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Rationale: Oxygen is essential for cellular energy metabolism. Neurons are particularly vulnerable to hypoxia. Increasing oxygen supply shortly after stroke onset could preserve the ischemic penumbra until revascularization occurs. Aims: PROOF investigates the use of normobaric oxygen (NBO) therapy within 6 h of symptom onset/notice for brain-protective bridging until endovascular revascularization of acute intracranial anterior-circulation occlusion. Methods and design: Randomized (1:1), standard treatment-controlled, open-label, blinded endpoint, multicenter adaptive phase IIb trial. Study outcomes: Primary outcome is ischemic core growth (mL) from baseline to 24 h (intention-to-treat analysis). Secondary efficacy outcomes include change in NIHSS from baseline to 24 h, mRS at 90 days, cognitive and emotional function, and quality of life. Safety outcomes include mortality, intracranial hemorrhage, and respiratory failure. Exploratory analyses of imaging and blood biomarkers will be conducted. Sample size: Using an adaptive design with interim analysis at 80 patients per arm, up to 456 participants (228 per arm) would be needed for 80% power (one-sided alpha 0.05) to detect a mean reduction of ischemic core growth by 6.68 mL, assuming 21.4 mL standard deviation. Discussion: By enrolling endovascular thrombectomy candidates in an early time window, the trial replicates insights from preclinical studies in which NBO showed beneficial effects, namely early initiation of near 100% inspired oxygen during short temporary ischemia. Primary outcome assessment at 24 h on follow-up imaging reduces variability due to withdrawal of care and early clinical confounders such as delayed extubation and aspiration pneumonia. Trial registrations: ClinicalTrials.gov: NCT03500939; EudraCT: 2017-001355-31. [ABSTRACT FROM AUTHOR]

Background and aims: Increased risk of stroke, particularly large artery stroke (LAS), has been observed in patients with COVID-19. The biological processes underlying the observed higher risk are still unknown. We explored the association between stroke subtypes and COVID-19 susceptibility to understand whether biological mechanisms specific to SARS-CoV-2 uptake/infection could be leading to excess stroke risk in this population. Patients and methods: We constructed a polygenic risk score (PRS) of COVID-19 susceptibility and tested its association with stroke subtypes using individual- and summary-level genetic data (SiGN, MEGASTROKE). We generated co-expression networks of genes involved in SARS-CoV-2 uptake/infection (ACE2, TMPRSS2, BEST3, ISLR2 and ADAM17) based on existing tissue expression libraries. Gene-based association testing was performed using S-PrediXcan and VEGAS2. Permutation independence tests were performed to assess SARS-CoV-2-related gene enrichment in stroke and its subtypes. Results: Our PRS demonstrated an association between COVID-19 susceptibility and LAS in SiGN (OR = 1.05 per SD increase, 95% CI: (1.00, 1.10), p = 0.04) and MEGASTROKE (β = 0.510, 95% CI: (0.242, 0.779), FDR-p = 0.0019). The SARS-CoV-2 risk-related ISLR2 co-expression gene network was significantly associated with genetic risk of LAS in aorta, tibial arteries, and multiple brain regions (P < 0.05). Conclusion: Presence of genetic correlation and significant pathway enrichment suggest that increases in LAS risk reported in COVID-19 patients may be intrinsic to the viral infection, rather than a more generalized response to severe illness. [ABSTRACT FROM AUTHOR]

Rationale About 20% of stroke patients develop dementia within a few months after their event, but the determinants and mechanisms of poststroke dementia are insufficiently understood. Aims To identify and characterize the determinants of cognitive impairment poststroke. Design Observational prospective study in patients with acute stroke and no prior dementia. Six hundred subjects will be characterized by detailed interview, standardized clinical examinations, biometric measures (intima-media thickness, waist-hip ratio, and ankle-brachial index), multimodal imaging (magnetic resonance imaging, fluorodeoxyglucose-positron emission tomography ( FDG-PET), amyloid-positron emission tomography (amyloid- PET), and retinal imaging), analysis of biomarkers derived from blood and cerebrospinal fluid, and detailed cognitive testing at repeat time points. Patients will be followed for five-years with a total of five personal visits and three telephone interviews. Study Outcomes Primary end-point is the occurrence of poststroke dementia. Secondary end-points include poststroke cognitive impairment-no dementia, stroke recurrence, and death. Predictive factors for poststroke dementia will be identified by multiple Cox proportional-hazards model. Results Baseline characteristics of the first 71 patients (study inclusion between May 2011 and August 2012) are as follows: median age, 70 years (interquartile range, 65-75); female gender, 25 (35%); median National Institutes of Health Stroke Scale at admission, 2 (1-4); and etiological stroke subtypes according to TOAST classification, 15% large artery disease, 18% small vessel disease, 35% cardioembolic, and 32% undetermined or multiple competing etiologies. Discussion This study will provide insights into the mechanisms of poststroke dementia and hold the potential to identify novel diagnostic markers and targets for preventive therapies. The study is registered at ( NCT01334749) and will be extended as a multicenter study starting 2013. [ABSTRACT FROM AUTHOR]

Rationale Long-term risk of vascular disease is substantially increased after stroke with several models proposed to predict subsequent stroke and other vascular events after an index event. However, recent validation studies demonstrate limited predictive properties of available prognostic models. Aims We aim to determine prediction models of different complexity for the combined vascular end-point of stroke, myocardial infarction, and vascular death at three-years after first-ever stroke. An independent external validation of the developed models will be performed. Design Prospective observational hospital-based cohort study of patients after first-ever stroke. Methods The new predictive models will be developed using the following steps: (1) Development of a basic score based on clinical history data (e.g. hypertension, myocardial infarction, and atrial fibrillation); (2) Development of an advanced score including additional factors such as blood-based biomarkers and results of vascular imaging; (3) Comparing the models fit using different methods (discrimination, calibration); (4) Assessment of clinical utility of an advanced score using methods based on reclassification tables (e.g. net reclassification improvement, integrated discrimination improvement, decision curve analysis); and (5) Investigation of external validity. Outcomes Primary outcome is a combined vascular end-point composed of stroke, myocardial infarction, and vascular death at three-years after stroke. Furthermore, each component of the composite end-point will be investigated individually and the patterns and time points of risk transitions between vascular end-points and stroke sub-types will be determined. [ABSTRACT FROM AUTHOR]

Background and aims Acute occlusions of the large intracranial arteries are relatively resistant to intravenous thrombolysis. Therefore, multimodal approaches combining intravenous thrombolysis with endovascular mechanical recanalization are increasingly being applied. In this setting, intravenous thrombolysis may facilitate subsequent mechanical thrombectomy. To test this hypothesis, we analyzed the influence of intravenous thrombolysis on net intervention time in subsequent endovascular mechanical recanalization. Methods In this retrospective single-center analysis, we compared net intervention time with and without preceding intravenous thrombolysis in patients treated by endovascular mechanical recanalization between 01/2003 and 06/2010. The net intervention time was defined as the interval between the onset of endovascular thrombus manipulation and successful vessel recanalization. Results We identified 65 eligible patients, 35 of whom were treated by intravenous thrombolysis before mechanical therapy. Recanalization was achieved in 26 patients with (74%) and 23 patients without preceding intravenous thrombolysis (77%). In the case of successful recanalization, the net intervention time was significantly shorter in patients with preceding intravenous thrombolysis (24·8 ± 22·8 vs. 44·2 ± 40·5 min; P<0·05). This difference remained significant after restricting the analysis to the patients treated by the Penumbra Stroke System© ( n=32). After three-months, patients with preceding intravenous thrombolysis were more likely to be functionally independent (modified Rankin Scale≤2) than those without ( P<0·05). Conclusions Our findings suggest that preceding intravenous thrombolysis may reduce the intervention time in patients treated by endovascular mechanical recanalization. However, due to the retrospective design of our study, these findings have to be interpreted with caution and need confirmation in a larger patient population. [ABSTRACT FROM AUTHOR]

A letter to the editor regarding effect of statins on cerebral perfusion in patients with leukoaraiosis is presented.