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Background: Based on the inclusion criteria of clinical trials, the degree of cervical carotid artery stenosis is often used as an indication for stent placement in the setting of extracranial carotid atherosclerotic disease. However, the rigor and consistency with which stenosis is measured outside of clinical trials are unclear. In an agreement study using a cross-sectional sample, we compared the percent stenosis as measured by real-world physician operators to that measured by independent expert reviewers. Methods: As part of the carotid stenting facility accreditation review, images were obtained from 68 cases of patients who underwent carotid stent placement. Data collected included demographics, stroke severity measures, and the documented degree of stenosis, termed operator-reported stenosis (ORS), by 34 operators from 14 clinical sites. The ORS was compared with reviewer-measured stenosis (RMS) as assessed by 5 clinicians experienced in treating carotid artery disease. Results: The median ORS was 90.0% (interquartile range, 80.0%–90.0%) versus a median RMS of 61.1% (interquartile range, 49.8%–73.6%), with a median difference of 21.8% (interquartile range, 13.7%–34.4%), P P =0.406). The median difference between ORS and RMS for facilities granted initial accreditation was smaller compared with facilities whose accreditation was delayed (17.9% versus 25.5%, P =0.035). The intraclass correlation between ORS and RMS was 0.16, indicating poor agreement. If RMS measurements were used, 72% of symptomatic patients and 10% of asymptomatic patients in the population examined would meet the Centers for Medicare and Medicaid Services criteria for stent placement. Conclusions: Real-world operators tend to overestimate carotid artery stenosis compared with external expert reviewers. Measurements from facilities granted initial accreditation were closer to expert measurements than those from facilities whose accreditation was delayed. Since decisions regarding carotid revascularization are often based on percent stenosis, such measuring discrepancies likely lead to increased procedural utilization.

Background: Although stimulation of Wnt/β-catenin signaling is an important strategy to treat ischemic stroke, its signaling pathway has not been fully clarified yet. Recently, RSPO3 (R-spondin 3)/LGR4 (leucine-rich repeat-containing G protein-coupled receptor 4) signaling has resolved TLR4 (toll-like receptor 4)-induced inflammation in lung injury; however, whether this signal is critical in the ischemic brain remains unknown. Therefore, we investigated the role of RSPO3/LGR4 signaling in the ischemic brain. Methods: BALB/c mice were exposed to permanent distal middle cerebral artery and common carotid artery occlusion. Temporal RSPO3 and LGR4 expressions were examined, and the mice were randomly assigned to receive vehicle or recombinant RSPO3. The underlying mechanisms were investigated using microglial cell lines and primary mixed glia-endothelia-neuron and primary neuronal cultures. Results: In the ischemic brain, RSPO3 and LGR4 were expressed in endothelial cells and microglia/macrophages and neurons, respectively. Stimulation of RSPO3/LGR4 signaling by recombinant RSPO3 recovered neurological deficits with decreased Il1β and iNOS mRNA on day 3 and increased Gap43 on day 9. In cultured cells, LGR4 was expressed in neuron and microglia, whereas RSPO3 promoted nuclear translocation of β-catenin. Neuroprotective effects with reduced expression of inflammatory cytokines were observed in lipopolysaccharide-stimulated glia-endothelium-neuron cultures but not in glutamate-, CoCl 2 -, H 2 O 2 -, or oxygen glucose deprivation-stimulated neuronal cultures, indicating that RSPO3/LGR4 can protect neurons by regulating inflammatory cytokines. LGR4-Fc chimera, which was used to block endogenous RSPO3/LGR4 signaling, increased LPS-induced production of inflammatory cytokines, suggesting that endogenous RSPO3 suppresses inflammation. RSPO3 decreased TLR4-related inflammatory cytokine expression by decreasing TLR4 expression without affecting the M1/M2 phenotype. RSPO3 also inhibited TLR2- and TLR9-induced inflammation but not TLR7-induced inflammation, and promoted neurite outgrowth. Conclusions: RSPO3/LGR4 signaling plays a critical role in regulating TLR-induced inflammation and neurite outgrowth in the ischemic brain. Enhancing this signal will be a promising approach for treating ischemic stroke.

The branched-chain amino acids: leucine, isoleucine and valine occupy a special place among the essential amino acids because of their importance not only in the structure of proteins but also in general and cerebral metabolism. Among the first amino acids absorbed after food intake, they play a major role in the regulation of protein synthesis and insulin secretion. They are involved in the modulation of brain uptake of monoamine precursors with which they may compete for occupancy of a common transporter. In the brain, branched-chain amino acids are involved not only in protein synthesis but also in the metabolic cycles of GABA and Glutamate, and in energy metabolism. In particular, they can affect GABAergic neurons and the excitation/inhibition balance. Branched-chain amino acids are known for the 24-hour rhythmicity of their plasma concentrations, which is remarkably conserved in rodent models. This rhythmicity is partly circadian, independent of sleep and food. Moreover, their concentration increases when sleep is disturbed and in obesity and diabetes. The mechanisms regulating these rhythms and their physiological impact remain poorly understood. In this context, the Drosophila model has not yet been widely used, but it is highly relevant and the first results indicate that it can generate new concepts. The elucidation of the metabolism and fluxes of branched-chain amino acids is beginning to shed light on the mysterious connections between clock, sleep, and metabolism, opening the possibility of new therapies., Les acides aminés branchés : leucine, isoleucine et valine occupent une place particulière parmi les acides aminés essentiels de par leur importance non seulement dans la structure des protéines mais aussi dans le métabolisme général et cérébral. Ils sont parmi les premiers acides aminés absorbés après la prise alimentaire et jouent un rôle majeur dans la régulation de la synthèse protéique et de la sécrétion d’insuline. Ils participent à la modulation de l’import cérébral des précurseurs de monoamines avec lesquels ils peuvent entrer en compétition pour l’occupation d’un transporteur commun. Dans le cerveau, les acides aminés branchés interviennent également dans les cycles métaboliques du GABA et du Glutamate, et dans le métabolisme énergétique. Ils peuvent notamment affecter les neurones GABAergiques et la balance excitation/inhibition. Les acides aminés branchés sont connus pour la rythmicité sur 24h de leurs concentrations plasmatiques qui est remarquablement conservée chez les modèles rongeurs. Cette rythmicité est en partie circadienne, indépendante du sommeil et de l’alimentation. Par ailleurs leur concentration augmente lorsque le sommeil est perturbé ainsi que dans l’obésité et le diabète. Les mécanismes régulant ces rythmes et leur impact physiologique restent mal compris. Dans ce contexte, le modèle drosophile a encore été peu utilisé, mais il a toute sa pertinence et les premiers résultats indiquent qu’il peut générer de nouveaux concepts. L’élucidation du métabolisme et des flux des acides aminés branchés commence à éclairer les connections mystérieuses qui existent entre horloge, sommeil, et métabolisme, ouvrant la possibilité de nouvelles thérapies.

Abstract: Neuronal injury during acute hypoxia, ischemia, and following reperfusion are partially attributable to oxidative damage caused by deleterious fluctuations of reactive oxygen species (ROS). In particular, mitochondrial superoxide (O2•-) production is believed to upsurge during lowoxygen conditions and also following reperfusion, before being dismutated to H2O2 and released into the cell. However, disruptions of redox homeostasis may be beneficially attenuated in the brain of hypoxia-tolerant species, such as the naked mole-rat (NMR, Heterocephalus glaber). As such, we hypothesized that ROS homeostasis is better maintained in the brain of NMRs during severe hypoxic/ ischemic insults and following reperfusion. We predicted that NMR brain would not exhibit substantial fluctuations in ROS during hypoxia or reoxygenation, unlike previous reports from hypoxiaintolerant mouse brain. To test this hypothesis, we measured cortical ROS flux using corrected total cell fluorescence measurements from live brain slices loaded with the MitoSOX red superoxide (O2•-) indicator or chloromethyl 2’,7’-dichlorodihydrofluorescein diacetate (CM-H2-DCFDA; which fluoresces with whole-cell hydrogen peroxide (H2O2) production) during various low-oxygen treatments, exogenous oxidative stress, and reperfusion. We found that NMR cortex maintained ROS homeostasis during low-oxygen conditions, while mouse cortex exhibited a ~40% increase and a ~30% decrease in mitochondrial O2•- and cellular H2O2 production, respectively. Mitochondrial ROS homeostasis in NMRs was only disrupted following sodium cyanide application, which was similarly observed in mice. Our results suggest that NMRs have evolved strategies to maintain ROS homeostasis during acute bouts of hypoxia and reoxygenation, potentially as an adaptation to life in an intermittently hypoxic environment.

Background: The Heidelberg Bleeding Classification, developed for computed tomography, is also frequently used to classify intracranial hemorrhage (ICH) on magnetic resonance imaging. Additionally, the presence of any ICH is frequently used as (safety) outcome measure in clinical stroke trials that evaluate acute interventions. We assessed the interobserver agreement on the presence of any ICH and the type of ICH according to the Heidelberg Bleeding Classification on magnetic resonance imaging in patients treated with reperfusion therapy. Methods: We used 300 magnetic resonance imaging scans including susceptibility-weighted imaging or T2*-weighted gradient echo imaging of ischemic stroke patients within 1 week after reperfusion therapy. Six observers, blinded to clinical characteristics except for suspected location of the infarction, independently rated ICH according to the Heidelberg Bleeding Classification in random pairs. Percent agreement and Cohen’s kappa (κ) were estimated for the presence of any ICH (yes/no), and for agreement on the Heidelberg Bleeding Classification class 1 and 2. For the Heidelberg Bleeding Classification class 1 and 2, weighted κ was estimated to take the degree of disagreement into account. Results: In 297 of 300 scans, the quality of scans was sufficient to score ICH. Observers agreed on the presence or absence of any ICH in 264 of 297 scans (88.9%; κ 0.78 [95% CI, 0.71–0.85]). There was agreement on the Heidelberg Bleeding Classification class 1 and 2 and no ICH in class 1 and 2 in 226 of 297 scans (76.1%; κ 0.63 [95% CI, 0.56–0.69]; weighted κ 0.90 [95% CI, 0.87–0.93]). Conclusions: The presence of any ICH can be reliably scored on magnetic resonance imaging and can, therefore, be used as (safety) outcome measure in clinical stroke trials that evaluate acute interventions. Agreement of ICH types according to the Heidelberg Bleeding Classification is substantial and disagreements are small.

Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is increasingly recognized in children. Some children have isolated disease while others relapse. The study evaluates clinical, demographic and imaging features children with positive anti-MOG antibodies comparing to previously reported findings and correlate patterns on MR imaging with a relapsing course in MOGAD.All pediatrics patients with serum anti-MOG antibodies were reviewed. Demographic, clinical, and imaging data were evaluated. Patients with a relapsing course were compared to those with a single event. We assessed initial MR images of the brain, orbits and spine obtained at the onset of clinical symptoms, whether performed at our institution or elsewhere.Thirty patients were included, fourteen with a single event and sixteen with more than one clinical event. The mean age was 8.1 years, with a mean follow-up of 58 months (range of 0.67 to 238 months). The relapsing patients had a mean of 3.5 relapses (range 2-12). 55% of patients had long segment optic nerve lesions, 53% of patients had cortical or peripheral white matter lesions, and 46% of patients had thalamic lesions. 43% of patients had spinal cord lesions, with 39% involving the central cord and 26% with long segment involvement. The imaging features between the groups were not statistically significant.There were no distinguishing features in relapsing versus non-relapsing patients. In the absence of any predictive characteristics for future relapse, patients should have regular clinical and imaging follow up.

New onset refractory status epilepticus (NORSE), including its subtype with a preceding febrile illness known as febrile infection-related epilepsy syndrome (FIRES), is one of the most severe forms of status epilepticus. The exact causes of NORSE are currently unknown, and there is so far no disease-specific therapy. Identifying the underlying pathophysiology and discovering specific biomarkers, whether immunologic, infectious, genetic, or other, may help physicians in the management of patients with NORSE. A broad spectrum of biomarkers has been proposed for status epilepticus patients, some of which were evaluated for patients with NORSE. Nonetheless, none has been validated, due to significant variabilities in study cohorts, collected biospecimens, applied analytical methods, and defined outcome endpoints, and to small sample sizes. The NORSE Institute established an open NORSE/FIRES biorepository for health-related data and biological samples allowing the collection of biospecimens worldwide, promoting multicenter research and sharing of data and specimens. Here, we suggest standard operating procedures for biospecimen collection and biobanking in this rare condition. We also propose criteria for the appropriate use of previously collected biospecimens. We predict that the widespread use of standardized procedures will reduce heterogeneity, facilitate the future identification of validated biomarkers for NORSE, and provide a better understanding of the pathophysiology and best clinical management for these patients.

Background: Adult hypertension is a well-established risk factor for stroke in young adults (aged Methods: A nationwide, retrospective cohort study of adolescents (aged 16–19 years) who were medically evaluated before compulsory military service in Israel during 1985 to 2013. For each candidate for service, hypertension was designated after constructed screening, and the diagnosis was confirmed through a comprehensive workup process. The primary outcome was ischemic and hemorrhagic stroke incidence as registered at the national stroke registry. Cox proportional-hazards models were used. We conducted sensitivity analyses by excluding people with a diabetes diagnosis at adolescence or a new diabetes diagnosis during the follow-up period, analysis of adolescents with overweight, and adolescents with baseline unimpaired health status. Results: The final sample included 1 900 384 adolescents (58% men; median age, 17.3 years). In total, 1474 (0.08%) incidences of stroke (1236 [84%] ischemic) were recorded, at a median age of 43 (interquartile range, 38–47) years. Of these, 18 (0.35%) occurred among the 5221 people with a history of adolescent hypertension. The latter population had a hazard ratio of 2.4 (95% CI, 1.5–3.9) for incident stroke after adjustment for body mass index and baseline sociodemographic factors. Further adjustment for diabetes status yielded a hazard ratio of 2.1 (1.3–3.5). We found similar results when the outcome was ischemic stroke with a hazard ratio of 2.0 (1.2–3.5). Sensitivity analyses for overall stroke, and ischemic stroke only, yielded consistent findings. Conclusions: Adolescent hypertension is associated with an increased risk of stroke, particularly ischemic stroke, in young adulthood.

BackgroundNatalizumab is effective in the treatment of multiple sclerosis (MS). In 2021, the European Medicines Agency approved the subcutaneous (SC) variant of natalizumab which can be used instead of intravenous administration. However, the course of drug levels varies between administration routes, and the Food and Drug Administration rejected the request for approval of natalizumab SC for reasons that were not disclosed. Our objective was to evaluate the course of natalizumab trough drug levels in patients who switched from natalizumab intravenous to SC on various treatment intervals.MethodsThe NEXT-MS trial (N=382) investigates personalised treatment of natalizumab, in which infusion intervals are prolonged based on individual natalizumab trough drug levels. In 2021, an amendment was approved allowing participants to switch from intravenous to SC administration with frequent measurements of natalizumab drug levels and antidrug antibodies (ADAs). Results were compared with linear mixed model analyses.ResultsUntil December 2022, 15 participants switched to SC natalizumab. Natalizumab drug levels with SC administration were on average 55% lower compared with intravenous administration (Exp (estimate) 0.45, 95% CI 0.39 to 0.53, pConclusionsNatalizumab trough drug levels can decrease after switching from natalizumab intravenous to SC administration. We advise to monitor trough drug levels in patients with low natalizumab drug levels during intravenous treatment, patients with higher body mass index or patients on extended treatment intervals who switch to SC administration of natalizumab.

Background: Robot-assisted arm training is generally delivered in the robot-like manner of planar or mechanical 3-dimensional movements. It remains unclear whether integrating upper extremity (UE) natural coordinated patterns into a robotic exoskeleton can improve outcomes. The study aimed to compare conventional therapist-mediated training to the practice of human-like gross movements derived from 5 typical UE functional activities managed with exoskeletal assistance as needed for patients after stroke. Methods: In this randomized, single-blind, noninferiority trial, patients with moderate-to-severe UE motor impairment due to subacute stroke were randomly assigned (1:1) to receive 20 sessions of 45-minute exoskeleton-assisted anthropomorphic movement training or conventional therapy. Treatment allocation was masked from independent assessors, but not from patients or investigators. The primary outcome was the change in the Fugl-Meyer Assessment for Upper Extremity from baseline to 4 weeks against a prespecified noninferiority margin of 4 points. Superiority would be tested if noninferiority was demonstrated. Post hoc subgroup analyses of baseline characteristics were performed for the primary outcome. Results: Between June 2020 and August 2021, totally 80 inpatients (67 [83.8%] males; age, 51.9±9.9 years; days since stroke onset, 54.6±38.0) were enrolled, randomly assigned to the intervention, and included in the intention-to-treat analysis. The mean Fugl-Meyer Assessment for Upper Extremity change in exoskeleton-assisted anthropomorphic movement training (14.73 points; [95% CI, 11.43–18.02]) was higher than that of conventional therapy (9.90 points; [95% CI, 8.15–11.65]) at 4 weeks (adjusted difference, 4.51 points [95% CI, 1.13–7.90]). Moreover, post hoc analysis favored the patient subgroup (Fugl-Meyer Assessment for Upper Extremity score, 23–38 points) with moderately severe motor impairment. Conclusions: Exoskeleton-assisted anthropomorphic movement training appears to be effective for patients with subacute stroke through repetitive practice of human-like movements. Although the results indicate a positive sign for exoskeleton-assisted anthropomorphic movement training, further investigations into the long-term effects and paradigm optimization are warranted. Registration: URL: https://www.chictr.org.cn ; Unique identifier: ChiCTR2100044078.

Abstract: Mitochondria regulate multiple aspects of neuronal development, physiology, plasticity, and pathology through their regulatory roles in bioenergetic, calcium, redox, and cell survival/death signalling. While several reviews have addressed these different aspects, a comprehensive discussion focussing on the relevance of isolated brain mitochondria and their utilities in neuroscience research has been lacking. This is relevant because the employment of isolated mitochondria rather than their in situ functional evaluation, offers definitive evidence of organelle-specificity, negating the interference from extra mitochondrial cellular factors/signals. This mini-review was designed primarily to explore the commonly employed in organello analytical assays for the assessment of mitochondrial physiology and its dysfunction, with a particular focus on neuroscience research. The authors briefly discuss the methodologies for biochemical isolation of mitochondria, their quality assessment, and cryopreservation. Further, the review attempts to accumulate the key biochemical protocols for in organello assessment of a multitude of mitochondrial functions critical for neurophysiology, including assays for bioenergetic activity, calcium and redox homeostasis, and mitochondrial protein translation. The purpose of this review is not to examine each and every method or study related to the functional assessment of isolated brain mitochondria, but rather to assemble the commonly used protocols of in organello mitochondrial research in a single publication. The hope is that this review will provide a suitable platform aiding neuroscientists to choose and apply the required protocols and tools to address their particular mechanistic, diagnostic, or therapeutic question dealing within the confines of the research area of mitochondrial patho-physiology in the neuronal perspective.

Although cross-sectional studies show heterogeneity in emotional cognition in bipolar disorder (BD), the temporal course within subgroups is unclear. In this prospective, longitudinal study we assessed the trajectories of emotional cognition subgroups within a 16-month follow-up period in recently diagnosed BD patients compared to healthy controls (HC). Recently diagnosed BD patients and HC underwent comprehensive emotional and non-emotional testing at baseline and again at follow-up. We employed hierarchical cluster analysis at baseline to identify homogenous emotional cognition subgroups of patients, and changes across the subgroups of BD and HC were assessed with linear mixed-model analyses. We found two emotional cognition subgroups: subgroup 1 (65%, n = 179), showing heightened negative emotional reactivity in neutral and negative social scenarios and faster recognition of emotional facial expressions than HC (ps

Background: Although early brain injury (EBI) is recognized as a critical step following subarachnoid hemorrhage (SAH), its pathophysiology and underlying mechanisms remain poorly understood. Herein, we investigated the role of cerebral circulation in the acute phase using patient data and a mouse SAH model and evaluated its regulation via the sympathetic nervous system. Methods: The cerebral circulation time and neurological outcomes in the human body were retrospectively examined in 34 SAH cases with ruptured anterior circulation aneurysms and 85 cases with unruptured anterior circulation cerebral aneurysms at Kanazawa University Hospital from January 2016 to December 2021. In a mouse study, a SAH model was created via endovascular perforation, and India-ink angiography was performed over time. Additionally, bilateral superior cervical ganglionectomy was performed immediately before surgery, and neurological scores and brain water content were evaluated after SAH. Results: Cerebral circulation time was prolonged in the acute phase of SAH compared with that in the unruptured cerebral aneurysm group, especially in those with electrocardiographic changes. Furthermore, it was more prolonged in the poor prognosis group (modified Rankin Scale scores 3–6) than in the good prognosis group (modified Rankin Scale scores 0–2) at discharge. In mice, cerebral perfusion was significantly reduced at 1 and 3 hours after SAH and recovered at 6 hours. superior cervical ganglionectomy improved cerebral perfusion without altering the diameter of the middle cerebral artery at 1 hour and improved neurological outcomes at 48 hours after SAH. Consistently, brain edema, quantified by brain water content, was improved by superior cervical ganglionectomy 24 hours after SAH. Conclusions: Sympathetic hyperactivity may play a critical role in the development of EBI by impairing cerebral microcirculation and edema in the acute phase following SAH.