BACKGROUND:This study aimed to compare the real-world efficacy and safety of rituximab and inebilizumab in patients with aquaporin-4 immunoglobulin G (AQP4-IgG) seropositive neuromyelitis optica spectrum disorder (NMOSD). METHODS:This retrospective study included patients treated with rituximab or inebilizumab at two tertiary hospitals in China between January 2015 and June 2025. Propensity score matching was conducted to reduce between-group imbalance. The primary endpoint was time to first confirmed relapse. Secondary outcomes included changes in annualized relapse frequency, EDSS scores, and serum IgG and AQP4-IgG levels. Safety profiles were also assessed. RESULTS:A total of 276 patients were analyzed (rituximab: 211; inebilizumab: 65), yielding 61 well-balanced pairs after propensity score matching. In terms of efficacy, clinical outcomes and AQP4-IgG dynamics were comparable between groups in pre- and post-matching analyses, although inebilizumab exhibited a significantly greater reduction in serum IgG levels at 6 months. Safety profiles differed. Rituximab was associated with a higher incidence of overall adverse events, driven primarily by infusion-related reactions, whereas other adverse events remained comparable. CONCLUSIONS:In our real-world study of 276 patients, rituximab and inebilizumab demonstrated comparable efficacy in the medium term but differed in their safety profiles, with a significantly higher incidence of infusion-related reactions observed in the rituximab group.

Traumatic brain injury (TBI) disproportionately affects the elderly, yet the underlying mechanisms remain unclear. Here, we demonstrate that aged TBI brains predominantly harbor proinflammatory NLRP3 + microglia, in stark contrast to the neuroprotective Lysozyme + microglia prevalent in young TBI brains. This age-dependent microglial dichotomy correlates with elevated mortality and impaired recovery in aged TBI mice. By leveraging an integrative multiomics approach combined with metabolomics and epigenome analysis, we identified a previously unrecognized link between enhanced glycolysis and the proinflammatory chromatin landscape in NLRP3 + microglia. Further investigation identified ELF1 as a key transcription factor driving NLRP3 + microglia formation. Importantly, ablation of ELF1 reversed age-associated microglial dysfunction and improved TBI outcomes. Finally, we report that Imeglimin, a clinically approved antihyperglycemic agent capable of crossing the blood-brain barrier, inhibits ELF1 and reverses microglial phenotype, reducing acute mortality rate and leading to improved functional recovery of aged mice with TBI. Our work elucidates the mechanistic basis of age-dependent TBI outcomes, reveals the crosstalk between metabolic rewiring and epigenetic regulation in microglial aging, and identifies ELF1 as a promising therapeutic target for improving TBI outcomes.

Transient ischemia attack (TIA) is a brief episode of neurological dysfunction caused by a transient but reversible disruption of blood supply to a specific region of brain without demonstrated tissue injury. Although TIA has long been regarded as a benign cerebral ischemia event, it in fact represents a critical warning for patients and their caregivers, as approximately 23

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system mediated by autoimmune demyelination. While treatments targeting the peripheral immune system have been effective in reducing relapse risks for MS patients, the neuroinflammation within the central nervous system, which is believed to contribute to neurodegeneration, has not been successfully addressed. Human Dental Pulp Stem Cells (hDPSCs) have shown potential in entering the CNS and exerting anti-inflammatory effects, making them a promising candidate for treating neurological disorders. In experimental autoimmune encephalomyelitis (EAE) models, intravenously administered hDPSCs ameliorated clinical scores, decreased demyelinated lesion volume, and reduced inflammatory infiltration. Given the established safety profile, hDPSCs could potentially be developed as a new approach to combat disease progression of MS by inhibiting compartmentalized neuroinflammation.

Background Central nervous system (CNS) accessibility constitutes a major hurdle for drug development to treat neurological diseases. Existing drug delivery methods rely on breaking the blood-brain barrier (BBB) for drugs to penetrate the CNS. Researchers have discovered natural microchannels between the skull bone marrow and the dura mater, providing a pathway for drug delivery through the skull bone marrow. However, there has been no research on the feasibility, safety, and efficacy of this delivery method for drug treatment of stroke. Methods We used a microporous method for intracalvariosseous (ICO) injection to deliver drugs directly into brain parenchyma through skull bone marrow. Safety of ICO was assessed by monitoring changes in skull and peripheral blood neutrophil counts, and FITC-dextran extravasation across the BBB. Drug delivery pathways were observed through transparent skull-dura mater-brain tissue. In a rodent stroke model, NA-1 or Y-3 neuroprotective agents were administered via ICO to evaluate safety and efficacy by assessing neurological deficits, infarct size, neuroinflammatory factors, neuronal apoptosis, and liver/kidney function. Drug concentration in tissues was measured using fluorescence tracing and high-performance liquid chromatography to gauge ICO delivery efficiency. Findings ICO injection delivers drugs to the brain parenchyma through microchannels between the skull bone marrow and the dura mater, offering higher delivery efficiency than intravenous injection. After ICO injection, there were no changes in neutrophil counts in the skull bone marrow and peripheral blood, and the amount of FITCdextran passing through the BBB remained unchanged. This confirmed that ICO injection does not cause skull infection or break BBB, which suggested ICO injection is safe and feasible. In the treatment of stroke with neuroprotective agents, although the drug dosage of ICO injection was lower than intravenous injection, drug accumulation in the brain increased after ICO injection, which helped repair nerve damage, reduce neuronal apoptosis, and decrease the expression of inflammatory factors. Interpretation ICO injection is a central nervous system drug delivery method that utilizes natural microchannels between the skull and dura mater for efficient drug delivery. Our results assessed the feasibility and safety of ICO injection at the preclinical level and evaluated its efficacy in animal models of stroke. The findings provided a foundation for the clinical translation of ICO injection.

The brain vasculature supplies neurons with glucose and oxygen, but little is known about how vascular plasticity contributes to brain function. Using longitudinal in vivo imaging, we report that a substantial proportion of blood vessels in the adult mouse brain sporadically occlude and regress. Their regression proceeds through sequential stages of blood-flow occlusion, endothelial cell collapse, relocation or loss of pericytes, and retraction of glial endfeet. Regressing vessels are found to be widespread in mouse, monkey and human brains. We further reveal that blood vessel regression cause a reduction of neuronal activity due to a dysfunction in mitochondrial metabolism and glutamate production. Our results elucidate the mechanism of vessel regression and its role in neuronal function in the adult brain.

The activation and infiltration of immune cells are hallmarks of ischemic stroke. However, the precise origins and the molecular alterations of these infiltrating cells post-stroke remain poorly characterized. Here, a murine model of stroke (permanent middle cerebral artery occlusion [p-MCAO]) is utilized to profile single-cell transcriptomes of immune cells in the brain and their potential origins, including the calvarial bone marrow (CBM), femur bone marrow (FBM), and peripheral blood mononuclear cells (PBMCs). This analysis reveals transcriptomically distinct populations of cerebral myeloid cells and brain-resident immune cells after stroke. These include a novel CD14+ neutrophil subpopulation that transcriptomically resembles CBM neutrophils. Moreover, the sequential activation of transcription factor regulatory networks in neutrophils during stroke progression is delineated, many of which are unique to the CD14+ population and underlie their acquisition of chemotaxis and granule release capacities. Two distinct origins of post-stroke disease-related immune cell subtypes are also identified: disease inflammatory macrophages, likely deriving from circulating monocytes in the skull, and transcriptionally immature disease-associated microglia, possibly arising from pre-existing homeostatic microglia. Together, a comprehensive molecular survey of post-stroke immune responses is performed, encompassing both local and distant bone marrow sites and peripheral blood.

Background Stroke-induced transient immune suppression is believed to contribute to post-stroke infections. The β-adrenergic receptor antagonist, propranolol, has been shown to prevent stroke-associated pneumonia (SAP) via reversing post-stroke immunosuppression in preclinical studies and in retrospective analysis in stroke patients. However, whether propranolol can reduce the risk of SAP has not been tested in prospective, randomised controlled trials.Aim To describe the rationale and design of a multicentre, prospective, open-label, endpoint-blinded, randomised controlled study to evaluate the safety and efficacy of propranolol hydrochloride injection for the prevention of SAP in patients with intracerebral haemorrhage (ICH) (PROCHASE).Design In this investigator-initiated trial, we compare the safety of the standard medical treatment to standard medical treatment plus intravenous propranolol hydrochloride administration (5 mg daily on days 1–7) in patients with ICH and the efficacy of this intervention to reduce the occurrence of SAP. All patients will be followed up for 90±7 days.Study outcomes The primary efficacy outcome is SAP within 7±1 days diagnosed by the defined algorithm based on a diagnosis of SAP recommendations from the pneumonia in stroke consensus group. The primary safety outcome is defined as severe or moderate bradycardia within 7±1 days. The secondary outcome is a modified Rankin score of 0–3 at 90±7 days after randomisation.Discussion The PROCHASE trial aims to generate clinical evidence regarding the safety and efficacy of propranolol in preventing SAP in patients with ICH.

Traumatic brain injury (TBI) presents a major clinical burden, often resulting in both acute neurological impairment and pulmonary dysfunction, underscoring the complex and poorly understood brain–lung axis. Although dual-organ injury is well-documented, the mechanistic basis linking brain trauma to peripheral organ damage has remained elusive. In this study, we integrate clinical observations, single-cell RNA sequencing of skull bone marrow (BM) from TBI patients, and preclinical mouse models to uncover a rapid, IL-1-driven emergency monopoiesis response initiated within 24 h post-injury. We demonstrate that TBI induces accelerated, myeloid-skewed hematopoiesis in the cranial BM, marked by the expansion and mobilization of proinflammatory monocytes. This immune activation correlates strongly with both neurological decline and acute lung injury. Mechanistically, we identify IL-1 signaling as a master regulator of this pathological hematopoietic reprogramming. Disruption of IL-1R1 signaling, either globally or selectively within the hematopoietic compartment, attenuates emergency monopoiesis, preserves blood-brain barrier integrity, and reduces inflammatory infiltration in both the brain and lungs. These findings establish emergency monopoiesis as a central driver of multi-organ injury in TBI and reveal the BM niche as a critical yet underappreciated target in post-traumatic systemic pathology. By targeting IL-1R1-dependent hematopoietic activation, this study proposes a novel therapeutic strategy to interrupt the harmful brain–lung immune crosstalk and improve clinical outcomes in acute TBI.

BACKGROUND:Post-stroke immunosuppression elevates the risk of stroke-associated pneumonia (SAP). Our earlier research indicated that perihematomal neuron-derived PD-L1 may play a role in peripheral immunosuppression following intracerebral hemorrhage (ICH); however, the specific carriers of PD-L1 and its potential as a predictor for SAP risk are yet to be determined. MATERIALS AND METHODS:We hypothesize that elevated levels of exosomal PD-L1 in peripheral blood after ICH mediate immune suppression and increase the risk of SAP. This observational study aimed to investigate the levels of exosomal PD-L1 post-ICH and their relationship with SAP. In an exploratory cohort of 39 patients with ICH and 24 healthy controls and a validation cohort of 144 patients with ICH. RESULTS:At admission, patients with ICH exhibited significantly increased exosome numbers in their peripheral blood, with these exosomes showing high expression of the neuronal marker neural cell adhesion molecule L1, suggesting a brain origin. Exosomal PD-L1 levels were elevated in patients with ICH compared to healthy controls and were higher in patients with SAP than those without. After adjusting for confounders, exosomal PD-L1 was confirmed to be independently associated with SAP in both the exploratory cohort and validation cohort. CONCLUSIONS:Brain-derived exosomes with high expression of PD-L1 are substantially released into the periphery after ICH. Elevated exosomal PD-L1 levels correlate with an increased risk of SAP.

The healthy young brain is free of lymphocyte infiltration, yet this protection declines with aging. Accumulation of peripheral lymphocytes in the aged brain is linked to increased neuroinflammation and neurodegeneration. Whether brain-specific factors limit lymphocyte infiltration, proliferation and activation in the brain, thereby protecting it from inflammatory damage, remains unknown. Here, we identified the programmed death ligand 1 (PD-L1) as a key factor restricting lymphocyte accumulation in the brain. PD-L1 is selectively expressed in neurons and declines with age in both humans and mice, correlating with the accumulation of CD8⁺ T cells in the aging brain. Genetic ablation or pharmacological blockade of PD-L1 in young mice recapitulated aged brain phenotypes, such as increased CD8⁺ T cell infiltration, enhanced IFN-γ and granzyme B production, and impaired cognition. Mechanistically, these age-dependent phenotypes were mediated by ubiquitination-dependent degradation of PD-L1, driven by upregulation of UBR4 E3 ligase expression. Restoration of neuronal PD-L1 expression in aged mice via adeno-associated virus transduction mitigated neuroinflammation and rescued cognitive decline. Our findings establish neuronal PD-L1 as a guardian of brain immune homeostasis, which is compromised during aging.

Cerebral small vessel disease (CSVD) leads to an extensive white matter damage associated with cognitive decline, yet the underlying damaging mechanisms remain incompletely understood. Here we established a positive correlation between plasma levels of serine proteinase elastase ELANE and periventricular white matter hyperintensity (PV-WMH) in a cohort of CSVD patients. In a CSVD murine model induced by bilateral carotid artery stenosis (BCAS), upregulated ELANE was detected both in microglia and peripheral blood neutrophils. Genetic ELANE deficiency significantly alleviated oligodendrocyte loss, thereby reducing white matter lesions (WMLs) as well as ameliorating sensorimotor and cognitive impairments in BCAS mice. In vitro studies demonstrated that ELANE triggered time-dependent and dose-dependent oligodendrocyte lineage cell death. Bone marrow transplantation showed that ELANE from microglia and peripheral blood both contributed to WML development and BCAS-induced neurological deficits. Mechanistically, ELANE, accumulated by oligodendrocytes, cleaved the phosphodiesterase domain of 2,3-cyclic nucleotide 3-phosphodiesterase (CNPase). Pharmacological inhibition of ELANE with Sivelestat reduced oligodendrocyte loss and WMLs leading to the restoration of white matter integrity and neurological improvements in BCAS mice. In post-mortem brain specimens of CSVD patients ELANE accumulated within WMLs being predominantly localized in microglia (and hence defined as microglial ELANE) rather than in the brain-infiltrating neutrophils. We therefore posit microglial ELANE as an instigator of whiter matter injury in CSVD and suggest its potential therapeutic relevance. ### Competing Interest Statement The authors have declared no competing interest.

Damage or microstructural alterations of the white matter can cause dysfunction of the intrinsic neural networks in a condition termed as white matter disease (WMD). Frequently detected on brain computed tomography and magnetic resonance imaging scans, WMD is commonly presented in inflammatory demyelinating diseases like multiple sclerosis (MS) and vascular diseases such as cerebral small vessel disease (CSVD). Prevention of MS and CSVD progression requires early treatments with drastically different medications and approaches, as such, early and accurate diagnosis of WMD, derived from vascular or demyelinating etiologies, is of paramount importance. However, the clinical and imaging similarities between MS, especially during the early stage, and CSVD, pose a significant dilemma in differentiating these two conditions. In this review, we attempt to summarize and contrast the distinguishing features of MS and CSVD for aiding accurate diagnosis to ensure timely corresponding management in the early stages of MS and CSVD.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune astrocytopathy of the central nervous system, mediated by antibodies against aquaporin-4 water channel protein (AQP4-Abs), resulting in damage of astrocytes with subsequent demyelination and axonal damage. Extracellular communication through astrocyte-derived extracellular vesicles (ADEVs) has received growing interest in association with astrocytopathies. However, to what extent ADEVs contribute to NMOSD pathogenesis remains unclear. Here, through proteomic screening of patient-derived ADEVs, we observed an increase in apolipoprotein E (APOE)-rich ADEVs in patients with AQP4-Abs-positive NMOSD. Intracerebral injection of the APOE-mimetic peptide APOE130-149 attenuated microglial reactivity, neuroinflammation, and brain lesions in a mouse model of NMOSD. The protective effect of APOE in NMOSD pathogenesis was further established by the exacerbated lesion volume in APOE-deficient mice, which could be rescued by exogenous APOE administration. Genetic knockdown of the APOE receptor lipoprotein receptor-related protein 1 (LRP1) could block the restorative effects of APOE130-149 administration. The transfusion ADEVs derived from patients with NMOSD and healthy controls also alleviated astrocyte loss, reactive microgliosis, and demyelination in NMOSD mice. The slightly larger beneficial effect of patient-derived ADEVs as compared to ADEVs from healthy controls was further augmented in APOE-/- mice. These results indicate that APOE from astrocyte-derived extracellular vesicles could mediate disease-modifying astrocyte-microglia cross-talk in NMOSD.

Keywords: brain injury, secondary injury cascade, neurological disorder, diagnosis and targeted therapy, emerging technology

Background: Rituximab effectively targets B cells and reduces relapses in neuromyelitis optica spectrum disorder (NMOSD). But the ideal dosage and treatment intervals remain unanswered. We aimed to assess the efficacy and safety of low and ultralow-dose rituximab in NMOSD. Methods: We conducted a retrospective analysis of NMOSD patients treated with rituximab at two Chinese tertiary hospitals. Patients received either a low-dose regimen (500 mg reinfusion every 6 months) or an ultralowdose regimen: 100 to 300 mg rituximab based on CD19+B cells (100 mg for 1-1.5% of peripheral blood mononuclear cells, 200 mg for 1.5-5%, and 300 mg for over 5%). Results: We analyzed data from 136 patients (41 in the low-dose group, 95 in the ultralow-dose group) with median follow-up durations of 43 and 34.2 months, respectively. Both groups exhibited similar sex distribution, age at disease onset, annual relapse rate, and baseline disease duration. Survival analysis showed that ultralowdose rituximab was noninferior to low-dose rituximab in preventing relapses. Infusion reactions occurred in 20 of 173 (11.6%) low-dose treatments and 9 of 533 (1.7%) ultralow-dose treatments. B-cell re-emergence was observed in 137 of 236 (58.1%) monitors in the low-dose group and 367 of 1136 (32.3%) monitors in the ultralow-dose group. Conclusion: Ultralow dose rituximab was noninferior to low-dose rituximab in preventing NMOSD relapses. A randomized controlled trial is essential to validate these findings.

AbstractIntravenous thrombolysis using recombinant tissue plasminogen activator (tPA) remains the primary treatment for patients with acute ischemic stroke (AIS). However, the mechanism of tPA-related hemorrhagic transformation (HT) remains poorly understood. Elevation of histidine-rich glycoprotein (HRG) expression was detected by nano-liquid chromatography tandem mass spectrometry at 1 h following tPA infusion as compared to baseline prior to tPA infusion (discovery cohort, n = 10), which was subsequently confirmed in a validation cohort (n = 157) by ELISA. Surprisingly, no elevation of HRG was detected in individuals who subsequently developed HT. During in vitro experiments, HRG reduced neutrophil NETosis, inflammatory cytokine production, and migration across the blood–brain barrier induced by tPA. In a photothrombotic murine AIS model, HRG administration ameliorated HT with delayed thrombolysis, by inhibiting neutrophil immune infiltration and downregulating pro-inflammatory signaling pathways. Neutrophil depletion or NETosis inhibition also alleviated HT, whereas HRG siRNA treatment exacerbated HT. In conclusion, fluctuations in HRG levels may reflect tPA therapy and its associated HT. The inhibitory effect of HRG on neutrophils may counteract tPA-induced immune abnormalities and HT in patients with AIS.

AIMS:Autonomic dysfunction with central autonomic network (CAN) damage occurs frequently after intracerebral hemorrhage (ICH) and contributes to a series of adverse outcomes. This review aims to provide insight and convenience for future clinical practice and research on autonomic dysfunction in ICH patients. DISCUSSION:We summarize the autonomic dysfunction in ICH from the aspects of potential mechanisms, clinical significance, assessment, and treatment strategies. The CAN structures mainly include insular cortex, anterior cingulate cortex, amygdala, hypothalamus, nucleus of the solitary tract, ventrolateral medulla, dorsal motor nucleus of the vagus, nucleus ambiguus, parabrachial nucleus, and periaqueductal gray. Autonomic dysfunction after ICH is closely associated with neurological functional outcomes, cardiac complications, blood pressure fluctuation, immunosuppression and infection, thermoregulatory dysfunction, hyperglycemia, digestive dysfunction, and urogenital disturbances. Heart rate variability, baroreflex sensitivity, skin sympathetic nerve activity, sympathetic skin response, and plasma catecholamine concentration can be used to assess the autonomic functional activities after ICH. Risk stratification of patients according to autonomic functional activities, and development of intervention approaches based on the restoration of sympathetic-parasympathetic balance, would potentially improve clinical outcomes in ICH patients. CONCLUSION:The review systematically summarizes the evidence of autonomic dysfunction and its association with clinical outcomes in ICH patients, proposing that targeting autonomic dysfunction could be potentially investigated to improve the clinical outcomes.

Aged patients often suffer poorer neurological recovery than younger patients after traumatic brain injury (TBI), but the mechanisms underlying this difference remain unclear. Here, we demonstrate abnormal myelopoiesis characterized by increased neutrophil and classical monocyte output but impaired nonclassical patrolling monocyte population in aged patients with TBI as well as in an aged murine TBI model. Retrograde and anterograde nerve tracing indicated that increased adrenergic input through the central amygdaloid nucleus–bone marrow axis drives abnormal myelopoiesis after TBI in a β2-adrenergic receptor–dependent manner, which is notably enhanced in aged mice after injury. Selective blockade of β2-adrenergic receptors rebalances abnormal myelopoiesis and improves the outcomes of aged mice after TBI. We therefore demonstrate that increased β2-adrenergic input-driven abnormal myelopoiesis exacerbates post-TBI neuroinflammation in the aged, representing a mechanism underlying the poorer recovery of aged patients and that blockade of β2-adrenergic receptor is a potential approach to promote neurological recovery after TBI.