Bone marrow hematopoiesis drives multiple sclerosis progression.

Multiple sclerosis (MS) is a T cell-mediated autoimmune disease of the central nervous system (CNS). Bone marrow hematopoietic stem and progenitor cells (HSPCs) rapidly sense immune activation, yet their potential interplay with autoreactive T cells in MS is unknown. Here, we report that bone marrow HSPCs are skewed toward myeloid lineage concomitant with the clonal expansion of T cells in MS patients. Lineage tracing in experimental autoimmune encephalomyelitis, a mouse model of MS, reveals remarkable bone marrow myelopoiesis with an augmented output of neutrophils and Ly6Chigh monocytes that invade the CNS. We found that myelin-reactive T cells preferentially migrate into the bone marrow compartment in a CXCR4-dependent manner. This aberrant bone marrow myelopoiesis involves the CCL5-CCR5 axis and augments CNS inflammation and demyelination. Our study suggests that targeting the bone marrow niche presents an avenue to treat MS and other autoimmune disorders.

Brain Ischemia Suppresses Immunity in the Periphery and Brain via Different Neurogenic Innervations.

Brain ischemia inhibits immune function systemically, with resulting infectious complications. Whether in stroke different immune alterations occur in brain and periphery and whether analogous mechanisms operate in these compartments remains unclear. Here we show that in patients with ischemic stroke and in mice subjected to middle cerebral artery occlusion, natural killer (NK) cells display remarkably distinct temporal and transcriptome profiles in the brain as compared to the periphery. The activation of catecholaminergic and hypothalamic-pituitary-adrenal axis leads to splenic atrophy and contraction of NK cell numbers in the periphery through a modulated expression of SOCS3, whereas cholinergic innervation-mediated suppression of NK cell responses in the brain involves RUNX3. Importantly, pharmacological or genetic ablation of innervation preserved NK cell function and restrained post-stroke infection. Thus, brain ischemia compromises NK cell-mediated immune defenses through mechanisms that differ in the brain versus the periphery, and targeted inhibition of neurogenic innervation limits post-stroke infection.

Endothelial BACE1 Impairs Cerebral Small Vessels via Tight Junctions and eNOS.

BACKGROUND: Cerebral small vessel injury, including loss of endothelial tight junctions, endothelial dysfunction, and blood-brain barrier breakdown, is an early and typical pathology for Alzheimer's disease, cerebral amyloid angiopathy, and hypertension-related cerebral small vessel disease. Whether there is a common mechanism contributing to these cerebrovascular alterations remains unclear. Studies have shown an elevation of BACE1 (ß-site amyloid precursor protein cleaving enzyme 1) in cerebral vessels from cerebral amyloid angiopathy or Alzheimer's disease patients, suggesting that vascular BACE1 may involve in cerebral small vessel injury. METHODS: To understand the contribution of vascular BACE1 to cerebrovascular impairments, we combined cellular and molecular techniques, mass spectrometry, immunostaining approaches, and functional testing to elucidate the potential pathological mechanisms. RESULTS: We observe a 3.71-fold increase in BACE1 expression in the cerebral microvessels from patients with hypertension. Importantly, we discover that an endothelial tight junction protein, occludin, is a completely new substrate for endothelial BACE1. BACE1 cleaves occludin with full-length occludin reductions and occludin fragment productions. An excessive cleavage by elevated BACE1 induces membranal accumulation of caveolin-1 and subsequent caveolin-1-mediated endocytosis, resulting in lysosomal degradation of other tight junction proteins. Meanwhile, membranal caveolin-1 increases the binding to eNOS (endothelial nitric oxide synthase), together with raised circulating Aß (ß-amyloid peptides) produced by elevated BACE1, leading to an attenuation of eNOS activity and resultant endothelial dysfunction. Furthermore, the initial endothelial damage provokes chronic reduction of cerebral blood flow, blood-brain barrier leakage, microbleeds, tau hyperphosphorylation, synaptic loss, and cognitive impairment in endothelial-specific BACE1 transgenic mice. Conversely, inhibition of aberrant BACE1 activity ameliorates tight junction loss, endothelial dysfunction, and memory deficits. CONCLUSIONS: Our findings establish a novel and direct relationship between endothelial BACE1 and cerebral small vessel damage, indicating that abnormal elevation of endothelial BACE1 is a new mechanism for cerebral small vessel disease pathogenesis.

Neurovascular Inflammation and Complications of Thrombolysis Therapy in Stroke.

Intravenous thrombolysis via tPA (tissue-type plasminogen activator) is the only approved pharmacological treatment for acute ischemic stroke, but its benefits are limited by hemorrhagic transformation. Emerging evidence reveals that tPA swiftly mobilizes immune cells which extravasate into the brain parenchyma via the cerebral vasculature, augmenting neurovascular inflammation, and tissue injury. In this review, we summarize the pronounced alterations of immune cells induced by tPA in patients with stroke and experimental stroke models. We argue that neuroinflammation, triggered by ischemia-induced cell death and exacerbated by tPA, compromises neurovascular integrity and the microcirculation, leading to hemorrhagic transformation. Finally, we discuss current and future approaches to attenuate thrombolysis-associated hemorrhagic transformation via uncoupling immune cells from the neurovascular unit.

tPA Mobilizes Immune Cells That Exacerbate Hemorrhagic Transformation in Stroke.

RATIONALE: Hemorrhagic complications represent a major limitation of intravenous thrombolysis using tPA (tissue-type plasminogen activator) in patients with ischemic stroke. The expression of tPA receptors on immune cells raises the question of what effects tPA exerts on these cells and whether these effects contribute to thrombolysis-related hemorrhagic transformation. OBJECTIVE: We aim to determine the impact of tPA on immune cells and investigate the association between observed immune alteration with hemorrhagic transformation in ischemic stroke patients and in a rat model of embolic stroke. METHODS AND RESULTS: Paired blood samples were collected before and 1 hour after tPA infusion from 71 patients with ischemic stroke. Control blood samples were collected from 27 ischemic stroke patients without tPA treatment. A rat embolic middle cerebral artery occlusion model was adopted to investigate the underlying mechanisms of hemorrhagic transformation. We report that tPA induces a swift surge of circulating neutrophils and T cells with profoundly altered molecular features in ischemic stroke patients and a rat model of focal embolic stroke. tPA exacerbates endothelial injury, increases adhesion and migration of neutrophils and T cells, which are associated with brain hemorrhage in rats subjected to embolic stroke. Genetic ablation of annexin A2 in neutrophils and T cells diminishes the effect of tPA on these cells. Decoupling the interaction between mobilized neutrophils/T cells and the neurovascular unit, achieved via a S1PR (sphingosine-1-phosphate receptor) 1 modulator RP101075 and a CCL2 (C-C motif chemokine ligand 2) synthesis inhibitor bindarit, which block lymphocyte egress and myeloid cell recruitment, respectively, attenuates hemorrhagic transformation and improves neurological function after tPA thrombolysis. CONCLUSIONS: Our findings suggest that immune invasion of the neurovascular unit represents a previously unrecognized mechanism underlying tPA-mediated brain hemorrhage, which can be overcome by precise immune modulation during thrombolytic therapy.

IL (Interleukin)-15 Bridges Astrocyte-Microglia Crosstalk and Exacerbates Brain Injury Following Intracerebral Hemorrhage.

Background and Purpose- Microglia are among the first cells to respond to intracerebral hemorrhage (ICH), but the mechanisms that underlie their activity following ICH remain unclear. IL (interleukin)-15 is a proinflammatory cytokine that orchestrates homeostasis and the intensity of the immune response following central nervous system inflammatory events. The goal of this study was to investigate the role of IL-15 in ICH injury. Methods- Using brain slices of patients with ICH, we determined the presence and cellular source of IL-15. A transgenic mouse line with targeted expression of IL-15 in astrocytes was generated to determine the role of astrocytic IL-15 in ICH. The expression of IL-15 was controlled by a glial fibrillary acidic protein promoter (GFAP-IL-15tg). ICH was induced by intraparenchymal injection of collagenase or autologous blood. Results- In patients with ICH and wild-type mice subjected to experimental ICH, we found a significant upregulation of IL-15 in astrocytes. In GFAP-IL-15tg mice, we found that astrocyte-targeted expression of IL-15 exacerbated brain edema and neurological deficits following ICH. This aggravated ICH injury in GFAP-IL-15tg mice is accompanied by increased microglial accumulation in close proximity to astrocytes in perihematomal tissues. Additionally, microglial expression of CD86, IL-1ß, and TNF-α is markedly increased in GFAP-IL-15tg mice following ICH. Furthermore, depletion of microglia using a colony stimulating factor 1 receptor inhibitor diminishes the exacerbation of ICH injury in GFAP-IL-15tg mice. Conclusions- Our findings identify IL-15 as a mediator of the crosstalk between astrocytes and microglia that exacerbates brain injury following ICH.

Chronic inflammation, cognitive impairment, and distal brain region alteration following intracerebral hemorrhage.

Delayed cognitive decline commonly occurs following intracerebral hemorrhage (ICH), but the mechanisms underlying this phenomenon remain obscure. We therefore investigated the potential mechanisms responsible for impaired cognitive function in a mouse collagenase model of ICH. Following recovery of motor and sensory deficits in the chronic phase of ICH, we noted significant cognitive impairment, which was assessed by the Morris water maze. This finding was accompanied by reduced dendrite spine density of ipsilateral hippocampal CA1 neurons. Reduced synaptic plasticity, manifested by impaired long-term potentiation in hippocampal neurons, was also evident in both ipsilateral and contralateral hemispheres, suggesting that ICH also induces functional alterations in distal brain regions remote from the site of injury. In addition, the accumulation of microglia, infiltration of peripheral immune cells, and generation of reactive oxygen species were observed in both contralateral and ipsilateral hemispheres up to 5 wk post-ICH. Furthermore, depletion of microglia using PLX3397, which inhibits colony stimulating factor 1 receptor, ameliorated this delayed cognitive impairment. Collectively, these results suggest that persistent and diffuse brain inflammation may contribute to cognitive impairment in the chronic stage of ICH recovery.-Shi, E., Shi, K., Qiu, S., Sheth, K. N., Lawton, M. T., Ducruet, A. F. Chronic inflammation, cognitive impairment, and distal brain region alteration following intracerebral hemorrhage.

Fingolimod enhances the efficacy of delayed alteplase administration in acute ischemic stroke by promoting anterograde reperfusion and retrograde collateral flow.

OBJECTIVE: The present study was undertaken to determine the efficacy of coadministration of fingolimod with alteplase in acute ischemic stroke patients in a delayed time window. METHODS: This was a prospective, randomized, open-label, blinded endpoint clinical trial, enrolling patients with internal carotid artery or middle cerebral artery proximal occlusion within 4.5 to 6 hours from symptom onset. Patients were randomly assigned to receive alteplase alone or alteplase with fingolimod. All patients underwent pretreatment and 24-hour noncontrast computed tomography (CT)/perfusion CT/CT angiography. The coprimary endpoints were the decrease of National Institutes of Health Stroke Scale scores over 24 hours and the favorable shift of modified Rankin Scale score (mRS) distribution at day 90. Exploratory outcomes included vessel recanalization, anterograde reperfusion, and retrograde reperfusion of collateral flow. RESULTS: Each treatment group included 23 patients. Compared with alteplase alone, patients receiving fingolimod plus alteplase exhibited better early clinical improvement at 24 hours and a favorable shift of mRS distribution at day 90. In addition, patients who received fingolimod and alteplase exhibited a greater reduction in the perfusion lesion accompanied by suppressed infarct growth by 24 hours. Fingolimod in conjunction with alteplase significantly improved anterograde reperfusion of downstream territory and prevented the failure of retrograde reperfusion from collateral circulation. INTERPRETATION: Fingolimod may enhance the efficacy of alteplase administration in the 4.5- to 6-hour time window in patients with a proximal cerebral arterial occlusion and salvageable penumbral tissue by promoting both anterograde reperfusion and retrograde collateral flow. These findings are instructive for the design of future trials of recanalization therapies in extended time windows. Ann Neurol 2018;84:725-736.

Organ- and cell-specific immune responses are associated with the outcomes of intracerebral hemorrhage.

Severe brain injury significantly influences immune responses; however, the levels at which this influence occurs and which neurogenic pathways are involved are not well defined. Here, we used MRI to measure spleen volume and tissue diffusion changes in patients with intracerebral hemorrhage (ICH). We observed increased capillary exchange and spleen shrinkage by d 3 post-ICH, with recovery by d 14. The extent of spleen shrinkage was associated with brain hematoma size, and a reduced progression of perihematomal edema was observed in the presence of severe spleen shrinkage. At the cellular level, lymphopenia was present in patients with ICH at admission and persisted up to 14 d. Lymphopenia did not parallel the observed spleen alteration. In addition, patients with ICH with infection had significant deficiencies of T and NK cells and poor functional outcomes. Finally, in mouse models of ICH, spleen shrinkage could be related to innervations from adrenergic input and the hypothalamus-pituitary-adrenal (HPA) axis. In sum, the profound impact of ICH on the immune system involves the coordinated actions of sympathetic innervation and the HPA axis, which modulate spleen shrinkage and cellular immunity.-Zhang, J., Shi, K., Li, Z., Li, M., Han, Y., Wang, L., Zhang, Z., Yu, C., Zhang, F., Song, L., Dong, J.-F., La Cava, A., Sheth, K. N., Shi, F.-D. Organ- and cell-specific immune responses are associated with the outcomes of intracerebral hemorrhage.

Bidirectional degeneration in the visual pathway in neuromyelitis optica spectrum disorder (NMOSD).

OBJECTIVE: This study aims to investigate whether bidirectional degeneration occurs within the visual pathway and, if so, the extent of such changes in neuromyelitis optica spectrum disorder (NMOSD). METHODS: In total, 36 NMOSD and 24 healthy controls (HCs) were enrolled. Three-dimensional T1-weighted magnetic resonance imaging (MRI) and diffusion tensor imaging were used to analyze damage to the posterior visual pathway. Damage to the anterior visual pathway was measured by optical coherence tomography. RESULTS: In total, 24 NMOSD with prior optic neuritis (NMOON) patients showed significant reduction of peripapillary retinal nerve fiber layer, inner and outer retinal thickness, lateral geniculate nucleus volume, primary visual cortex volume, and decreased integrity of optic radiations, compared with 12 NMOSD without prior optic neuritis (NMONON) patients and 24 HCs. In NMONON, only the inner retinal thickness and the integrity of optic radiations were significantly reduced in comparison with HCs. Moreover, patients with optic neuritis showed severe bidirectional degeneration, the loss of the RNFL was greater than the atrophy of V1. CONCLUSION: Our study indicated the presence of trans-synaptic degeneration in NMOSD. Damage to the inner retina and optic radiations can be observed even in NMONON. After an episode of optic neuritis, the anterior visual pathway damage is greater than the posterior visual pathway damage.

CFHR1-Modified Neural Stem Cells Ameliorated Brain Injury in a Mouse Model of Neuromyelitis Optica Spectrum Disorders.

A major hurdle for effective stem cell therapy is ongoing inflammation in the target organ. Reconditioning the lesion microenvironment may be an effective way to promote stem cell therapy. In this study, we showed that engineered neural stem cells (NSCs) with complement factor H-related protein 1, a complement inhibitor protein, can attenuate inflammatory infiltration and immune-mediated damage of astrocytes, an important pathogenic progress in patients with neuromyelitis optica spectrum disorders. Furthermore, we demonstrated that transplantation of the complement factor H-related protein 1-modified NSCs effectively blocked the complement activation cascade and inhibited formation of the membrane attack complex, thus contributing to the protection of endogenous and transplanted NSC-differentiated astrocytes. Therefore, manipulation of the lesion microenvironment contributes to a more effective cell replacement therapeutic strategy for autoimmune diseases of the CNS.

Low expression of complement inhibitory protein CD59 contributes to humoral autoimmunity against astrocytes.

Neuromyelitis optica spectrum disorder is primarily an anti-aquaporin 4 autoantibody-mediated, central nervous system-restricted channelopathy. Patients frequently develop central nervous system-restricted lesions even though autoantigen aquaporin 4 in neuromyelitis optica spectrum disorder is broadly distributed in the central nervous system and peripheral organs. The cause of such tissue-specific immune response remains largely unknown. We confirmed here that CD59, an inhibitory regulator of the complement membrane attack complex, is expressed and co-localized with aquaporin 4 in peripheral organs but is only minimally expressed in astrocytes in the central nervous system. In addition, we further found that CD59 overexpression in mouse brains decreased demyelination, blocked the loss of astrocytes and aquaporin 4, and inhibited membrane attack complex formation and infiltration of inflammatory cells. Inactivation of CD59 in mouse peripheral aquaporin 4-expressing cells and tissues led to complement-dependent cytotoxicity. In accordance with the mouse data, human samples presented higher expression of CD59 in many aquaporin 4-expressing peripheral tissues but not in astrocytes. Silencing or blocking CD59 in aquaporin 4-expressing human tracheal epithelial and skeletal muscle cells induced membrane attack complex formation and cytotoxicity, which suggests a protective role of CD59 in anti-aquaporin 4 antibodies-mediated complement toxicity. Our findings suggest that low CD59 expression in astrocytes may contribute to central nervous system-restricted lesions in neuromyelitis optica spectrum disorder. Restoring CD59 expression in astrocytes may serve as a novel therapeutic target of neuromyelitis optica spectrum disorder.

Selective Sphingosine-1-Phosphate Receptor 1 Modulation Attenuates Experimental Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: Preclinical studies and a proof-of-concept clinical study have shown that sphingosine-1-phosphate receptor (S1PR) modulator, fingolimod, improves the clinical outcome of intracerebral hemorrhage (ICH). However, the specific subtype of the S1PRs through which immune modulation provides protection in ICH remains unclear. In addition, fingolimod-induced adverse effects could limit its use in patients with stroke because of interactions with other S1PR subtypes, particularly with S1PR3. RP101075 is a selective S1PR1 agonist with superior cardiovascular safety profile. In this study, we investigated the impact of RP101075 treatment in a mouse model of ICH. METHODS: ICH was induced by injection of autologous blood in 294 male C57BL/6J and Rag2(-/-) mice. ICH mice randomly received vehicle, RP101075, or RP101075 plus S1PR1 antagonist W146 by daily oral gavage for three consecutive days, starting from 30 minutes after surgery. Neurodeficits, brain edema, brain infiltration of immune cells, blood-brain barrier integrity, and cell death were assessed after ICH. RESULTS: RP101075 significantly attenuated neurological deficits and reduced brain edema in ICH mice. W146 blocked the effects of RP101075 on neurodeficits and brain edema. RP101075 reduced the counts of brain-infiltrating lymphocytes, neutrophils, and microglia, as well as cytokine expression after ICH. Enhanced blood-brain barrier integrity and alleviated neuronal death were also seen in ICH mice after RP101075 treatment. CONCLUSIONS: S1PR1 modulation via RP101075 provides protection in experimental ICH. Together with the advantageous pharmacological features of RP101075, these results warrant further investigations of its mechanisms of action and translational values in ICH patients.

Autonomic dysfunction and treatment strategies in intracerebral hemorrhage.

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.

Efficacy and safety of low- and ultralow-dose rituximab in neuromyelitis optica spectrum disorder.

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 ultralow-dose 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 ultralow-dose 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.

APOE from patient-derived astrocytic extracellular vesicles alleviates neuromyelitis optica spectrum disorder in a mouse model.

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.

Targeting CCL5 signaling attenuates neuroinflammation after seizure.

BACKGROUND: Epilepsy is a neurological condition that causes unprovoked, recurrent seizures. Accumulating evidence from clinical and experimental studies indicates that neuroinflammation exacerbates seizure activity. METHODS: We investigated the transcriptional changes occurring in specific brain domains of a seizure mouse model, using 10× Genomics spatial transcriptomics. Differential gene expression and pathway analysis were applied to investigate potential signaling targets for seizure, including CCL5/CCR5 pathway. Maraviroc, an FDA-approved C-C chemokine receptor 5 (CCR5) antagonist, was used to verify the impact of CCL5/CCR5 signaling in seizure mice. RESULTS: We found distinguished regional transcriptome features in the hippocampus of seizure mice. The hippocampus exhibited unique inflammatory gene signatures, including glia activation, apoptosis, and immune response in seizure mice. Especially, we observed notable expression of C-C chemokine ligand 5 (CCL5) throughout the entire seizure hippocampus. Blockade of CCL5/CCR5 signaling via maraviroc prevented microglia activation and neuron degeneration in seizure mice. CONCLUSIONS: This study supports the potential of CCL5/CCR5 signaling for targeting neuroinflammation after seizure.

Plasma Neurofilament Light Chain Predicts Mortality and Long-Term Neurological Outcomes in Patients with Intracerebral Hemorrhage.

Patients with intracerebral hemorrhage (ICH) often suffer from heterogeneous long-term neurological deficits, such as cognitive decline. Our ability to measure secondary brain injury to predict the long-term outcomes of these patients is limited. We investigated whether the blood neurofilament light chain (NfL) can monitor brain injury and predict long-term outcomes in patients with ICH. We enrolled 300 patients with first-episode ICH within 24 h recruited in the Chinese Cerebral Hemorrhage Mechanisms and Intervention study cohort from January 2019 to June 2020. Patients were prospectively followed up for 12 months. Blood samples were collected from 153 healthy participants. Plasma NfL levels determined using a single-molecule array revealed a biphasic increase in plasma NfL in ICH patients compared to healthy controls, with the first peak at around 24 h and a second elevation from day 7 through day 14 post-ICH. Plasma NfL levels were positively correlated with hemorrhage volume, National Institute of Health Stroke Scale, and Glasgow Coma Scale scores of ICH patients. Higher NfL concentration within 72 h after ictus was independently associated with 6- and 12-month worsened functional outcomes (modified Rankin Scale ≥ 3) and higher all-cause mortality. Magnetic resonance imaging and cognitive function evaluation were available for 26 patients at 6 months post-ICH, and NfL levels measured 7 days post-ictus correlated with decreased white matter fiber integrity and poor cognitive function at 6 months after stroke. These findings suggest that blood NfL is a sensitive marker for monitoring axonal injury post-ICH and can predict long-term functional ability and survival.

White matter disease derived from vascular and demyelinating origins.

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.

CD4+ T cells aggravate hemorrhagic brain injury.

Leukocyte infiltration accelerates brain injury following intracerebral hemorrhage (ICH). Yet, the involvement of T lymphocytes in this process has not been fully elucidated. Here, we report that CD4+ T cells accumulate in the perihematomal regions in the brains of patients with ICH and ICH mouse models. T cells activation in the ICH brain is concurrent with the course of perihematomal edema (PHE) development, and depletion of CD4+ T cells reduced PHE volumes and improved neurological deficits in ICH mice. Single-cell transcriptomic analysis revealed that brain-infiltrating T cells exhibited enhanced proinflammatory and proapoptotic signatures. Consequently, CD4+ T cells disrupt the blood-brain barrier integrity and promote PHE progression through interleukin-17 release; furthermore, the TRAIL-expressing CD4+ T cells engage DR5 to trigger endothelial death. Recognition of T cell contribution to ICH-induced neural injury is instrumental for designing immunomodulatory therapies for this dreadful disease.