Sex-Stratified Genome-Wide Association Study in the Spanish Population Identifies a Novel Locus for Lacunar Stroke.

BACKGROUND: Ischemic stroke (IS) represents a significant health burden globally, necessitating a better understanding of its genetic underpinnings to improve prevention and treatment strategies. Despite advances in IS genetics, studies focusing on the Spanish population and sex-stratified analyses are lacking. METHODS: A case-control genome-wide association study was conducted with 9081 individuals (3493 IS cases and 5588 healthy controls). IS subtypes using Trial of ORG 10172 in Acute Stroke Treatment criteria were explored in a sex-stratified approach. Replication efforts involved the MEGASTROKE, GIGASTROKE, and the UK Biobank international cohorts. Post-genome-wide association study analysis included: in silico proteomic analysis, gene-based analysis, quantitative trait loci annotation, transcriptome-wide association analysis, and bioinformatic analysis using chromatin accessibility data. RESULTS: Identified as associated with IS and its subtypes were 4 significant and independent loci. Replication confirmed 5p15.2 as a new locus associated with small-vessel occlusion stroke, with rs59970332-T as the lead variant (beta [SE], 0.13 [0.02]; P=4.34×10-8). Functional analyses revealed CTNND2 given proximity and its implication in pathways involved in vascular integrity and angiogenesis. Integration of Hi-C data identified additional potentially modulated genes, and in silico proteomic analysis suggested a distinctive blood proteome profile associated with the lead variant. Gene-set enrichment analyses highlighted pathways consistent with small-vessel disease pathogenesis. Gene-based associations with known stroke-related genes such as F2 and FGG were also observed, reinforcing the relevance of our findings. CONCLUSIONS: We found CTNND2 as a potential key molecule in small-vessel occlusion stroke risk, and predominantly in males. This study sheds light on the genetic architecture of IS in the Spanish population, providing novel insights into sex-specific associations and potential molecular mechanisms. Further research, including replication in larger cohorts, is essential for a comprehensive understanding of these findings and for their translation to clinical practice.

Asymptomatic parenchymal haemorrhage following endovascular treatment: Impact on functional outcome in patients with acute ischaemic stroke.

BACKGROUND AND PURPOSE: In patients with acute ischaemic stroke (AIS), haemorrhagic transformation (HT) following endovascular treatment (EVT) is associated with poor functional outcome. However, the impact of asymptomatic HT, not linked to neurological deterioration in the acute phase, is unknown. We aimed to investigate the impact of asymptomatic PH1 (aPH1) and PH2 (aPH2) subtypes of HT on the functional outcome of patients treated with EVT. METHODS: We conducted a retrospective study of patients with AIS who were consecutively admitted to our comprehensive stroke centre between January 2019 and December 2022, and who underwent EVT. We collected clinical, radiological, and procedural data. HTs were categorized according to the Heidelberg classification. The primary outcome was the shift on the modified Rankin Scale (mRS) at 3 months of follow-up. We performed bivariate and multivariable ordinal regression analyses to test the association between aPH1/aPH2 and the primary outcome. RESULTS: We included 314 patients (mean age = 72.5 years [SD = 13.6], 171 [54.5%] women). We detected 54 (17.2%) patients with HT; 23 (7.3%) were classified as PH2 (11 asymptomatic) and 17 (5.4%) as PH1 (16 asymptomatic). The adjusted common odds ratio for aPH2 of worsening 1 point on the 3-month mRS was 3.32 (95% confidence interval = 1.16-9.57, p = 0.026). No association was observed for aPH1. aPH2 was also independently associated with lower odds of achieving a favourable outcome (mRS = 0-2). Neither aPH1 nor aPH2 was associated with mortality. CONCLUSIONS: In patients with AIS treated with EVT, aPH2 is independently associated with unfavourable functional outcome.

A Randomized Trial on Hemodynamic Optimization of Cerebral Perfusion after Successful Endovascular Therapy in Patients with Acute Ischemic Stroke (HOPE).

INTRODUCTION: In patients with acute ischemic stroke (AIS) secondary to intracranial large vessel occlusion, optimal blood pressure (BP) management following endovascular treatment (EVT) has not yet been established. The randomized trial on Hemodynamic Optimization of Cerebral Perfusion after Successful Endovascular Therapy in Patients with Acute Ischemic Stroke (HOPE) (clinicaltrials.gov id: NCT04892511) aims to demonstrate whether hemodynamic optimization using different systolic BP targets following EVT according to the degree of final recanalization, is more effective than currently recommended BP management in improving functional outcomes of patients with AIS. METHODS: HOPE is an investigator-initiated multicenter clinical trial with randomized allocation, open-label treatment, and blinded endpoint evaluation (PROBE). Patients with an anterior circulation AIS within 24 h of symptom onset, treated with EVT, and showing successful recanalization (mTICI ≥2b) at the end of the procedure, are equally allocated (1:1) to hemodynamic optimization according to the study protocol versus BP management according to current guidelines (≤180/105 mm Hg). The protocol includes two different targets of systolic BP depending on the recanalization status (mTICI = 2b: 140-160 mm Hg; mTICI = 2c/3: 100-140 mm Hg). The protocol is applied within the first 72 h and includes BP lowering as well as vasopressor therapies when needed. The primary outcome is the proportion of favorable outcome (modified Rankin Scale [mRS] 0-2) at 90 days. Secondary outcomes include the shift on the mRS score, neurological deterioration, symptomatic intracerebral hemorrhage, and mortality. CONCLUSION: The HOPE trial will provide new information on the safety and efficacy of different BP targets following EVT according to the degree of final recanalization in patients with AIS.

Left atrial appendage occlusion in patients with spontaneous intracerebral hemorrhage: An observational study.

BACKGROUND: Patients with atrial fibrillation (AF) and intracerebral hemorrhage (ICH) are at high risk of ischemic and recurrent bleeding events. Therefore, the decision of restarting or avoiding anticoagulation is challenging. Left atrial appendage occlusion (LAAO) is an alternative for these patients. However, few data are available about safety of early LAAO and factors associated with ischemic stroke and ICH recurrence. METHODS: A unicentric, observational, retrospective study including all patients with AF and a previous ICH who underwent LAAO. We analyzed baseline clinical and neuroimaging characteristics, procedural outcomes, post-procedural therapies and long-term follow-up. RESULTS: Forty patients were included, whose mean age was 76.6 ±7.6 years and 73 % were men. In patients in whom a Magnetic Resonance (MR) was performed (n=22, 55 %), cortical microbleeds were detected in 15 (68 %) and cortical superficial siderosis in one patient. The procedure was successful and safe in 100 % of the patients and it was performed within 30 days of the ICH in 37 % of them. After a median follow up of 46.2 months [26-69], intracranial hemorrhage (ICrH) recurrence occurred in 6 patients (5 ICH and 1 subdural hematoma -SDH-) and the index ICH was lobar in all of them. Ischemic events were significantly lower than expected according to the CHA2DS2-VASc score (7.5 % vs. 16.6 %, p=0.048) and bleeding events were similar to expected by the HAS-BLED score (20 % vs 23.4 %, p=0.63). CONCLUSIONS: In patients with ICH and AF, early LAAO was found to be safe and associated with a reduction in ischemic stroke. However, recurrent ICH risk remains high, and it appears to be mainly driven by cerebral amyloid angiopathy.

Soluble low-density lipoprotein receptor-related protein 1 as a surrogate marker of carotid plaque inflammation assessed by 18F-FDG PET in patients with a recent ischemic stroke.

BACKGROUND: 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) identifies carotid plaque inflammation and predicts stroke recurrence. AIM: Our aim was to evaluate the performance of soluble low-density lipoprotein receptor-related protein 1 (sLRP1) as an indicator of carotid plaque inflammation. METHODS: A prospective study was conducted among adult patients with recent (< 7 days) anterior circulation ischemic stroke and at least one atherosclerotic plaque in the ipsilateral internal carotid artery. Patients underwent an early (< 15 days from inclusion) 18F-FDG PET, and the maximum standardized uptake value (SUVmax) within the plaque was measured. sLRP1 levels were measured in plasma samples by ELISA. The association of sLRP1 with SUVmax was assessed using bivariate and multivariable linear regression analyses. Hazard ratios (HR) were estimated with Cox regression to evaluate the association between circulating sLRP1 and stroke recurrence. RESULTS: The study was conducted with 64 participants, of which 57.8% had ≥ 50% carotid stenosis. The multivariable linear and logistic regression analyses showed that sLRP1 was independently associated with (i) SUVmax within the plaque (ß = 0.159, 95% CI 0.062-0.257, p = 0.002) and (ii) a probability of presenting SUVmax ≥ 2.85 g/mL (OR = 1.31, 95% CI 1.00-1.01, p = 0.046), respectively. Participants with stroke recurrence showed higher sLRP1 levels at baseline [6447 ng/mL (4897-11163) vs. 3713 ng/mL (2793-4730); p = 0.018]. CONCLUSIONS: sLRP1 was independently associated with carotid plaque inflammation as measured by 18F-FDG PET in patients with recent ischemic stroke and carotid atherosclerosis.

Ischaemic stroke patients present sex differences in gut microbiota.

BACKGROUND: Gut microbiota plays a role in the pathophysiology of ischaemic stroke (IS) through the bidirectional gut-brain axis. Nevertheless, little is known about sex-specific microbiota signatures in IS occurrence. METHODS: A total of 89 IS patients and 12 healthy controls were enrolled. We studied the taxonomic differences of the gut microbiota between men and women with IS by shotgun metagenomic sequencing. To evaluate the causal effect of several bacteria on IS risk, we performed a two-sample Mendelian randomisation (MR) with inverse-variance weighting (IVW) using genome-wide association analysis (GWAS) summary statistics from two cohorts of 5959 subjects with genetic and microbiota data and 1,296,908 subjects with genetic and IS data, respectively. RESULTS: α-Diversity analysis measured using Observed Species (p = 0.017), Chao1 (p = 0.009) and Abundance-based Coverage Estimator (p = 0.012) indexes revealed that IS men have a higher species richness compared with IS women. Moreover, we found sex-differences in IS patients in relation to the phylum Fusobacteria, class Fusobacteriia, order Fusobacteriales and family Fusobacteriaceae (all Bonferroni-corrected p < 0.001). MR confirmed that increased Fusobacteriaceae levels in the gut are causally associated with an increased risk of IS (IVW p = 0.02, ß = 0.32). CONCLUSIONS: Our study is the first to indicate that there are gut microbiome differences between men and women with IS, identifying high levels of Fusobacteriaceae in women as a specific risk factor for IS. Incorporating sex stratification analysis is important in the design, analysis and interpretation of studies on stroke and the gut microbiota.

Novel Therapeutic Approaches to Prevent Atherothrombotic Ischemic Stroke in Patients with Carotid Atherosclerosis.

Atherothrombotic stroke represents approximately 20% of all ischemic strokes. It is caused by large-artery atherosclerosis, mostly in the internal carotid artery, and it is associated with a high risk of early recurrence. After an ischemic stroke, tissue plasminogen activator is used in clinical practice, although it is not possible in all patients. In severe clinical situations, such as high carotid stenosis (≥70%), revascularization by carotid endarterectomy or by stent placement is carried out to avoid recurrences. In stroke prevention, the pharmacological recommendations are based on antithrombotic, lipid-lowering, and antihypertensive therapy. Inflammation is a promising target in stroke prevention, particularly in ischemic strokes associated with atherosclerosis. However, the use of anti-inflammatory strategies has been scarcely studied. No clinical trials are clearly successful and most preclinical studies are focused on protection after a stroke. The present review describes novel therapies addressed to counteract inflammation in the prevention of the first-ever or recurrent stroke. The putative clinical use of broad-spectrum and specific anti-inflammatory drugs, such as monoclonal antibodies and microRNAs (miRNAs) as regulators of atherosclerosis, will be outlined. Further studies are necessary to ascertain which patients may benefit from anti-inflammatory agents and how.

Clinical characteristics and outcome of amaurosis fugax due to transient retinal ischemia: Results from a contemporary cohort.

BACKGROUND: Whether presenting an episode of amaurosis fugax (AFx) increases the risk of ischemic stroke is controversial and there is a lack of consensus in the following management. We aimed to describe the clinical characteristics and prognosis of patients with AFx due to suspected transient retinal ischemia. METHODS: Observational, retrospective study of patients admitted in a Comprehensive Stroke Center with diagnosis of AFx due to suspected transient retinal ischemia between 2015 and 2020. Clinical characteristics and diagnostic-therapeutic data were collected, as well as recurrences (new episodes of amaurosis and/or ischemic strokes). Multivariable Cox regression analyses were performed to study factors associated with the risk of recurrence. RESULTS: We included 91 patients with a mean age of 67.9±14.8 years, 43(47.3%) were women. After the diagnostic workup 14(15.4%) AFx were attributed to an atherothrombotic etiology, 4(4.4%) cardioembolic source, 10(11%) other determined cause (TOAST-OC) and 63(69,2%) indeterminate etiology. 71(78%) patients started antiplatelet therapy and 2(2.2%) anticoagulant therapy. After a median follow-up of 3.5 years (IQR 1.8-5.2), at least one recurrence was recorded in eight (8.8%) patients (four new AFx and four cerebral infarctions). TOAST-OC (HR=9.66, 95% CI 2.41-38.70; p=0.001) and prior history of ischemic stroke (HR=4.21. 95% CI 1.01-17.66; p=0.049) were both independently associated with the risk of recurrence. CONCLUSIONS: In two out of three patients, AFx due to transient retinal ischemia was of undetermined cause. The risk of stroke recurrence after a first episode of AFx in our cohort was 8.8%. Patients with TOAST-OC etiology identified were at highest risk of recurrence.

Predictors of Functional Outcome After Thrombectomy in Patients With Prestroke Disability in Clinical Practice.

BACKGROUND AND PURPOSE: Mechanical thrombectomy (MT) in ischemic stroke patients with poor prestroke conditions remains controversial. We aimed to analyze the frequency of previously disabled patients treated with MT in clinical practice, the safety and clinical response to MT of patients with preexisting disability, and the disabled patient characteristics associated with a better response to MT. METHODS: We studied all consecutive patients with anterior circulation occlusion treated with MT from January 2017 to December 2019 included in the Codi Ictus Catalunya registry-a government-mandated, prospective, hospital-based data set. Prestroke disability was defined as modified Rankin Scale score 2 or 3. Functional outcome at 90 days was centrally assessed by a blinded evaluator of the Catalan Stroke Program. Favorable outcome (to return at least to prestroke modified Rankin Scale at 90 days) and safety and secondary outcomes were compared with patients without previous disability. Logistic regression analysis was used to assess the association between prestroke disability and outcomes and to identify a disabled patient profile with favorable outcome after MT. RESULTS: Of 2487 patients included in the study, 409 (17.1%) had prestroke disability (313 modified Rankin Scale score 2 and 96 modified Rankin Scale score 3). After adjustment for covariates, prestroke disability was not associated with a lower chance of achieving favorable outcome at 90 days (24% versus 30%; odds ratio, 0.79 [0.57-1.08]), whereas it was independently associated with a higher risk of symptomatic intracranial hemorrhage (5% versus 3%; odds ratio, 2.04 [1.11-3.72]) and long-term mortality (31% versus 18%; odds ratio, 1.74 [1.27-2.39]) compared with patients without disability. Prestroke disabled patients without diabetes, Alberta Stroke Program Early CT Score >8 and National Institutes of Health Stroke Scale score <17 showed similar safety and outcome results after MT as patients without prestroke disability. CONCLUSIONS: Despite a higher mortality and risk of symptomatic intracranial hemorrhage, prestroke-disabled patients return as often as independent patients to their prestroke level of function, especially those nondiabetic patients with favorable early ischemic signs profile. These data support a potential benefit of MT in patients with previous mild or moderate disability after large anterior vessel occlusion stroke.

Biological Age Acceleration Is Lower in Women With Ischemic Stroke Compared to Men.

BACKGROUND: Stroke onset in women occurs later in life compared with men. The underlying mechanisms of these differences have not been established. Epigenetic clocks, based on DNA methylation (DNAm) profiles, are the most accurate biological age estimate. Epigenetic age acceleration (EAA) measures indicate whether an individual is biologically younger or older than expected. Our aim was to analyze whether sexual dichotomy at age of stroke onset is conditioned by EAA. METHODS: We used 2 DNAm datasets from whole blood samples of case-control genetic studies of ischemic stroke (IS), a discovery cohort of 374 IS patients (N women=163, N men=211), from GRECOS (Genotyping Recurrence Risk of Stroke) and SEDMAN (Dabigatran Study in the Early Phase of Stroke, New Neuroimaging Markers and Biomarkers) studies and a replication cohort of 981 IS patients (N women=411, N men=570) from BASICMAR register. We compared chronological age, 2 DNAm-based biomarkers of aging and intrinsic and extrinsic epigenetic age acceleration EAA (IEAA and extrinsic EAA, respectively), in IS as well as in individual IS etiologic subtypes. Horvath and Hannum epigenetic clocks were used to assess the aging rate. A proteomic study using the SOMAScan multiplex assay was performed on 26 samples analyzing 1305 proteins. RESULTS: Women present lower Hannum-extrinsic EAA values, whereas men have higher Hannum-extrinsic EAA values (women=-0.64, men=1.24, P=1.34×10-2); the same tendency was observed in the second cohort (women=-0.57, men=0.79, P=0.02). These differences seemed to be specific to cardioembolic and undetermined stroke subtypes. Additionally, 42 blood protein levels were associated with Hannum-extrinsic EAA (P<0.05), belonging to the immune effector process (P=1.54×10-6) and platelet degranulation (P<8.74×10-6) pathways. CONCLUSIONS: This study shows that sex-specific underlying biological mechanisms associated with stroke onset could be due to differences in biological age acceleration between men and women.

Effect of Intra-arterial Alteplase vs Placebo Following Successful Thrombectomy on Functional Outcomes in Patients With Large Vessel Occlusion Acute Ischemic Stroke: The CHOICE Randomized Clinical Trial.

Importance: It is estimated that only 27% of patients with acute ischemic stroke and large vessel occlusion who undergo successful reperfusion after mechanical thrombectomy are disability free at 90 days. An incomplete microcirculatory reperfusion might contribute to these suboptimal clinical benefits. Objective: To investigate whether treatment with adjunct intra-arterial alteplase after thrombectomy improves outcomes following reperfusion. Design, Setting, and Participants: Phase 2b randomized, double-blind, placebo-controlled trial performed from December 2018 through May 2021 in 7 stroke centers in Catalonia, Spain. The study included 121 patients with large vessel occlusion acute ischemic stroke treated with thrombectomy within 24 hours after stroke onset and with an expanded Treatment in Cerebral Ischemia angiographic score of 2b50 to 3. Interventions: Participants were randomized to receive intra-arterial alteplase (0.225 mg/kg; maximum dose, 22.5 mg) infused over 15 to 30 minutes (n = 61) or placebo (n = 52). Main Outcomes and Measures: The primary outcome was the difference in proportion of patients achieving a score of 0 or 1 on the 90-day modified Rankin Scale (range, 0 [no symptoms] to 6 [death]) in all patients treated as randomized. Safety outcomes included rate of symptomatic intracranial hemorrhage and death. Results: The study was terminated early for inability to maintain placebo availability and enrollment rate because of the COVID-19 pandemic. Of 1825 patients with acute ischemic stroke treated with thrombectomy at the 7 study sites, 748 (41%) patients fulfilled the angiographic criteria, 121 (7%) patients were randomized (mean age, 70.6 [SD, 13.7] years; 57 women [47%]), and 113 (6%) were treated as randomized. The proportion of participants with a modified Rankin Scale score of 0 or 1 at 90 days was 59.0% (36/61) with alteplase and 40.4% (21/52) with placebo (adjusted risk difference, 18.4%; 95% CI, 0.3%-36.4%; P = .047). The proportion of patients with symptomatic intracranial hemorrhage within 24 hours was 0% with alteplase and 3.8% with placebo (risk difference, -3.8%; 95% CI, -13.2% to 2.5%). Ninety-day mortality was 8% with alteplase and 15% with placebo (risk difference, -7.2%; 95% CI, -19.2% to 4.8%). Conclusions and Relevance: Among patients with large vessel occlusion acute ischemic stroke and successful reperfusion following thrombectomy, the use of adjunct intra-arterial alteplase compared with placebo resulted in a greater likelihood of excellent neurological outcome at 90 days. However, because of study limitations, these findings should be interpreted as preliminary and require replication. Trial Registration: ClinicalTrials.gov Identifier: NCT03876119; EudraCT Number: 2018-002195-40.

Frequency, Predictors, Etiology, and Outcomes for Deep Intracerebral Hemorrhage without Hypertension.

OBJECTIVES: Some patients with deep intracerebral hemorrhage (ICH) have a transient hypertensive response and they may be erroneously classified as secondary to hypertension. We investigated frequency, risk factors, and outcomes for patients with deep ICH without hypertension. MATERIALS AND METHODS: We consecutively recruited patients with spontaneous ICH attending two Spanish stroke centers (January 2015-June 2019). Excluded were patients with lobar/infratentorial ICH and patients who died during hospitalization. We defined deep ICH without hypertension when the bleeding was in a deep structure, no requirement for antihypertensive agents during follow-up and no evident chronic hypertension markers evaluated by transthoracic echocardiography, 24 h ambulatory blood pressure monitoring and/or electrocardiography. We compared clinical, radiological, and 3-month functional outcome data for deep-ICH patients with hypertension versus those without hypertension. RESULTS: Of 759 patients with ICH, 219 (mean age 69.6 ± 15.4 years, 54.8% men) met the inclusion criteria and 36 (16.4%) did not have hypertension. Of these 36 patients, 19 (52.7%) had a transient hypertensive response. Independent predictors of deep ICH without hypertension were age (adjusted OR:0.94;95%CI:0.91-0.96) and dyslipidemia (adjusted OR:0.27;95% CI:0.08-0.85). One third of deep ICH without hypertension were secondary to vascular malformations. Favorable outcomes (modified Rankin Scale 0-2) were more frequent in patients with deep ICH without hypertension compared to those with hypertension (70.9% vs 33.8%; p < 0.001). CONCLUSION: Of patients with deep ICH, 16.4% were unrelated with hypertension, around half showed hypertensive response, and around a third had vascular malformations. We suggest studying hypertension markers and performing a follow-up brain MRI in those patients with deep ICH without prior hypertension.

Reasons for Not Performing Mechanical Thrombectomy: A Population-Based Study of Stroke Codes.

Background and Purpose: Mechanical thrombectomy (MT) is effective for acute ischemic stroke (AIS) in selected patients with large intracranial vessel occlusion. A minority of patients with AIS receive MT. We aimed to describe the reasons for excluding patients with AIS for MT. Methods: We evaluated patients with AIS in a prospective population-based multicenter registry (Codi Ictus Catalunya registry) that includes all stroke code activations from January to June 2018 in Catalonia, Spain. We analyzed the major reasons for not treating with MT. Results: Stroke code was activated in 3060 patients. Excluding 355 intracranial hemorrhages and 502 stroke mimics, resulted in 2203 patients with AIS (mean age 72.8±13.8 years; 44.6% were women). Of the patients with AIS, 405 (18.4%) were treated with MT. We analyzed the reasons for not treating with MT. The following reasons were considered not modifiable: absence of large intracranial vessel occlusion (922, 41.9%), transient ischemic attack (206, 9.4%), and more than one cause (124, 5.6%). The potentially modifiable reasons for not performing MT by changing selection criteria were as follows: an intracranial artery occlusion that was considered inaccessible or not indicated (48, 2.2%); clinical presentation that was considered too mild to be treated (222, 10.1%); neuroimaging criteria (129, 5.9%), age/prior modified Rankin Scale score/medical comorbidities (129, 5.9%), and therapeutic time window >8 hours (16, 0.7%). Conclusions: In our area, considering all potentially modifiable causes for not performing MT, the percentage of patients with AIS eligible for MT could increase from 18.4% to a maximum of 43.1%. The clinical benefit of this increase is still uncertain and should be confirmed in future trials. Criteria for stroke code activation must be considered for the generalizability of these results.

Impact of COVID-19 Infection on the Outcome of Patients With Ischemic Stroke.

BACKGROUND AND PURPOSE: We evaluated whether stroke severity, functional outcome, and mortality are different in patients with ischemic stroke with or without coronavirus disease 2019 (COVID-19) infection. METHODS: A prospective, observational, multicentre cohort study in Catalonia, Spain. Recruitment was consecutive from mid-March to mid-May 2020. Patients had an acute ischemic stroke within 48 hours and a previous modified Rankin Scale (mRS) score of 0 to 3. We collected demographic data, vascular risk factors, prior mRS score, National Institutes of Health Stroke Scale score, rate of reperfusion therapies, logistics, and metrics. Primary end point was functional outcome at 3 months. Favourable outcome was defined depending on the previous mRS score. Secondary outcome was mortality at 3 months. We performed mRS shift and multivariable analyses. RESULTS: We evaluated 701 patients (mean age 72.3±13.3 years, 60.5% men) and 91 (13%) had COVID-19 infection. Median baseline National Institutes of Health Stroke Scale score was higher in patients with COVID-19 compared with patients without COVID-19 (8 [3-18] versus 6 [2-14], P=0.049). Proportion of patients with a favourable functional outcome was 33.7% in the COVID-19 and 47% in the non-COVID-19 group. However, after a multivariable logistic regression analysis, COVID-19 infection did not increase the probability of unfavourable functional outcome. Mortality rate was 39.3% among patients with COVID-19 and 16.1% in the non-COVID-19 group. In the multivariable logistic regression analysis, COVID-19 infection was a risk factor for mortality (hazard ratio, 3.14 [95% CI, 2.10-4.71]; P<0.001). CONCLUSIONS: Patients with ischemic stroke and COVID-19 infection have more severe strokes and a higher mortality than patients with stroke without COVID-19 infection. However, functional outcome is comparable in both groups.

Defining Minor Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: The minor stroke concept has not been analyzed in intracerebral hemorrhage (ICH) patients. Our purpose was to determine the optimal cut point on the NIH Stroke Scale (NIHSS) for defining a minor ICH (mICH) in patients with primary ICH. METHODS: An ICH was considered minor if associated with a favorable 3-month outcome (modified Rankin Scale score ≤2). For supratentorial ICH, the discovery cohort consisted of 478 patients prospectively admitted at University Hospital del Mar. Association between NIHSS at admission and 3-month outcome was evaluated with area under the curve-receiver operating characteristics (AUC-ROC) and Youden's index to identify the optimal NIHSS cutoff point to define mICH. External validation was performed in a cohort of 242 supratentorial ICH patients from University Hospital Sant Pau. For infratentorial location, patients from both hospitals (n = 85) were analyzed together. RESULTS: The best -NIHSS cutoff point defining supratentorial-mICH was 6 (AUC-ROC = 0.815 [0.774-0.857] in the discovery cohort and AUC-ROC = 0.819 [0.756-0.882] in the external validation cohort). For infratentorial ICH, the best cutoff point was 4 (AUC-ROC = 0.771 [0.664-0.877]). Using these cutoff points, 40.5% of all primary ICH cases were mICH. Of these, 70.2% were living independently at 3-month follow-up (72% for supratentorial ICH and 56.1% for infratentorial ICH) and 6.5% had died (5.3% for supratentorial ICH, and 14.6% for infratentorial ICH). For patients identified as non-mICH, good 3-month outcome was observed in 11.3% of cases; mortality was 51%. CONCLUSIONS: The definition of mICH using the NIHSS cutoff point of 6 for supratentorial ICH and 4 for infratentorial ICH is useful to identify good outcome in ICH patients.

Blood flow response to orthostatic challenge identifies signatures of the failure of static cerebral autoregulation in patients with cerebrovascular disease.

BACKGROUND: The cortical microvascular cerebral blood flow response (CBF) to different changes in head-of-bed (HOB) position has been shown to be altered in acute ischemic stroke (AIS) by diffuse correlation spectroscopy (DCS) technique. However, the relationship between these relative ΔCBF changes and associated systemic blood pressure changes has not been studied, even though blood pressure is a major driver of cerebral blood flow. METHODS: Transcranial DCS data from four studies measuring bilateral frontal microvascular cerebral blood flow in healthy controls (n = 15), patients with asymptomatic severe internal carotid artery stenosis (ICA, n = 27), and patients with acute ischemic stroke (AIS, n = 72) were aggregated. DCS-measured CBF was measured in response to a short head-of-bed (HOB) position manipulation protocol (supine/elevated/supine, 5 min at each position). In a sub-group (AIS, n = 26; ICA, n = 14; control, n = 15), mean arterial pressure (MAP) was measured dynamically during the protocol. RESULTS: After elevated positioning, DCS CBF returned to baseline supine values in controls (p = 0.890) but not in patients with AIS (9.6% [6.0,13.3], mean 95% CI, p < 0.001) or ICA stenosis (8.6% [3.1,14.0], p = 0.003)). MAP in AIS patients did not return to baseline values (2.6 mmHg [0.5, 4.7], p = 0.018), but in ICA stenosis patients and controls did. Instead ipsilesional but not contralesional CBF was correlated with MAP (AIS 6.0%/mmHg [- 2.4,14.3], p = 0.038; ICA stenosis 11.0%/mmHg [2.4,19.5], p < 0.001). CONCLUSIONS: The observed associations between ipsilateral CBF and MAP suggest that short HOB position changes may elicit deficits in cerebral autoregulation in cerebrovascular disorders. Additional research is required to further characterize this phenomenon.

Endothelial Progenitor Cells Count after Acute Ischemic Stroke Predicts Functional Outcome in Patients with Carotid Atherosclerosis.

OBJECTIVES: Circulating Endothelial Progenitor Cells (EPCs) predict cardiovascular outcomes in patients with coronary disease. However, the predictive value of EPCs after ischemic stroke is not well established. We aimed to study the prognostic role of EPCs in patients with acute ischemic stroke and carotid atherosclerosis, focusing on post-stroke functional outcome and stroke recurrences. MATERIALS AND METHODS: We studied consecutive adult patients with an acute (<7 days) anterior circulation ischemic stroke and carotid atherosclerosis. Cardioembolic strokes were excluded. We measured circulating EPCs by flow cytometry (CD34+/CD133+/KDR+) at inclusion (7±1 days after stroke) and at one year of follow-up. At three months and at one year we registered the modified Rankin Scale score, stroke recurrences and coronary syndromes during the follow-up. RESULTS: We studied 80 patients with a mean age of 74.3±10.4 years. We divided the population in tertiles according to the EPCs count. At three months we observed a favorable outcome in 25/36 (69.4%) patients in the lowest, 19/22 (86.4%) in the medium and 21/22 (95.5%) in the highest tercile (p=0.037). In the multivariable analysis a higher EPCs count was associated with favorable functional outcome after adjusting for age and baseline NIHSS score (OR=3.61, 95%CI 1.34-9.76; p=0.011). This association persisted at one year of follow-up. We did not find association between counts of EPCs and stroke recurrence. CONCLUSIONS: In patients with acute ischemic stroke and carotid atherosclerosis, a higher count of EPCs was associated with favorable functional outcome in the mid and long-term follow-up. Counts of EPCs did not predict stroke recurrences.

A Risk Score Including Carotid Plaque Inflammation and Stenosis Severity Improves Identification of Recurrent Stroke.

Background and Purpose- In randomized trials of symptomatic carotid endarterectomy, only modest benefit occurred in patients with moderate stenosis and important subgroups experienced no benefit. Carotid plaque 18F-fluorodeoxyglucose uptake on positron emission tomography, reflecting inflammation, independently predicts recurrent stroke. We investigated if a risk score combining stenosis and plaque 18F-fluorodeoxyglucose would improve the identification of early recurrent stroke. Methods- We derived the score in a prospective cohort study of recent (<30 days) non-severe (modified Rankin Scale score ≤3) stroke/transient ischemic attack. We derived the SCAIL (symptomatic carotid atheroma inflammation lumen-stenosis) score (range, 0-5) including 18F-fluorodeoxyglucose standardized uptake values (SUVmax <2 g/mL, 0 points; SUVmax 2-2.99 g/mL, 1 point; SUVmax 3-3.99 g/mL, 2 points; SUVmax ≥4 g/mL, 3 points) and stenosis (<50%, 0 points; 50%-69%, 1 point; ≥70%, 2 points). We validated the score in an independent pooled cohort of 2 studies. In the pooled cohorts, we investigated the SCAIL score to discriminate recurrent stroke after the index stroke/transient ischemic attack, after positron emission tomography-imaging, and in mild or moderate stenosis. Results- In the derivation cohort (109 patients), recurrent stroke risk increased with increasing SCAIL score (P=0.002, C statistic 0.71 [95% CI, 0.56-0.86]). The adjusted (age, sex, smoking, hypertension, diabetes mellitus, antiplatelets, and statins) hazard ratio per 1-point SCAIL increase was 2.4 (95% CI, 1.2-4.5, P=0.01). Findings were confirmed in the validation cohort (87 patients, adjusted hazard ratio, 2.9 [95% CI, 1.9-5], P<0.001; C statistic 0.77 [95% CI, 0.67-0.87]). The SCAIL score independently predicted recurrent stroke after positron emission tomography-imaging (adjusted hazard ratio, 4.52 [95% CI, 1.58-12.93], P=0.005). Compared with stenosis severity (C statistic, 0.63 [95% CI, 0.46-0.80]), prediction of post-positron emission tomography stroke recurrence was improved with the SCAIL score (C statistic, 0.82 [95% CI, 0.66-0.97], P=0.04). Findings were confirmed in mild or moderate stenosis (adjusted hazard ratio, 2.74 [95% CI, 1.39-5.39], P=0.004). Conclusions- The SCAIL score improved the identification of early recurrent stroke. Randomized trials are needed to test if a combined stenosis-inflammation strategy improves selection for carotid revascularization where benefit is currently uncertain.

Serum neurofilament light chain predicts long-term prognosis in Guillain-Barré syndrome patients.

OBJECTIVE: To study baseline serum neurofilament light chain (sNfL) levels as a prognostic biomarker in Guillain-Barré syndrome (GBS). METHODS: We measured NfL in serum (98 samples) and cerebrospinal fluid (CSF) (24 samples) of patients with GBS prospectively included in the International GBS Outcome Study (IGOS) in Spain using single-molecule array (SiMoA) and compared them with 53 healthy controls (HCs). We performed multivariable regression to analyse the association between sNfL levels and functional outcome at 1 year. RESULTS: Patients with GBS had higher NfL levels than HC in serum (55.49 pg/mL vs 9.83 pg/mL, p<0.0001) and CSF (1308.5 pg/mL vs 440.24 pg/mL, p=0.034). Patients with preceding diarrhoea had higher sNfL than patients with respiratory symptoms or no preceding infection (134.90 pg/mL vs 47.86 pg/mL vs 38.02 pg/mL, p=0.016). sNfL levels correlated with Guillain-Barré Syndrome Disability Score and Inflammatory Rasch-built Overall Disability Scale (I-RODS) at every timepoint. Patients with pure motor variant and Miller Fisher syndrome showed higher sNfL levels than patients with sensorimotor GBS (162.18 pg/mL vs 95.50 pg/mL vs 38.02 pg/mL, p=0.025). Patients with acute motor axonal neuropathy cute motor axonal neuropathy had higher sNfL levels than other variants (190.55 pg/mL vs 46.79 pg/mL, p=0.013). sNfL returned to normal levels at 1 year. High baseline sNfL levels were associated with inability to run (OR=1.65, 95% CI 1.14 to 2.40, p=0.009) and lower I-RODS (ß -2.60, 95% CI -4.66 to -0.54, p=0.014) at 1 year. Cut-off points predicting clinically relevant outcomes at 1 year with high specificity were calculated: inability to walk independently (>319 pg/mL), inability to run (>248 pg/mL) and ability to run (<34 pg/mL). CONCLUSION: Baseline sNfL levels are increased in patients with GBS, are associated with disease severity and axonal variants and have an independent prognostic value in patients with GBS.

Search for Reliable Circulating Biomarkers to Predict Carotid Plaque Vulnerability.

Atherosclerosis is responsible for 20% of ischemic strokes, and the plaques from the internal carotid artery the most frequently involved. Lipoproteins play a key role in carotid atherosclerosis since lipid accumulation contributes to plaque progression and chronic inflammation, both factors leading to plaque vulnerability. Carotid revascularization to prevent future vascular events is reasonable in some patients with high-grade carotid stenosis. However, the degree of stenosis alone is not sufficient to decide upon the best clinical management in some situations. In this context, it is essential to further characterize plaque vulnerability, according to specific characteristics (lipid-rich core, fibrous cap thinning, intraplaque hemorrhage). Although these features can be partly detected by imaging techniques, identifying carotid plaque vulnerability is still challenging. Therefore, the study of circulating biomarkers could provide adjunctive criteria to predict the risk of atherothrombotic stroke. In this regard, several molecules have been found altered, but reliable biomarkers have not been clearly established yet. The current review discusses the concept of vulnerable carotid plaque, and collects existing information about putative circulating biomarkers, being particularly focused on lipid-related and inflammatory molecules.