Overexpression of low-density lipoprotein receptor prevents neurotoxic polarization of astrocytes via inhibiting NLRP3 inflammasome activation in experimental ischemic stroke.

JOURNAL/nrgr/04.03/01300535-202502000-00027/figure1/v/2024-05-28T214302Z/r/image-tiff Neurotoxic astrocytes are a promising therapeutic target for the attenuation of cerebral ischemia/reperfusion injury. Low-density lipoprotein receptor, a classic cholesterol regulatory receptor, has been found to inhibit NLR family pyrin domain containing protein 3 (NLRP3) inflammasome activation in neurons following ischemic stroke and to suppress the activation of microglia and astrocytes in individuals with Alzheimer's disease. However, little is known about the effects of low-density lipoprotein receptor on astrocytic activation in ischemic stroke. To address this issue in the present study, we examined the mechanisms by which low-density lipoprotein receptor regulates astrocytic polarization in ischemic stroke models. First, we examined low-density lipoprotein receptor expression in astrocytes via immunofluorescence staining and western blotting analysis. We observed significant downregulation of low-density lipoprotein receptor following middle cerebral artery occlusion reperfusion and oxygen-glucose deprivation/reoxygenation. Second, we induced the astrocyte-specific overexpression of low-density lipoprotein receptor using astrocyte-specific adeno-associated virus. Low-density lipoprotein receptor overexpression in astrocytes improved neurological outcomes in middle cerebral artery occlusion mice and reversed neurotoxic astrocytes to create a neuroprotective phenotype. Finally, we found that the overexpression of low-density lipoprotein receptor inhibited NLRP3 inflammasome activation in oxygen-glucose deprivation/reoxygenation injured astrocytes and that the addition of nigericin, an NLRP3 agonist, restored the neurotoxic astrocyte phenotype. These findings suggest that low-density lipoprotein receptor could inhibit the NLRP3-meidiated neurotoxic polarization of astrocytes and that increasing low-density lipoprotein receptor in astrocytes might represent a novel strategy for treating cerebral ischemic stroke.

Trimethylamine N-Oxide Aggravates Neuro-Inflammation via lncRNA Fendrr/miR-145-5p/PXN Axis in Vascular Dementia Rats.

Purpose: Vascular dementia (VaD) is the second most common dementia in the world. An increasing number of studies have demonstrated the important role of long non-coding RNAs (lncRNAs) in VaD. Our previous investigation demonstrated that Trimethylamine-N-oxide (TMAO) exacerbates cognitive impairment and neuropathological alterations in VaD rats. Thus, we hypothesized that TMAO could play an injury role in VaD by regulating lncRNAs. Materials and Methods: The rats using the bilateral common carotid artery (2VO) model were administered TMAO (120 mg/kg) for 8 consecutive weeks, 4 weeks preoperatively and 4 weeks postoperatively. High-throughput sequencing was conducted to investigate the effects of TMAO treatment on lncRNA expression in rat hippocampus and bioinformatics analysis was performed to identify potential downstream targets. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to detect the levels of lncRNA fetal-lethal noncoding developmental regulatory RNA (Fendrr), miR-145-5p, and paxillin (PXN). Learning and spatial memory capacities were measured, as well as inflammatory factors. Nissl staining was used to observe neuronal injury in the CA1 area of the hippocampus. Furthermore, we used the Fendrr loss-of-function assay, miR-145-5p gain-of-function assays and PXN loss-of-function assay to explore the mechanisms by which TMAO acts on VaD. Results: TMAO administration upregulated lncRNA Fendrr expression in the rat hippocampus, while the damaging effects of TMAO were counteracted after knockdown of Fendrr. Fendrr exhibits highly expressed in 2VO rats and sponged miR-145-5p, which targets PXN. Silencing of Fendrr or PXN, or promotion of miR-145-5p improved neurological function injury, reduced neuronal damage, as well as repressed inflammation response. Inhibition of miR-145-5p abrogated up Fendrr knockdown mediated influence on 2VO rats. Conclusion: The results of this study indicated that TMAO inhibits the miR-145-5p/PXN axis by increasing the Fendrr expression, thus exacerbating the development of VaD.

Whole Transcriptome Sequencing of Peripheral Blood Identifies the Alzheimer's Disease-Related circRNA-miRNA-lncRNA Pathway.

BACKGROUND: Previous studies on transcriptional profiles suggested dysregulation of multiple RNA species in Alzheimer's disease. However, despite recent investigations revealing various aspects of circular RNA (circRNA)-associated competing endogenous RNA (ceRNA) networks in Alzheimer's Disease (AD) pathogenesis, few genome-wide studies have explored circRNA-associated profiles in AD patients exhibiting varying degrees of cognitive loss. OBJECTIVE: To investigate the potential pathogenesis-related molecular biological changes in the various stages of AD progression. METHODS: Whole transcriptome sequencing was performed on the peripheral blood of 7 normal cognition (NC) subjects, 8 patients with mild cognitive impairment, 8 AD patients with mild dementia (miD), and 7 AD patients with moderate dementia (moD). Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were conducted to predict the potential functions of the maternal genes of microRNAs (miRNAs), circRNAs and long non-coding RNAs (lncRNAs). The construction of ceRNA network was performed between the NC group and each diseased group based on the differently expressed RNAs. RESULTS: In total, 3568 messenger RNAs (mRNAs), 142 miRNAs, 990 lncRNAs, and 183 circRNAs were identified as significantly differentially expressed across the four groups. GO and KEGG enrichment analysis revealed the significant roles of GTPase activity and the MAPK signaling pathway in AD pathogenesis. A circRNA-miRNA-lncRNA ceRNA pathway, characterized by the downregulated hsa-miR-7-5p and upregulated hsa_circ_0001170, was identified based on the differentially expressed RNAs between the NC group and the moD group. CONCLUSION: The study suggests that circRNAs may be independent of mRNAs in AD pathogenesis and holds promise as potential biomarkers for AD clinical manifestations and pathological changes.

Prevotella histicola Transplantation Ameliorates Cognitive Impairment and Decreases Oxidative Stress in Vascular Dementia Rats.

Vascular dementia is a type of dementia from brain damage caused by cerebrovascular lesions and vascular risk factors. Prevotella histicola is a species of Prevotella, belonging to the category of obligate anaerobe. The purpose of our work was to study the protection of Prevotella histicola on cognitive function in rats subjected to vascular dementia (VaD) and investigate underlying molecular mechanisms. The rats were randomly divided into three groups: control group, 2VO group and 2VO + Prevotella histicola group. The VaD rats (the 2VO group and 2VO + Prevotella histicola group) were generated by bilateral common carotid artery occlusion (2VO). Rats in the 2VO+ Prevotella histicola group were administered with Prevotella histicola twice daily. In comparison with the rats in the 2VO group, rats in the 2VO + Prevotella histicola group presented an enhanced cognitive ability, increased synapse-associated protein expression, a downregulation of proinflammatory factors and an upregulation of neurotrophic factors. The relevant mechanism of the protective effect of Prevotella histicola may be associated with the inhibition of glial cell-associated inflammation by regulating phosphorylation of CaMKII. In conclusion, Prevotella histicola attenuates neurological impairments via regulating synapse-associated protein expression and the liberation of inflammatory elements in vascular dementia rats. The findings above might benefit the development of Prevotella histicola transplantation as a promising treatment of VaD.

The Potential of Gut Microbiota in Prediction of Stroke-Associated Pneumonia.

BACKGROUND: Stroke-associated pneumonia (SAP) is a common stroke complication, and the changes in the gut microbiota composition may play a role. Our study aimed to evaluate the predictive ability of gut microbiota for SAP. METHODS: Acute ischemic stroke patients were prospectively enrolled and divided into two groups based on the presence or absence of SAP. The composition of gut microbiota was characterized by the 16S RNA Miseq sequencing. The gut microbiota that differed significantly between groups were incorporated into the conventional risk scores, the Acute Ischemic Stroke-Associated Pneumonia Score (AIS-APS), and the Age, Atrial fibrillation, Dysphagia, Sex, Stroke Severity Score (A2DS2). The predictive performances were assessed in terms of the area under the curve (AUC), the Net Reclassification Improvement (NRI), and the Integrated Discrimination Improvement (IDI) indices. RESULTS: A total of 135 patients were enrolled, of whom 43 had SAP (31%). The short-chain fatty acids (SCFAs)-producing bacteria, such as Bacteroides, Fusicatenibacter, and Butyricicoccus, were decreased in the SAP group. The integrated models showed better predictive ability for SAP (AUC = 0.813, NRI = 0.333, p = 0.052, IDI = 0.038, p = 0.018, for AIS-APS; AUC = 0.816, NRI = 0.575, p < 0.001, IDI = 0.043, p = 0.007, for A2DS2) in comparison to the differential genera (AUC = 0.699) and each predictive score (AUCAISAPS = 0.777; AUCA2DS2 = 0.777). CONCLUSIONS: The lower abundance of SCFAs-producing gut microbiota after acute ischemic stroke was associated with SAP and may play a role in SAP prediction.

Malnutrition and poststroke depression in patients with ischemic stroke.

BACKGROUND: Identifying high-risk patients based on modifiable clinical characteristics, such as malnutrition, is critical to intervening with these variables to reduce the risk of post-stroke depression (PSD). The aim of this study was to investigate the effect of nutritional status on the risk of incident PSD and the trajectory of PSD risk. METHODS: Consecutive patients with acute ischemic stroke were recruited in this observational cohort and followed up for 1 year. Multivariate logistic regressions and multilevel mixed-effects logistic regressions with random intercepts and slopes were used to investigate the effects of nutritional indexes [the Controlling Nutritional Status (CONUT) score, the Nutritional Risk Index (NRI), and the Prognostic Nutritional Index (PNI)] and body mass index (BMI) on the risk of incident PSD and the trajectory of PSD risk over the 12-month observation period. RESULTS: A total of 538 patients were included in the final analysis. Worsening CONUT [odds ratio (OR) = 1.36; confidence interval (CI): 1.15-1.61], NRI (OR = 0.91; CI: 0.87-0.96) and PNI (OR = 0.89; CI: 0.84-0.95) scores were significantly associated with an increased risk of incident PSD. Moderate and severe risk malnutrition statuses were associated with higher incidences of PSD regardless of the malnutrition index (CONUT, NRI or PNI). Additionally, PSD risk decreased over time with a significant two-way interaction between time and CONUT, NRI, and PNI, implying that patients with elevated exposure to malnutrition showed a slower decline in PSD risk. BMI had no significant effect on the occurrence and development of PSD. CONCLUSION: Malnutrition, but not BMI, was associated with a higher probability of incident PSD and was more likely to lead to a slower rate of decline in PSD risk.

Concordance of Intrinsic Brain Connectivity Measures Is Disrupted in Alzheimer's Disease.

Background: Recently, a new resting-state functional magnetic resonance imaging (rs-fMRI) measure to evaluate the concordance between different rs-fMRI metrics has been proposed and has not been investigated in Alzheimer's disease (AD). Methods: 3T rs-fMRI data were obtained from healthy young controls (YC, n = 26), healthy senior controls (SC, n = 29), and AD patients (n = 35). The fractional amplitude of low-frequency fluctuations (fALFF), regional homogeneity (ReHo), and degree centrality (DC) were analyzed, followed by the calculation of their concordance using Kendall's W for each brain voxel across time. Group differences in the concordance were compared globally, within seven intrinsic brain networks, and on a voxel-by-voxel basis with covariates of age, sex, head motion, and gray matter volume. Results: The global concordance was lowest in AD among the three groups, with similar differences for the single metrics. When comparing AD to SC, reductions of concordance were detected in each of the investigated networks apart from the limbic network. For SC in comparison to YC, lower global concordance without any network-level difference was observed. Voxel-wise analyses revealed lower concordance in the right middle temporal gyrus in AD compared to SC and lower concordance in the left middle frontal gyrus in SC compared to YC. Lower fALFF were observed in the right angular gyrus in AD in comparison to SC, but ReHo and DC showed no group differences. Conclusions: The concordance of resting-state measures differentiates AD from healthy aging and may represent a novel imaging marker in AD.

Associations of Lipoprotein(a) Level with Cerebral Small Vessel Disease in Patients with Alzheimer's Disease.

BACKGROUND: This study aimed to examine the association of lipoprotein(a) [Lp(a)] level with the burden of cerebral small vessel disease (CSVD) in patients with Alzheimer's disease (AD). METHODS: Data from 111 consecutive patients with AD admitted to Nanjing First Hospital from 2015 to 2022 were retrospectively analyzed in this study. Serum Lp(a) concentrations were grouped into tertiles (T1-T3). Brain magnetic resonance imaging (MRI) was rated for the presence of CSVD, including enlarged perivascular spaces (EPVS), lacunes, white-matter lesions, and cerebral microbleeds (CMBs). The CSVD burden was calculated by summing the scores of each MRI marker at baseline. A binary or ordinal logistic regression model was used to estimate the relationship of serum Lp(a) levels with CSVD burden and each MRI marker. RESULTS: Patients with higher tertiles of Lp(a) levels were less likely to have any CSVD (T1, 94.6%; T2, 78.4%; T3, 66.2%; p = 0.013). Multivariable analysis found that Lp(a) levels were inversely associated with the presence of CSVD (T2 vs. T1: adjusted odds ratio [aOR] 0.132, 95% confidence interval [CI] 0.018-0.946, p = 0.044; T3 vs. T1: aOR 0.109, 95% CI 0.016-0.737, p = 0.023) and CSVD burden (T3 vs. T1: aOR 0.576, 95% CI 0.362-0.915, p = 0.019). The independent relationship between Lp(a) levels and individual CSVD features was significant for moderate-to-severe EPVS in the centrum semiovale (T2 vs. T1: aOR 0.059, 95% CI 0.006-0.542, p = 0.012; T3 vs. T1: aOR 0.029, 95% CI 0.003-0.273, p = 0.002) and CMBs (T3 vs. T1: aOR 0.144, 95% CI 0.029-0.716, p = 0.018). CONCLUSIONS: In this study, serum Lp(a) level was inversely associated with CSVD in AD patients.

Higher Circulating Trimethylamine N-Oxide Aggravates Cognitive Impairment Probably via Downregulating Hippocampal SIRT1 in Vascular Dementia Rats.

Oxidative stress and inflammation damage play pivotal roles in vascular dementia (VaD). Trimethylamine N-oxide (TMAO), an intestinal microbiota-stemming metabolite, was reported to promote inflammation and oxidative stress, involved in the etiology of several diseases. Still, these effects have not been investigated in VaD. Here, we tested whether pre-existing, circulating, high levels of TMAO could affect VaD-induced cognitive decline. TMAO (120 mg/kg) was given to rats for a total of 8 weeks, and these rats underwent a sham operation or bilateral common carotid artery (2VO) surgery after 4 weeks of treatment. Four weeks after surgery, the 2VO rats exhibited hippocampal-dependent cognitive function declines and synaptic plasticity dysfunction, accompanied by an increase in oxidative stress, neuroinflammation, and apoptosis. TMAO administration, which increased plasma and hippocampal TMAO at 4 weeks postoperatively, further aggravated these effects, resulting in exaggerated cognitive and synaptic plasticity impairment, though not within the Sham group. Moreover, TMAO treatment activated the NLRP3 inflammasome and decreased SIRT1 protein expression within the hippocampus. However, these effects of TMAO were significantly attenuated by the overexpression of SIRT1. Our findings suggest that TMAO increases oxidative stress-induced neuroinflammation and apoptosis by inhibiting the SIRT1 pathway, thereby exacerbating cognitive dysfunction and neuropathological changes in VaD rats.

Association of Trimethylamine N-Oxide with Normal Aging and Neurocognitive Disorders: A Narrative Review.

Aging-related neurocognitive disorder (NCD) is a growing health concern. Trimethylamine-N-oxide (TMAO), a gut microbiota-derived metabolite from dietary precursors, might emerge as a promising biomarker of cognitive dysfunction within the context of brain aging and NCD. TMAO may increase among older adults, Alzheimer's disease patients, and individuals with cognitive sequelae of stroke. Higher circulating TMAO would make them more vulnerable to age- and NCD-related cognitive decline, via mechanisms such as promoting neuroinflammation and oxidative stress, and reducing synaptic plasticity and function. However, these observations are contrary to the cognitive benefit reported for TMAO through its positive effects on blood-brain barrier integrity, as well as from the supplementation of TMAO precursors. Hence, current disputable evidence does not allow definite conclusions as to whether TMAO could serve as a critical target for cognitive health. This article provides a comprehensive overview of TMAO documented thus far on cognitive change due to aging and NCD.

High-frequency repetitive transcranial magnetic stimulation (rTMS) protects against ischemic stroke by inhibiting M1 microglia polarization through let-7b-5p/HMGA2/NF-κB signaling pathway.

BACKGROUND: Microglia assume opposite phenotypes in response to ischemic brain injury, exerting neurotoxic and neuroprotective effects under different ischemic stages. Modulating M1/M2 polarization is a potential therapy for treating ischemic stroke. Repetitive transcranial magnetic stimulation (rTMS) held the capacity to regulate neuroinflammation and astrocytic polarization, but little is known about rTMS effects on microglia. Therefore, the present study aimed to examine the rTMS influence on microglia polarization and the underlying possible molecular mechanisms in ischemic stroke models. METHODS: Previously reported 10 Hz rTMS protocol that regulated astrocytic polarization was used to stimulate transient middle cerebral artery occlusion (MCAO) rats and oxygen and glucose deprivation/reoxygenation (OGD/R) injured BV2 cells. Specific expression levels of M1 marker iNOS and M2 marker CD206 were measured by western blotting and immunofluorescence. MicroRNA expression changes detected by high-throughput second-generation sequencing were validated by RT-PCR and fluorescence in situ hybridization (FISH) analysis. Dual-luciferase report assay and miRNA knock-down were applied to verify the possible mechanisms regulated by rTMS. Microglia culture medium (MCM) from different groups were collected to measure the TNF-α and IL-10 concentrations, and detect the influence on neuronal survival. Finally, TTC staining and modified Neurological Severity Score (mNSS) were used to determine the effects of MCM on ischemic stroke volume and neurological functions. RESULTS: The 10 Hz rTMS inhibited ischemia/reperfusion induced M1 microglia and significantly increased let-7b-5p level in microglia. HMGA2 was predicted and proved to be the target protein of let-7b-5p. HMGA2 and its downstream NF-κB signaling pathway were inhibited by rTMS. Microglia culture medium (MCM) collected from rTMS treated microglia contained lower TNF-α concentration but higher IL-10 concentration than no rTMS treated MCM, reducing ischemic volumes and neurological deficits of MCAO mice. However, knockdown of let-7b-5p by antagomir reversed rTMS effects on microglia phenotype and associated HMGA/NF-κB activation and neurological recovery. CONCLUSION: High-frequency rTMS could alleviate ischemic stroke injury through inhibiting M1 microglia polarization via regulating let-7b-5p/HMGA2/NF-κB signaling pathway in MCAO models.

Functional analysis of variants in DMD exon/intron 10 predicted to affect splicing.

Duchenne muscular dystrophy (DMD, MIM #310200) and Becker muscular dystrophy (BMD, MIM #300376) are X-linked recessive hereditary diseases caused by pathogenic variants in the DMD gene. Genetic testing of DMD identifies a certain number of variants of uncertain clinical significance (VUS) whose functional interpretations pose a challenge for gene-based diagnosis. To improve the accuracy of variant interpretation in public mutation repositories, we used computational tools to prioritize VUS and developed a cell-based minigene assay to confirm aberrant splicing. Using this procedure, we evaluated rare variants in exon and intron 10 of the DMD gene. We demonstrated that 16 variants, including both canonical and non-canonical splice sites, altered RNA splicing in variable patterns. Using the example of exon and intron 10 of the DMD gene, we demonstrated the utility of the in vitro minigene assay in the effective assessment of the spliceogenic effect for VUS identified in clinical practice and underlined the necessity of precise variant classification. This is the first systematic characterization of DMD splicing variants, besides, through our study, some undetermined variants are demonstrated to be pathogenic by altering RNA splicing of DMD.

Clopidogrel with Aspirin versus Aspirin Alone following Intravenous Thrombolysis in Minor Stroke: A 1-Year Follow-Up Study.

OBJECTIVE: The objective of this study was to investigate the long-term effect of dual antiplatelet therapy (DAPT) using clopidogrel plus aspirin versus aspirin monotherapy after intravenous thrombolysis on functional outcomes in patients with minor stroke. METHODS: Patients with acute ischemic stroke with a National Institutes of Health Stroke Scale score ≤ 5 who received either DAPT or aspirin monotherapy following recombinant tissue plasminogen activator intravenous thrombolysis were studied. Data recorded between January 2017 and December 2020 were retrospectively analyzed. The primary efficacy outcome was functional improvement at 1 year, measured by a 1-point decrease across modified Rankin Scale (mRS) scores. Secondary outcomes included complete rehabilitation (mRS = 0), an excellent outcome (mRS = 0-1), and a favorable outcome (mRS = 0-2) at 1 year, as well as the rates of stroke recurrence and all-cause mortality within 1 year. RESULTS: A total of 238 patients were included, and follow-up data were available for 205 patients (86.1%). The distribution of 1-year outcomes on the mRS favored DAPT over aspirin monotherapy (adjusted common odds ratio (OR), 2.19; 95% confidence interval (CI), 1.12-4.28; p = 0.022). Patients who received DAPT, compared with those receiving aspirin alone, were more likely to achieve complete rehabilitation (adjusted OR, 2.44; 95% CI, 1.21-4.95; p = 0.013) at the 1-year follow-up. Additionally, the percentages of an excellent outcome and a favorable outcome did not differ, and the rates of stroke recurrence and all-cause mortality were comparable during the 1-year follow-up. CONCLUSIONS: Clopidogrel with aspirin following intravenous thrombolysis was associated with improved functional outcome at the 1-year follow-up for patients with minor stroke, and it did not increase the stroke recurrence rate and mortality.

A Novel Nomogram for Predicting Prognosis after Mechanical Thrombectomy in Patients with Acute Ischemic Stroke.

BACKGROUND: Mounting evidence has shown that mechanical thrombectomy (MT) improves clinical outcomes for large vessel occlusions (LVOs) in patients with acute ischemic stroke (AIS) of the anterior circulation. The present study aimed to provide a comprehensive analysis of risk factors associated with clinical outcomes in AIS patients receiving MT. METHODS: A total of 212 consecutive patients who underwent MT for AIS were enrolled in the present study. Clinical characteristics were recorded at admission. Two endpoints were defined according to the 3-month modified Rankin scale (mRS) score after AIS (good outcome, mRS 0-2; and death, mRS 6). Additionally, we compared the clinical outcomes and safety of MT alone and bridging therapy in AIS patients. RESULTS: Of the 212 patients treated with MT, 114 (53.77%) patients had a good outcome and 31 (14.62%) died. The incidence of a worse outcome after MT was significantly elevated in males and patients with high WBC counts, high admission blood glucose levels, high baseline NIHSS scores and a long interval time from groin puncture to reperfusion in AIS patients treated with MT after adjustment for covariates (P<0.05); these risk factors were further confirmed by our constructed nomograms. In addition, we observed no significant benefit of bridging therapy compared to MT alone in AIS patients. CONCLUSION: Our constructed nomogram based on male sex, admission WBC, admission blood glucose, NIHSS, and the interval time from groin puncture to reperfusion predicts prognosis after mechanical thrombectomy in patients with acute ischemic stroke.

Roseburia Abundance Associates With Severity, Evolution and Outcome of Acute Ischemic Stroke.

Stroke induces disorder of gut microbiota, however, whether this disorder differs according to stroke severity and its role in the evolution and outcome of stroke is currently unknown. Here we explored the composition and structure of fecal microbiome based on 68 acute ischemic stroke patients presenting with minor symptoms (admission National Institute of Health Stroke Scale (NIHSS) ≤ 3) and 67 patients with non-minor stroke (admission NIHSS 4-34) using high-throughput Illumina sequencing of the 16S rRNA. There was no significant difference in α-diversity indices, but the principal coordinate analysis of the microbiota indicated clear separation of the two groups. The significantly enriched butyrate-producing genus Roseburia in the minor stroke group was negatively correlated with fasting glucose, while the Erysipelotrichaceae incertae sedis abundant in non-minor stroke patients was positively correlated with stress hyperglycemia (i.e. fasting glucose/glycated hemoglobin ratio). Moreover, the relative abundance of genus Roseburia was also significantly associated with the dynamic changes of NIHSS score, as well as short-term and long-term functional outcomes. Our results suggested that stroke affects microbiota composition in a manner differentiated by stroke severity, and the enrichment of genus Roseburia may play a protective role in stroke evolution and outcome. Our findings strengthen the relevance of specific taxa for stroke severity that might allow targeted therapy in acute ischemic stroke.

Endovascular treatment of acute ischemic stroke due to anterior circulation large vessel occlusion beyond 6 hours: a real-world study in China.

BACKGROUND: We aimed to assess the safety and efficacy of endovascular treatment (EVT) in patients with anterior circulation emergent large vessel occlusion (ELVO) beyond 6 h from symptom onset in a real-world cohort of patients in China. METHODS: We retrospectively examined 305 patients with anterior circulation ELVO treated with EVT. Patients were divided into two groups: treated with known onset within 6 h (n = 238) and beyond 6 h (n = 67). Multivariable logistic regression and ordinal shift analyses were used to evaluate the associations between onset-to-groin puncture time and safety and efficacy outcomes. RESULTS: Treatment beyond 6 h was not associated with symptomatic intracranial hemorrhage within 48 h (sICH; odds ratio [OR] 2.03, 95% confidence interval [CI] 0.48-8.57, p = 0.334), in-hospital mortality (OR 1.95, 95% CI 0.48-7.91, p = 0.348), successful recanalization (modified Thrombolysis in Cerebral Infarction score 2b or 3; OR 0.73, 95% CI 0.31-1.73, p = 0.470), favorable functional outcome (modified Rankin Scale score 0-2; OR 0.55, 95% CI 0.25-1.23, p = 0.145), and functional improvement (modified Rankin Scale shift by 1-point decrease; common OR 0.80, 95%CI 0.45-1.42, p = 0.450) at 3 months compared with treatment within 6 h. Futher interaction analysis showed that stroke etiology did not modify the associations between onset-to-groin puncture time and outcomes (p > 0.05). CONCLUSIONS: In this real-world study, after careful assessment, EVT beyond 6 h from known stroke onset was safe, effective and had comparable short-term outcomes to EVT within 6 h.

Gut Microbiota Dysbiosis in Acute Ischemic Stroke Associated With 3-Month Unfavorable Outcome.

BACKGROUND: Alterations in the gut microbiota after ischemic stroke have been demonstrated, whereas the effect on stroke outcome remains to be established. METHODS: A total of 132 consecutive patients with acute ischemic stroke were prospectively enrolled. Their gut microbiomes within 24 h of admission were profiled using 16S ribosomal RNA (rRNA) gene (V3-V4 region) sequencing. Microbiota comparisons were made between groups with good outcome (n = 105) and poor outcome (n = 27) based on 3-month modified Rankin Scale scores of 0-2 and 3-6. Propensity score-matching (PSM) analysis was conducted to assess the robustness of our findings. The functional potential was predicted using the Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt). RESULTS: Patients in the poor outcome group were characterized by a significant reduction in the alpha diversity (Shannon index, p = 0.025; Simpson index, p = 0.010), an increase in the pathogenic bacteria (e.g., Enterococcaceae and Enterococcus), and a decrease in the short-chain fatty acids (SCFAs)-producing bacteria (e.g., Bacteroidaceae, Ruminococcaceae, and Faecalibacterium) to those with good outcome group (all p < 0.05). Similar results of microbial composition were obtained after PSM. The PICRUSt revealed that the pathway for membrane transport was relatively dominant in patients with poor outcome (p < 0.05). CONCLUSION: This study demonstrated that stroke patients with 3-month poor outcome had baseline gut microbiota dysbiosis featured by increased pathogenic bacteria and decreased SCFAs-producing bacteria.

Admission blood cell counts are predictive of stroke-associated infection in acute ischemic stroke patients treated with endovascular therapy.

Stroke-associated infection (SAI) is a major medical complication in acute ischemic stroke patients (AIS) treated with endovascular therapy (EVT). Three hundred thirty-three consecutive patients with AIS caused by a large vessel occlusion in the anterior circulation who received EVT (142 (42.6%) of them were given IV tPA as bridging therapy) and 337 AIS patients who received IV tPA only (non-EVT) were enrolled in the study and evaluated to determine the association of inflammatory factors on admission with SAI. Among the 333 AIS patients undergoing EVT, SAI occurred in 219 (65.8%) patients. Patients with SAI had higher baseline National Institutes of Health Stroke Scale (NIHSS) total scores, white blood cell (WBC) and neutrophil counts, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) than those without SAI (P < 0.05). The multivariable logistic regression analyses showed that older age in addition to higher diastolic blood pressure (DBP), NIHSS score, fasting blood glucose, WBC and neutrophil counts, NLR, and PLR were significantly associated with SAI (P < 0.05). However, these associations were not revealed in 337 non-EVT AIS patients. Furthermore, based on the inflammatory markers, we developed a nomogram that provided the opportunity for more accurate predictions (compared with conventional factors) and appeared a better prognostic tool for SAI according to the decision curve analysis. In summary, if proven externally valid, our nomogram that included WBC count, NLR, and PLR may be a useful tool for SAI prediction in clinical practice.

A systematic review of neurological symptoms and complications of COVID-19.

OBJECTIVE: To study the frequency of neurological symptoms and complications in COVID-19 patients in a systematic review of the literature. METHODS: Relevant studies were identified through electronic explorations of PubMed, medRxiv, and bioRxiv. Besides, three Chinese databases were searched. A snowballing method searching the bibliographies of the retrieved references was applied to identify potentially relevant articles. Articles published within 1 year prior to April 20th, 2020, were screened with no language restriction imposed. Databases were searched for terms related to SARS-CoV-2/COVID-19 and neurological manifestations, using a pre-established protocol registered on the International Prospective Register of Systematic Reviews database (ID: CRD42020187994). RESULTS: A total of 2441 articles were screened for relevant content, of which 92 full-text publications were included in the analyses of neurological manifestations of COVID-19. Headache, dizziness, taste and smell dysfunctions, and impaired consciousness were the most frequently described neurological symptoms, the latter more often among patients with a severe or critical disease course. To date, only smaller cohort studies or single cases have reported cerebrovascular events, seizures, meningoencephalitis, and immune-mediated neurological diseases, not suitable for quantitative analysis. CONCLUSION: The most frequent neurological symptoms reported in association with COVID-19 are non-specific for the infection with SARS-CoV-2. Although SARS-CoV-2 may have the potential to gain direct access to the nervous system, so far, SARS-CoV-2 was detected in the cerebrospinal fluid in two cases only. Standardized international registries are needed to clarify the clinical relevance of the neuropathogenicity of SARS-CoV-2 and to elucidate a possible impact of SARS-CoV-2 infection on common neurological disease, such as Alzheimer's, Parkinson's disease or multiple sclerosis.

Diagnostic accuracy of cognitive screening tools under different neuropsychological definitions for poststroke cognitive impairment.

OBJECTIVES: The accuracy of cognitive screening tools to detect poststroke cognitive impairment (PSCI) was investigated using various neuropsychological definitions. METHODS: Hospital-based stroke patients underwent a comprehensive neuropsychological assessment. The rate of PSCI was estimated using thresholds of 1, 1.5, or 2 standard deviations below the normal control and memory impairment defined by a single or multiple tests. Meanwhile, the diagnostic accuracy of cognitive screening through face-to-face assessment using the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment Scale (MoCA), and telephone assessment using a 5-minute NINDS-Canadian Stroke Network (NINDS-CSN) scale and a six-item screener (SIS), was both tested under different definitions, with the optimal cutoff selected based on the highest Youden index. RESULTS: In stroke patients, the rate of PSCI ranged from 46.3% to 76.3% upon different definitions. The face-to-face MoCA was more consistent with the comprehensive cognitive assessment compared to MMSE. The optimal cutoff of PSCI was MMSE ≤ 27 and MoCA ≤ 19. For the telephone tests, the 5-minute NINDS-CSN assessment was more reliable, and the optimal cutoff was ≤23, while for SIS ≤ 4. CONCLUSIONS: Cognitive screening tools including the face-to-face MMSE and MoCA, together with the telephone assessment of NINDS-CSN 5-minute protocol and SIS, were simple and effective for detecting PSCI in stroke patients. The corresponding threshold values for PSCI were 27 points, 19 points, 23 points, and 4 points.