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Following ischemic stroke, substance P (SP)-mediated neurogenic inflammation is associated with profound blood-brain barrier (BBB) dysfunction, cerebral edema, and elevated intracranial pressure (ICP). SP elicits its effects by binding the neurokinin 1 tachykinin receptor (NK1-R), with administration of an NK1-R antagonist shown to ameliorate BBB dysfunction and cerebral edema in rodent and permanent ovine stroke models. Given the importance of reperfusion in clinical stroke, this study examined the efficacy of NK1-R antagonist treatment in reducing cerebral edema and ICP in an ovine model of transient middle cerebral artery occlusion (tMCAo). Anesthetized sheep ( n =  24) were subject to 2-hours tMCAo and randomized ( n =  6/group) to receive early NK1-R treatment (days 1-3 post-stroke), delayed NK1-R treatment (day 5 post-stroke), or saline vehicle. At 6-days post-stroke animals were re-anaesthetized and ICP measured, followed by MRI to evaluate infarction, edema and BBB dysfunction. Following both early and delayed NK1-R antagonist administration, ICP was significantly reduced on day 6 compared to vehicle animals (p < 0.05), accompanied by a reduction in cerebral edema, midline shift and BBB dysfunction (p < 0.05). This study demonstrates that NK1-R antagonist treatment is an effective novel therapy for cerebral edema and elevated ICP following stroke in an ovine model, warranting future clinical evaluation., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The NK1-R antagonist drug (EU-C-001) was kindly donated by PresSura Neuro, however, they had no input in the experimental design, conduct of the study, nor data analysis.

Background: Cerebral edema is a secondary complication of acute ischemic stroke, but its time course and imaging markers are not fully understood. Recently, net water uptake (NWU) has been proposed as a novel marker of edema., Aims: Studying the RHAPSODY trial cohort, we sought to characterize the time course of edema and test the hypothesis that NWU provides distinct information when added to traditional markers of cerebral edema after stroke by examining its association with other markers., Methods: A total of 65 patients had measurable supratentorial ischemic lesions. Patients underwent head computed tomography (CT), brain magnetic resonance imaging (MRI) scans, or both at the baseline visit and after 2, 7, 30, and 90 days following enrollment. CT and MRI scans were used to measure four imaging markers of edema: midline shift (MLS), hemisphere volume ratio (HVR), cerebrospinal fluid (CSF) volume, and NWU using semi-quantitative threshold analysis. Trajectories of the markers were summarized, as available. Correlations of the markers of edema were computed and the markers compared by clinical outcome. Regression models were used to examine the effect of 3K3A-activated protein C (APC) treatment., Results: Two measures of mass effect, MLS and HVR, could be measured on all imaging modalities, and had values available across all time points. Accordingly, mass effect reached a maximum level by day 7, normalized by day 30, and then reversed by day 90 for both measures. In the first 2 days after stroke, the change in CSF volume was associated with MLS (ρ = -0.57, p  = 0.0001) and HVR (ρ = -0.66, p  < 0.0001). In contrast, the change in NWU was not associated with the other imaging markers (all p  ⩾ 0.49). While being directionally consistent, we did not observe a difference in the edema markers by clinical outcome. In addition, baseline stroke volume was associated with all markers (MLS ( p  < 0.001), HVR ( p  < 0.001), change in CSF volume ( p  = 0.003)) with the exception of NWU ( p  = 0.5). Exploratory analysis did not reveal a difference in cerebral edema markers by treatment arm., Conclusions: Existing cerebral edema imaging markers potentially describe two distinct processes, including lesional water concentration (i.e. NWU) and mass effect (MLS, HVR, and CSF volume). These two types of imaging markers may represent distinct aspects of cerebral edema, which could be useful for future trials targeting this process., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: TPD and JHG are consultants to ZZ Biotech, LLC. BVZ is scientific founder of ZZ Biotech LLC and chairs its Scientific Advisory Board. WTK reports research grants from Biogen, consulting fees from NControl Therapeutics, and equity in Woolsey Pharmaceuticals. All other authors report no conflicts of interest.

Several metabolite markers are independently associated with incident ischemic stroke. However, prior studies have not accounted for intercorrelated metabolite networks. We used exploratory factor analysis (EFA) to determine if metabolite factors were associated with incident ischemic stroke. Metabolites (n = 162) were measured in a case-control cohort nested in the REasons for Geographic and Racial Differences in Stroke (REGARDS) study, which included 1,075 ischemic stroke cases and 968 random cohort participants. Cox models were adjusted for age, gender, race, and age-race interaction (base model) and further adjusted for the Framingham stroke risk factors (fully adjusted model). EFA identified fifteen metabolite factors, each representing a well-defined metabolic pathway. Of these, factor 3, a gut microbiome metabolism factor, was associated with an increased risk of stroke in the base (hazard ratio per one-unit standard deviation, HR = 1.23; 95%CI = 1.15-1.31; P = 1.98 × 10 -10 ) and fully adjusted models (HR = 1.13; 95%CI = 1.06-1.21; P = 4.49 × 10 -4 ). The highest tertile had a 45% increased risk relative to the lowest (HR = 1.45; 95%CI = 1.25-1.70; P = 2.24 × 10 -6 ). Factor 3 was also associated with the Southern diet pattern, a dietary pattern previously linked to increased stroke risk in REGARDS (β = 0.11; 95%CI = 0.03-0.18; P = 8.75 × 10 -3 ). These findings highlight the role of diet and gut microbial metabolism in relation to incident ischemic stroke.

Background: Time-dependent change in the level of biomarkers after stroke is not well understood. We sought to compare fatty acid-binding protein 4 (FABP4), Galectin-3, and soluble ST2 to ascertain for a change in prediction of outcome at admission and 48 h later., Methods: Plasma FABP4, Galectin-3, and soluble ST2 were measured in biospecimens from acute stroke patients at the time of admission ( n  = 383) and 48 h later ( n  = 244). Functional outcome was assessed at 90 days using the modified Rankin Scale and dichotomized into good (modified Rankin Scale 0-2) and poor outcome (modified Rankin Scale 3-6)., Results: On admission, elevated levels of each biomarker predicted poor outcome (FABP4: OR 1.92, 95% CI 1.42-2.59, P  < 0.0001; Galectin-3: OR 1.85, 95% CI 1.42-2.40, P  < 0.0001; soluble ST2: OR 1.55, 95% CI 1.22-1.97, P  < 0.0001) and death (FABP4: OR 2.45; 95% CI 1.51-3.98; P  < 0.0001; Galectin-3: OR 2.12; 95% CI 1.50-3.30; P  < 0.0001; soluble ST2: OR 2.17; 95% CI 1.58-2.99; P  < 0.0001). At 48 h, soluble ST2 predicted poor outcome (OR 2.62, 95% CI 1.77-3.88, P  < 0.0001) and mortality (OR 3.36, 95% CI 2.06-5.48, P  < 0.0001), and Galectin-3 predicted mortality only (OR 1.81, 95% CI 1.05-3.10, P  = 0.033). FABP4 measured at 48 h was not predictive of outcome or death. Associations of Galectin-3 and soluble ST2 with outcome or mortality were independent of age, sex, and NIHSS, whereas those with FABP4 were not., Conclusions: Galectin-3 performed better when measured on admission, whereas soluble ST2 was predictive at admission and better at 48 h after stroke. The time-dependent differences may reflect the evolving role of these pathways after acute stroke.

Rapid revascularization is highly effective for acute stroke, but animal studies suggest that reperfusion edema may attenuate its beneficial effects. We investigated the relationship between reperfusion and edema in patients from the Echoplanar Imaging Thrombolysis Evaluation Trial (EPITHET) and Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE) cohorts. Reperfusion percentage was measured as the difference in perfusion-weighted imaging lesion volume between baseline and follow-up (day 3-5 for EPITHET; day 6-8 for MR RESCUE). Midline shift (MLS) and swelling volume were quantified on follow-up MRI. We found that reperfusion was associated with less MLS (EPITHET: Spearman ρ = -0.46; P < 0.001, and MR RESCUE: Spearman ρ = -0.49; P < 0.001) and lower swelling volume (EPITHET: Spearman ρ = -0.56; P < 0.001, and MR RESCUE: Spearman ρ = -0.27; P = 0.026). Multivariable analyses performed in EPITHET and MR RESCUE demonstrated that reperfusion independently predicted both less MLS (ß coefficient = -0.056; P = 0.025, and ß coefficient = -0.38; P = 0.028, respectively) and lower swelling volumes (ß coefficient = -4.7; P = 0.007, and ß coefficient = -10.7; P = 0.009, respectively), after adjusting for age, sex, NIHSS, admission glucose and follow-up lesion size. Taken together, our data suggest that even modest improvement in perfusion is associated with less brain edema in EPITHET and MR RESCUE.

Hyperglycemia is a common complication after ischemic stroke, but its link to worse outcome is not well understood. We hypothesized that hyperglycemia may reflect an impaired metabolic response that is associated with worse cytotoxic brain injury. We performed retrospective analysis of magnetic resonance imaging from a cohort of acute ischemic stroke patients prospectively collected from 2006 to 2010 with baseline demographic and laboratory data as well as three-month outcomes. The severity of cytotoxic injury was quantified in vivo using apparent diffusion coefficient imaging by measuring the signal intensity within the stroke relative to the normal signal intensity of the contralateral hemisphere. Both hyperglycemia and lower apparent diffusion coefficient signal were associated with worse outcome after ischemic stroke (OR 0.239, p = 0.017; OR 1.11, p < 0.0001, respectively). Hyperglycemia was also associated with lower apparent diffusion coefficient (r = -0.32, p < 0.001). In multivariate analysis, apparent diffusion coefficient but not hyperglycemia was associated with outcome, suggesting that cytotoxicity may mediate the effect of hyperglycemia. For interventions designed to target hyperglycemia in acute ischemic stroke, a concomitant effect on the evolution of apparent diffusion coefficient may provide insight into whether hyperglycemia leads to or reflects worse cytotoxic injury.

Background Deterioration in the National Institutes of Health Stroke Scale (NIHSS) in the early days after stroke is associated with progressive infarction, brain edema, and/or hemorrhage, leading to worse outcome. Aims We sought to determine whether a stable NIHSS score represents an adverse or favorable course. Methods Brain magnetic resonance images from a research cohort of acute ischemic stroke patients were analyzed. Using NIHSS scores at baseline and follow-up (day 3-5), patients were categorized into early neurological deterioration (ΔNIHSS ≥ 4), early neurological recovery (ΔNIHSS ≤ -4) or early neurological stability (ΔNIHSS between -3 and 3). The association between these categories and volume of infarct growth, volume of swelling, parenchymal hemorrhage, and 3-month modified Rankin Scale score were evaluated. Results Patients with early neurological deterioration or early neurological stability were less likely to be independent (modified Rankin Scale = 0-2) at 3 months compared to those with early neurological recovery ( P < 0.001). Patients with early neurological deterioration or early neurological stability were observed to have significantly greater infarct growth and swelling volumes than those with early neurological recovery ( P = 0.03; P < 0.001, respectively). Brain edema was more common than the other imaging markers investigated and was independently associated with a stable or worsening NIHSS score after adjustment for age, baseline stroke volume, infarct growth volume, presence of parenchymal hemorrhage, and reperfusion ( P < 0.0001). Conclusions Stable NIHSS score in the subacute period after ischemic stroke may not be benign and is associated with tissue injury, including infarct growth and brain edema. Early improvement is considerably more likely to occur in the absence of these factors.