Knowledge atlas of white matter microstructure: a bibliometric analysis.

Background: White matter microstructure is valued for being an indicator of neural network integrity, which plays an indispensable role in the execution of advanced brain functions. Although the number of publications has increased in the past 10 years, no comprehensive analysis has yet been conducted of this field. Therefore, this study aimed to identify the research hotspots and trends in research on white matter microstructure using a bibliometric analysis of the related literature published from 2013 to 2022. Methods: VOSviewer and CiteSpace were used to objectively analyze the research articles concerning white matter microstructure, which were retrieved from the Web of Science Core Collection (WoSCC). Results: A total of 5,806 publications were obtained, with the number of published articles increasing annually over the past decade. The United States, China, the United Kingdom, and Canada maintained the top positions worldwide and had strong cooperative relationships. The top institution and journal were Harvard Medical School and Neuroimage, respectively. Alexander Leemans, Marek Kubicki, and Martha E Shenton were the most productive authors. Thematic keywords mainly included "diffusion tensor imaging" (DTI), "white matter integrity", and "connectivity". The keyword analysis revealed that DTI has a critical role in detecting white matter microstructure integrity and that fractional anisotropy is the main parameter in the assessment process. Keyword burst detection identified four research hotspots: movement, distortion correction, voxelwise analysis, and fixel-based analysis. Conclusions: This bibliometric analysis provided a systematic understanding of the research on white matter microstructure and identified the current frontiers. This may help clinicians and researchers comprehensively identify hotspots and trends in this field.

Research hotspots and trends on neuromyelitis optica spectrum disorders: insights from bibliometric analysis.

Neuromyelitis optica spectrum disorders (NMOSD) are demyelinating diseases of the central nervous system, have drawn the attention of many researchers due to the relapsing courses and cumulative disability. A first bibliometric analysis of NMOSD was conducted to identify the research hotspots and emerging trends. Articles relevant to NMOSD published in the core collection of Web of Science were retrieved and analyzed through visualized analysis using CiteSpace and VOSviewer, focusing on annual publication trends, countries, institutions, authors, journals, and keywords. The analysis showed that over the past 30 years, publications related to NMOSD had shown steady growth with slight fluctuations. The United States played an important part in this field, with the highest outputs and the greatest number of citations. Research hotspots of NMOSD had gradually shifted from the definition, biomarkers, and diagnostic criteria to diagnosis and treatment, particularly immunotherapy. This bibliometric analysis provides researchers with a theoretical basis for studying NMOSD and offers guidance for future research directions.

Human spinal GABA neurons survive and mature in the injured nonhuman primate spinal cord.

Spinal cord injury (SCI) leads to permanent neural dysfunction without effective therapies. We previously showed that human pluripotent stem cell (hPSC)-derived spinal GABA neurons can alleviate spasticity and promote locomotion in rats after SCI, but whether this strategy can be translated into the clinic remains elusive. Here, a nonhuman primate (NHP) model of SCI was established in rhesus macaques (Macaca mulatta) in which the T10 spinal cord was hemisected, resulting in neural conduction failure and neural dysfunction, including locomotion deficits, pain, and spasms. Grafted human spinal GABA neurons survived for up to 7.5 months in the injured monkey spinal cord and retained their intrinsic properties, becoming mature and growing axons and forming synapses. Importantly, they are functionally alive, as evidenced by designer receptors exclusively activated by designer drug (DREADD) activation. These findings represent a significant step toward the clinical translation of human spinal neuron transplantation for treating SCI.

Prevalence and risk factors of stroke in China: a national serial cross-sectional study from 2003 to 2018.

Stroke imposes a substantial burden worldwide. With the rapid economic and lifestyle transition in China, trends of the prevalence of stroke across different geographic regions in China remain largely unknown. Capitalizing on the data in the National Health Services Surveys (NHSS), we assessed the prevalence and risk factors of stroke in China from 2003 to 2018. In this study, data from 2003, 2008, 2013, and 2018 NHSS were collected. Stroke cases were based on participants' self-report of a previous diagnosis by clinicians. We estimated the trends of stroke prevalence for the overall population and subgroups by age, sex, and socioeconomic factors, then compared across different geographic regions. We applied multivariable logistic regression to assess associations between stroke and risk factors. The number of participants aged 15 years or older were 154,077, 146,231, 230,067, and 212,318 in 2003, 2008, 2013, and 2018, respectively, among whom, 1435, 1996, 3781, and 6069 were stroke patients. The age and sex standardized prevalence per 100,000 individuals was 879 in 2003, 1100 in 2008, 1098 in 2013, and 1613 in 2018. Prevalence per 100,000 individuals in rural areas increased from 669 in 2003 to 1898 in 2018, while urban areas had a stable trend from 1261 in 2003 to 1365 in 2018. Across geographic regions, the central region consistently had the highest prevalence, but the western region has an alarmingly increasing trend from 623/100,000 in 2003 to 1898/100,000 in 2018 (P trend<0.001), surpassing the eastern region in 2013. Advanced age, male sex, rural area, central region, hypertension, diabetes, depression, low education and income level, retirement or unemployment, excessive physical activity, and unimproved sanitation facilities were significantly associated with stroke. In conclusion, the increasing prevalence of stroke in China was primarily driven by economically underdeveloped regions. It is important to develop targeted prevention programs in underdeveloped regions. Besides traditional risk factors, more attention should be paid to nontraditional risk factors to improve the prevention of stroke.

Heart rate variability is associated with cerebral small vessel disease in patients with diabetes.

Objective: Low heart rate variability (HRV), an indicator of autonomic nervous system dysfunction, has been associated with increased all-cause and cardiovascular mortality and incident stroke. However, the relationship between HRV and cerebral small vessel disease (CSVD) showed contradictory results. We aimed to examine the relationship of HRV and total burden of CSVD and each of the magnetic resonance imaging (MRI) markers of CSVD. Methods: We recruited 435 patients who attended our hospital for physical examination between June 2020 and August 2021. All underwent 24-h Holter monitoring and MRI scan. The standard deviation of normal-to-normal intervals (SDNN) was selected as the method for HRV assessment. The presence of severe white matter hyperintensity, lacunes, and >10 enlarged basal ganglia perivascular spaces, and cerebral microbleeds were added for estimating the CSVD score (0-4). Multivariate logistic analyses was performed to assess whether HRV was independently associated with the burden of CSVD and each of the MRI markers of CSVD, with and without stratification by prevalent diabetes. Results: This study included 435 subjects with a mean age of 64.0 (57.0-70.0) years; 49.4% of the patients were male, and 122 (28.0%) had a history of diabetes. In multivariate analyses, lower SDNN was independently associated with total burden of CSVD and the presence of enlarged perivascular spaces in all subjects. According to diabetes stratification, lower SDNN was independently associated with total burden of CSVD and each MRI markers of CSVD separately only in the diabetic group. Conclusions: Lower HRV was associated with total burden of CSVD and each MRI markers of CSVD separately among diabetic patients, but not among non-diabetic patients.

Depletion of regulatory T cells exacerbates inflammatory responses after chronic cerebral hypoperfusion in mice.

Vascular cognitive impairment is the second most common cause of dementia which can be induced by chronic cerebral hypoperfusion. Regulatory T cells (Tregs) have been proven to provide beneficial effects in several central nervous system (CNS) diseases, but the roles of Tregs in chronic cerebral hypoperfusion-induced white matter damage have not been explored. In this study, Foxp3-diphtheria toxin receptor (DTR) mice treated with diphtheria toxin (DT) and wild type C57BL/6 mice treated with anti-CD25 antibody were subjected to bilateral carotid artery stenosis (BCAS). Flow cytometry analysis showed Tregs were widely distributed in spleen whereas barely distributed in brain under normal conditions. The distribution of lymphocytes and Tregs did not change significantly in spleen and brain after BCAS. Depletion of Tregs decreased the numbers of mature oligodendrocytes and anti-inflammatory microglia at 14 days and 28 days following BCAS. And pro-inflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and interferon-γ (IFN-γ) showed higher expression after Tregs depletion. In contrast, Tregs depletion did not change the overall severity of white matter injury as shown by the expression of myelin-associated glycoprotein (MAG), myelin basic protein (MBP), luxol fast blue (LFB) staining and electron microscopy assay. Moreover, Tregs depletion had marginal effect on cognition defects after BCAS revealed by Morris water maze and novel object recognition examination at 28 days after BCAS. In summary, our results suggest an anti-inflammatory role of Tregs with marginal effects on white matter damage in mice after BCAS-induced chronic cerebral hypoperfusion.

Sleep duration, daytime napping, and risk of incident stroke: Nuances by metabolic syndrome from the China health and retirement longitudinal study.

Background and purpose: The relationship between sleep duration and stroke are inconclusive in China, especially in those individuals with metabolic syndrome. We aimed to investigate the association between sleep duration and incident stroke in participants with metabolic syndrome or its specific components in China. Materials and methods: Data were taken from the 2011 and 2015 waves of China Health and Retirement Longitudinal Study (CHARLS). Habitual sleep duration (≤6, 6∼8 [reference], >8 h), daytime napping (0, 1∼60 [reference], and >60 min) were determined by self-reported questionnaires. Metabolic syndrome was defined by blood assessment and biomarkers combined with self-reported doctors' diagnosis. Incident stroke was determined by reported stroke from 2011 to 2015 wave. Cross-sectional and longitudinal associations between sleep and (incident) stroke at baseline and 4-year follow-up period were tested among the population with metabolic syndrome and its components. Results: A U-shaped relationship was observed between sleep duration and stroke in cross-sectional analysis. Sleep ≤ 6 h/night had a greater risk of incident stroke (hazard ratio [HR] 1.65; 95% confidence interval [CI] 1.04-2.61) compared with sleep 6∼8 h/night. And the HR of stroke was 1.62 (95%CI, 1.03-2.53) for sleep < 7 h/day compared to 7∼9 h/day. These associations were more evident in the female and individuals aged 45-65 years. Furthermore, the effect of short sleep duration on incident stroke was different in each component of metabolic syndrome, which was more pronounced in participants with elevated blood pressure. And a significant joint effect of sleeping ≤ 6 h/night and no napping on risk of stroke was observed (HR 1.82, 95%CI 1.06-3.12). Conclusion: Short sleep duration was an independent risk factor for incident stroke, especially among females, individuals aged 45-65 years, or those with some components of metabolic syndrome, such as hypertension. Napping could buffer the risk of short sleep duration on incident stroke.

Abnormalities of retinal structure and microvasculature are associated with cerebral white matter hyperintensities.

BACKGROUND AND PURPOSE: Whilst retinal microvasculature represents cerebral small vessels, the retinal nerve fiber layer is the extended white matter of the brain. The aim was to investigate the correlation between changes in retina and white matter hyperintensities (WMHs). METHODS: Sixty-four candidates with WMHs received an optical coherence tomography angiography examination. WMHs were divided into mild or moderate/severe groups according to the Fazekas score. After imaging the superficial capillary plexus (SCP) and deep capillary plexus (DCP), the microvascular density parameters (vascular perfusion density [VPD], vascular length density [VLD] and fovea avascular zone area) and morphological parameters (vessel diameter index [VDI], fractal dimension [FD] and vessel tortuosity) were identified. A software algorithm measured the thickness of the peripapillary retina nerve fiber layer (PRNFL). RESULTS: Thirty-two were classified as having mild WMHs and 32 were moderate/severe. The median (interquartile range) ages of the two groups were 58 (54-64) and 61 (57-67) years, respectively. A decrease of FD, VPD and VLD in either SCP or DCP appeared with an increased risk of moderate/severe WMHs. Although changes of capillary plexus were not associated with paraventricular WMHs, decreased FD, VPD, VLD and fovea avascular zone area in either SCP or DCP were associated with an increased risk of moderate/severe deep WMHs (DWMHs). Participants with moderate/severe WMHs demonstrated reduced PRNFL thickness, particularly in the DWMHs, compared with mild WMHs. CONCLUSIONS: Abnormalities of retinal microvascular density, morphological parameters and PRNFL thickness are correlated with the incidence of moderate/severe WMHs, particularly the DWMHs, suggesting that arteriosclerosis and hypoperfusion are the causes of DWMHs.

Apolipoprotein E ε4 Polymorphism as a Risk Factor for Ischemic Stroke: A Systematic Review and Meta-Analysis.

INTRODUCTION: Rising studies indicate that the apolipoprotein E (APOE) gene is related to the susceptibility of ischemic stroke (IS). However, certain consensus is limited by the lack of a large sample size of researches. This meta-analysis was performed to explore the potential association between the APOE gene and IS. METHODS: To identify relevant case control studies in English publications by October 2020, we searched PubMed, Embase, Web of Science, and the Cochrane Library. Pooled odds ratios (ORs) with fixed- or random-effect models and corresponding 95% confidence intervals (CIs) were calculated to analyze potential associations. RESULTS: A total of 55 researches from 32 countries containing 12207 IS cases and 27742 controls were included. The association between APOE gene ε4 mutation and IS was confirmed (ε4 vs. ε3 allele: pooled OR = 1.374, 95% CI, 1.214-1.556; ε2/ε4 vs. ε3/ε3: pooled OR = 1.233, 95% CI, 1.056-1.440; ε3/ε4 vs. ε3/ε3: pooled OR = 1.340, 95% CI, 1.165-1.542; ε4/ε4 vs. ε3/ε3: pooled OR = 1.833, 95% CI, 1.542-2.179; and APOE ε4 carriers vs. non-ε4 carriers: pooled OR = 1.377; 95% CI, 1.203-1.576). Interestingly, APOE ε4 mutation showed a dose-response correlation with IS risk (ε4/ε4 vs. ε2/ε4: pooled OR = 1.625; 95% CI, 1.281-2.060; ε4/ε4 vs. ε3/ε4: pooled OR = 1.301; 95% CI, 1.077-1.571). Similar conclusions were drawn in the small artery disease (SAD) subtype, but not in large artery atherosclerosis (LAA) or in cardioaortic embolism (CE), by subgroup analysis. CONCLUSIONS: These observations reveal that specific APOE ε4 mutation was significantly associated with the risk of IS in a dose-dependent manner, while APOE ε4 mutation was related to SAD subtype onset without a cumulative effect.

Digoxin Ameliorates Glymphatic Transport and Cognitive Impairment in a Mouse Model of Chronic Cerebral Hypoperfusion.

The glymphatic system plays a pivotal role in maintaining cerebral homeostasis. Chronic cerebral hypoperfusion, arising from small vessel disease or carotid stenosis, results in cerebrometabolic disturbances ultimately manifesting in white matter injury and cognitive dysfunction. However, whether the glymphatic system serves as a potential therapeutic target for white matter injury and cognitive decline during hypoperfusion remains unknown. Here, we established a mouse model of chronic cerebral hypoperfusion via bilateral common carotid artery stenosis. We found that the hypoperfusion model was associated with significant white matter injury and initial cognitive impairment in conjunction with impaired glymphatic system function. The glymphatic dysfunction was associated with altered cerebral perfusion and loss of aquaporin 4 polarization. Treatment of digoxin rescued changes in glymphatic transport, white matter structure, and cognitive function. Suppression of glymphatic functions by treatment with the AQP4 inhibitor TGN-020 abolished this protective effect of digoxin from hypoperfusion injury. Our research yields new insight into the relationship between hemodynamics, glymphatic transport, white matter injury, and cognitive changes after chronic cerebral hypoperfusion.

Recurrent Anti-AMPA Receptor Limbic Encephalitis: A Case Report and Literature Review.

Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor encephalitis is a relatively rare anti-neuronal surface antigen autoimmune encephalitis (LE). We described a case of a 47-year-old Chinese man having anti-AMPA receptor limbic encephalitis initially presented with cognitive decline, undetectable antibodies, and normal imaging findings in magnetic resonance image (MRI) and then developed into typical autoimmune limbic encephalitis a few months later with a course of multiple relapses. In addition, we found progressive brain atrophy in our case, which was a rare presentation of LE. This report also summarized the characteristics of nine reported cases of anti-AMPA receptor limbic encephalitis with relapse up to date. This case highlighted that autoimmune limbic encephalitis is an important differential diagnosis for patients with typical symptoms even when the MRI and antibodies are normal, and more attention should be paid to the relapse of anti-AMPA receptor encephalitis.

Decreased blood CD4+ T lymphocyte helps predict cognitive impairment in patients with amyotrophic lateral sclerosis.

BACKGROUND: ALS patients have changed peripheral immunity. It is unknown whether peripheral immunity is related to cognitive dysfunction in ALS patients. OBJECTIVE: To explore the relationship between the peripheral blood lymphocyte subsets and the cognitive status in ALS patients. METHODS: Among 81 ALS patients, we compared the demographic, clinical, and peripheral levels of total T lymphocyte, CD4+ T lymphocyte, CD8+ T lymphocyte, B lymphocyte, and NK cell between those with cognitive impairment (ALS-ci) and those without (ALS-nci). The cognitive status was evaluated via the Chinese version of the Edinburgh cognitive and behavioral screen (ECAS). Significant predictors of cognitive impairment in univariate logistic regression analysis were further examined using multivariate logistic regression analysis. RESULTS: 39.5% of all ALS patients had cognitive impairment. The ALS-ci group had shorter education time, older age at both symptom onset and testing, longer disease duration, and lower levels of peripheral total, CD4+, and CD8+ T lymphocyte and B lymphocyte than the ALS-nci group. Frequency of behavioral impairment did not differ between the two groups. While parameters with significant differences identified by group comparison were also significant predictors of cognitive impairment in univariate logistic regression analysis except the level of B lymphocyte, only older age at testing, education time less than 9 years, and lower level of CD4+ T lymphocyte remained significant in multivariate logistic regression analysis. The predictive model combining these three parameters had an area under the receiver operating characteristic curve value of 0.842 with a sensitivity of 90.6% and a specificity of 67.3%. CONCLUSION: In Chinese ALS patients, blood CD4+ T lymphocyte might help evaluate cognitive impairment along with age and education level.

Serum Cortisol Is Associated With Cerebral Small Vessel Disease-Related Brain Changes and Cognitive Impairment.

OBJECTIVE: To evaluate the relationship between serum cortisol, cerebral small vessel disease (CSVD) neuroimaging markers, and cognitive performance. METHODS: We recruited patients over 50 years old who attended our hospital for physical examination between November 2020 and July 2021. All participants were subject to brain magnetic resonance imaging (MRI), serum cortisol examination, and the Montreal cognitive function assessment (MoCA). On brain MRI, we scored the presence of each marker of CSVD, including white matter hyperintensity (WMH), lacunes, cerebral microbleeds (CMBs), and enlarged perivascular spaces (EPVS). One point was awarded for the presence of each marker, producing a score between 0 and 4. RESULTS: In total, 158 participants were included in this study with a mean age of 60.5 (56.0-66.3) years; 55.1% were male. In the multivariable analyses, serum cortisol level was an independent predictor of WMH severity, the presence of lacunes/CMBs, moderate-severe EPVS and total CSVD burden after adjusting for confounding factors. Serum cortisol level had positive associations with periventricular/deep Fazekas score, burdens of lacunes/CMBs, moderate-severe EPVS, and total CSVD burden in dose-dependent manner, and was an independent predictor of cognitive impairment. Furthermore, the results of the receiver operating characteristic (ROC) curve analysis revealed an area under curve (AUC) of 0.745 with 64.1% sensitivity and 82.5% specificity, and an AUC of 0.705 with 52.1% sensitivity and 85.5 specificity of cortisol in detecting patients with high CSVD burden and MCI, respectively. CONCLUSIONS: Serum cortisol level is independently associated with each CSVD MRI markers, total CSVD burden and cognitive impairment. These findings provide clues for pathological mechanisms and suggest serum cortisol as a promising biomarker associated with CSVD.

Dynamic changes of peripheral blood lymphocyte subsets in acute ischemic stroke and prognostic value.

OBJECTIVE: To explore dynamic changes of peripheral blood lymphocyte subsets in patients with acute ischemic stroke (AIS) and the relationship with stroke severity and long-term outcomes. METHODS: A total of 96 consecutive patients with AIS and 28 age- and gender-matched healthy controls were recruited. Peripheral blood samples were collected, and the percentages of lymphocyte subsets were analyzed by flow cytometry. The dynamic changes in lymphocyte subsets and their correlation with clinical parameters, such as National Institutes of Health Stroke Scale (NIHSS) scores at onset and modified Rankin scale (mRS) scores 3 months later, were evaluated. RESULTS: In our study, we observed a decrease in the percentages of T-lymphocytes (T cells), helper/inducible T-lymphocytes (Th cells) and suppressor/cytotoxic T-lymphocytes (Ts cells) in AIS patients as compared to controls. The frequencies of T cells and Ts cells on day 8-14 after stroke in NIHSS ≤4 group were significantly higher than those in NIHSS >4 group. The percentages of T cells and Th cells on day 1-3 after stroke in the mRS ≤2 group were higher than those in the mRS >2 group. CONCLUSION: The frequencies of T cells, Th cells, and Ts cells in AIS are declined dramatically at least 14 days after stroke. Lower frequencies of T cells and Ts cells on day 8-14 after stroke represent more severe disease conditions, and the percentages of T cells and Th cells within 72 hr after stroke are negatively correlated with 3-month outcomes, which might have a potential for predicting long-term prognosis of stroke.

Cerebral Small-Vessel Disease and Risk of Incidence of Depression: A Meta-Analysis of Longitudinal Cohort Studies.

Background Results of several longitudinal cohort studies suggested an association between cerebral small-vessel disease and depression. Therefore, we performed a meta-analysis to explore whether cerebral small-vessel disease imparts increased risk for incident depression. Methods and Results We searched prospective cohort studies relevant to the relationship between cerebral small-vessel disease and incident depression published through September 6, 2019, which yielded 16 cohort studies for meta-analysis based on the relative odds ratio (OR) calculated with fixed- and random-effect models. Baseline white matter hyperintensities (WMHs) (pooled OR, 1.37; 95% CI, 1.14-1.65), enlarged perivascular spaces (pooled OR, 1.33; 95% CI, 1.03-1.71), and cerebral atrophy (pooled OR, 2.83; 95% CI, 1.54-5.23) were significant risk factors for incident depression. Presence of deep WMHs (pooled OR, 1.47; 95% CI, 1.05-2.06) was a stronger predictor of depression than were periventricular WMHs (pooled OR, 1.31; 95% CI, 0.93-1.86). What's more, the pooled OR increased from 1.20 for the second quartile to 1.96 for the fourth quartile, indicating that higher the WMH severity brings greater risk of incident depression (25th-50th: pooled OR, 1.20; 95% CI, 0.68-2.12; 50th-75th; pooled OR, 1.42; 95% CI, 0.81-2.46; 75th-100th: OR, 1.96; 95% CI, 1.06-3.64). These results were stable to subgroup analysis for age, source of participants, follow-up time, and methods for assessing WMHs and depression. Conclusions Cerebral small-vessel disease features such as WMHs, enlarged perivascular spaces, and cerebral atrophy, especially the severity of WMHs and deep WMHs, are risk factors for incident depression.

Polyunsaturated fatty acid supplement alleviates depression-incident cognitive dysfunction by protecting the cerebrovascular and glymphatic systems.

INTRODUCTION: Depression, the most prevalent mood disorder, has high comorbidity with cerebrovascular disease and cognitive decline. However, there is little understanding of the cellular mechanisms involved in depression and its comorbid cerebrovascular damage and cognition impairment. Here, we tested the prediction that the chronic unpredictable mild stress (CUMS) mouse model would manifest in disturbed glymphatic function and that dietary supplementation with polyunsaturated fatty acids (PUFA) could ameliorate these deficits while alleviating the depression-associated cognitive decline. METHODS: To test the treatment effects of PUFA or Es on behaviours, we applied the tail suspension, open field, and sucrose preference tests to assess depressive symptoms, and applied the Morris water maze test to assess cognition in groups of control, chronic unpredictable mild stress (CUMS), PUFA, and escitalopram (Es) treatment. We measured the extracellular concentrations of dopamine (DA), 5-hydroxytryptamine (5-HT) and noradrenaline (NA) in microdialysates from prefrontal cortex (PFC) by liquid chromatography mass spectrometry. Glia cells and inflammatory factors were analysed with fluorescent immunochemistry and western blot, respectively. We tested brain vasomotor function with two-photon and laser speckle imaging in vivo, and measured glymphatic system function by two-photon imaging in vivo and fluorescence tracer imaging ex vivo, using awake and anesthetized mice. Besides, we monitored cortical spreading depression by laser speckle imaging system. AQP4 depolarization is analysed by fluorescent immunochemistry and western blot. RESULTS: We confirmed that CUMS elicited depression-like and amnestic symptoms, accompanied by decreased monoamines neurotransmitter concentration in PFC and upregulated neuroinflammation markers. Moreover, CUMS mice showed reduced arterial pulsation and compliance in brain, and exhibited depolarized expression of AQP4, thus indicating glymphatic dysfunction both in awake and anesthetized states. PUFA supplementation rescued depression-like behaviours of CUMS mice, reduced neuroinflammation and cerebrovascular dysfunction, ultimately improved cognitive performance, all of which accompanied by restoring glymphatic system function. In contrast, Es treatment alleviated only the depression-like behavioural symptoms, while showing no effects on glymphatic function and depression-incident cognitive deficits. CONCLUSIONS: The CUMS depression model entails suppression of the glymphatic system. PUFA supplementation rescued most behavioural signs of depression and the associated cognitive dysfunction by restoring the underlying glymphatic system disruption and protecting cerebral vascular function.

Tamoxifen promotes white matter recovery and cognitive functions in male mice after chronic hypoperfusion.

Cerebral white matter lesions (WMLs) induced by chronic cerebral hypoperfusion are one of the major components of stroke pathology and closely associated with cognitive impairment. However, the repair and related pathophysiology of white matter after brain injury remains relatively elusive and underexplored. Successful neuroregeneration is a method for the potential treatment of central nervous system (CNS) disorders. A non-steroidal estrogen receptor modulator, Tamoxifen, is an effective inhibitor of cell-swelling-activated anion channels and can mimic neuroprotective effects of estrogen in experimental ischemic stroke. However, its remains unclear whether Tamoxifen has beneficial effects in the pathological process after WMLs. In the present study, we investigated the efficacy of Tamoxifen on multiple elements of oligovascular niche of the male C57BL/6 mice brain after bilateral carotid artery stenosis (BCAS) - induced WMLs. Tamoxifen was injected intraperitoneally once daily from 1 day after BCAS until 1 day before sacrificed. Following chronic hypoperfusion, BCAS mice presented white matter demyelination, loss of axon-glia integrity, activated inflammatory response, and cognitive impairments. Tamoxifen treatment significantly facilitated functional restoration of working memory impairment in mice after white matter injury, thus indicating a translational potential for this estrogen receptor modulator given its clinical safety and applicability for WMLs, which lack of currently available treatments. Furthermore, Tamoxifen treatment reduced microglia activation and inflammatory response, favored microglial polarization toward to the M2 phenotype, enhanced oligodendrocyte precursor cells proliferation and differentiation, and promoted remyelination after chronic hypoperfusion. Together, our data indicate that Tamoxifen could alleviate white matter injury and play multiple targets protective effects following chronic hypoperfusion, which is a promising candidate for the therapeutic target for ischemic WMLs and other demyelination diseases associated cognitive impairment.

Deficiency of TREK-1 potassium channel exacerbates blood-brain barrier damage and neuroinflammation after intracerebral hemorrhage in mice.

BACKGROUND: Intracerebral hemorrhage (ICH) is a devastating medical emergency with high mortality and severe neurological deficit. ICH-related poor outcomes are due to a combination of pathological processes that could be complicated by secondary insults. TWIK-related K+ channel 1 (TREK-1) is a two-pore-domain potassium channel that is highly expressed in the mammalian nervous system. Previous studies have shown that TREK-1 channels play important roles in various central nervous system diseases. However, its role in the secondary injuries after intracerebral hemorrhage remains unknown. In this study, we explored the function of TREK-1 in secondary blood-brain barrier injuries and neuroinflammation after intracerebral hemorrhage in mice. METHODS: Adult male TREK-1-/- mice and WT mice were subjected to a collagenase-induced ICH model. Immunostaining, western blot, and enzyme-linked immunosorbent assay were used to assess inflammatory infiltration and neuronal death. Blood-brain barrier compromise was assessed using electron microscopy and Evans Blue dye injection on days 1 and 3 after intracerebral hemorrhage. Magnetic resonance imaging and behavioral assessments were conducted to evaluate the neurologic damage and recovery after intracerebral hemorrhage. RESULTS: Genetic deficiency of TREK-1 channel exacerbated blood-brain barrier impairment and promoted cerebral edema after intracerebral hemorrhage. Meanwhile, TREK-1 deficiency aggravated focal inflammatory featured by the increased recruitment of microglia and neutrophils, the enhanced secretion of proinflammatory factors interleukin-1 beta (IL-1ß), tumor necrosis factor alpha (TNF-α), and cell adhesion molecules (CAMs). Furthermore, TREK-1 deficiency promoted neuronal injury and neurological impairment. CONCLUSIONS: These results establish the first in vivo evidence for the protective role of TREK-1 in blood-brain barrier injury and neuroinflammation after intracerebral hemorrhage. TREK-1 may thereby be harnessed to a potential therapeutical target for the treatment of intracerebral hemorrhage.

Molecular and clinical relationship between live-attenuated Japanese encephalitis vaccination and childhood onset myasthenia gravis.

OBJECTIVE: The incidence of childhood onset myasthenia gravis (CMG) in China is higher than that in other countries; however, the reasons for this are unclear. METHODS: We investigated the clinical and immunological profiles of CMG, and assessed the potential precipitating factors. For the mouse studies, the possible implication of vaccination in the pathogenesis was explored. RESULTS: In our retrospective study, 51.22% of the 4,219 cases of myasthenia gravis (MG) were of the childhood onset type. The cohort study uncovered that the pathophysiology of CMG was mediated by immune deviation, rather than through gene mutations or virus infections. The administration of the live-attenuated Japanese encephalitis vaccine (LA-JEV), but not the inactivated vaccine or other vaccines, in mice induced serum acetylcholine receptor (AChR) antibody production, reduced the AChR density at the endplates, and decreased both muscle strength and response to repetitive nerve stimulation. We found a peptide (containing 7 amino acids) of LA-JEV similar to the AChR-α subunit, and immunization with a synthesized protein containing this peptide reproduced the MG-like phenotype in mice. INTERPRETATION: Our results describe the immunological profile of CMG. Immunization with LA-JEV induced an autoimmune reaction against the AChR through molecular mimicry. These findings might explain the higher occurrence rate of CMG in China, where children are routinely vaccinated with LA-JEV, compared with that in countries, where this vaccination is not as common. Efforts should be made to optimize immunization strategies and reduce the risk for developing autoimmune disorders among children. Ann Neurol 2018;84:386-400.

Endovascular thrombectomy versus medical treatment for large vessel occlusion stroke with mild symptoms: A meta-analysis.

It remains controversial as to whether mechanical thrombectomy (MT) is safer and more beneficial in patients with large vessel occlusion stroke (LVOS) presenting with a National Institutes of Health Stroke Scale score ≤ 8. We therefore conducted a meta-analysis of the published data.We searched PubMed and Embase and pooled relevant data in the meta-analyses using fixed effects models. Only studies that directly compared best medical therapy alone (BMT) with MT were included. We used odds ratios to analyze the associations between MT and 90-day functional outcome (evaluated using the modified Rankin Scale (mRS)), mortality, and rates of symptomatic intracerebral hemorrhage (sICH) in patients with LVOS and minor symptoms. Five studies including a total of 581 patients met our inclusion criteria. A significant difference was found that the patients treated with MT were associated with improved 90-day mRS score (OR, 1.68; 95% CI, 1.08-2.61) compared with BMT group. There was no difference in 90-day mortality between the two groups. However, sICH occurred more frequently in the MT group than the BMT group (OR, 3.89; 95% CI, 1.83-8.27). Patients with LVOS with minor or mild symptoms who underwent primary thrombectomy had a significantly improved 90-day mRS score compared to those who received BMT alone. Meanwhile, the risk of sICH was higher in the MT group than that in BMT group. Future randomized clinical controlled trials evaluating the role of endovascular reperfusion for LVOS with minimal symptoms are warranted.