Neuroprotective strategies for ischemic stroke—Future perspectives

Ischemic stroke is the main cause of death and the most common cause of acquired physical disability worldwide. Recent demographic changes increase the relevance of stroke and its sequelae. The acute treatment for stroke is restricted to causative recanalization and restoration of cerebral blood flow, including both intravenous thrombolysis and mechanical thrombectomy. Still, only a limited number of patients are eligible for these time-sensitive treatments. Hence, new neuroprotective approaches are urgently needed. Neuroprotection is thus defined as an intervention resulting in the preservation, recovery, and/or regeneration of the nervous system by interfering with the ischemic-triggered stroke cascade. Despite numerous preclinical studies generating promising data for several neuroprotective agents, successful bench-to-bedside translations are still lacking. The present study provides an overview of current approaches in the research field of neuroprotective stroke treatment. Aside from “traditional” neuroprotective drugs focusing on inflammation, cell death, and excitotoxicity, stem-cell-based treatment methods are also considered. Furthermore, an overview of a prospective neuroprotective method using extracellular vesicles that are secreted from various stem cell sources, including neural stem cells and bone marrow stem cells, is also given. The review concludes with a short discussion on the microbiota–gut–brain axis that may serve as a potential target for future neuroprotective therapies

Preconditioning concepts for the therapeutic use of extracellular vesicles against stroke

Various preclinical stroke models have demonstrated the neuroprotective effects of extracellular vesicles (EVs) obtained from several types of cells, including neurons, astrocytes, microglia, neuronal progenitor cells, bone marrow stem cells, and mesenchymal stem cells. EVs interfere with key mechanisms in stroke pathophysiology such as cell death, neuroinflammation, autophagy, and angiogenesis. The mode of action and efficacy depend on the specific EV content, including miRNAs, proteins, and lipids, which can be modified through (I) bioengineering methods, (II) choice of source cells, and (III) modification of the source cell environment. Indeed, modifying the environment by preconditioning the EV-secreting cells with oxygen-glucose deprivation or medium modification revealed superior neuroprotective effects in stroke models. Although the concept of preconditioned EVs is relatively novel, it holds promise for the future treatment of ischemic stroke. Here, we give a brief overview about the main mechanisms of EV-induced neuroprotection and discuss the current status of preconditioning concepts for EV-treatment of ischemic stroke

High-resolution magnetic resonance imaging in isolated, traumatic oculomotor nerve palsy: A case report

Traumatic, isolated oculomotor nerve palsy is a rare clinical finding and only few reports demonstrate associated magnetic resonance imaging (MRI) findings. Here, we present the case of a 70-year-old woman with left-sided oculomotor nerve palsy following a mild head trauma due to an e-bike accident. Post-traumatic cerebral computed tomography revealed punctiform hemorrhage in the left interpeduncular cistern and the following MRI confirmed an intraneural hemorrhage of the left oculomotor nerve. Nine weeks later, the follow-up MRI showed progressive atrophy and contrast-enhancement of the left oculomotor nerve. To support functional recovery, a treatment with intravenous corticosteroids was started. Six months later, the patient presented with improved oculomotor nerve function and partial recovery of ptosis and diplopia. In accordance, MRI demonstrated recurrent contrast-enhancement of the atrophic nerve. In conclusion, high-resolution MRI allows the reliable delineation of the oculomotor nerve and can support diagnosis in trauma patients with isolated oculomotor nerve palsy

Peak Troponin I Levels Are Associated with Functional Outcome in Intracerebral Hemorrhage

Background: Troponin I is a widely used and reliable marker of myocardial damage and its levels are routinely measured in acute stroke care. So far, the influence of troponin I elevations during hospital stay on functional outcome in patients with atraumatic intracerebral hemorrhage (ICH) is unknown. Methods: Observational single-center study including conservatively treated ICH patients over a 9-year period. Patients were categorized according to peak troponin I level during hospital stay (≤0.040, 0.041–0.500, > 0.500 ng/mL) and compared regarding baseline and hematoma characteristics. Multivariable analyses were performed to investigate independent associations of troponin levels during hospital stay with functional outcome – assessed using the modified Rankin Scale (mRS; favorable 0–3/unfavorable 4–6) – and mortality after 3 and 12 months. To account for possible confounding propensity score (PS)-matching (1: 1; caliper 0.1) was performed accounting for imbalances in baseline characteristics to investigate the impact of troponin I values on outcome. Results: Troponin elevations (> 0.040 ng/mL) during hospital stay were observed in 308 out of 745 (41.3%) patients and associated with poorer status on admission (Glasgow Coma Scale/National Institute of Health Stroke Scale). Multivariable analysis revealed troponin I levels during hospital stay to be independently associated with unfavorable outcome after 12 months (risk ratio [95% CI]: 1.030 [1.009–1.051] per increment of 1.0 ng/mL; p = 0.005), but not with mortality. After PS-matching, patients with troponin I elevation (≥0.040 ng/mL) versus those without had a significant higher rate of ­unfavorable outcome after 3 and 12 months (mRS 4–6 at 3 months: < 0.04 ng/mL: 159/265 [60.0%] versus ≥0.04 ng/mL: 199/266 [74.8%]; p < 0.001; at 12 months: < 0.04 ng/mL: 141/248 [56.9%] versus ≥0.04 ng/mL: 179/251 [71.3%]; p = 0.001). Conclusions: Troponin I elevations during hospital stay occur frequently in ICH patients and are independently associated with functional outcome after 3 and 12 months but not with mortality

TREM2 regulates microglial lipid droplet formation and represses post-ischemic brain injury

Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane receptor protein predominantly expressed in microglia within the central nervous system (CNS). TREM2 regulates multiple microglial functions, including lipid metabolism, immune reaction, inflammation, and microglial phagocytosis. Recent studies have found that TREM2 is highly expressed in activated microglia after ischemic stroke. However, the role of TREM2 in the pathologic response after stroke remains unclear. Herein, TREM2-deficient microglia exhibit an impaired phagocytosis rate and cholesteryl ester (CE) accumulation, leading to lipid droplet formation and upregulation of Perilipin-2 (PLIN2) expression after hypoxia. Knockdown of TREM2 results in increased lipid synthesis (PLIN2, SOAT1) and decreased cholesterol clearance and lipid hydrolysis (LIPA, ApoE, ABCA1, NECH1, and NPC2), further impacting microglial phenotypes. In these lipid droplet-rich microglia, the TGF-β1/Smad2/3 signaling pathway is downregulated, driving microglia towards a pro-inflammatory phenotype. Meanwhile, in a neuron-microglia co-culture system under hypoxic conditions, we found that microglia lost their protective effect against neuronal injury and apoptosis when TREM2 was knocked down. Under in vivo conditions, TREM2 knockdown mice express lower TGF-β1 expression levels and a lower number of anti-inflammatory M2 phenotype microglia, resulting in increased cerebral infarct size, exacerbated neuronal apoptosis, and aggravated neuronal impairment. Our work suggests that TREM2 attenuates stroke-induced neuroinflammation by modulating the TGF-β1/Smad2/3 signaling pathway. TREM2 may play a direct role in the regulation of inflammation and also exert an influence on the post-ischemic inflammation and the stroke pathology progression via regulation of lipid metabolism processes. Thus, underscoring the therapeutic potential of TREM2 agonists in ischemic stroke and making TREM2 an attractive new clinical target for the treatment of ischemic stroke and other inflammation-related diseases.National Natural Science Foundation of China ; Science and Technology Commission of Shanghai Municipality ; China Scholarship Counci

Ischemic stroke and dose adjustment of oral Factor Xa inhibitors in patients with atrial fibrillation

Abstract Background Oral Factor Xa inhibitors for the prevention of stroke in atrial fibrillation require dose adjustment based on certain clinical criteria, but the off-label use of the reduced doses is common. Methods Data from an observational registry including patients admitted with acute cerebral ischemia while taking oral Factor Xa inhibitors for atrial fibrillation between April 2016 and December 2018 were investigated. The dose regimen of the Xa inhibitor was classified as “appropriate”, “underdosed” and “overdosed” in conformity with the European Medicines Agency labelling. The effect of underdosing on the functional factor Xa plasma level on admission, the clinical stroke severity and the functional outcome after 3 months were investigated. Results 254 patients with cerebral ischemia while on Factor Xa inhibitors were included. The dose regimen of the Factor Xa inhibitor was appropriate in 166 patients (65%), underdosed in 67 patients (26%) and overdosed in 21 patients (8%). Underdosing was associated with female sex, diabetes mellitus and higher CHA2DS2–Vasc scores. Underdosing independently predicted lower anti-Xa plasma levels on admission [median 69.4 ng/ml (IQR 0.0–121.6) vs. 129.2 ng/ml (65.5–207.2); p < 0.001], was associated with higher NIHSS scores on admission [median 5 (IQR 1–10) vs. 3 (1–7); p = 0.041] and worse functional outcome after 3 months (favorable outcome 26.9% vs. 46.9%; p = 0.025). Conclusion One in three patients with ischemic stroke during treatment with oral Xa inhibitors used inappropriate dose regimens. Underdosing was associated with lower functional plasma levels, higher clinical stroke severity and worse functional outcome

Preconditioned extracellular vesicles from hypoxic microglia reduce poststroke AQP4 depolarization, disturbed cerebrospinal fluid flow, astrogliosis, and neuroinflammation

Background: Stroke stimulates reactive astrogliosis, aquaporin 4 (AQP4) depolarization and neuroinflammation. Preconditioned extracellular vesicles (EVs) from microglia exposed to hypoxia, in turn, reduce poststroke brain injury. Nevertheless, the underlying mechanisms of such effects are elusive, especially with regards to inflammation, AQP4 polarization, and cerebrospinal fluid (CSF) flow. Methods: Primary microglia and astrocytes were exposed to oxygen-glucose deprivation (OGD) injury. For analyzing the role of AQP4 expression patterns under hypoxic conditions, a co-culture model of astrocytes and microglia was established. Further studies applied a stroke model, where some mice also received an intracisternal tracer infusion of rhodamine B. As such, these in vivo studies involved the analysis of AQP4 polarization, CSF flow, astrogliosis, and neuroinflammation as well as ischemia-induced brain injury. Results: Preconditioned EVs decreased periinfarct AQP4 depolarization, brain edema, astrogliosis, and inflammation in stroke mice. Likewise, EVs promoted postischemic CSF flow and cerebral blood perfusion, and neurological recovery. Under in vitro conditions, hypoxia stimulated M2 microglia polarization, whereas EVs augmented M2 microglia polarization and repressed M1 microglia polarization even further. In line with this, astrocytes displayed upregulated AQP4 clustering and proinflammatory cytokine levels when exposed to OGD, which was reversed by preconditioned EVs. Reduced AQP4 depolarization due to EVs, however, was not a consequence of unspecific inflammatory regulation, since LPS-induced inflammation in co-culture models of astrocytes and microglia did not result in altered AQP4 expression patterns in astrocytes. Conclusions: These findings show that hypoxic microglia may participate in protecting against stroke-induced brain damage by regulating poststroke inflammation, astrogliosis, AQP4 depolarization, and CSF flow due to EV release

Peak Troponin I Levels Are Associated with Functional Outcome in Intracerebral Hemorrhage

Background: Troponin I is a widely used and reliable marker of myocardial damage and its levels are routinely measured in acute stroke care. So far, the influence of troponin I elevations during hospital stay on functional outcome in patients with atraumatic intracerebral hemorrhage (ICH) is unknown. Methods: Observational single-center study including conservatively treated ICH patients over a 9-year period. Patients were categorized according to peak troponin I level during hospital stay (≤0.040, 0.041–0.500, > 0.500 ng/mL) and compared regarding baseline and hematoma characteristics. Multivariable analyses were performed to investigate independent associations of troponin levels during hospital stay with functional outcome – assessed using the modified Rankin Scale (mRS; favorable 0–3/unfavorable 4–6) – and mortality after 3 and 12 months. To account for possible confounding propensity score (PS)-matching (1: 1; caliper 0.1) was performed accounting for imbalances in baseline characteristics to investigate the impact of troponin I values on outcome. Results: Troponin elevations (> 0.040 ng/mL) during hospital stay were observed in 308 out of 745 (41.3%) patients and associated with poorer status on admission (Glasgow Coma Scale/National Institute of Health Stroke Scale). Multivariable analysis revealed troponin I levels during hospital stay to be independently associated with unfavorable outcome after 12 months (risk ratio [95% CI]: 1.030 [1.009–1.051] per increment of 1.0 ng/mL; p = 0.005), but not with mortality. After PS-matching, patients with troponin I elevation (≥0.040 ng/mL) versus those without had a significant higher rate of ­unfavorable outcome after 3 and 12 months (mRS 4–6 at 3 months: < 0.04 ng/mL: 159/265 [60.0%] versus ≥0.04 ng/mL: 199/266 [74.8%]; p < 0.001; at 12 months: < 0.04 ng/mL: 141/248 [56.9%] versus ≥0.04 ng/mL: 179/251 [71.3%]; p = 0.001). Conclusions: Troponin I elevations during hospital stay occur frequently in ICH patients and are independently associated with functional outcome after 3 and 12 months but not with mortality

Functional Long-Term Outcome after Left- versus Right-Sided Intracerebral Hemorrhage

Background and Purpose: Hemispheric location might influence outcome after intracerebral hemorrhage (ICH). INTERACT suggested higher short-term mortality in right hemispheric ICH, yet statistical imbalances were not addressed. This study aimed at determining the differences in long-term functional outcome in patients with right- vs. left-sided ICH with a priori-defined sub-analysis of lobar vs. deep bleedings. Methods: Data from a prospective hospital registry were analyzed including patients with ICH admitted between January 2006 and August 2014. Data were retrieved from institutional databases. Outcome was assessed using the modified Rankin Scale (mRS) score. Outcome measures (long-term mortality and functional outcome at 12 months) were correlated with ICH location and hemisphere, and the imbalances of baseline characteristics were addressed by propensity score matching. Results: A total of 831 patients with supratentorial ICH (429 left and 402 right) were analyzed. Regarding clinical baseline characteristics in the unadjusted overall cohort, there were differences in disfavor of right-sided ICH (antiplatelets: 25.2% in left ICH vs. 34.3% in right ICH; p < 0.01; previous ischemic stroke: 14.7% in left ICH vs. 19.7% in right ICH; p = 0.057; and presence/extent of intraventricular hemorrhage: 45.0% in left ICH vs. 53.0% in right ICH; p = 0.021; Graeb-score: 0 [0-4] in left ICH vs. 1 [0-5] in right ICH; p = 0.017). While there were no differences in mortality and in the proportion of patients with favorable vs. unfavorable outcome (mRS 0-3: 142/375 [37.9%] in left ICH vs. 117/362 [32.3%] in right ICH; p = 0.115), patients with left-sided ICH showed excellent outcome more frequently (mRS 0-1: 64/375 [17.1%] in left ICH vs. 43/362 [11.9%] in right ICH; p = 0.046) in the unadjusted analysis. After adjusting for confounding variables, a well-balanced group of patients (n = 360/hemisphere) was compared showing no differences in long-term functional outcome (mRS 0-3: 36.4% in left ICH vs. 33.9% in right ICH; p = 0.51). Sub-analyses of patients with deep vs. lobar ICH revealed also no differences in outcome measures (mRS 0-3: 53/151 [35.1%] in left deep ICH vs. 53/165 [32.1%] in right deep ICH; p = 0.58). Conclusion: Previously described differences in clinical end points among patients with left- vs. right-hemispheric ICH may be driven by different baseline characteristics rather than by functional deficits emerging from different hemispheric functions affected. After statistical corrections for confounding variables, there was no impact of hemispheric location on functional outcome after ICH

Influence of Early Enteral Nutrition on Clinical Outcomes in Neurocritical Care Patients With Intracerebral Hemorrhage

Objective: Early enteral nutrition (EEN) represents the current standard of care for patients treated in general intensive care units (ICU). Specific nutritional recommendations for patients receiving dedicated neurocritical care are not established. This study investigated associations of EEN with clinical outcomes for patients suffering from intracerebral hemorrhage treated at a neurological ICU (NICU). Methods: This retrospective cohort study included patients admitted to the NICU with atraumatic ICH over a 4-year period. Nutritional data, demographic, clinical, radiological, and laboratory characteristics were assessed. EEN was defined as any enteral nutrition within 48 hours after admission. Comparisons were undertaken for patients with EEN vs. those without, further propensity score (PS) matching (caliper 0.2; one: many) was used to account for baseline imbalances. Primary outcome was the modified Rankin Scale (0–3 = favorable, 4–6 = unfavorable) at 12 months, secondary outcomes comprised perihemorrhagic edema (PHE) volume, infectious complications during the hospital stay, and mRS at 3 months, as well as mortality rates at 3 and 12 months. Results: Of 166 ICH-patients treated at the NICU, 51 (30.7%) patients received EEN, and 115 (69.3%) patients received no EEN (nEEN). After propensity score matching, calories delivered from enteral nutrition (EEN 161.4 [106.4–192.3] kcal/day vs. nEEN 0.0 [0.0–0.0], P < 0.001) and the total calories (EEN 190.0 [126.0–357.0] kcal/day vs. nEEN 33.6 [0.0–190.0] kcal/day, P < 0.001) were significantly different during the first 48 h admitted in NICU. Functional outcome at 12 months (mRS 4–6, EEN 33/43 [76.7%] vs. nEEN, 49/64 [76. 6%]; P = 1.00) was similar in the two groups. There were neither differences in mRS at 3 months, nor in mortality rates at 3 and 12 months between the two groups. EEN did not affect incidence of infective complications or gastrointestinal adverse events during the hospital stay; however, EEN was associated with significantly less extent of PHE evolution [maximum absolute PHE (OR 0.822, 95% CI 0.706–0.957, P = 0.012); maximum relative PHE (OR 0.784, 95% CI 0.646–0.952, P = 0.014)]. Conclusion: In our study, EEN was associated with reduced PHE in ICH-patients treated at a NICU. However, this observation did not translate into improved survival or functional outcome at 3 and 12 months