardial ischemia and neurodegeneration. However, it remains to be established whether LRP6 is also involved in ischemic brain injury. We used LRP6+/- mice to examine the role of this receptor in the mechanisms of focal cerebral ischemia. METHODS: Focal cerebral ischemia was induced by transient occlusion of the middle cerebral artery. Motor deficits and infarct volume were assessed 3 days later. Glycogen-synthase-kinase-3ß (GSK-3ß) phosphorylation was examined by Western blotting with phosphospecific antibodies, and the mitochondrial membrane potential changes induced by Ca2+ were also assessed. RESULTS: LRP6+/- mice have larger stroke and more severe motor deficits, effects that were independent of intraischemic cerebral blood flow, vascular factors, or cytosolic ß-catenin levels. Rather, LRP6 haploinsufficiency increased the activating phosphorylation and decreased the inhibitory phosphorylation of GSK-3ß, a kinase involved in proinflammatory signaling and mitochondrial dysfunction. Accordingly, postischemic inflammatory gene expression was enhanced in LRP6+/- mice. Furthermore, the association of mitochondria with activated GSK-3ß was increased in LRP6+/- mice, resulting in a reduction in the Ca2+ handling ability of mitochondria. The mitochondrial dysfunction was reversed by pharmacological inhibition of GSK-3ß. CONCLUSIONS: LRP6 activates an endogenous neuroprotective pathway that acts independently of ß-catenin by controlling GSK-3ß activity and preventing its deleterious mitochondrial and proinflammatory effects. The findings raise the possibility that emerging treatment strategies for diseases attributable to LRP6 loss-of-function mutations could also lead to new therapeutic avenues for ischemic stroke.