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Early neuroinflammatory injury plays a crucial role in initiating and progressing multiple sclerosis (MS). Neutrophils are forerunners to neural lesions in MS, yet the temporal alterations of their functions in MS remains unclear. This study demonstrated a positive correlation between circulatory neutrophil counts and disease activity and severity in treatment-naïve MS patients. In experimental autoimmune encephalomyelitis (EAE), we documented the recruitment of neutrophils to spinal cord during the preclinical phase, with these cells contributing to the disruption of the blood-spinal cord barrier (BSCB) during the onset of the disease. Furthermore, during the peak phase, infiltrated neutrophils promoted demyelination through formation of neutrophil extracellular traps (NETs), cytokine secretion and antigen presentation. Notably, the inhibition of neutrophil infiltration using a CXCR2 inhibitor effectively mitigated white matter damage and physical disability, underscoring their potential as therapeutic targets. In conclusion, neutrophils represent promising candidates for both disease treatment and prognosis evaluation in MS. By elucidating their temporal roles and mechanisms of action, we can potentially harness their modulation to improve patient outcomes and disease management.

Gut microbiota of centenarians has garnered significant attention in recent years, with most studies concentrating on the analysis of microbial composition. However, there is still limited knowledge regarding the consistent signatures of specific species and their biological functions, as well as the potential causal relationship between gut microbiota and longevity. To address this, we performed the fecal metagenomic analysis of eight longevous populations at the species and functional level, and employed the Mendelian randomization (MR) analysis to infer the causal associations between microbial taxa and longevity-related traits. We observed that several species including Eisenbergiella tayi, Methanobrevibacter smithii, Hungatella hathewayi, and Desulfovibrio fairfieldensis were consistently enriched in the gut microbiota of long-lived individuals compared to younger elderly and young adults across multiple cohorts. Analysis of microbial pathways and enzymes indicated that E. tayi plays a role in the protein N-glycosylation, while M. smithii is involved in the 3-dehydroquinate and chorismate biosynthesis. Furthermore, H. hathewayi makes a distinct contribution to the purine nucleobase degradation I pathway, potentially assisting the elderly in maintaining purine homeostasis. D. fairfieldensis contributes to the menaquinone (vitamin K2) biosynthesis, which may help prevent age-related diseases such as osteoporosis-induced fractures. According to MR results, Hungatella was significantly positively correlated with parental longevity, and Desulfovibrio also exhibited positive associations with lifespan and multiple traits related to parental longevity. Additionally, Alistipes and Akkermansia muciniphila were consistently enriched in the gut microbiota of the three largest cohorts of long-lived individuals, and MR analysis also suggests their potential causal relationships with longevity. Our findings reveal longevity-associated gut microbial signatures, which are informative for understanding the role of microbiota in regulating longevity and aging.

Gut microbiome plays a pivotal role in combating diseases and facilitating healthy aging, and natural products derived from biosynthetic gene clusters (BGCs) of the human microbiome exhibit significant biological activities. However, the natural products of the gut microbiome in long-lived populations remain poorly understood. Here, we integrated six cohorts of long-lived populations, encompassing a total of 1029 fecal metagenomic samples, and employed the metagenomic single sample assembled BGCs (MSSA-BGCs) analysis pipeline to investigate the natural products and their associated species. Our findings reveal that the BGC composition of the extremely long-lived group differed significantly from that of younger elderly and young individuals across five cohorts. Terpene and Type I PKS BGCs were enriched in the extremely long-lived, whereas cyclic-lactone-autoinducer BGCs were more prevalent in the young. Association analysis indicated that terpene BGCs were strongly associated with the abundance of Akkermansia muciniphila, which was also more abundant in the long-lived elderly across at least three cohorts. We assembled 18 A. muciniphila draft genomes using metagenomic data from the extremely long-lived group across six cohorts and discovered that they all harbor two classes of terpene BGCs, which aligns with the 97 complete genomes of A. muciniphila strains retrieved from the NCBI database. The core domains of these two BGC classes are squalene/phytoene synthases involved in the biosynthesis of tri- and tetraterpenes. Furthermore, the abundance of fecal A. muciniphila was significantly associated with eight types of triterpenoids. Targeted terpenoid metabolomic analysis revealed that two triterpenoids, Holstinone C and colubrinic acid, were enriched in the A. muciniphila culture solution compared to the medium, thereby confirming the production of triterpenoids by A. muciniphila. The natural products derived from the gut of long-lived populations provide intriguing indications of their potential beneficial roles in regulating health.

Abstract Cerebral amyloid angiopathy (CAA) is the leading cause of vascular dementia among the elderly. Neuropsychiatric symptoms are commonly manifested in cerebral amyloid angiopathy patients but are usually considered as consequences of cerebral amyloid angiopathy pathology. Here, it is reported that chronic stress promotes cerebral amyloid angiopathy progression, which enhances deposition of amyloid protein beta (Aβ) in brain blood vessels and exacerbates subsequent brain injury. Mechanistically, neutrophil is implicated in cerebral amyloid angiopathy development. Aβ that accumulates in brain vasculature induces neutrophil extracellular traps (NETs) by activating STAT6 signaling, which inhibits neutrophil apoptosis and switches the programmed cell death toward NETosis. During chronic stress, circulatory Norepinephrine (NE) strengthens STAT6 activation in neutrophil and promotes NET formation, thus exacerbates the NET‐dependent angiopathy. It is demonstrated that inhibiting neutrophil chemotaxis towards brain or suppressing NET formation both ameliorate cerebral amyloid angiopathy severity in the context of chronic stress. Therefore, it is proposed that stress‐associated psychological disorders and NETs are promising therapeutic targets in cerebral amyloid angiopathy.

Arteriosclerotic cerebral small vessel disease (aCSVD) is a major cause of stroke and dementia. Although its underlying pathogenesis remains poorly understood, both inflammaging and gut microbiota dysbiosis have been hypothesized to play significant roles. This study investigated the role of gut microbiota in the pathogenesis of aCSVD through a comparative analysis of the gut microbiome and metabolome between CSVD patients and healthy controls. The results showed that patients with aCSVD exhibited a marked reduction in potentially beneficial bacterial species, such as Faecalibacterium prausnitzli and Roseburia intestinalis, alongside an increase in taxa from Bacteroides and Proteobacteria. Integrated metagenomic and metabolomic analyses revealed that alterations in microbial metabolic pathways, including LPS biosynthesis and phenylalanine-tyrosine metabolism, were associated with the status of aCSVD. Our findings indicated that microbial LPS biosynthesis and phenylalanine-tyrosine metabolism potentially influenced the symptoms and progression of aCSVD via pro-inflammatory effect and modulation of systemic neurotransmitters, respectively. These results imply that gut microbiota characteristics may serve as indicators for early detection of aCSVD and as potential gut-directed therapeutic intervention target.

Background: The comorbidities of ischemic stroke (IS) are increasing worldwide. This study aimed to quantitatively assess the effect of different types of comorbidity on readmission and hospitalization expenditures of patients with IS. Methods: A retrospective observational study was conducted from the basic insurance claims database of a large city in China, between January 1, 2018, and May 31, 2022. We identified patients with IS aged 18 years and over, who experienced the first episode of IS and had one-year follow-up records. This study divided eighteen different comorbid conditions into two categories (concordant comorbidity and discordant comorbidity) and the IS patients were further categorized into four groups. Multivariable logistic regression models and generalized linear models with log-link and gamma distribution were to estimate the effect of different comorbidity groups on one-year readmission rates and annual hospitalization expenditures. Results: In total, 99,649 adult patients with IS were identified. Approximately 94.0 % of patients with IS had at least one comorbidity, and 63.8 % reported concordant comorbidity only. Patients with IS had a readmission rate of 26.7 %, and the mean of annual hospitalization expenditure and annual hospitalization out-of-pocket expenditure (OOPE) were 28086.6 Chinese Yuan (CNY) and 8267.3 CNY, respectively. After adjustment for covariates, the concordant comorbidity-only group had the highest readmission rate, annual hospitalization expenditure, and OOPE compared with the other groups, furthermore, these results increased as the number of comorbidity increased and had statistically significant positive associations. Conclusions: The readmission and annual hospitalization expenditures of patients with IS were associated with different comorbidities. Concordant comorbidity increased hospital readmission risk and health expenditures. To better manage the comorbidities of patients with IS, especially concordant comorbidities, it is necessary to establish a routine care strategy specifically for comorbid conditions.

Abstract Adaptive metabolic responses and innate metabolites hold promising therapeutic potential for stroke, while targeted interventions require a thorough understanding of underlying mechanisms. Adiposity is a noted modifiable metabolic risk factor for stroke, and recent research suggests that it benefits neurological rehabilitation. During the early phase of experimental stroke, the lipidomic results showed that fat depots underwent pronounced lipolysis and released fatty acids (FAs) that feed into consequent hepatic FA oxidation and ketogenesis. Systemic supplementation with the predominant ketone beta‐hydroxybutyrate (BHB) is found to exert discernible effects on preserving blood‐brain barrier (BBB) integrity and facilitating neuroinflammation resolution. Meanwhile, blocking FAO‐ketogenesis processes by administration of CPT1α antagonist or shRNA targeting HMGCS2 exacerbated endothelial damage and aggravated stroke severity, whereas BHB supplementation blunted these injuries. Mechanistically, it is unveiled that BHB infusion is taken up by monocarboxylic acid transporter 1 (MCT1) specifically expressed in cerebral endothelium and upregulated the expression of tight junction protein ZO‐1 by enhancing local β‐hydroxybutyrylation of H3K9 at the promoter of TJP1 gene. Conclusively, an adaptive metabolic mechanism is elucidated by which acute lipolysis stimulates FAO‐ketogenesis processes to restore BBB integrity after stroke. Ketogenesis functions as an early metabolic responder to restrain stroke progression, providing novel prospectives for clinical translation.

Abstract Background Cerebral microbleeds (CMBs) serve as neuroimaging biomarkers to assess risk of intracerebral hemorrhage and diagnose cerebral small vessel disease (CSVD). Therefore, detecting CMBs can evaluate the risk of intracerebral hemorrhage and use its presence to support CSVD classification, both are conducive to optimizing CSVD management. This study aimed to develop and test a deep learning (DL) model based on susceptibility-weighted MR sequence (SWS) to detect CMBs and classify CSVD to assist neurologists in optimizing CSVD management. Patients with arteriolosclerosis (aSVD), cerebral amyloid angiopathy (CAA), and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) treated at three centers were enrolled between January 2017 and May 2022 in this retrospective study. The SWSs of patients from two centers were used as the development set, and the SWSs of patients from the remaining center were used as the external test set. The DL model contains a Mask R-CNN for detecting CMBs and a multi-instance learning (MIL) network for classifying CSVD. The metrics for model performance included intersection over union (IoU), Dice score, recall, confusion matrices, receiver operating characteristic curve (ROC) analysis, accuracy, precision, and F1-score. Results A total of 364 SWS were recruited, including 336 in the development set and 28 in the external test set. IoU for the model was 0.523 ± 0.319, Dice score 0.627 ± 0.296, and recall 0.706 ± 0.365 for CMBs detection in the external test set. For CSVD classification, the model achieved a weighted-average AUC of 0.908 (95% CI 0.895–0.921), accuracy of 0.819 (95% CI 0.768–0.870), weighted-average precision of 0.864 (95% CI 0.831–0.897), and weighted-average F1-score of 0.829 (95% CI 0.782–0.876) in the external set, outperforming the performance of the neurologist group. Conclusion The DL model based on SWS can detect CMBs and classify CSVD, thereby assisting neurologists in optimizing CSVD management.

Abstract Background Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease that carries mutations in NOTCH3. The clinical manifestations are influenced by genetic and environmental factors that may include gut microbiome. Results We investigated the fecal metagenome, fecal metabolome, serum metabolome, neurotransmitters, and cytokines in a cohort of 24 CADASIL patients with 28 healthy household controls. The integrated-omics study showed CADASIL patients harbored an altered microbiota composition and functions. The abundance of bacterial coenzyme A, thiamin, and flavin-synthesizing pathways was depleted in patients. Neurotransmitter balance, represented by the glutamate/GABA (4-aminobutanoate) ratio, was disrupted in patients, which was consistent with the increased abundance of two major GABA-consuming bacteria, Megasphaera elsdenii and Eubacterium siraeum. Essential inflammatory cytokines were significantly elevated in patients, accompanied by an increased abundance of bacterial virulence gene homologs. The abundance of patient-enriched Fusobacterium varium positively correlated with the levels of IL-1β and IL-6. Random forest classification based on gut microbial species, serum cytokines, and neurotransmitters showed high predictivity for CADASIL with AUC = 0.89. Targeted culturomics and mechanisms study further showed that patient-derived F. varium infection caused systemic inflammation and behavior disorder in Notch3 R170C/+ mice potentially via induction of caspase-8-dependent noncanonical inflammasome activation in macrophages. Conclusion These findings suggested the potential linkage among the brain-gut-microbe axis in CADASIL. Video Abstract

Abstract Accumulation of amyloid beta protein (Aβ) in brain vessels damages blood brain barrier (BBB) integrity in cerebral amyloid angiopathy (CAA). Macrophage lineage cells scavenge Aβ and produce disease-modifying mediators. Herein, we report that Aβ40-induced macrophage-derived migrasomes are sticky to blood vessels in skin biopsy samples from CAA patients and brain tissue from CAA mouse models (Tg-SwDI/B and 5xFAD mice). We show that CD5L is packed in migrasomes and docked to blood vessels, and that enrichment of CD5L impairs the resistance to complement activation. Increased migrasome-producing capacity of macrophages and membrane attack complex (MAC) in blood are associated with disease severity in both patients and Tg-SwDI/B mice. Of note, complement inhibitory treatment protects against migrasomes-mediated blood-brain barrier injury in Tg-SwDI/B mice. We thus propose that macrophage-derived migrasomes and the consequent complement activation are potential biomarkers and therapeutic targets in CAA.

Abstract Background Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a severe autoimmune neuropsychiatric disease. Brain access of anti-NMDAR autoantibody through the blood–brain barrier (BBB) is essential for pathogenesis. Most previous animal models limit the investigation of etiologies of BBB damage in patients. Methods In this study, we established a novel humanized mouse model of anti-NMDAR encephalitis by intraperitoneal injection of patients’ peripheral blood mononuclear cells (PBMCs) into BALB/c Rag2 −/− Il2rg −/− Sirpα NOD Flk2 −/− mice. Results We found that engraftment of patients’ PBMCs not only produced potent anti-GluN1 autoantibodies, but also disrupted BBB integrity to allow brain access of autoantibodies, resulting in a hyperactive locomotor phenotype, anxiety- and depressive-like behaviors, cognitive deficits, as well as functional changes in corresponding brain regions. Transcriptome analysis suggested an exaggerated immune response and impaired neurotransmission in the mouse model and highlighted Il-1β as a hub gene implicated in pathological changes. We further demonstrated that Il-1β was produced by endothelial cells and disrupted BBB by repressing tight junction proteins. Treatment with Anakinra, an Il-1 receptor antagonist, ameliorated BBB damage and neuropsychiatric behaviors. Conclusions Our study provided a novel and clinically more relevant humanized mouse model of anti-NMDAR encephalitis and revealed an intrinsic pathogenic property of the patient’s lymphocytes.

Abstract Background and objective The pathogenesis and pathophysiology of idiopathic normal pressure hydrocephalus (iNPH) remain unclear. Homocysteine may reduce the compliance of intracranial arteries and damage the endothelial function of the blood-brain barrier (BBB), which may be the underlying mechanism of iNPH. The overlap cases between deep perforating arteriopathy (DPA) and iNPH were not rare for the shared risk factors. We aimed to investigate the relationship between serum homocysteine and iNPH in DPA. Methods A total of 41 DPA patients with iNPH and 49 DPA patients without iNPH were included. Demographic characteristics, vascular risk factors, laboratory results, and neuroimaging data were collected. Multivariable logistic regression analysis was performed to investigate the relationship between serum homocysteine and iNPH in DPA patients. Results Patients with iNPH had significantly higher homocysteine levels than those without iNPH (median, 16.34 mmol/L versus 14.28 mmol/L; P = 0.002). There was no significant difference in CSVD burden scores between patients with iNPH and patients without iNPH. Univariate logistic regression analysis demonstrated that patients with homocysteine levels in the Tertile3 were more likely to have iNPH than those in the Tertile1 (OR, 4.929; 95% CI, 1.612–15.071; P = 0.005). The association remained significant after multivariable adjustment for potential confounders, including age, male, hypertension, diabetes mellitus, atherosclerotic cardiovascular disease (ASCVD) or hypercholesterolemia, and eGFR level. Conclusion Our study indicated that high serum homocysteine levels were independently associated with iNPH in DPA. However, further research is needed to determine the predictive value of homocysteine and to confirm the underlying mechanism between homocysteine and iNPH.

Wire icing events pose a significant threat to the southern power grid’s transmission lines in China. Fifteen such events were identified from 2018 to 2020 on the Guilin-Haiyang Mountain transmission line. Hourly measurements of ice thickness and concurrent meteorological data were analyzed using the Makkonen model’s freezing rate formula to categorize the events into distinct growth patterns: dry and wet. The relationship between wire icing and meteorological factors across different micro-topography (windward slope, leeward slope, and pass) was further explored. Several key conclusions can be drawn. First, the altitude is positively correlated to the icing thickness, but relatively independent of the icing rate; however, such independence between the icing rate and altitude cannot be interpreted by the negative correlation of altitude with temperature and the positive relationship between wind speed and liquid water content. Second, a pronounced connection of the icing rate with meteorological factors is not shown until the wet and dry patterns are separated. Notably, the correlations differ between these two patterns, with icing rate being negatively correlated with temperature for the wet growth process, but positively correlated with wind speed and liquid water content for the dry growth process. Third, both wet and dry growth processes exist across the icing events. A shift from wet to dry growth was evident with increasing altitude. At the mountain’s base, wet growth predominates, with the icing rate determined by the temperature close to the freezing point, whereas the higher temperature and lower liquid water flux account for the shorter wire icing duration, lower icing rate, and thus the thinner icing thickness at the leeward slope compared to the windward slope at a similar altitude. This study sheds light on the variations in icing rates under different micro-topographies and the underlying physical mechanisms governing icing growth patterns and provides a much-needed understanding of these distinct growth processes on the development of a more sophisticated predictive model for conductor icing.

Severe wind gusts produced by squall lines are difficult to monitor and forecast. This paper assessed and improved the physics-based Brasseur WGE (wind gust estimate) method for diagnosing wind gust of squall lines by coupling the WGE methods with the WRF (Weather Research and Forecasting) model. The simulation results show that the Brasseur WGE method accurately captured the strong gust feature with 32 m·s−1 maximum wind speed during the disastering Shipwreck event occurred over Yangtze River on 1 June 2015, but overestimated the extended area of severe gust speeds. Analysis of the kinematic structure and boundary-layer conditions of the squall line confirmed the theoretical applicability of the Brasseur WGE method for squall lines. A novel gust-front-area limiting method was introduced to modify the Brasseur WGE method, which effectively reduces its gust wind overestimation area. Furthermore, five squall line events occurred in the middle China during 2021 were simulated to test the modified WGE method and the results exhibit significant improvements to the wind gust forecasts, with an average false alarm rate decreased from 0.89 to 0.54, and the critical success index(CSI) increased from 0.1 to 0.4.

Summary: Cognitive impairment has been associated with an age-related decline in adult hippocampal neurogenesis (AHN). The molecular basis of declining neurogenesis in the aging hippocampus remains to be elucidated. Here, we show that pleiotrophin (PTN) expression is decreased with aging in neural stem and progenitor cells (NSPCs). Mice lacking PTN exhibit impaired AHN accompanied by poor learning and memory. Mechanistically, we find that PTN engages with protein tyrosine phosphatase receptor type Z1 (PTPRZ1) to promote NSPC proliferation and differentiation by activating AKT signaling. PTN overexpression or pharmacological activation of AKT signaling in aging mice restores AHN and alleviates relevant memory deficits. Importantly, we also find that PTN overexpression improves impaired neurogenesis in senescence-accelerated mouse prone 8 (SAMP8) mice. We further confirm that PTN is required for enriched environment-induced increases in AHN. These results corroborate the significance of AHN in aging and reveal a possible therapeutic intervention by targeting PTN.

Abstract Background Previous studies on unilateral internal carotid artery occlusive disease have focused on the mechanisms of ipsilateral hemispheric stroke, and contralateral stroke is considered to be an accidental phenomenon. Little is known about the relationship between severe stenosis (including occlusion) of the unilateral extracranial segment of the internal carotid artery and contralateral cerebral stroke, and the infarct patterns and pathogenesis require further study. The purpose of this study was to investigate the clinical characteristics and pathogenesis of contralateral acute stroke with unilateral extracranial internal carotid artery stenosis (including occlusion). Methods Thirty‐four patients were enrolled in this study, and all patients underwent routine clinical evaluation, including medical history, physical examination, laboratory tests, and various imaging evaluations. The morphological characteristics of diffusion‐weighted magnetic resonance imaging were applied to determine infarct patterns. The etiological classification was confirmed according to the TOAST classification. Results There were six distinctive lesion patterns: small subcortical infarcts (six patients), large subcortical infarcts (one patient), diffuse infarcts (eight patients), multiple anterior circulation infarcts (eight patients), multiple posterior circulation infarcts (two patients), and multiple anterior and posterior circulation infarcts (nine patients). Conclusion Diffuse and multiple infarcts were the most common topographic patterns in ischemic stroke contralateral to internal carotid artery stenosis or occlusion. Hemodynamic impairment of the contralateral hemisphere due to hypoperfusion and blood theft is regarded as the basis of stroke occurrence. Low ischemic tolerance and embolism are the main causes of acute ischemic stroke.

Abstract Pneumonia is one of the leading causes of death in patients with acute ischemic stroke (AIS). Antibiotics fail to improve prognosis of patients with post‐stroke pneumonia, albeit suppressing infection, due to adverse impacts on the immune system. The current study reports that bone marrow mesenchymal stem cells (BM‐MSC) downregulate bacterial load in the lungs of stroke mice models. RNA‐sequencing of the lung from BM‐MSC‐treated stroke models indicates that BM‐MSC modulates pulmonary macrophage activities after cerebral ischemia. Mechanistically, BM‐MSC promotes the bacterial phagocytosis of pulmonary macrophages through releasing migrasomes, which are migration‐dependent extracellular vesicles. With liquid chromatography‐tandem mass spectrometry (LC‐MS/MS), the result shows that BM‐MSC are found to load the antibacterial peptide dermcidin (DCD) in migrasomes upon bacterial stimulation. Besides the antibiotic effect, DCD enhances LC3‐associated phagocytosis (LAP) of macrophages, facilitating their bacterial clearance. The data demonstrate that BM‐MSC is a promising therapeutic candidate against post‐stroke pneumonia, with dual functions of anti‐infection and immunol modulation, which is more than a match for antibiotics treatment.

Objectives The aims of the study were to assess the management of low-density lipoprotein cholesterol (LDL-C) and the goal achievement, as well as to investigate the association between baseline LDL-C level, lipid-lowering treatment (LLT), and stroke recurrence in patients with ischaemic stroke or transient ischaemic attack (TIA).Design Our study was a post hoc analysis of the Third China National Stroke Registry (CNSR-III).Setting We derived data from the CNSR-III - a nationwide clinical registry of ischaemic stroke and TIA based on 201 participating hospitals in mainland China.Participants 15,166 patients were included in this study with demographic characteristics, etiology, imaging, and biological markers from August 2015 to March 2018.Primary and secondary outcome measures The primary outcome was a new stroke, LDL-C goal (LDL-C

Abstract Background A high-salt diet (HSD) is one of the major risk factors for acute ischemic stroke (AIS). As a potential mechanism, surplus salt intake primes macrophages towards a proinflammatory phenotype. In this study, whether HSD could blunt the efferocytic capability of macrophages after ischemic stroke, thus exacerbating post-stroke neural inflammation, was investigated. Methods Wild-type male C57BL/6 mice were fed with fodder containing 8% sodium chloride for 4 weeks and subjected to transient middle cerebral occlusion (tMCAO). Disease severity, macrophage polarization as well as efferocytic capability were evaluated. Bone marrow-derived macrophages were cultured in vitro, and the impact of high salinity on their efferocytic activity, as well as their expression of phagocytic molecules, were analyzed. The relationships among sodium concentration, macrophage phenotype, and disease severity in AIS patients were explored. Results HSD-fed mice displayed increased infarct volume and aggravated neurological deficiency. Mice fed with HSD suffered exacerbated neural inflammation as shown by higher inflammatory mediator expression and immune cell infiltration levels. Infiltrated macrophages within stroke lesions in HSD-fed mice exhibited a shift towards proinflammatory phenotype and impaired efferocytic capability. As assessed with a PCR array, the expression of triggering receptor expressed on myeloid cells 2 (TREM2), a receptor relevant to phagocytosis, was downregulated in high-salt-treated bone marrow-derived macrophages. Enhancement of TREM2 signaling restored the efferocytic capacity and cellular inflammation resolution of macrophages in a high salinity environment in vitro and in vivo. A high concentration of urine sodium in AIS patients was found to be correlated with lower TREM2 expression and detrimental stroke outcomes. Conclusions HSD inhibited the efferocytic capacity of macrophages by downregulating TREM2 expression, thus impeding inflammation resolution after ischemic stroke. Enhancing TREM2 signaling in monocytes/macrophages could be a promising therapeutic strategy to enhance efferocytosis and promote post-stroke inflammation resolution.

Abstract Background Systemic cardiac hypoperfusion is a well-acknowledged contributor to ischemic leukoencephalopathy. However, it has remained elusive how atherosclerosis-mediated cardiac remodelling modifies cerebral perfusion homeostasis as well as neuroimaging burden in cerebral small vessel disease (CSVD) development. Methods This retrospective study identified 103 arteriosclerotic CSVD (aCSVD) patients (CSVD burdenlow 0 ~ 1, n = 61 and CSVD burdenhigh 2 ~ 4, n = 42) from Sep. 2017 to Dec. 2019 who underwent transthoracic echocardiography(n = 81), structural magnetic resonance imaging and arterial spin labelling (ASL). Total CSVD burden was graded according to the ordinal “small vessel disease” rating score (0–4). We investigated the univariate and multivariate linear regression of mean deep regional cerebral blood flow (CBF) as well as logistic regression analysis of CSVD burdenhigh. Results Right atrial diameter (B coefficient, − 0.289; 95% CI, − 0.578 to − 0.001; P = 0.049) and left ventricular ejection fraction (B coefficient, 32.555; 95% CI, 7.399 to 57.711; P = 0.012) were independently associated with deep regional CBF in aCSVD patients. Binary logistic regression analysis demonstrated decreased deep regional CBF (OR 0.894; 95% CI 0.811–0.985; P = 0.024) was independently associated with higher CSVD burden after adjusted for clinical confounders. Multivariate receiver operating characteristics curve integrating clinical risk factors, mean deep CBF and echocardiographic parameters showed predictive significance for CSVD burdenhigh diagnosis (area under curve = 84.25, 95% CI 74.86–93.65%, P

Abstract Paraneoplastic autoimmune encephalitis (PAE) represents a group of rare neurological syndromes associated with neoplastic diseases. Here, we report a case that multiple anti‐neuronal antibodies were present in a patient with PAE who developed both small cell lung cancer and colorectal adenocarcinoma. Furthermore, the immunopathological investigation of the colorectal adenocarcinoma revealed the formation of abnormal neuronal antigens and a massive infiltration of plasma cells in the tumor tissue. These findings support the hypothesis that expression of neuronal antigens in neoplasm initiates autoimmune responses in PAE.

Abstract Background Early stage neuromyelitis optica spectrum disorders (NMOSD) with non-opticospinal manifestations as initial symptoms are easily misdiagnosed; however, data on the full symptom profile are limited. Moreover, the clinical characteristics and long-term outcomes of these patients remain unknown. We sought to analyze the clinical characteristics, imaging features, and long-term outcomes of NMOSD with non-opticospinal manifestations as initial symptoms. Methods We retrospectively included relevant patients from our center. Clinical, demographic, magnetic resonance imaging, treatment, and outcome data were compared according to the non-opticospinal vs. opticospinal initial symptoms. Results We identified 43 (9.13 %) patients with non-opticospinal initial symptoms among 471 patients with NMOSD. Of these, 88.37 % developed optic neuritis/myelitis during an average follow-up period of 6.33 years. All the non-opticospinal symptoms were brain/brainstem symptoms. Most of the symptoms and associated brain lesions were reversible. These patients had a younger onset age (P

Abstract Background Sleep fragmentation was shown to be positively associated with cognitive impairment in patients with cerebral small vessel disease (CSVD); however, the underlying mechanisms are not well characterized. In this study, we sought to clarify this issue by investigating the relationship between non breathing-related sleep fragmentation and brain imaging markers in patients with CSVD. Methods Eighty-four CSVD patients and 24 age- and sex-matched healthy controls were prospectively recruited. All subjects underwent 3.0 T superconducting magnetic resonance imaging and overnight polysomnography. Polysomnography parameters including sleep onset latency (SOL), total sleep time (TST); sleep efficiency (SE), wake after sleep onset (WASO), percentage of each sleep stage (N1, N2, N3 and rapid eye movement [REM]), arousal index (ArI), periodic limb movement in sleep index (PLSMI), and periodic limb movement related arousal index (PLMAI) were compared between CSVD patients and healthy controls. The relationship between arousal index and CSVD markers was explored in the CSVD group. Results On polysomnography, CSVD patients showed significantly higher ArI, WASO, PLSMI, and PLMAI, and lower sleep efficiency and N− 3 ratio compared to healthy controls (p

Background Small single subcortical infarction (SSSI) may be classified as parent artery disease-related or only branch involved according to the stenosis of parent artery. The study aimed to evaluate short-term and long-term prognoses and the effectiveness of antiplatelet therapy in SSSI.Methods We prospectively enrolled 2890 patients with SSSI from the Third China National Stroke Registry (CNSR-III) database from August 2015 to March 2018. We assessed clinical outcomes and antiplatelet treatment effects in patients with SSSI with and without parent artery stenosis (PAS) identified by magnetic resonance angiography.Results Among 2890 patients with SSSI in the perforator territory of the middle cerebral artery and the basilar artery, there were 680 (23.53%) patients with PAS and 2210 (76.47%) patients without PAS, respectively. After adjusting for potential confounders, the PAS group had a greater initial stroke severity (OR 1.262, 95% CI 1.058 to 1.505; p=0.0097) and a higher risk of ischaemic stroke recurrence at 3 months (OR 2.266, 95% CI 1.631 to 3.149; p

Abstract Background Preserving the integrity of the blood-brain barrier (BBB) is beneficial to avoid further brain damage after acute ischemic stroke (AIS). Astrocytes, an important component of the BBB, promote BBB breakdown in subjects with AIS by secreting inflammatory factors. The glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4 (Ex-4) protects the BBB and reduces brain inflammation from cerebral ischemia, and GLP-1R is expressed on astrocytes. However, the effect of Ex-4 on astrocytes in subjects with AIS remains unclear. Methods In the present study, we investigated the effect of Ex-4 on astrocytes cultured under oxygen-glucose deprivation (OGD) plus reoxygenation conditions and determined whether the effect influences bEnd.3 cells. We used various methods, including permeability assays, western blotting, immunofluorescence staining, and gelatin zymography, in vitro and in vivo. Results Ex-4 reduced OGD-induced astrocyte-derived vascular endothelial growth factor (VEGF-A), matrix metalloproteinase-9 (MMP-9), chemokine monocyte chemoattractant protein-1 (MCP-1), and chemokine C-X-C motif ligand 1 (CXCL-1). The reduction in astrocyte-derived VEGF-A and MMP-9 was related to the increased expression of tight junction proteins (TJPs) in bEnd.3 cells. Ex-4 improved neurologic deficit scores, reduced the infarct area, and ameliorated BBB breakdown as well as decreased astrocyte-derived VEGF-A, MMP-9, CXCL-1, and MCP-1 levels in ischemic brain tissues from rats subjected to middle cerebral artery occlusion. Ex-4 reduced the activation of the JAK2/STAT3 signaling pathway in astrocytes following OGD. Conclusion Based on these findings, ischemia-induced inflammation and BBB breakdown can be improved by Ex-4 through an astrocyte-dependent manner.

Abstract Background and purpose Regulation of neural inflammation is considered as a vital therapeutic target in ischemic stroke. All-trans retinoic acid (atRA), a potent immune modulator, has raised interest in the field of stroke therapy. However, the immunological mechanisms for atRA-mediated neuroprotection remain elusive. The current study evaluated the impact of atRA on post-stroke neural inflammation and elucidated the mechanisms involved in the regulation of related neutrophil functions. Methods atRA was prophylactically administered to mice 1 day before transient middle cerebral artery occlusion (tMCAO, 1 h) and repeated daily immediately after reperfusion for 3 days. Stroke outcomes, neutrophil polarization, and formation of neutrophil extracellular traps (NETs) in the stroke lesion were assessed. Neutrophil depletion was induced with anti-Ly6G antibodies. Primary neutrophil cultures were used to explore the mechanisms of atRA treatment. Results Prophylactic atRA treatment reduced infarct volumes and neurological deficits at 1 day after tMCAO. Post-stroke neural inflammation was attenuated and neutrophil accumulation in lesion was downregulated. atRA treatment skewed neutrophil toward N2 phenotype which facilitated its clearance by macrophage and inhibited NETs formation. The functions of neutrophil were indispensable in the protective effects of atRA and were associated with suppression to STAT1 signaling by atRA. Administration of atRA after stroke still provided efficient protection to cerebral ischemia. Conclusion atRA displays potent therapeutic efficacy in ischemic stroke by attenuating neural inflammation. Treatment of atRA impeded neutrophil accumulation, favored N2 polarization, and forbade NETs formation in ischemic lesion. STAT1 signaling played a decisive role in the mechanisms of atRA-afforded regulation to neutrophil.

Abstract Background Loss-of-function mutations in the CLCN2 gene were recently discovered to be a cause of a type of leukodystrophy named CLCN2-related leukoencephalopathy (CC2L), which is characterized by intramyelinic edema. Herein, we report a novel mutation in CLCN2 in an individual with leukodystrophy. Case presentation A 38-year-old woman presented with mild hand tremor, scanning speech, nystagmus, cerebellar ataxia in the upper limbs, memory decline, tinnitus, and dizziness. An ophthalmologic examination indicated macular atrophy, pigment epithelium atrophy and choroidal capillary atrophy. Brain magnetic resonance imaging (MRI) showed the diffuse white matter involvement of specific white matter tracts. Decreased diffusion anisotropy was detected in various brain regions of the patient. Diffusion tensor tractography (DTT) showed obviously thinner tracts of interest than in the controls, with a decreased fiber number (FN), increased radial diffusivity (RD) and unchanged axial diffusivity (AD). A novel homozygous c.2257C > T (p.Arg753Ter) mutation in exon 20 of the CLCN2 gene was identified. Conclusion CC2L is a rare condition characterized by diffuse edema involving specific fiber tracts that pass through the brainstem. The distinct MRI patterns could be a strong indication for CLCN2 gene analysis. The findings of our study may facilitate the understanding of the pathophysiology and clinical symptoms of this disease.

ObjectiveTo explore the outcomes of NMOSD attacks and investigate serum biomarkers for prognosis and severity.MethodPatients with NMOSD attacks were prospectively and observationally enrolled from January 2019 to December 2020 at four hospitals in Guangzhou, southern China. Data were collected at attack, discharge and 1/3/6 months after acute treatment. Serum cytokine/chemokine and neurofilament light chain (NfL) levels were examined at the onset stage.ResultsOne hundred patients with NMOSD attacks were included. The treatment comprised intravenous methylprednisolone pulse therapy alone (IVMP, 71%), IVMP combined with apheresis (8%), IVMP combined with intravenous immunoglobulin (18%) and other therapies (3%). EDSS scores decreased significantly from a medium of 4 (interquartile range 3.0–5.5) at attack to 3.5 (3.0–4.5) at discharge, 3.5 (2.0–4.0) at the 1-month visit and 3.0 (2.0–4.0) at the 3-month visit (p

Stereotactic biopsies for lesions in the brainstem and deep brain are rare. This study aimed to summarize our 6-year experience in the accurate diagnosis of lesions in the brain stem and deep brain and to discuss the technical note and strategies. From December 2011 to January 2018, 72 cases of intracranial lesions in the brainstem or deep in the lobes undergoing stereotactic biopsy were retrospectively reviewed. An individualized puncture path was designed based on the lesion's location and the image characteristics. The most common biopsy targets were deep in the lobes (43 cases, 59.7%), including frontal lobe (33 cases, 45.8%), temporal lobe (4 cases, 5.6%), parietal lobe (3 cases, 4.2%), and occipital lobe (3 cases, 4.2 %). There were 12 cases (16.7%) of the brainstem, including 8 cases (11.1%) of midbrain, and 4 cases (5.6%) of pons or brachium pontis. Other targets included internal capsule (2 cases, 2.8%), thalamus (3 cases, 4.2%), and basal ganglion (12 cases, 16.7%). As for complications, one patient developed acute intracerebral hemorrhage in the biopsy area at 2 h post-operation, and one patient had delayed intracerebral hemorrhage at 7 days post-operation. The remaining patients recovered well after surgery. There was no surgery-related death. The CT-MRI-guided stereotactic biopsy of lesions in the brainstem or deep in the brain has the advantages of high safety, accurate diagnosis, and low incidence of complications. It plays a crucial role in the diagnosis of atypical, microscopic, diffuse, multiple, and refractory lesions.

Background: The inflammasome represents a highly pro-inflammatory mechanism. It has been identified that inflammasome was activated after ischemic stroke. However, the impact of inflammasomes on stroke outcomes remains contradictory. The participating molecules and the functioning arena of post-stroke inflammasome activation are still elusive.Methods: In the present study, blood samples from stroke patients were collected and analyzed with flow cytometry to evaluate the correlation of inflammasome activation and stroke outcomes. A stroke model was established using male C57/Bl6 mice with transient middle cerebral artery occlusion (tMCAO, 1 h). The dynamics of inflammasome components, cell type, and location of inflammasome activation and the therapeutic effects of inhibiting post-stroke inflammasome executors were evaluated.Results: We found that a high level of inflammasome activation might indicate detrimental stroke outcomes in patients and mice models. Post-stroke inflammasome activation, especially NLRP3, cleaved Caspase-1, cleaved Caspase-11, IL-1β, IL-18, and GSDMD, peaked at 3–5 days and declined at 7 days with the participation of multiple components in mice. Macrophage that infiltrated into the ischemic lesion was the main arena for post-stroke inflammasome activation among myeloid cells according to the data of mice. Among all the members of the Caspase family, Caspase-1 and −11 served as the main executing enzymes. Inhibiting Caspase-1/−11 signaling efficiently suppressed DAMPs-induced macrophage inflammasome activation and displayed neuroprotection to stroke models including infarct size (Control: 48.05 ± 14.98; Cas1.i: 19.34 ± 12.21; Cas11.i: 21.43 ± 14.67, P < 0.001) and neurological deficit score (0 d-Control: 2.20 ± 0.63; 0 d-Cas1.i: 2.20 ± 0.63; 0 d-Cas11.i: 2.20 ± 0.63; 1 d-Control: 2.50 ± 0.53; 1 d-Cas1.i: 1.50 ± 0.71; 1 d-Cas11.i: 2.00 ± 0.67; 2 d-Control: 2.30 ± 0.48; 2 d-Cas1.i: 1.30 ± 0.48; 2 d-Cas11.i: 1.50 ± 0.53; 3 d-Control: 2.00 ± 0.67; 3 d-Cas1.i: 1.20 ± 0.42; 3 d-Cas11.i: 1.30 ± 0.48, P < 0.001).Conclusions: Taken together, inflammasome activation played a detrimental role in stroke pathology. Targeting post-stroke inflammasome executing enzymes fitting in the dynamics of macrophages might obtain potential and efficient therapeutic effects.

Central nervous system immune reconstitution inflammatory syndrome (CNS-IRIS) describes clinical characteristics that may be observed in previously immunocompromised patients during rapid restoration of immunity function in the presence of a pathogen. There have been no reports about CNS-IRIS related to bacterial meningitis so far. Here, we report a 24-year-old pregnant female patient with bacterial meningitis. Her clinical and neuroradiological condition worsened after induced labor despite great effective anti-infective therapy. CNS-IRIS was considered. Corticosteroids were administered, and the patient gradually recovered. We present the first case of CNS-IRIS associated with bacterial meningitis.

Aging of the central nervous system (CNS) is closely associated with chronic sterile low-grade inflammation in older organisms and related immune response. As an amplifier for neuro-inflammaging, immunosenescence remodels and deteriorates immune systems gradually with the passage of time, and finally contributes to severe outcomes like stroke, dementia and neurodegeneration in elderly adults. Cerebral small vessel disease (CSVD), one of the major causes of vascular dementia, has an intensive connection with the inflammatory response and immunosenescence plays a crucial role in the pathology of this disorder. In this review, we discuss the impact of immunosenescence on the development of CSVD and its underlying mechanism. Furthermore, the clinical practice significance of immunosenescence management and the diagnosis and treatment of CSVD will be also discussed.

Neuroinflammation plays a crucial role in the development and progression of Alzheimer's disease (AD), in which activated microglia are found to be associated with neurodegeneration. However, there is limited evidence showing how neuroinflammation and activated microglia are directly linked to neurodegeneration in vivo. Besides, there are currently no effective anti-inflammatory drugs for AD. In this study, we report on an effective anti-inflammatory lipid, linoleic acid (LA) metabolite docosapentaenoic acid (DPAn-6) treatment of aged humanized EFAD mice with advanced AD pathology. We also report the associations of neuroinflammatory and/or activated microglial markers with neurodegeneration in vivo. First, we found that dietary LA reduced proinflammatory cytokines of IL1-β, IL-6, as well as mRNA expression of COX2 toward resolving neuroinflammation with an increase of IL-10 in adult AD models E3FAD and E4FAD mice. Brain fatty acid assays showed a five to six-fold increase in DPAn-6 by dietary LA, especially more in E4FAD mice, when compared to standard diet. Thus, we tested DPAn-6 in aged E4FAD mice. After DPAn-6 was administered to the E4FAD mice by oral gavage for three weeks, we found that DPAn-6 reduced microgliosis and mRNA expressions of inflammatory, microglial, and caspase markers. Further, DPAn-6 increased mRNA expressions of ADCYAP1, VGF, and neuronal pentraxin 2 in parallel, all of which were inversely correlated with inflammatory and microglial markers. Finally, both LA and DPAn-6 directly reduced mRNA expression of COX2 in amyloid-beta42 oligomer-challenged BV2 microglial cells. Together, these data indicated that DPAn-6 modulated neuroinflammatory responses toward resolution and improvement of neurodegeneration in the late stages of AD models.

Cerebrovascular disease (CeVD) is one of the leading global causes of death and severe disability. To date, retinal microangiopathy has become a reflection of cerebral microangiopathy, mirroring the vascular pathological modifications in vivo. To evaluate the retinal structure and microvasculature in patients with CeVD, we conducted a cross-sectional study in Zhongshan Ophthalmic Center and Department of Neurology of Third Affiliated Hospital, Sun Yat-sen University using optical coherence tomography angiography (OCTA). CeVD patients (n = 121; 238 eyes) and healthy controls (n = 44; 57 eyes) were included in the analysis. The CeVD group showed significant thinning of the peripapillary retinal nerve fiber layer (pRNFL) thickness in the temporal and nasal quadrants, and thinning of the macular ganglion cell-inner plexiform layer (GC-IPL) in the inferior quadrant, while macular microvasculature reduction was prominent in all nine quadrants. There were significant correlations between OCTA parameters, visual acuity, and transcranial doppler parameters in the CeVD group. The specific structural parameters combining microvasculature indices showed the best diagnostic accuracies (AUC = 0.918) to discriminate CeVD group from healthy controls. To conclude, we proved that OCTA reveals specific patterns of retinal structural changes and extensive macular microvascular changes in CeVD. Additionally, these retinal abnormalities could prove useful disease biomarkers in the management of individuals at high risk of debilitating complications from a cerebrovascular event.

Objective: The triglyceride-glucose (TyG) index is a reliable surrogate of insulin resistance and a marker for ischemic stroke (IS) incident. Whether the TyG index predicts stroke outcome remains uncertain. This study investigated the prognostic value of the TyG index in critically ill stroke patients.Methods: This was a retrospective observational study that included stroke patients, and all data were extracted from the eICU Collaborative Research Database. The TyG index was calculated as the ln [fasting glucose level (mg/dL) × triglyceride level (mg/dL)/2]. Outcomes included the hospital and intensive care unit (ICU) death. Multivariate logistic regression was used to determine independent risk factors. The smoothing curves and forest plots were illustrated.Results: A total of 4,570 eligible subjects were enrolled. The mean level of TyG index was 9.1 ± 0.7. The hospital and ICU mortality rate were 10.3 and 5.0%, respectively. TyG index as a continuous variable was associated hospital mortality in univariate analysis (OR 1.723, 95% CI 1.524–1.948, P < 0.001), adjusted model 1 (OR 1.861, 95% CI 1637–2.116, P < 0.001), and adjusted model 2 (OR 2.543, 95% CI 1.588–4.073, P < 0.001). TyG was also associated ICU mortality in univariate analysis (OR 2.146, 95% CI 1.826–2.523, P < 0.001), adjusted model 1 (OR 2.183, 95% CI 1.847–2.580, P < 0.001), and adjusted model 2 (OR 2.672, 95% CI 1.376–5.188, P < 0.001). The smoothing curves observed a continuous linear association after adjusting all covariates both in hospital and ICU mortality. Subgroup analysis demonstrated TyG index was associated with increased risk of hospital and ICU death in critically ill IS (P < 0.05), but not in hemorrhage stroke (P > 0.05).Conclusion: The TyG index is a potential predictor for hospital and ICU mortality in critically ill stroke patients, especially in IS patients.

BackgroundChronic insomnia is common in patients with arteriosclerotic cerebral small vessel disease (CSVD) and aggravates the cognitive impairment caused by CSVD. Low-dose trazodone is effective in treating insomnia, but it is unclear whether it can also improve cognitive function in CSVD patients. This study was performed to explore the effects of trazodone on sleep quality and cognitive function in CSVD comorbid with chronic insomnia.MethodsThis was a randomized, double-blind, placebo-controlled pilot study. Forty patients suffering from arteriosclerotic CSVD and insomnia were recruited from an outpatient clinic. Participants were randomized individually to receive either trazodone (study group) or a placebo (control group) for 4 weeks. The primary outcome was the cognitive score on the Montreal Cognitive Assessment scale (MoCA). Secondary outcomes included sleep parameters measured with polysomnography (PSG) and the Pittsburgh Sleep Quality Index.ResultsTrazodone caused significantly better improvements in concentration and recall abilities, measured with MoCA, as well as in PSG parameters such as sleep efficiency, N3 sleep ratio, and sleep continuity than the placebo, with no significant differences in the occurrence of side effects. The improvement of sleep quality was correlated with increased concentration and recall abilities.ConclusionsA low dose of trazodone seems acceptable and effective in reducing insomnia severity and improving concentration and recall abilities in this pilot study. The improvement of cognition could be achieved by alleviation of insomnia severity. Considering the high incidence of insomnia in CSVD patients, the results of this preliminary study support the use of low-dose trazodone to deal with insomnia and cognitive impairment in CSVD.

Abstract Background Besides CSF-flow obstruction, syringomyelia is associated with inflammatory spinal cord lesions. However, syringomyelia-like syndrome concomitant with neuromyelitis optica spectrum disorder (NMOSD) and primary Sjogren’s syndrome (pSS) is extremely rare. Here, we would like to report a case of a patient with syringomyelia-like syndrome in NMOSD complicated with Sjogren’s Syndrome. Case presentation A 64-old male Han Chinese, presented with three episodes of acute demyelinating processes in the central nervous system within 5 years. Firstly, he presented with ascending left lower extremity weakness and numbness, and initially progressive loss of vision in the right eye before 5 years, and subsequently in the right eye 2 months later. High dose corticosteroid therapy was prescribed for this attack. Second, he suffered from refractory gastrointestinal symptoms. such as nausea, vomiting, abdominal pain and early satiety. After the second episode, he received long-term azathioprine and prednisone treatment in low dosages. Six months before admission, he developed the lower back pain and numbness in lower limbs, and urinary incontinence. This time, he complained of acute onset of right lower limb paralysis, paresthesia and urinary incontinence. MRI of the spine revealed a syringomyelia extending from the C7 to T4 levels with serum positive anti-aquaporin-4 antibodies (AQP4-Ab) (indirect immunofluorescence on AQP4 transfected cells). he was serologically positive for both anti-Sjögren’s syndrome-related antigen A and B antibodies and there was reduced salivary flow on scintigraphy. Lip salivary gland (LSG) biopsies were graded (grade four lymphocytic infiltration) according to the Chisholm and Mason classification system and by morphometric analysis. And finally, diagnosed as syringomyelia-like syndrome in NMOSD complicated with Sjogren’s syndrome. Conclusions Although extremely rare, This index patient highlights that syringomyelia could be associated with underlying NMOSD and pSS, and autoimmune disorders should be considered in the initial differential diagnosis, This is very helpful for the therapeutic implications and evaluating curative effect.

Background/Aims: Atherosclerosis, a multifactorial chronic disease, is the main cause of death and impairment in the world. Endothelial cells (ECs) apoptosis plays a crucial role in the onset and development of atherosclerosis, whereas the underlying molecular mechanisms are unclear. MicroRNA-142-3p (miR-142-3p) is a well-defined tumor suppressor in several types of cancer, while the role of miR-142-3p in ECs apoptosis and the development of atherosclerosis has yet to be elucidated. Therefore, the present study aimed to investigate the role of miR-142-3p in ECs apoptosis during atherosclerosis and the underlying mechanism. Methods: Human aortic endothelial cells (HAECs) were treated with oxidized low-density lipoprotein (ox-LDL). The expression level of miR-142-3p was detected using qRT-PCR. Apoptosis was determined via flow cytometry and Caspase-3 activity assay. Prediction of the binding between miR-142-3p and 3’-UTR of Rictor mRNA was performed by bioinformatics analyses and confirmed by a dual luciferase reporter assay. The effects of miR-142-3p on endothelial apoptosis and atherosclerosis were further analyzed in an in vivo model using ApoE-/- mice fed with high-fat diet (HFD). Results: MiR-142-3p expression was substantially up-regulated during the ox-LDL-elicited apoptosis in HAECs. Forced expression of miR-142-3p exacerbated apoptosis in ECs whereas inhibition of miR-142-3p could partly alleviate apoptotic cell death mediated by ox-LDL. Further analysis identified Rictor as a direct target of miR-142-3p, and Rictor knockdown abolished the anti-apoptotic effect of miR-142-3p inhibitor. Moreover, the Akt/endothelial nitric oxide synthase (eNOS) signaling pathway was found to mediate the beneficial effect of miR-142-3p inhibitor on endothelial apoptosis. Finally, systemic treatment with miR-142-3p antagomir attenuated endothelial apoptosis and retarded the progression of atherosclerosis in the aorta of ApoE-/- mice. Conclusions: Down-regulation of miR-142-3p inhibited ECs apoptosis and atherosclerotic development by up-regulating the expression of Rictor and activating the Akt/eNOS signaling pathway. This indicates that miR-142-3p may be a potential target for the prevention and treatment of atherosclerosis.

Objective:To observe whether baicalein have therapeutic value on diabetes mellitus (DM) with cerebral small vessel disease (CSVD) so as to explore the pathogenesis and therapy of the cognitive ability and behavioral function disorder caused by chronic cerebral ischemia and hypoxia.Methods:A total of thirty male SD rats were randomly divided into normal control group, model group and treatment group, 10 rats in each group. After the stable models of DM with CSVD were established, cognitive function scores of all rats were evaluated by Morris water maze test, and the levels of acetylcholine (Ach) and acetylcholinesterase (AchE) in brain were assessed to evaluate the protective effects of baicalein.Results:Morris water maze test showed that learning and memory function had been significantly impaired in rats of DM with CSVD since the 7th day of modeling. Spatial probe test founded that the times of crossing platform in the model group were significantly lower than those in the normal control group (PPPP

Abstract Background Fatal familial insomnia (FFI) is a rare autosomal dominant disease caused by the PRNP D178N/129 M mutation. Routine brain CT and MRI usually reveal non-specific features. We report a patient with FFI presenting with diffuse abnormal signals on MRI, later confirmed as combined with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Case presentation The patient was a 58-year-old female, whose main clinical manifestations were insomnia, movement disorders, autonomic hyperactivity and mental deterioration. The patient also suffered a typical episode of transient global amnesia. MRI indicated a diffuse white matter abnormality and microbleeding on the susceptibility-weighted imaging. On biopsy, the brain tissue sections showed spongiform changes with gliosis, neuronal degeneration, and prion protein deposition in a portion of the neurons. In addition, arteriosclerosis was prominent. Transmission electron microscopy showed osmiophilic particle deposition in the matrix of medial smooth muscle cells. Gene sequencing confirmed a diagnosis of FFI with CADASIL. Conclusions This case is a compelling example that even with evidence of leukoencephalopathy, prion disease should be an important differential diagnosis of rapidly progressive dementia and related diseases. In cases of genetic diseases with atypical manifestations, the coexistence of two or even more diseases should be considered as a possible explanation.

Objective: The aim of this retrospective study was to investigate the relationship between serum systemic autoantibodies and anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis.Methods: Thirty-nine patients with anti-NMDAR encephalitis were examined for serum systemic autoantibodies (antinuclear antibodies, extractable nuclear antigen autoantibodies, rheumatoid factors, and anti-neutrophil cytoplasmic antibodies), in comparison with 39 neuromyelitis optica spectrum disorder (NMOSD) and 78 healthy controls. Clinical features, cerebrospinal fluid characteristics, and outcomes were compared between the two subgroups of anti-NMDAR patients with positive and negative systemic autoantibodies, respectively.Results: Anti-NMDAR encephalitis patients had higher frequency of positive serum systemic autoantibodies than healthy controls (23.1 vs. 2.6%, p = 0.001) and lower frequency than NMOSD (23.1 vs. 48.7%, p = 0.018). No patients were diagnosed comorbidities with non-organ-specific autoimmune diseases. Consciousness disturbance was more frequent in autoantibodies positive group than in the negative group (88.9 vs. 40.0%, p = 0.02). Autoantibody positive group had a poorer outcome than autoantibody negative group (55.6 vs. 86.7%, p = 0.043). There was a negative correlation between serum autoantibodies and outcomes in anti-NMDAR encephalitis patients (r = −0.325, p = 0.044).Conclusion: Our data demonstrated serum systemic autoantibodies were more frequent in anti-NMDAR encephalitis patients than in healthy controls and less frequent than NMOSD, which were associated with higher severity of disease.

Background. Wnt/β-catenin signaling has been reported to exert cytoprotective effects in a cellular model of Parkinson’s disease (PD). Glutamate excitotoxicity has been suggested to contribute to the pathogenesis of PD, and excitatory amino acid transporters (EAATs) play a predominant role in clearing excessive glutamate. EAAT2 is mainly expressed in astrocytes, which are an important source of Wnt signaling in the brain. Methods. Wnt1-overexpressing U251 astrocytes were indirectly cocultured with dopaminergic SH-SY5Y cells treated with 6-hydroxydopamine (6-OHDA). Cell toxicity was determined by cell viability and flow cytometric detection. Glutamate level in the culture medium was determined by enzyme-linked immunosorbent assay (ELISA). Western blot analysis was used to detect the expression of Wnt1, β-catenin, and EAAT2. Immunofluorescence was used to display the expression and translocation of NF-κB p65. Results. 6-OHDA treatment significantly decreased cell viability in both U251 cells and SH-SY5Y cells, inhibited the expression of Wnt1, β-catenin, and EAAT2 in U251 cells, and increased the glutamate level in the culture medium. Coculture with Wnt1-overexpressing U251 cells attenuated 6-OHDA-induced apoptosis in SH-SY5Y cells. Overexpression of Wnt1 decreased the glutamate level in the culture media, upregulated β-catenin, EAAT2, and NF-κB levels, and promoted the translocation of NF-κB from the cytoplasm to the nucleus in U251 cells. Conclusion. Wnt1 promoted EAAT2 expression and mediated the cytoprotective effects of astrocytes on dopaminergic cells. NF-κB might be involved in the regulation of EAAT2 by Wnt1.

A 34-year-old Chinese Han female complaining of general muscle weakness and wasting for 9 years. She was admitted for aggravation of her symptoms caused by respiratory distress. She also suffered from bulbar palsy. She had no hearing loss, visual problems, or cerebellar signs. Her parents had a consanguineous marriage, though there was no family history of these symptoms. Pure tone audiometric findings demonstrated no definite abnormality. Electromyography demonstrated neurogenic damage. Brain magnetic resonance imaging revealed cerebellar atrophy, dominantly in anterior lobe. Gene sequencing of whole gene exomes was negative. She was finally diagnosed with Madras motor neuron disease (MMND), a rare subtype of motor neuron disease. No definite therapy was available for MMND, and she died of respiratory tract infection 1 year later. Previous studies have shown that cerebellar signs are positive in 17.2% patients of MMND, but no case with cerebellar atrophy has been reported before. Thus, here we describe cerebellar atrophy as a new clinical feature of MMND.

Objective: To evaluate the efficacy and safety of low-dose mycophenolate mofetil (MMF, 1,000 mg/day) treatment of neuromyelitis optica spectrum disorders (NMOSDs).Methods: This study was a multicenter, open, prospective, follow-up clinical trial. The data include retrospective clinical data from the pretreatment phase and prospective data from the post-treatment phase. From September 2014 to February 2017, NMOSD patients seropositive for aquaporin 4-IgG (AQP4-IgG) were treated with low-dose MMF.Results: Ninety NMOSD patients were treated with MMF for a median duration of 18 months (range 6–40 months). The median annual recurrence rate (ARR) decreased from 1.02 before treatment to 0 (P < 0.0001) after treatment, and the Expanded Disability Status Scale (EDSS) score decreased from 4 to 3 (P < 0.0001). The EDSS score was significantly lower (P = 0.038) after the first 90 days of treatment. The serum AQP4-IgG titer decreased in 50 cases (63%). The median Simple McGill pain score (SF-MPQ) was reduced in 65 patients (88%) with myelitis from 17 (range 0–35) to 11 (range 0–34) after treatment (P < 0.0001). The median Hauser walking index (Hauser Walk Rating Scale) was reduced from 2 (range 1–9) before treatment to 1 (range 0–7) after treatment (P < 0.0001). Adverse events were documented in 43% of the patients, and eight patients discontinued MMF due to intolerable adverse events. Fourteen (16%) of the total patients discontinued MMF after our last follow-up for various reasons and switched to azathioprine or rituximab.Conclusion: Low-dose MMF reduced clinical relapse and disability in NMOSD patients in South China. However, some patients still suffered from adverse events at this dosage.Clinical Trial Registration: www.ClinicalTrials.gov, identifier : NCT02809079.

Purpose: Perforating Artery Infarcts (PAIs) can be divided into two subtypes based on their etiologies: branch Atheromatous Disease (BAD) and Lacunar Infarct (LI). Recent studies have shown that while both subtypes can be caused by large artery lesions, the different mechanisms that underlie their development are not clear. This study was designed to use High-Resolution Magnetic Resonance Imaging (HRMRI) to explore the differences that contribute to the occurrence of these two subtypes in large artery lesions in the anterior circulation.Methods: Fifty patients with an acute PAI in the anterior circulation were enrolled (32 BAD and 18 LI patients). The ipsilateral middle cerebral artery (MCA) was scanned with HRMRI to analyze the atherosclerosis plaques. Artery remodeling and plaque characteristics of MCA lesions were compared between the two subtypes.Results: The rate of MCA lesions was significantly higher in BAD and substantially lower in LI (P = 0.033). LAs for the lumen areas in Bad, they were smaller than LI (P < 0.001), Additionally, the plaque area (P = 0.001) and plaque burden (P < 0.001) were superior in the BAD group. Most BAD patients displayed non-positive remodeling, while the great majority of LI patients showed positive remodeling (P < 0.001).Conclusion: In the anterior circulation, a considerable amount of BAD and LI share similarities with atherosclerotic plaques in large arteries. BAD patients mainly showed relatively large and stable atherosclerotic plaques in large arteries, while LI patients mainly exhibited relatively small and unstable atherosclerotic plaques.Clinical Trial Registration: This clinical trial is a retrospective study and therefore does not require registration.

The course of myasthenia gravis (MG) is complicated by increased reports of cognitive defects in both human and animal models, which suggests potential central nervous system (CNS) damage. We conducted a systematic review of the relationships between MG and cognitive function. This systematic review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Major databases were searched to examine the neuropsychological studies of adults with MG. Weighted effect sizes were pooled by cognitive domain. Eight studies representing 300 subjects were included. Eight cognitive domain categories were identified: (i) Mini-Mental State Examination (MMSE), (ii) language, (iii) processing speed, (iv) verbal learning and memory, (v) visual learning and memory, (vi) attention span, (vii) response fluency, and (viii) motor performance. Nine (cognitive domain categories, MMSE, language, processing speed, verbal learning and memory (except for delayed recall memory), and motor performance) of 16 cognitive tasks revealed significant moderate effect sizes. Verbal logical-delayed memory, finger tapping with the preferred hand, and the Symbol Digit Modalities Test showed a greater magnitude relationship to cognitive function than did other specific cognitive domains. Verbal learning and memory seems to be the most significant affected according to cognitive domain categories. For MG, the ability of attention, response fluency, visual learning, and memory seems to be reserved. The MG patients seem to perform significantly worse than the non-MG controls in a range of cognitive domains. Our findings should be interpreted with caution because of the clinical and methodological heterogeneity of included studies.

Background and objectiveWhite matter hyperintensities can be easily identified by brain imaging. Juxtacortical small lesion (JCSL) is a special type of white matter lesion, defined as no greater than 5 mm in diameter and adjacent to the cerebral cortex in location. We notice lately that JCSLs alone may be associated to various neurological symptoms. Here, we design the present study to determine the risk factors for JCSLs and their clinical manifestations in patients in our neurology clinic.Methods206 participants suffered from neurological disorders and completed magnetic resonance imaging (MRI) examinations were divided into two groups: patients with JCSLs and patients without lesions on MRI. Meanwhile, 129 age- and sex-matched healthy volunteers were also recruited. Laboratory examinations and the phenotypes and distributions of the symptoms of the three groups were compared.ResultsThe serum levels of apoB and homocysteine (HCY) were independently related to the appearance of JCSLs and HCY level was also associated with the number of JCSLs. Patients with JCSLs might present with headache, insomnia, and/or anxiety/depression, which were related with the anatomical locations of the lesions.ConclusionThese data suggest that JCSLs are symptomatic and might in result fromarteriole atherosclerosis, which should raise our attention.

The spatiotemporal and especially the vertical distributions of dust aerosols play crucial roles in the climatic effect of dust aerosol. In the present study, the spatial-temporal distribution of dust aerosols over East Asia was investigated using Cloud-Aerosol Lidar and Infrared Pathfinder Satellite Observations (CALIPSO) retrievals (01/2007–12/2011) from the perspective of the frequency of dust occurrence (FDO), dust top layer height (TH) and profile of aerosol subtypes. The results showed that a typical dust belt was generated from the dust source regions (the Taklimakan and Gobi Deserts), in the latitude range of 25°N~45°N and reaching eastern China, Japan and Korea and, eventually, the Pacific Ocean. High dust frequencies were found over the dust source regions, with a seasonal sequence from high to low as follows: spring, summer, autumn and winter. Vertically, FDOs peaked at about 2 km over the dust source regions. In contrast, FDOs decreased with altitude over the downwind regions. On the dust belt from dust source regions to downwind regions, the dust top height (TH) was getting higher and higher. The dust TH varied in the range of 1.9–3.1 km above surface elevation (a.s.e.), with high values over the dust source regions and low values in the downwind areas, and a seasonally descending sequence of summer, spring, autumn and winter in accord with the seasonal variation of the boundary layer height. The annual AOD (Aerosol Optical Depth) was generally characterized by two high and two low AOD centers over East Asia. The percent contribution of the Dust Aerosol Optical Depth to the total AOD showed a seasonal variation from high to low as follows: spring, winter, autumn and summer. The vertical profile of the extinction coefficient revealed the predominance of pure dust particles in the dust source regions and a mixture of dust particles and pollutants in the downwind regions. The dust extinction coefficients over the Taklimakan Desert had a seasonal pattern from high to low as follows: spring, winter, summer and autumn. The results of the present study offered an understanding of the horizontal and vertical structures of dust aerosols over East Asia and can be used to evaluate the performance aerosol transport models.