Lipopolysaccharide-induced intestinal inflammation on AIM2-mediated pyroptosis in the brain of rats with cerebral small vessel disease.

Cerebral small vessel disease (CSVD) is a cerebral vascular disease with insidious onset and poor clinical treatment effect, which is related to neuroinflammation. This study investigated whether lipopolysaccharide-induced intestinal inflammation enhanced the level of pyroptosis in the brain of rats with CSVD. The bilateral carotid artery occlusion (BCAO) model was selected as the object of study. Firstly, behavioral tests and Hematoxylin-eosin staining (HE staining) were performed to determine whether the model was successful, and then the AIM2 inflammasome and pyroptosis indexes (AIM2, ASC, Caspase-1, IL-1ß, GSDMD, N-GSDMD) in the brain were detected by Western blotting and Immunohistochemistry (IHC). Finally, a single intraperitoneal injection of lipopolysaccharide (LPS) was used to induce intestinal inflammation in rats, the expression of GSDMD and N-GSDMD in the brain was analyzed by Western blotting and to see if pyroptosis caused by intestinal inflammation can be inhibited by Disulfiram, an inhibitor of pyroptosis. The results showed that the inflammatory response and pyroptosis mediated by the AIM2 inflammasome in BCAO rats were present in both brain and intestine. The expression of N-GSDMD, a key marker of pyroptosis, in the brain was significantly increased and inhibited by Disulfiram after LPS-induced enhancement of intestinal inflammation. This study shows that AIM2-mediated inflammasome activation and pyroptosis exist in both brain and intestine in the rat model of CSVD. The enhancement of intestinal inflammation will increase the level of pyroptosis in the brain. In the future, targeted regulation of the AIM2 inflammasome may become a new strategy for the clinical treatment of CSVD.

PFASs in Cerebrospinal Fluids and Blood-CSF Barrier Permeability in Patients with Cognitive Impairment.

Attention has been drawn to the associations between PFASs and human cognitive decline. However, knowledge on the occurrence and permeability of PFASs in the brains of patients with cognitive impairment has not been reported. Here, we determined 30 PFASs in paired sera and cerebrospinal fluids (CSFs) from patients with cognitive impairment (n = 41) and controls without cognitive decline (n = 18). We revealed similar serum PFAS levels but different CSF PFAS levels, with lower CSF PFOA (median: 0.125 vs 0.303 ng/mL, p < 0.05), yet higher CSF PFOS (0.100 vs 0.052 ng/mL, p < 0.05) in patients than in controls. Blood-brain transfer rates also showed lower RCSF/Serum values for PFOA and higher RCSF/Serum values for PFOS in patients, implying potential heterogeneous associations with cognitive function. The RCSF/Serum values for C4-C14 perfluoroalkyl carboxylates exhibited a U-shape trend with increasing chain length. Logistic regression analyses demonstrated that CSF PFOS levels were linked to the heightened risk of cognitive impairment [odds ratio: 3.22 (1.18-11.8)] but not for serum PFOS. Toxicity inference results based on the Comparative Toxicogenomics Database suggested that PFOS in CSF may have a greater potential to impair human cognition than other PFASs. Our results contribute to a better understanding of brain PFAS exposure and its potential impact on cognitive function.

The relationship between APOE genotype, CSF Tau and cognition across the Alzheimer's disease spectrum, moderation and mediation role of insula network connectivity.

AIMS: To investigate whether insula network connectivity modulates the relationship between apolipoprotein E (APOE) ε4 genotype, cerebrospinal fluid (CSF) biomarkers (Aß, Tau, and pTau) and cognition across Alzheimer's disease (AD) spectrum. METHODS: Forty-six cognitive normal (CN), 35 subjective memory complaint (SMC), 41 mild cognitive impairment (MCI), and 32 AD subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were obtained. Multivariable linear regression analyses were conducted to investigate the main effects and interaction of the APOE genotype and disease status on the insula functional connectivity (IFC) network. Mediation and moderation analysis were performed to investigate whether IFC strengths regulate the association between APOE genotype, CSF biomarkers and cognition. Additionally, the support vector machine (SVM) model integrating APOE genotype, CSF biomarkers, and neuroimaging biomarkers (insula volumes and altered regional IFCs) was used to classify the AD spectrum. RESULTS: The interactive effect of the APOE genotype and disease on the insula network was found in the left medial superior frontal gyrus (SFGmed.L), right anterior medial prefrontal cortex (aMPFC.R), and bilateral thalamus (THA.B). The functional connectivities (FCs) in the left insula (LIns) connecting with the left posterior middle temporal gyrus (pMTG.L), SFGmed.L, and right lingual gyrus (LING.R) were correlated with cognition. LIns-SFGmed.L and LIns-pMTG.L FCs could moderate the effects of Tau on cognition. Furthermore, LIns-SFGmed.L FC may suppress the association between APOE genotype and cognition. More importantly, the integrated biomarkers from the SVM model yielded strong powers for classifying the AD spectrum. CONCLUSIONS: Insula functional connectivity regulated the association between APOE genotype, CSF Tau and cognition and provided stage-dependent biomarkers for early differentiation of the AD spectrum. The present study used a cross-sectional design. Follow-up studies are needed to validate the relationship.

Investigation of brain iron levels in Chinese patients with Alzheimer's disease.

Introduction: We aimed (i) to explore the diagnostic value of deep gray matter magnetic susceptibility in Alzheimer's disease (AD) in China and (ii) to analyze its correlation with neuropsychiatric scales. Moreover, we conducted subgroup analysis based on the presence of the APOE-ε4 gene to improve the diagnosis of AD. Methods: From the prospective studies of the China Aging and Neurodegenerative Initiative (CANDI), a total of 93 subjects who could undergo complete quantitative magnetic susceptibility imaging and APOE-ε4 gene detection were selected. Differences in quantitative susceptibility mapping (QSM) values between and within groups, including AD patients, individuals with mild cognitive impairment (MCI), and healthy controls (HCs), both APOE-ε4 carriers and non-carriers, were analyzed. Results: In primary analysis, the magnetic susceptibility values of the bilateral caudate nucleus and right putamen in the AD group and of the right caudate nucleus in the MCI group were significantly higher than those in the HCs group (P < 0.05). In APOE-ε4 non-carriers, there were significant differences in more regions between the AD, MCI, and HCs groups, such as the left putamen and the right globus pallidus (P < 0.05). In subgroup analysis, the correlation between QSM values in some brain regions and neuropsychiatric scales was even stronger. Discussion: Exploration of the correlation between deep gray matter iron levels and AD may provide insight into the pathogenesis of AD and facilitate early diagnosis in elderly Chinese. Further subgroup analysis based on the presence of the APOE-ε4 gene may further improve the diagnostic efficiency and sensitivity.

Changes in CSF sPDGFRß level and their association with blood-brain barrier breakdown in Alzheimer's disease with or without small cerebrovascular lesions.

BACKGROUND: CSF-soluble platelet-derived growth factor receptor beta (sPDGFRß) is closely associated with pericyte damage. However, the changes in CSF sPDGFRß levels and their role in blood-brain barrier (BBB) leakage at different stages of Alzheimer's disease (AD), with or without cerebral small vessel disease (CSVD) burden, remain unclear. METHODS: A total of 158 individuals from the China Aging and Neurodegenerative Disorder Initiative cohort were selected, including 27, 48, and 83 individuals with a clinical dementia rating (CDR) score of 0, 0.5, and 1-2, respectively. CSF total tau, phosphorylated tau181 (p-tau181), Aß40, and Aß42 were measured using the Simoa assay. Albumin and CSF sPDGFRß were measured by commercial assay kits. CSVD burden was assessed by magnetic resonance imaging. RESULTS: CSF sPDGFRß was the highest level in the CDR 0.5 group. CSF sPDGFRß was significantly correlated with the CSF/serum albumin ratio (Q-alb) in the CDR 0-0.5 group (ß = 0.314, p = 0.008) but not in the CDR 1-2 group (ß = - 0.117, p = 0.317). In the CDR 0-0.5 group, CSF sPDGFRß exhibited a significant mediating effect between Aß42/Aß40 levels and Q-alb (p = 0.038). Q-alb, rather than CSF sPDGFRß, showed a significant difference between individuals with or without CSVD burden. Furthermore, in the CDR 0.5 group, CSF sPDGFRß was higher in subjects with progressive mild cognitive impairment than in those with stable mild cognitive impairment subjects (p < 0.001). Meanwhile, CSF sPDGFRß was significantly associated with yearly changes in MMSE scores in the CDR 0.5 group (ß = - 0.400, p = 0.020) and CDR 0.5 (A+) subgroup (ß = - 0.542, p = 0.019). CONCLUSIONS: We provide evidence that increased CSF sPDGFRß is associated with BBB leakage in the early cognitive impairment stage of AD, which may contribute to cognitive impairment in AD progression.

A combination model of AD biomarkers revealed by machine learning precisely predicts Alzheimer's dementia: China Aging and Neurodegenerative Initiative (CANDI) study.

INTRODUCTION: To test the utility of the "A/T/N" system in the Chinese population, we study core Alzheimer's disease (AD) biomarkers in a newly established Chinese cohort. METHODS: A total of 411 participants were selected, including 96 cognitively normal individuals, 94 patients with mild cognitive impairment (MCI) patients, 173 patients with AD, and 48 patients with non-AD dementia. Fluid biomarkers were measured with single molecule array. Amyloid beta (Aß) deposition was determined by 18 F-Flobetapir positron emission tomography (PET), and brain atrophy was quantified using magnetic resonance imaging (MRI). RESULTS: Aß42/Aß40 was decreased, whereas levels of phosphorylated tau (p-tau) were increased in cerebrospinal fluid (CSF) and plasma from patients with AD. CSF Aß42/Aß40, CSF p-tau, and plasma p-tau showed a high concordance in discriminating between AD and non-AD dementia or elderly controls. A combination of plasma p-tau, apolipoprotein E (APOE) genotype, and MRI measures accurately predicted amyloid PET status. DISCUSSION: These results revealed a universal applicability of the "A/T/N" framework in a Chinese population and established an optimal diagnostic model consisting of cost-effective and non-invasive approaches for diagnosing AD.

Different Complement Activation Pathways Underly Cognitive Impairment and Type 2 Diabetes Mellitus Combined With Cognitive Impairment.

Background: The immune response and the complement system are associated with cognitive impairment and diabetes mellitus, respectively. Activation of the complement system in these diseases occurs mainly through either the classical pathway or the alternative pathway. However, the specific complement proteins involved in the development of the type 2 diabetes mellitus (T2DM) and cognitive impairment are still unclear. Here, we investigated complement proteins in serum from patients with T2DM, cognitive impairment, or both T2DM and cognitive impairment. Objective: To investigate the levels of serum immune complement proteins in patients with T2DM, cognitive impairment, or T2DM combined with cognitive impairment and the associations between these complement proteins and risk factors for T2DM or cognitive impairment. Methods: Clinical markers were collected from blood samples of 264 participants. Luminex multiplex assays were used to detect serum complement proteins. All statistical analyses were performed using Prism or R studio. Results: There was a difference in serum levels of the complement proteins C1q, C3, C3b, and FH between the three different groups. Hyperglycemia was significantly correlated with elevated C3b or reduced C3, C1q, and FH. In addition, hyperlipidemia was positively correlated with elevated levels of C3, C4, C1q, and FH proteins. There was an association between C1q, C3, C4, and FH and ß-pancreas cell function, whereas only FH was associated with insulin resistance. Higher serum C1q was significantly associated with an increased risk of cognitive impairment. Conclusion: Serum levels of complement proteins were closely associated with hyperglycemia and hyperlipidemia. We found that classical complement pathway activation mainly occurred in the cognitive impairment only group, whereas the alternative pathway may reflect T2DM and T2DM with cognitive impairment.

Correlation Between Apelin and Collateral Circulation in Patients with Middle Cerebral Artery Occlusion and Moyamoya Disease.

BACKGROUND AND OBJECTIVES: Moyamoya disease (MMD) is a unique cerebrovascular occlusive disease with abnormal vascular hyperplasia, which causes cerebrovascular accidents like intracranial arteriosclerosis. This study aimed to explore whether plasma apelin levels are related to good collateral circulation in ischemic diseases, which may be higher in patients with MMD than middle cerebral artery (MCA) occlusion or healthy controls, and may have a connection with the MMD grades. METHODS: We recruited 68 MMD patients and 25 MCA occlusion patients diagnosed by angiography, including 29 patients without cerebrovascular problems as controls. We examined the plasma apelin, serum nitric oxide (NO), and vascular endothelial growth factor (VEGF) levels of all subjects by ELISA kit. We compared the relationship between apelin, NO, and VEGF in the blood of three groups, to explore the relationship. We also investigated whether the plasma apelin-13, apelin-17, and apelin-36 levels correlate with the MMD classification. RESULTS: Univariate analyses indicated that the MMD group had the higher plasma apelin-13, apelin-17, apelin-36, and serum NO levels than the MCA occlusion and healthy control groups. Binary logistic regression analyses further showed that the apelin-13 level was substantially higher in MMD patients than in MCA occlusion patients. Patients with MMD were significantly younger than patients with MCA occlusion by their mean ages. Linear regression analyses were performed to compare apelin levels between different grades of the patients with MMD. Apelin-13, apelin-17, and apelin-36 levels increased with the gradual increase of compensation grades level independent of NO and VEGF. Apelin-13 and apelin-36 showed a positive effect on the compensation scores in MMD. CONCLUSION: Our study demonstrated that apelin-13 was significantly increased in patients with MMD than patients with MCA occlusion independent of NO and VEGF. Moreover, plasma apelin-13, apelin-17, and apelin-36 levels increase with the grades of MMD.

Influence of Hospital Outdoor Space on Physiological Electroencephalography (EEG) Feedback of Staff.

OBJECTIVES: To investigate the differences and relationships between different outdoor spaces of hospitals on the physiological electroencephalography (EEG) feedback (PEEGF) of staff. BACKGROUND: Relieving the pressure of hospital staff is essential, and several studies have revealed that even short-term exposure to outdoor space has a decompression effect. Yet, the focus is scarcely centered on the differences and influential relationships between the PEEGF from different outdoor spaces where the staff spend time, particularly in large-scale hospitals in China. METHODS: EEG measurement equipment was utilized to obtain the value of ß wave (vßw) that represents the stress and anxiety of staff in three different outdoor spaces: open, traffic, and rest. On the basis of EEG data, correlation analysis was conducted in accordance with the proportion of space elements. RESULTS: The proportion of natural elements, such as landscape (r = -.800** p=.005) and waterscape (r = -.782* p=.013), were negatively correlated with the vßw produced by staff, while the proportion of hard paving was positive (r = .817** p=.004) with more vßw produced by staff. In other words, the percentage of landscape and waterscape can reduce stress, while hard paving has the opposite effect. Further, there was a difference in the amount of vßw generated between nurses and administrators in the open space at the entrance of the main building (p = .043). CONCLUSIONS: The present study revealed the influence of different outdoor space elements of the hospital on the physiological feedback of staff, demonstrated the practical necessity of evidence-based design, and proposed relevant optimization suggestions.

Interictal Activity Is Associated With Slower Binocular Rivalry in Idiopathic Generalized Epilepsy.

Objective: Perceptual alternations evoked by binocular rivalry (BR) reflect cortical dynamics strongly dependent on the excitatory-inhibitory balance, suggesting potential utility as a biomarker for epileptogenesis. Therefore, we investigated the characteristics of BR in patients with idiopathic generalized epilepsy (IGE) and potential associations with clinical variables. Methods: Sixty-two healthy controls (HCs) and 94 IGE patients completed BR task. Perceptual alternation rates were compared between HC and IGE groups as well as among the HC group and IGE patients stratified according to the presence or absence of interictal activity on the ambulatory electroencephalogram (EEG), termed the abnormal ambulatory EEG group (AB-AEEG, n = 64) and normal ambulatory EEG group (N-AEEG, n = 30), respectively. Results: The IGE patients demonstrated a slower rate of BR perceptual alternation than HC subjects (t = -4.364, p < 0.001). The alternation rate also differed among the HC, AB-AEEG, and N-AEEG groups (F = 44.962, df = 2, p < 0.001), and post hoc comparisons indicated a significantly slower alternation rate in the AB-AEEG group compared with the N-AEEG and HC groups (0.28 vs. 0.46, and 0.43 Hz). Stepwise linear regression revealed positive correlations between the BR alternation rate and both the ambulatory EEG status (ß, 0.173; standard error, 0.022 p < 0.001) and Montreal Cognitive Assessment score (ß, 0.013; standard error, 0.004; p = 0.003). Receiver operating characteristic curve analysis of the BR alternation rate distinguished AB-AEEG from N-AEEG subjects with 90.00% sensitivity and 76.90% specificity (area under the curve = 0.881; 95% confidence interval = 0.801- 0.961, cut-off = 0.319). Alternatively, Montreal Cognitive Assessment score did not accurately distinguish AB-AEEG from N-AEEG subjects and the area under the receiver operating characteristic curve combining the BR alternation rate and Montreal Cognitive Assessment score was not markedly larger than that of the BR alternation rate alone (0.894, 95% confidence interval = 0.822-0.966, p < 0.001). K-fold cross-validation was used to evaluate the predictive performance of BR alternation rate, MoCA score, and the combination of both, which yielded average AUC values of 0.870, 0.584 and 0.847, average sensitivity values of 89.36, 92.73, and 91.28%, and average specificity values of 62.25, 13.42, and 61.78%, respectively. The number of interictal epileptiform discharges was significantly correlated with the alternation rate in IGE patients (r = 0.296, p = 0.018). A forward stepwise linear regression model identified the number of interictal epileptiform discharges (ß, 0.001; standard error, 0.001; p = 0.025) as an independent factor associated with BR alternation rate in these patients. Conclusion: These results suggest that interictal epileptiform discharges are associated with disruptions in perceptual awareness, and that the BR may be a useful auxiliary behavioral task to diagnosis and dynamically monitor IGE patients with interictal discharge.

Increased Accumulation of α-Synuclein in Inflamed Appendices of Parkinson's Disease Patients.

BACKGROUND: The accumulation of α-synuclein (α-Syn) aggregates that leads to the onset of Parkinson's disease (PD) has been postulated to begin in the gastrointestinal tract. The normal human appendix contains pathogenic forms of α-Syn, and appendectomy has been reported to affect the incidence of PD. OBJECTIVE: This study investigated appendix abnormality in patients with PD. METHODS: We assessed appendix morphology in 100 patients with PD and 50 control subjects by multislice spiral computed tomography. We analyzed the clinical characteristics of patients with PD with diseased appendices, which was confirmed in seven patients by histopathological analysis. RESULTS: Chronic appendicitis-like lesions were detected in 53% of patients with PD, but these were not associated with the duration of motor symptoms. Appendicitis-like lesions, impaired olfaction, and rapid eye movement sleep behavior disorder were risk factors for PD. The following clinical symptoms could be used to identify patients with PD with appendicitis-like lesions: first motor symptoms were bradykinesia/rigidity, onset of motor symptoms in the central axis or left limb, prodromal constipation, high ratio of Unified Parkinson's Disease Rating Scale Part III score to symptom duration, low Montreal Cognitive Assessment score, and high Epworth Sleepiness Scale score. The seven patients with PD who were diagnosed with chronic appendicitis underwent appendectomy, and histopathological analysis revealed structural changes associated with chronic appendicitis and α-Syn aggregation. CONCLUSIONS: These results indicate an association between chronic appendicitis-like lesions and PD, and suggest that α-Syn accumulation in the diseased appendix occurs in PD. © 2021 International Parkinson and Movement Disorder Society.

NLRP3 Is Involved in the Maintenance of Cerebral Pericytes.

Pericytes play a central role in regulating the structure and function of capillaries in the brain. However, molecular mechanisms that drive pericyte proliferation and differentiation are unclear. In our study, we immunostained NACHT, LRR and PYD domains-containing protein 3 (NLRP3)-deficient and wild-type littermate mice and observed that NLRP3 deficiency reduced platelet-derived growth factor receptor ß (PDGFRß)-positive pericytes and collagen type IV immunoreactive vasculature in the brain. In Western blot analysis, PDGFRß and CD13 proteins in isolated cerebral microvessels from the NLRP3-deficient mouse brain were decreased. We further treated cultured pericytes with NLRP3 inhibitor, MCC950, and demonstrated that NLRP3 inhibition attenuated cell proliferation but did not induce apoptosis. NLRP3 inhibition also decreased protein levels of PDGFRß and CD13 in cultured pericytes. On the contrary, treatments with IL-1ß, the major product of NLRP3-contained inflammasome, increased protein levels of PDGFRß, and CD13 in cultured cells. The alteration of PDGFRß and CD13 protein levels were correlated with the phosphorylation of AKT. Inhibition of AKT reduced both protein markers and abolished the effect of IL-1ß activation in cultured pericytes. Thus, NLRP3 activation might be essential to maintain pericytes in the healthy brain through phosphorylating AKT. The potential adverse effects on the cerebral vascular pericytes should be considered in clinical therapies with NLRP3 inhibitors.

Serum beta2-microglobulin levels are highly associated with the risk of acute ischemic stroke.

Inflammation is considered an important mechanism of cell death or survival after ischemic stroke. As an important marker of inflammation, the role of ß2-microglobulin (ß2M) in acute ischemic stroke is unclear. We investigated the relationship between serum ß2M and the risk of acute ischemic stroke (AIS). Patients with AIS (202 cases), intracerebral hemorrhage (ICH, 41 cases), and healthy controls (253 cases) were recruited. Clinical and biochemical characteristics were collected. We used three binary logistic regression models to evaluate the correlation of ß2M with the risk of AIS. Furthermore, we investigated the relationship between serum ß2M and the National Institute of Health Stroke Scale (NIHSS) score, the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) subtypes, and the Essen Stroke Risk Score (ESRS) in patients with AIS. Our results showed that serum ß2M levels in patients with AIS were much higher than those in patients with ICH and in the control subjects. Individuals with higher levels of ß2M had higher odds of AIS. Moreover, serum ß2M levels were significantly and positively correlated with ESRS. In addition, the levels of ß2M were varied with different subgroups of AIS (TOAST classification). Serum ß2M is highly associated with the risk of AIS.

Decreasing serum 25-hydroxyvitamin D levels and risk of early neurological deterioration in patients with ischemic stroke.

BACKGROUND AND AIMS: Vitamin D deficiency has been linked to a higher risk of ischemic stroke. We therefore explored the relationship between serum 25-hydroxyvitamin D [25(OH)D] levels and early neurological deterioration (END) after acute ischemic stroke in a hospital-based prospective study. METHODS: From June 2016 to June 2018, patients with ischemic stroke within 48 hr from symptom onset were consecutively recruited. Serum 25(OH)D levels were measured at admission. END was defined as an increase of ≥1 point in motor power or ≥2 points in the total National Institute of Health Stroke Scale score within 7 days after admission. Multiple logistic regression models were performed to calculate the odds ratio (OR) and confidence intervals (CI) of 25(OH)D levels in predicting END. RESULTS: A total of 478 subjects were enrolled, of which 136 (28.5%) patients developed END. The mean 25(OH)D levels were 49.5 ± 15.8 nmol/L. Univariate logistic regression analysis showed that advanced age, white matter lesions, high level of body mass index, diastolic blood pressure, fasting blood glucose and homocysteine, and low 25(OH)D levels were associated with END. Furthermore, multivariate regression analysis demonstrated that the first quartile of 25(OH)D concentrations [OR, 2.628; 95% CI,1.223-5.644; p = 0.013] was independently risk factor for END. CONCLUSIONS: This study illustrated that lower 25(OH)D levels might be associated with an increasing risk of END in acute ischemic stroke patients.

Clinical and Magnetic Resonance Imaging Features of Reversible Splenial Lesion Syndrome in Adults: A Small Case Series.

BACKGROUND: To study clinical and magnetic resonance imaging (MRI) features of reversible splenial lesion syndrome (RESLES) in adult patients. METHODS: A retrospective analysis was performed using clinical, cerebrospinal fluid (CSF), laboratory results, and neuroimaging data obtained from 6 adult RESLES patients. RESULTS: All 6 patients (3 male cases, 3 female cases) were determined to be acute or subacute onset, most of them associated with infection or fever. All initial MRI data exhibited splenium of corpus callosum lesions with hypointensity on T1WI, hyperintensity on T2WI, diffusion-weighted imaging (DWI) and Flair, without significant gadolinium enhancement. Five patients were treated with glucocorticoids and showed significant improvement in 1-15 days, with the lesion having disappeared or weakened, and one case was lost of follow-up. The cell number and protein amount in CSF were determined to be at normal levels, or slightly increased in 3 patients with thyroid dysfunction. CONCLUSION: The etiology of adult RESLES was observed to be complex and diverse, primarily related to infection, fever, and thyroid dysfunction. DWI was found to be more sensitive in these lesions, and CSF cytology was observed to be either normal or mildly abnormal. A majority of patients were found to be sensitive to glucocorticoid, and have a good prognosis with lesions that disappeared rapidly.

Serum ß2-Microglobulin Is Closely Associated With the Recurrence Risk and 3-Month Outcome of Acute Ischemic Stroke.

Background and Purpose: Inflammation plays a significant role in the pathogenesis of acute ischemic stroke (AIS). The role of ß2-microglobulin (ß2M) as a potential initiator of the inflammatory response in AIS is unclear. The purpose of this study was to analyze the relationship of serum ß2M with the recurrence risk and 3-month outcome of AIS. Methods: A total of 205 patients with AIS were recruited, and their clinical and biochemical characteristics were collected. All patients were followed up for 3 months after stroke onset, and the occurrence of death or major disability at 3 months after onset was the outcome of interest in this study. We evaluated the association of serum ß2M levels with the National Institute of Health Stroke Scale (NIHSS) scores, modified Rankin Scale (mRS) scores, and Essen Stroke Risk Score (ESRS) values in patients with AIS. Then, we used receiver operating curve analysis to calculate the optimal cutoff value for discriminating outcomes in patients with AIS and a binary logistic regression model to evaluate the risk factors for a poor outcome after AIS. Results: Our results showed that serum ß2M levels were significantly and positively correlated with ESRS values (r = 0.176, P < 0.001) and mRS scores (r = 0.402, P < 0.001), but the levels of ß2M were not correlated with NIHSS scores (r = 0.080, P = 0.255) or with infarct volume (r = 0.013, P = 0.859). In a further study, we found that 121 patients (59.02%) had poor outcomes. The optimal ß2M cutoff to predict the 3-month outcome of AIS in this study was 1.865 mg/l, and ß2M was independently associated with a poor outcome at 3 months (OR = 3.325, 95% confidence interval: 1.089~10.148). Conclusions: In conclusion, we inferred that serum ß2M was positively associated with the recurrence risk and 3-month outcome of AIS, but it did not appear to be directly related to the severity of AIS or the size of the infarct at admission.

Tanshinone IIA Protects Hippocampal Neuronal Cells from Reactive Oxygen Species Through Changes in Autophagy and Activation of Phosphatidylinositol 3-Kinase, Protein Kinas B, and Mechanistic Target of Rapamycin Pathways.

BACKGROUND: Tanshinone IIA is a key active ingredient of danshen, which is derived from the dried root or rhizome of Salviae miltiorrhizae Bge. The tanshinone IIA has protective effects against the focal cerebral ischemic injury. However, the underlying mechanisms remain unclear. METHODS: An in vitro model of cerebral ischemia was established by subjecting cultures of hippocampal neuronal cells to oxygen-glucose deprivation followed by reperfusion (OGD/R). The probes of 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate, acetyl ester (CMH2DCFDA) and 5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolylcarbocyanine,iodide (JC-1) were used to determine the mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) production. Western-blot was used to detect the expression of proteins in HT-22 cells. RESULTS: The results of cell proliferative assays showed that the tanshinone IIA attenuated OGD/Rmediated neuronal cell death, with the evidence of increased cell viability. In addition, OGD/R exposure led to increase the levels of intracellular reactive oxygen species (ROS), which were significantly suppressed by tanshinone IIA treatment. Furthermore, tanshinone IIA treatment inhibited elevations in MMP and autophagy following exposure to OGD/R. Additionally, OGD/R promoted cell death with concomitant inhibiting phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/ mammalian target of Rapamycin (mTOR) pathway, which was reversed by tanshinone IIA. CONCLUSION: These results suggest that the tanshinone IIA protects against OGD/R-mediated cell death in HT-22 cells, in part, due to activating PI3K/Akt/mTOR pathway.

Protective effect of tanshinone IIA on the brain and its therapeutic time window in rat models of cerebral ischemia-reperfusion.

The aims of the present study were to investigate the protective effect of tanshinone IIA on the brain and its therapeutic time window in a rat model of cerebral ischemia-reperfusion. The rat model of cerebral ischemia-reperfusion was established by suture occlusion. In an initial experiment, male Sprague-Dawley (SD) rats were randomly divided into control cerebral ischemia-reperfusion rat model, tanshinone IIA1 (TSA1), tanshinone IIA4 (TSA4), tanshinone IIA6 (TSA6) and tanshinone IIA12 (TSA12) groups (n=8 per group). The rats in the control group were given 4 ml phosphate-buffered saline (PBS) intraperitoneally following suture occlusion. The other groups were respectively treated with 25 mg/kg tanshinone IIA intraperitoneally at 1, 4, 6 and 12 h following the initiation of reperfusion and once a day for a total of three days. The grades of neurologic impairment and volume of cerebral infarction of each group were measured 72 h after suture occlusion. In another experiment, 16 male SD rats were randomly divided into a 6 h reperfusion group and a 24 h reperfusion group following drug administration. The rats in each group were further divided into a control subgroup (4 ml PBS) and a tanshinone IIA subgroup (25 mg/kg). The rats were immediately administered their respective treatments following the establishment of the model. The rats were decapitated 6 and 24 h after the initiation of reperfusion. The expression levels of cytoplasmic thioredoxin (Trx-1) and mitochondrial thioredoxin (Trx-2) in the ischemic penumbra were determined by western blot analysis. The nitric oxide (NO) levels, and total NO synthase (tNOS) and inducible NO synthase (iNOS) activities in the rat blood were measured using a reagent kit. The changes in cerebral blood flow were evaluated by Doppler imaging. The grade of neurological impairment of the TSA1 group was statistically lower than that of the other groups (P<0.05). The cerebral infarction volume results showed that the volumes of infarction in the TSA1 and TSA4 groups were lower than those in the other groups (P<0.05). Tanshinone IIA significantly increased cerebral blood flow compared with that of the control group (P<0.05). Moreover, tanshinone IIA significantly increased the expression levels of Trx-1 and Trx-2 compared with those in the control group (P<0.05). Tanshinone IIA significantly decreased the NO levels and iNOS and tNOS activities compared with those of the control group (P<0.05). However, the iNOS activity in the rats in the 6 h reperfusion group was not statistically significantly different from that of the respective control group (P>0.05). Tanshinone IIA has a protective effect on the cranial nerves when administered during the initial stages of cerebral ischemia. This protective effect is associated with an improvement of cerebral blood flow as well as an increase in anti-oxygen radical and anti-inflammatory activities.