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Reciprocal interactions between neurons and oligodendrocytes are not only crucial for myelination, but also for long-term survival of axons. Degeneration of axons occurs in several human myelin diseases, however the molecular mechanisms of axon-glia communication maintaining axon integrity are poorly understood. Here, we describe the signal-mediated transfer of exosomes from oligodendrocytes to neurons. These endosome-derived vesicles are secreted by oligodendrocytes and carry specific protein and RNA cargo. We show that activity-dependent release of the neurotransmitter glutamate triggers oligodendroglial exosome secretion mediated by Ca²⁺ entry through oligodendroglial NMDA and AMPA receptors. In turn, neurons internalize the released exosomes by endocytosis. Injection of oligodendroglia-derived exosomes into the mouse brain results in functional retrieval of exosome cargo in neurons. Supply of cultured neurons with oligodendroglial exosomes improves neuronal viability under conditions of cell stress. These findings indicate that oligodendroglial exosomes participate in a novel mode of bidirectional neuron-glia communication contributing to neuronal integrity.

Mechanisms underlying central neuropathic pain are poorly understood. Although glial dysfunction has been functionally linked with neuropathic pain, very little is known about modulation of pain by oligodendrocytes. Here we report that genetic ablation of oligodendrocytes rapidly triggers a pattern of sensory changes that closely resemble central neuropathic pain, which are manifest before overt demyelination. Primary oligodendrocyte loss is not associated with autoreactive T- and B-cell infiltration in the spinal cord and neither activation of microglia nor reactive astrogliosis contribute functionally to central pain evoked by ablation of oligodendrocytes. Instead, light and electron microscopic analyses reveal axonal pathology in the spinal dorsal horn and spinothalamic tract concurrent with the induction and maintenance of nociceptive hypersensitivity. These data reveal a role for oligodendrocytes in modulating pain and suggest that perturbation of oligodendrocyte functions that maintain axonal integrity can lead to central neuropathic pain independent of immune contributions. Whether oligodendrocytes have a role in the development of chronic pain is not clear. Here the authors show that oligodendrocyte depletion causes a neuropathic pain that sets in before demyelination and is independent of immune cell activation and infiltration.

It is widely thought that demyelination contributes to the degeneration of axons and, in combination with acute inflammatory injury, is responsible for progressive axonal loss and persistent clinical disability in inflammatory demyelinating disease. In this study we sought to characterize the relationship between demyelination, inflammation and axonal transport changes using a Plp1 ‐transgenic mouse model of Pelizaeus‐Merzbacher disease. In the optic pathway of this non‐immune mediated model of demyelination, myelin loss progresses from the optic nerve head towards the brain, over a period of months. Axonal transport is functionally perturbed at sites associated with local inflammation and ‘damaged’ myelin. Surprisingly, where demyelination is complete, naked axons appear well preserved despite a significant reduction of axonal transport. Our results suggest that neuroinflammation and/or oligodendrocyte dysfunction are more deleterious for axonal health than demyelination per se , at least in the short term.

Cervical artery dissection is a major cause of stroke in young people (aged <50 years). Historically, clinicians have preferred using oral anticoagulation with vitamin K antagonists for patients with cervical artery dissection, although some current guidelines—based on available evidence from mostly observational studies—suggest using aspirin. If proven to be non-inferior to vitamin K antagonists, aspirin might be preferable, due to its ease of use and lower cost. We aimed to test the non-inferiority of aspirin to vitamin K antagonists in patients with cervical artery dissection. We did a multicentre, randomised, open-label, non-inferiority trial in ten stroke centres across Switzerland, Germany, and Denmark. We randomly assigned (1:1) patients aged older than 18 years who had symptomatic, MRI-verified, cervical artery dissection within 2 weeks before enrolment, to receive either aspirin 300 mg once daily or a vitamin K antagonist (phenprocoumon, acenocoumarol, or warfarin; target international normalised ratio [INR] 2·0–3·0) for 90 days. Randomisation was computer-generated using an interactive web response system, with stratification according to participating site. Independent imaging core laboratory adjudicators were masked to treatment allocation, but investigators, patients, and clinical event adjudicators were aware of treatment allocation. The primary endpoint was a composite of clinical outcomes (stroke, major haemorrhage, or death) and MRI outcomes (new ischaemic or haemorrhagic brain lesions) in the per-protocol population, assessed at 14 days (clinical and MRI outcomes) and 90 days (clinical outcomes only) after commencing treatment. Non-inferiority of aspirin would be shown if the upper limit of the two-sided 95% CI of the absolute risk difference between groups was less than 12% (non-inferiority margin). This trial is registered with ClinicalTrials.gov, NCT02046460. Between Sept 11, 2013, and Dec 21, 2018, we enrolled 194 patients; 100 (52%) were assigned to the aspirin group and 94 (48%) were assigned to the vitamin K antagonist group. The per-protocol population included 173 patients; 91 (53%) in the aspirin group and 82 (47%) in the vitamin K antagonist group. The primary endpoint occurred in 21 (23%) of 91 patients in the aspirin group and in 12 (15%) of 82 patients in the vitamin K antagonist group (absolute difference 8% [95% CI −4 to 21], non-inferiority p=0·55). Thus, non-inferiority of aspirin was not shown. Seven patients (8%) in the aspirin group and none in the vitamin K antagonist group had ischaemic strokes. One patient (1%) in the vitamin K antagonist group and none in the aspirin group had major extracranial haemorrhage. There were no deaths. Subclinical MRI outcomes were recorded in 14 patients (15%) in the aspirin group and in 11 patients (13%) in the vitamin K antagonist group. There were 19 adverse events in the aspirin group, and 26 in the vitamin K antagonist group. Our findings did not show that aspirin was non-inferior to vitamin K antagonists in the treatment of cervical artery dissection. Swiss National Science Foundation, Swiss Heart Foundation, Stroke Funds Basel, University Hospital Basel, University of Basel, Academic Society Basel.

Introduction: Extracranial internal carotid artery dissection (eICAD) is a leading cause of stroke in younger patients. In this Cochrane Review update we compared benefits and harms of eICAD-patients treated with either antiplatelets or anticoagulants. Patients and methods: Eligible studies were identified through Cochrane Stroke Group Trials Register, CENTRAL, MEDLINE, and EMBASE and personal search until December 2023. We included randomized-controlled trials (RCTs) and non-randomized studies comparing anticoagulants with antiplatelets in eICAD-patients. Co-primary outcomes were (i) death (all causes) and (ii) death or disability. Secondary outcomes were ischemic stroke, symptomatic intracranial hemorrhage, and major extracranial hemorrhage. Odds ratios (OR) with 95% CIs were calculated for (i) all studies and (ii) separately for RCTs and non-randomized studies. Results: We meta-analyzed a total of 42 studies (2624 patients) including 2 RCTs (213 patients) for the primary outcome of death and 31 studies (1953 patients) including 1 RCT (115 patients) for the primary outcome of death or disability. Antiplatelet-treated patients had higher odds for death (ORall-studies 2.70, 95% CI 1.27–5.72; ORRTCs 6.80, 95% CI 0.14–345; ORnon-randomized studies 2.60, 95% CI 1.20–5.60) and death or disability (ORall-studies 2.1, 95% CI 1.58–2.66; ORRTCs 2.2, 95% CI 0.29–16.05; ORnon-randomized studies 2.1, 95% CI 1.58–2.66) than anticoagulated patients. Antiplatelet-treated patients had also higher odds for ischemic stroke, though this reached statistical significance only in the subgroup of RCTs (ORRTC 4.60, 95% CI 1.36–15.51). In turn, antiplatelet-treated patients had less symptomatic intracranial hemorrhage (ORall-studies 0.25, 95% CI 0.07–0.86) and a tendency toward less major extracranial hemorrhage (ORall-studies 0.17, 95% CI 0.03–1.03). Discussion and conclusion: The evidence considering antiplatelets as standard of care in eICAD is weak. Individualized treatment decisions balancing risks versus harms seem recommendable. Graphical abstract

Abstract Background and aims Timely treatment is crucial to improve stroke outcomes, yet prehospital and in-hospital delays remain significant challenges. Telestroke prehospital triage using real-time video communication between emergency medical services (EMS) personnel and hospital-based stroke physicians may expedite stroke care workflows. We assessed whether telestroke implementation reduces workflow times in patients undergoing endovascular treatment (EVT). Methods Prospective single-center cohort study in Basel, Switzerland. Individuals with suspected large vessel occlusion (LVO) were assessed via a live video link between EMS and a neurologist using the RACE-Score, a 5-item scale evaluating facial palsy, arm and leg motor function, head and gaze deviation, aphasia or agnosia. Patients were managed according to an established prenotification protocol that alerted all teams involved and allowed preparation of the angio suite before arrival. Telestroke cases were compared with propensity score-matched controls from the Swiss Stroke Registry. Results 132 patients undergoing thrombectomy were included (44 telestroke, median age 81.5 years, 21% female; 88 matched controls). Nineteen patients (10.9%) received bridging thrombolysis. Median door-to-puncture-time was significantly shorter in the telestroke group than in controls (65.5 [51.8-82.8] vs 85 [73.2-102.5] minutes; p = 0.001), while door-to-needle times were comparable (35 [30.0-43.5] vs 37 [51.8-82.8] minutes). No increase in onset-to-arrival time was observed. Conclusions Telestroke triage appears to reduce door-to-puncture times in LVO patients undergoing EVT without extending prehospital delays. These findings suggest telestroke could improve stroke workflow efficiency and expedite access to EVT, though further research is needed to assess its impact on clinical outcome and healthcare resources. Conflict of interest Sebastian Thilemann: nothing to disclose.

Background: Data on the impact of competing stroke etiologies in stroke patients with atrial fibrillation (AF) are scarce. Methods: We used prospectively obtained data from an observational registry (Novel-Oral-Anticoagulants-in-Ischemic-Stroke-Patients-(NOACISP)-LONGTERM) of consecutive AF-stroke patients treated with oral anticoagulants. We compared the frequency of (i) the composite outcome of recurrent ischemic stroke (IS), intracerebral hemorrhage (ICH) or all-cause death as well as (ii) recurrent IS alone among AF-stroke patients with versus without competing stroke etiologies according to the TOAST classification. We performed cox proportional hazards regression modeling adjusted for potential confounders. Furthermore, the etiology of recurrent IS was assessed. Results: Among 907 patients (median age 81, 45.6% female), 184 patients (20.3%) had competing etiologies, while 723 (79.7%) had cardioembolism as the only plausible etiology. During 1587 patient-years of follow-up, patients with additional large-artery atherosclerosis had higher rates of the composite outcome (adjusted HR [95% CI] 1.64 [1.11, 2.40], p = 0.017) and recurrent IS (aHR 2.96 [1.65, 5.35 ], p < 0.001), compared to patients with cardioembolism as the only plausible etiology. Overall 71 patients had recurrent IS (7.8%) of whom 26.7% had a different etiology than the index IS with large-artery-atherosclerosis (19.7%) being the most common non-cardioembolic cause. Conclusion: In stroke patients with AF, causes other than cardioembolism as competing etiologies were common in index or recurrent IS. Concomitant presence of large-artery-atherosclerosis seems to indicate an increased risk for recurrences suggesting that stroke preventive means might be more effective if they also address competing stroke etiologies in AF-stroke patients. Clinical Trial Registration: NCT 03826927 Graphical abstract

Background: Data on the safety and effectiveness of once-daily (QD) versus twice-daily (BID) direct oral anticoagulants (DOAC) in comparison to vitamin K antagonists (VKA) and to one another in patients with atrial fibrillation (AF) and recent stroke are scarce. Patients and methods: Based on prospectively obtained data from the observational registry Novel-Oral-Anticoagulants-in-Ischemic-Stroke-Patients(NOACISP)-LONGTERM (NCT03826927) from Basel, Switzerland, we compared the occurrence of the primary outcome – the composite of recurrent ischemic stroke, major bleeding, and all-cause death – among consecutive AF patients treated with either VKA, QD DOAC, or BID DOAC following a recent stroke using Cox proportional hazards regression including adjustment for potential confounders. Results: We analyzed 956 patients (median age 80 years, 46% female), of whom 128 received VKA (13.4%), 264 QD DOAC (27.6%), and 564 BID DOAC (59%). Over a total follow-up of 1596 patient-years, both QD DOAC and BID DOAC showed a lower hazard for the composite outcome compared to VKA (adjusted HR [95% CI] 0.69 [0.48, 1.01] and 0.66 [0.47, 0.91], respectively). Upon direct comparison, the hazard for the composite outcome did not differ between patients treated with QD versus BID DOAC (adjusted HR [95% CI] 0.94 [0.70, 1.26]). Secondary analyses focusing on the individual components of the composite outcome revealed no clear differences in the risk-benefit profile of QD versus BID DOAC. Discussion and conclusion: The overall benefit of DOAC over VKA seems to apply to both QD and BID DOAC in AF patients with a recent stroke, without clear evidence that one DOAC dosing regimen is more advantageous than the other.

Introduction Cerebral small vessel disease is an important cause for both ischaemic stroke and intracranial haemorrhage. To date, knowledge on the impact of small vessel disease on the clinical course in stroke patients treated with oral anticoagulation for atrial fibrillation is limited. Patients and Methods Registry-based prospective observational study of 320 patients (aged 78.2 ± 9.2 years) treated with anticoagulation following atrial fibrillation stroke. Patients underwent standardised magnetic-resonance-imaging assessing measures of small vessel disease, including cerebral microbleeds and white matter hyperintensities. Median follow-up was 754 (interquartile range = [708–828]) days. Using adjusted logistic and Cox regression, we assessed the association of imaging measures with clinical outcome including recurrent ischaemic stroke, intracranial haemorrhage and death and assessed disability (modified Rankin Scale). Results Overall, recurrent ischaemic stroke was more common than intracranial haemorrhage (22 versus 8, respectively). Cerebral microbleeds were related to an increased risk of the composite endpoint (ischaemic stroke, intracranial haemorrhage, death: odds ratio (OR) 2.05, 95% confidence interval (CI) 1.27–3.31; P = 0.003), as were white matter hyperintensities (OR 2.00, 95%CI 1.23–3.27, P = 0.005). This was also true in time-to-event analysis (cerebral microbleeds: HR 2.31, 95%CI 1.39–3.52; P < 0.001; white matter hyperintensities: HR 1.99, 95%CI 1.20–3.17; P = 0.007). Both measures were associated with an increased risk for recurrent ischaemic stroke (cerebral microbleeds: HR 4.42, 95%CI 1.07–18.20; P = 0.04; white matter hyperintensities: HR 5.27, 95%CI 1.08–25.79, P = 0.04) and intracranial haemorrhage (cerebral microbleeds: HR 2.43, 95%CI 1.04–5.69; P = 0.04; white matter hyperintensities: HR 2.57, 95%CI 1.11–5.98, P = 0.03). Furthermore, confluent white matter hyperintensities were associated with increased disability (OR 4.03; 95%CI 2.16–7.52; P < 0.001) and mortality (HR 1.81, 95%CI 1.04–3.14, P = 0.04). Discussion and conclusion In atrial fibrillation stroke patients treated with oral anticoagulation, small vessel disease is associated with an unfavourable outcome. The presence of microbleeds indicated a risk higher for recurrent ischaemic stroke than for intracranial haemorrhage.

Reciprocal interactions between neurons and oligodendrocytes are not only crucial for myelination, but also for long-term survival of axons. Degeneration of axons occurs in several human myelin diseases, however the molecular mechanisms of axon-glia communication maintaining axon integrity are poorly understood. Here, we describe the signal-mediated transfer of exosomes from oligodendrocytes to neurons. These endosome-derived vesicles are secreted by oligodendrocytes and carry specific protein and RNA cargo. We show that activity-dependent release of the neurotransmitter glutamate triggers oligodendroglial exosome secretion mediated by Ca2+ entry through oligodendroglial NMDA and AMPA receptors. In turn, neurons internalize the released exosomes by endocytosis. Injection of oligodendroglia-derived exosomes into the mouse brain results in functional retrieval of exosome cargo in neurons. Supply of cultured neurons with oligodendroglial exosomes improves neuronal viability under conditions of cell stress. These findings indicate that oligodendroglial exosomes participate in a novel mode of bidirectional neuron-glia communication contributing to neuronal integrity.