The associations between peripheral inflammatory and lipid parameters, white matter hyperintensity, and cognitive function in patients with non-disabling ischemic cerebrovascular events.

BACKGROUND: The global prevalence of VCI has increased steadily in recent years, but diagnostic biomarkers for VCI in patients with non-disabling ischemic cerebrovascular incidents (NICE) remain indefinite. The primary objective of this research was to investigate the relationship between peripheral serological markers, white matter damage, and cognitive function in individuals with NICE. METHODS: We collected clinical data, demographic information, and medical history from 257 patients with NICE. Using the MoCA upon admission, patients were categorized into either normal cognitive function (NCF) or VCI groups. Furthermore, they were classified as having mild white matter hyperintensity (mWMH) or severe WMH based on Fazekas scores. We then compared the levels of serological markers between the cognitive function groups and the WMH groups. RESULTS: Among 257 patients with NICE, 165 were male and 92 were female. Lymphocyte count (OR = 0.448, P < 0.001) and LDL-C/HDL-C (OR = 0.725, P = 0.028) were protective factors for cognitive function in patients with NICE. The sWMH group had a higher age and inflammation markers but a lower MoCA score, and lymphocyte count than the mWMH group. In the mWMH group, lymphocyte count (AUC = 0.765, P < 0.001) and LDL-C/HDL-C (AUC = 0.740, P < 0.001) had an acceptable diagnostic value for the diagnosis of VCI. In the sWMH group, no significant differences were found in serological markers between the NCF and VCI groups. CONCLUSION: Lymphocyte count, LDL-C/HDL-C were independent protective factors for cognitive function in patients with NICE; they can be used as potential biological markers to distinguish VCI in patients with NICE and are applicable to subgroups of patients with mWMH.

Hyperforin ameliorates neuroinflammation and white matter lesions by regulating microglial VEGFR2 /SRC pathway in vascular cognitive impairment mice.

AIM: To explore the neuroprotective potential of hyperforin and elucidate its underlying molecular mechanisms involved in its therapeutic effects against vascular cognitive impairment (VCI). METHODS: The active compounds and possible targets of Hypericum perforatum L. that may be effective against VCI were found by network pharmacology in this research. We utilized bilateral common carotid artery occlusion (BCCAO) surgery to induce a VCI mouse model. Morris water maze (MWM) and Y-maze tests were used to assess VCI mice's cognitive abilities following treatment with hyperforin. To evaluate white matter lesions (WMLs), we utilized Luxol fast blue (LFB) stain and immunofluorescence (IF). Neuroinflammation was assessed using IF, western blot (WB), and enzyme-linked immunosorbent assay (ELISA). The effects of hyperforin on microglia were investigated by subjecting the BV2 microglial cell line to oxygen-glucose deprivation/reperfusion (OGD/R) stimulation. The expressions of VEGFR2 , p-SRC, SRC, VEGFA, and inflammatory markers including IL-10, IL-1ß, TNF-α, and IL-6 were subsequently assessed. RESULTS: The VEGFR2 /SRC signaling pathway is essential for mediating the protective properties of hyperforin against VCI according to network pharmacology analysis. In vivo findings demonstrated that hyperforin effectively improved BCCAO-induced cognitive impairment. Furthermore, staining results showed that hyperforin attenuated WMLs and reduced microglial activation in VCI mice. The hyperforin treatment group's ELISA results revealed a substantial decrease in IL-1ß, IL-6, and TNF-α levels. According to the results of in vitro experiments, hyperforin decreased the release of pro-inflammatory mediators (TNF-α, IL-6, and IL-1ß) and blocked microglial M1-polarization by modulating the VEGFR2 /SRC signaling pathway. CONCLUSION: Hyperforin effectively modulated microglial M1 polarization and neuroinflammation by inhibiting the VEGFR2 /SRC signaling pathways, thereby ameliorating WMLs and cognitive impairment in VCI mice.

Ferroptosis-related genes as diagnostic markers for major depressive disorder and their correlations with immune infiltration.

Background: Major depression disorder (MDD) is a devastating neuropsychiatric disease, and one of the leading causes of suicide. Ferroptosis, an iron-dependent form of regulated cell death, plays a pivotal role in numerous diseases. The study aimed to construct and validate a gene signature for diagnosing MDD based on ferroptosis-related genes (FRGs) and further explore the biological functions of these genes in MDD. Methods: The datasets were downloaded from the Gene Expression Omnibus (GEO) database and FRGs were obtained from the FerrDb database and other literatures. Least absolute shrinkage and selection operator (LASSO) regression and stepwise logistic regression were performed to develop a gene signature. Receiver operating characteristic (ROC) curves were utilized to assess the diagnostic power of the signature. Gene ontology (GO) enrichment analysis was used to explore the biological roles of these diagnostic genes, and single sample gene set enrichment analysis (ssGSEA) algorithm was used to evaluate immune infiltration in MDD. Animal model of depression was constructed to validate the expression of the key genes. Results: Eleven differentially expressed FRGs were identified in MDD patients compared with healthy controls. A signature of three FRGs (ALOX15B, RPLP0, and HP) was constructed for diagnosis of MDD. Afterwards, ROC analysis confirmed the signature's discriminative capacity (AUC = 0.783, 95% CI = 0.719-0.848). GO enrichment analysis revealed that the differentially expressed genes (DEGs) related to these three FRGs were mainly involved in immune response. Furthermore, spearman correlation analysis demonstrated that these three FRGs were associated with infiltrating immune cells. ALOX15B and HP were significantly upregulated and RPLP0 was significantly downregulated in peripheral blood of the lipopolysaccharide (LPS)-induced depressive model. Conclusion: Our results suggest that the novel FRG signature had a good diagnostic performance for MDD, and these three FRGs correlated with immune infiltration in MDD.

Lower 25-hydroxyvitamin D is associated with severer white matter hyperintensity and cognitive function in patients with non-disabling ischemic cerebrovascular events.

OBJECTIVES: This study aimed to investigate the potential correlations among serum 25-hydroxyvitamin D [25(OH)D] levels, white matter hyperintensity (WMH) and cognitive function in patients with non-disabling ischemic cerebrovascular events (NICE). METHODS: This was a prospective investigation of 160 NICE patients with age of 40 years or older. Cognitive function was evaluated by the Montreal Cognitive Assessment (MoCA). White matter lesions were evaluated by WMH using Fazekas scores. Spearman correlation analysis and linear regression models were used to identify the associations between serum 25(OH)D levels and cognitive function. Binary logistic regression analysis models were used to evaluate the predictable value of serum 25(OH)D levels and WMH for cognitive impairment. RESULTS: Patients with inadequate 25(OH)D levels had lower MoCA score (P=0.008), and a higher proportion of severe WMH (P=0.043). Spearman correlation analysis demonstrated that serum 25(OH)D concentrations were positively associated with MoCA score (rs=0.185, P=0.019) while negatively related to the proportion of severe WMH (sWMH) (rs=-0.166, P=0.036).The association between 25(OH)D concentrations and MoCA score remained significant in linear regression (adjusted ß=0.012, 95%CI:0.001-0.203).Adjusted binary logistic regression analysis showed that the odds ratio of cognitive impairment with insufficient 25(OH)D concentration was 5.038 (95%CI:1.154-21.988) compared with the sufficient group and the sWMH (OR=2.728, 95%CI:1.230-6.051) was identified as an independent risk factor for cognitive decline in NICE patients. CONCLUSION: Serum 25(OH)D levels and white matter lesions were independently and significantly associated with cognitive impairment in NICE patients.

Prediction of subjective cognitive decline after corpus callosum infarction by an interpretable machine learning-derived early warning strategy.

Background and purpose: Corpus callosum (CC) infarction is an extremely rare subtype of cerebral ischemic stroke, however, the symptoms of cognitive impairment often fail to attract early attention of patients, which seriously affects the long-term prognosis, such as high mortality, personality changes, mood disorders, psychotic reactions, financial burden and so on. This study seeks to develop and validate models for early predicting the risk of subjective cognitive decline (SCD) after CC infarction by machine learning (ML) algorithms. Methods: This is a prospective study that enrolled 213 (only 3.7%) CC infarction patients from a nine-year cohort comprising 8,555 patients with acute ischemic stroke. Telephone follow-up surveys were carried out for the patients with definite diagnosis of CC infarction one-year after disease onset, and SCD was identified by Behavioral Risk Factor Surveillance System (BRFSS) questionnaire. Based on the significant features selected by the least absolute shrinkage and selection operator (LASSO), seven ML models including Extreme Gradient Boosting (XGBoost), Logistic Regression (LR), Light Gradient Boosting Machine (LightGBM), Adaptive Boosting (AdaBoost), Gaussian Naïve Bayes (GNB), Complement Naïve Bayes (CNB), and Support vector machine (SVM) were established and their predictive performances were compared by different metrics. Importantly, the SHapley Additive exPlanations (SHAP) was also utilized to examine internal behavior of the highest-performance ML classifier. Results: The Logistic Regression (LR)-model performed better than other six ML-models in SCD predictability after the CC infarction, with the area under the receiver characteristic operator curve (AUC) of 77.1% in the validation set. Using LASSO and SHAP analysis, we found that infarction subregions of CC infarction, female, 3-month modified Rankin Scale (mRS) score, age, homocysteine, location of angiostenosis, neutrophil to lymphocyte ratio, pure CC infarction, and number of angiostenosis were the top-nine significant predictors in the order of importance for the output of LR-model. Meanwhile, we identified that infarction subregion of CC, female, 3-month mRS score and pure CC infarction were the factors which independently associated with the cognitive outcome. Conclusion: Our study firstly demonstrated that the LR-model with 9 common variables has the best-performance to predict the risk of post-stroke SCD due to CC infarcton. Particularly, the combination of LR-model and SHAP-explainer could aid in achieving personalized risk prediction and be served as a decision-making tool for early intervention since its poor long-term outcome.

EEG assessment of brain dysfunction for patients with chronic primary pain and depression under auditory oddball task.

In 2019, the International Classification of Diseases 11th Revision International Classification of Diseases (ICD-11) put forward a new concept of "chronic primary pain" (CPP), a kind of chronic pain characterized by severe functional disability and emotional distress, which is a medical problem that deserves great attention. Although CPP is closely related to depressive disorder, its potential neural characteristics are still unclear. This paper collected EEG data from 67 subjects (23 healthy subjects, 22 patients with depression, and 22 patients with CPP) under the auditory oddball paradigm, systematically analyzed the brain network connection matrix and graph theory characteristic indicators, and classified the EEG and PLI matrices of three groups of people by frequency band based on deep learning. The results showed significant differences in brain network connectivity between CPP patients and depressive patients. Specifically, the connectivity within the frontoparietal network of the Theta band in CPP patients is significantly enhanced. The CNN classification model of EEG is better than that of PLI, with the highest accuracy of 85.01% in Gamma band in former and 79.64% in Theta band in later. We propose hyperexcitability in attentional control in CPP patients and provide a novel method for objective assessment of chronic primary pain.

Association of neutrophil to lymphocyte ratio and D-dimer with functional outcome in patients with cerebral venous sinus thrombosis.

BACKGROUND: Investigations on the risk factors for the prognosis of cerebral venous sinus thrombosis (CVST) are limited. This study aimed to explore whether specific inflammatory factors and coagulation indictors are associated with functional outcome in patients treated for CVST. METHODS: This retrospective study included 137 patients admitted to our hospital between January 2010 and October 2021. The functional outcome was assessed with the modified Rankin Scale (mRS) score at discharge. Patients were divided into two groups, 102 patients with favorable outcomes (mRS 0-1) and 35 patients with poor outcomes (mRS 2-6). The clinical indexes were compared between two groups. Multivariable logistic regression was performed to identify the independent influencing factors for poor outcomes of CVST patients. The prognostic indicators were analyzed using the receiver operating characteristic (ROC) curve. RESULTS: Compared with the favorable outcome group, the incidence of impaired consciousness and brain lesion, the levels of D-dimer, RDW, neutrophil count, neutrophil to lymphocyte ratio (NLR) and red blood cell distribution width to platelet ratio (%) on admission were significantly higher in the poor outcome group, while the level of lymphocyte count was significantly lower. After multivariable logistic regression analysis, baseline D-dimer level (odds ratio (OR), 1.180; 95% confidence interval (CI), 1.019-1.366, P = 0.027) and NLR (OR, 1.903; 95%CI, 1.232-2.938, P = 0.004) were significantly associated with unfavorable outcome at discharge. The ROC curve analysis showed that the areas under the curve of D-dimer, NLR and their combined detection for predicting worse outcome were 0.719, 0.707 and 0.786, respectively. CONCLUSIONS: Elevated D-dimer level and NLR on admission were associated with an increased risk of poor functional outcome in patients with CVST.

In Situ Halide Exchange of Cesium Lead Halide Perovskites for Blue Light-Emitting Diodes.

3D perovskites are promising to achieve efficient and bright deep-blue light-emitting diodes (LEDs), which are required for lighting and display applications. However, the efficiency of deep-blue 3D perovskite-based LEDs is limited by high density of defects in perovskites, and their deep-blue emission is not easy to achieve due to the halide phase separation and low solubility of chloride in precursor solutions. Here, an in situ halide exchange method is developed to achieve deep-blue 3D perovskites by spin-coating an organic halide salts solution to treat blue 3D perovskites. It is revealed that the halide-exchange process is mainly determined by halide ion diffusion targeting a concentration equalization, which leads to homogeneous 3D mixed-halide perovskites. By further introducing multifunctional organic ammonium halide salts into the exchange solution to passivate defects, high-quality deep-blue perovskites with reduced trap density can be obtained. This approach leads to efficient deep-blue perovskite LEDs with a peak external quantum efficiency (EQE) of 4.6% and a luminance of 1680 cd m-2 , which show color coordinates of (0.131, 0.055), very close to the Rec. 2020 blue standard. Moreover, the halide exchange method is bidirectional, and blue perovskite LEDs can be achieved with color coordinates of (0.095, 0.160), exhibiting a high EQE of 11.3%.

Correlations among peripheral blood markers, white matter hyperintensity, and cognitive function in patients with non-disabling ischemic cerebrovascular events.

Background: Both inflammation and cerebral white matter injury are closely associated with vascular cognitive impairment (VCI). The aim of this study was to analyze the correlation between peripheral serological markers, white matter injury, and cognitive function in patients with non-disabling ischemic cerebrovascular events (NICE); to identify potential biological markers for the diagnosis and prediction of VCI; and to provide a basis for the early diagnosis and intervention of VCI. Methods: We collected clinical data, along with demographic and medical history data, from 151 NICE patients. Fasting venous blood samples were collected. Based on the Montreal Cognitive Assessment (MoCA) after admission, we divided the patients into normal cognitive function (NCF) and VCI groups, and then classified them into mild white matter hyperintensity (mWMH) and severe white matter hyperintensity (sWMH) based on Fazekas scores. The differences in serological marker levels were compared between the cognitive function groups and the white matter hyperintensity groups. Binary logistic regression models and receiver operating characteristic curves were used to analyze the diagnostic predictive value of serological markers for VCI in patients with NICE and in the white matter hyperintensity subgroups. Results: Among 151 patients with NICE, 95 were male and 56 were female. Lymphocyte count (OR = 0.405, p = 0.010, 95% CI [0.201, 0.806]), red blood cell count (OR = 0.433, p = 0.010, 95% CI [0.228, 0.821]), and hemoglobin level (OR = 0.979, p = 0.046, 95% CI [0.958, 0.999]) were protective factors for cognitive function in patients with NICE. The sWMH group had a higher age, granulocyte/lymphoid ratio (NLR), and neutrophil percentage but a lower MoCA score, hemoglobin level, and lymphocyte count than the mWMH group. In the mWMH group, lymphocyte count (AUC = 0.713, p = 0.003, 95% CI [0.593, 0.833]) had an acceptable predictive value for the diagnosis of VCI, whereas white blood cell count (AUC = 0.672, p = 0.011, 95% CI [0.545, 0.799]), red blood cell count (AUC = 0.665, p = 0.014, 95% CI [0.545, 0.784]), and hemoglobin level (AUC = 0.634, p = 0.047, 95% CI [0.502, 0.765]) had marginal predictive value for the diagnosis of VCI. In the sWMH group, no significant differences were found in serological markers between the NCF and VCI groups. Conclusion: Lymphocyte count, red blood cell count, and hemoglobin level were independent protective factors for cognitive function in patients with NICE; they can be used as potential biological markers to distinguish VCI in patients with NICE and are applicable to subgroups of patients with mWMH.

Impact of Stress Hyperglycemia on Early Neurological Deterioration in Acute Ischemic Stroke Patients Treated With Intravenous Thrombolysis.

Background and Purpose: It has been widely reported that stress hyperglycemia contributes to poor prognosis in patients experiencing acute ischemic stroke (AIS). However, its predictive value for early neurological deterioration (END) after intravenous administration of recombinant tissue-type plasminogen activator (IV-rtPA) in AIS patients is still unclear. The aim of this study was to evaluate the impact of stress hyperglycemia on the risk of END after IV-rtPA. Methods: A total of 798 consecutive patients treated with IV-rtPA were included in this study. The stress hyperglycemia ratio (SHR) was calculated as fasting plasma glucose level at admission (mg/dl)/glycosylated hemoglobin (HbAlc) (%). END was defined as a National Institutes of Health Stroke Scale Score (NIHSS) ≥ 4 points 24 h after IV-rtPA, and poor functional outcome at discharge was defined as a modified Rankin Scale (mRS) score of 3-6 at discharge. Patients with a prior history of diabetes or HbAlc ≥ 6.5% were considered to have diabetes mellitus. Patients were grouped according to SHR values. Multivariate logistical regression was used to evaluate the risk of END for patients within specific SHR categories. Results: In total, 139 (17.4%) patients had END. After adjusting for confounders, the highest tertile group had higher risks of END and poor functional outcome at discharge than those of patients in the lowest tertile group (OR, 1.95; 95% CI, 1.21-3.15; p = 0.006) (OR, 1.85; 95% CI, 1.163-2.941; p = 0.009), and the predictive value of high SHR for END was also significant in patients with diabetes mellitus (OR, 3.05; 95% CI, 1.29-7.21; p = 0.011). However, a significant association of high SHR and poor functional outcome was only found in patients without diabetes (OR, 1.85; 95% CI, 1.002-3.399; p = 0.045). Conclusion: A higher SHR predicted that patients with severe stress hyperglycemia had higher risks of END and poor functional outcome at discharge after IV-rtPA.

A case of ischemic stroke secondary to varicella-zoster virus meningoencephalitis.

Varicella-zoster virus (VZV) lurks in cranial nerves and other brain ganglias after infection. Because middle cerebral artery (MCA) receives the ipsilateral trigeminal ganglia afferent innervations, the reactivated VZV infects the adventitia and intima of cerebral artery wall probably through this way and causes vascular inflammation, finally resulting in artery remodeling, vessel occlusion, and ischemia. In fact, there is a growing clinical recognition that there is an association between VZV reactivation and subsequent stroke. Here, we showed a case of ischemic stroke secondary to varicella-zoster virus meningoencephalitis and reviewed the literature to emphasize the importance of VZV-associated vasculopathy.

Cerebrovascular Complications After Adult-Onset Varicella-Zoster Virus Encephalitis in the Central Nervous System: A Literature Review.

BACKGROUND: Cerebrovascular complications after adult-onset varicella-zoster virus (VZV) encephalitis have been increasingly recognized. The aim of this study was to analyze clinical and neuroimaging findings, treatment and outcome of these patients. METHODS: Literature review from January 2000 to December 2019. We searched for studies published in PubMed, Embase and Chinese Biomedical Literature Database. Clinical symptoms, neuroimaging findings, treatment and outcome were evaluated. RESULTS: We analyzed 31 articles with a total of adult-onset 34 cases, including 25 cases of ischemic stroke, 6 of intracerebral hemorrhage and 3 with venous sinus thrombosis. Ischemic stroke was the major complication after VZV encephalitis accounting of 73.35%. There were more males than females in ischemia or venous sinus thrombosis groups. The middle-aged was prone to cerebral infarction, the elderly was for cerebral hemorrhage, and the young was for venous sinus thrombosis. Cognitive impairment was the most common symptom either in the ischemic group or hemorrhagic group. The lesions of VZV-associated cerebral infarction or hemorrhage were multifocal and mostly involved in the parietal lobe, followed by frontal or temporal lobes. Venous sinus thrombosis was common in the transverse sinus. Multiple stenosis of the anterior and posterior circulation vessels was found. A 60.87% of the patients with antiviral treatment in the ischemic group had favorable prognosis. All patients with anticoagulant therapy in venous sinus thrombosis group improved well; however, 60% of the patients with intracerebral hemorrhage had a poor prognosis or died. CONCLUSION: Ischemic stroke was the majority of cerebrovascular complications after VZV encephalitis, which mainly occurred in middle-aged men. The lesions of VZV-associated cerebral infarction or hemorrhage were multifocal and did not accord with the characteristics of cerebrovascular diseases induced by atherosclerosis. The patients with venous sinus thrombosis had a relatively good prognosis. When the patient represents with some neurological symptoms about one month after VZV encephalitis, and multiple lesions probably induced by vasculitis are showed in neuroimaging, cerebrovascular complications related to VZV infection should be considered.

Higher inflammation and cerebral white matter injury associated with cognitive deficit in asthmatic patients with depression.

OBJECTIVE: Depression is a common co-morbidity in asthma, worsening asthma control and impairing quality of life. Previous studies have reported a higher risk of cognitive deficit in depression, yet little research has focused on the level of cognition in asthmatic patients with depression. Evidence shows that inflammation may play an important role in both asthma and depression. Cerebral white matter injury, possibly induced by inflammation, has been associated with depression. This study assesses cognitive function in patients with asthma and a depression comorbidity, compared to patients with asthma only or depression only. METHODS: Four groups were studied: Asthma comorbid Depression group (A + D, n = 26), Depression group (D, n = 25), Asthma group (A, n = 33) and Normal controls (N, n = 28). Cognitive function was evaluated using Montreal Cognitive Assessment (MoCA). Inflammatory cytokines were measured, including interleukin-1ß (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), high-mobility group box 1(HMGB1) and Netrin-1. Cerebral white matter injury was assessed by serum myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG), and their correlations with cognitive performance were calculated. RESULTS: A + D group showed the highest incidence of cognitive deficit, with the cognitive domain particularly affected. Compared to N group, serum levels of IL-6, HMGB1, Netrin-1, MBP and MOG were significantly elevated in A + D group. MOG level negatively correlated with the MoCA score. CONCLUSION: Patients with comorbidities presented with more severe cognitive deficits and higher levels of inflammatory cytokines. Cerebral white matter injury may account for the cognitive deficit in patients and MOG could be a potential biomarker for this process.

Anti-neuron antibody syndrome: clinical features, cytokines/chemokines and predictors.

BACKGROUND: Neuroimmunology is a rapidly expanding field, and there have been recent discoveries of new antibodies and neurological syndromes. Most of the current clinical studies have focused on disorders involving one specific antibody. We have summarized a class of antibodies that target common neuronal epitopes, and we have proposed the term "anti-neuron antibody syndrome" (ANAS). In this study, we aimed to clarify the clinical range and analyse the clinical features, cytokines/chemokines and predictors in ANAS. METHODS: This was a retrospective cohort study investigating patients with neurological manifestations that were positive for anti-neuron antibodies. RESULTS: A total of 110 patients were identified, of which 43 patients were classified as having autoimmune encephalitis (AE) and the other 67 were classified as having paraneoplastic neurological syndrome (PNS). With regards to anti-neuron antibodies, 42 patients tested positive for anti-N-methyl-D-aspartate receptor (NMDAR) antibody, 19 for anti-Hu, 14 for anti-Yo and 12 for anti-PNMA2 (Ma2). There were significant differences between the ANAS and control groups in serum B cell-activating factor (BAFF) levels and in cerebrospinal fluid (CSF) C-X-C motif chemokine10 (CXCL10), CXCL13, interleukin10 (IL10), BAFF and transforming growth factor ß1 (TGFß1) levels. Predictors of poor outcomes included having tumours (P = 0.0193) and having a chronic onset (P = 0.0306), and predictors of relapses included having lower levels of CSF BAFF (P = 0.0491) and having a larger ratio of serum TGFß1/serum CXCL13 (P = 0.0182). CONCLUSIONS: Most patients with ANAS had a relatively good prognosis. Having tumours and a chronic onset were both associated with poor outcomes. CSF BAFF and the ratio of serum TGFß1/serum CXCL13 were associated with relapses.

N6-methyladenosine (m6A) modification and its clinical relevance in cognitive dysfunctions.

BACKGROUND: N6 adenosine methylation (m6A) is the most abundant internal RNA modification in eukaryotic cells. Dysregulation of m6A has been associated with the perturbations of cell proliferation and cell death in different diseases. However, the roles of m6A in the neurodegenerative process and cognitive dysfunction are unclear. METHODS: We systematically investigated the molecular alterations of m6A regulators and their clinical relevance with cognitive dysfunctions using published datasets of Alzheimer's Disease (AD), vascular dementia, and mild cognitive impairment (MCI). FINDINGS: The expressions of m6A regulators vary in different tissues and closely correlate with neurodegenerative pathways. We identified co-expressive m6A regulators SNRPG and SNRPD2 as potential biomarkers to predict transformation from MCI to AD. Moreover, we explored correlations between Apolipoprotein E4 and m6A methylations. INTERPRETATION: Collectively, these findings suggest that m6A methylations as potential biomarkers and therapeutic targets for cognitive dysfunction. FUNDING: This work was supported by the National Natural Science Foundation of China (81871040) and the Shanghai Health System Talent Training Program (2018BR29).

Low field magnetic stimulation promotes myelin repair and cognitive recovery in chronic cuprizone mouse model.

BACKGROUND: Multiple sclerosis (MS) is an inflammatory demyelinating disease featured with neuroinflammation, demyelination, and the loss of oligodendrocytes. Cognitive impairment and depression are common neuropsychiatric symptoms in MS that are poorly managed with the present interventions. OBJECTIVE: This study aimed to investigate the effects of low field magnetic stimulation (LFMS), a novel non-invasive neuromodulation technology, on cognitive impairment and depressive symptoms associated with MS using a mouse model of demyelination. METHODS: C57BL female mice were fed with a 0.2% cuprizone diet for 12 weeks to induce a chronic demyelinating model followed by 4 weeks of cuprizone withdrawal with either sham or LFMS treatment. RESULTS: Improved cognition and depression-like behaviour and restored weight gain were observed in mice with LFMS treatment. Immunohistochemical and immunoblotting data showed enhanced myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein expressions (MOG) in the prefrontal cortex of mice with LFMS treatment, supporting that myelin repair was promoted. LFMS also increased the protein expression of mature oligodendrocyte biomarker glutathione-S-transferase (GST-π). In addition, expression of TGF-ß and associated receptors were elevated with LFMS treatment, implicating this pathway in the response. CONCLUSION: Results from the present study revealed LFMS to have neuroprotective effects, suggesting that LFMS has potential therapeutic value for treating cognitive impairment and depression related to demyelination disorders.

Anxiety and Depression Diagnosis Method Based on Brain Networks and Convolutional Neural Networks.

At present, only professional doctors can use the professional scales to diagnose depression and anxiety in clinical practice. In recent years, the problems of detecting the presence of anxiety or depression using Electroencephalography (EEG) has received attention as a way to implement assistant diagnosis, and some researchers explored that there are differences in the degree of prefrontal lateralization and functional connectivity of brain networks between patients with anxiety and depression and normal people. In this paper, we proposed a new approach that combines functional connectivity of brain networks and convolutional neural networks (CNN) for EEG-based anxiety and depression recognition. EEG data are collected from subjects consisting ten healthy controls and ten patients with anxiety or depression. In this way, we achieved 67.67% classification accuracy. It points out the way to further explore the application of functional connectivity of brain networks and deep learning technology in EEG about patients with anxiety and depression.

Mesenchymal Stem Cells Attenuated Blood-Brain Barrier Disruption via Downregulation of Aquaporin-4 Expression in EAE Mice.

Blood-brain barrier disruption is one of the hallmarks of multiple sclerosis. Mesenchymal stem cells showed great potential for the multiple sclerosis therapy. However, the effect of mesenchymal stem cells on blood-brain barrier in multiple sclerosis remains unclear. Here, we investigated whether mesenchymal stem cells transplantation protected blood-brain barrier integrity and further explored possible underlying mechanisms. Adult female C57BL/6 mice were immunized with myelin oligodendrocyte glycoprotein peptide33-55 (MOG33-55) to induce experimental autoimmune encephalomyelitis (EAE). Mesenchymal stem cells (5 × 105) were transplanted via tail vein at disease onset. In the cell culture, we examined lipopolysaccharide-induced AQP4 upregulation in astrocytes. Results indicated that mesenchymal stem cells therapy improved neurobehavioral outcomes in EAE mice, reduced inflammatory cell infiltration, IgG protein leakage, and demyelination in spinal cord. Mesenchymal stem cells therapy also increased tight junction protein expression. In addition, mesenchymal stem cells downregulated AQP4 and A2B adenosine receptor (A2BAR) expression in EAE mice in spinal cord. We found that MSCs-conditioned medium (MCM) reduced the expression of inflammatory cytokines, AQP4 and A2BAR in lipopolysaccharide-activated astrocytes. BAY-60-6583 (a selective A2BAR agonist) reversed the MCM-induced AQP4 downregulation and increased p38 MAPK phosphorylation. Furthermore, the upregulation effects of A2BAR agonist were eliminated when treated with p38 MAPK inhibitor SB203580. Thus, we concluded that mesenchymal stem cells alleviated blood-brain barrier disruption by downregulating AQP4 in multiple sclerosis, possibly through inhibiting the A2BAR/p38 MAPK signaling pathway. Our work suggests that mesenchymal stem cells exert beneficial effect through maintaining blood-brain barrier integrity in EAE mice.

Involvement of Frontal Functions in Pain Tolerance in Aging: Evidence From Neuropsychological Assessments and Gamma-Band Oscillations.

Reduced pain tolerance may be one of the possible explanations for high prevalence of chronic pain among older people. We hypothesized that age-related alterations in pain tolerance are associated with functioning deterioration of the frontal cortex during normal aging. Twenty-one young and 41 elderly healthy participants underwent a tonic heat pain test, during which cerebral activity was recorded using electroencephalography (EEG). Elderly participants were divided into two subgroups according to their scores on executive tests, high performers (HPs; n = 21) and low performers (LPs; n = 20). Pain measures [exposure times (ETs) and perceived pain ratings] and cerebral activity were compared among the three groups. ETs were significantly lower in elderly LPs than in young participants and elderly HPs. Electroencephalographic analyses showed that gamma-band oscillations (GBOs) were significantly increased in pain state for all subjects, especially in the frontal sites. Source analysis showed that GBO increase in elderly LPs was contributed not only by frontal but also by central, parietal, and occipital regions. These findings suggest that better preservation of frontal functions may result in better pain tolerance by elderly subjects.