Suppression of neuronal CDK9/p53/VDAC signaling provides bioenergetic support and improves post-stroke neuropsychiatric outcomes.

Bioenergy decline occurs with reperfusion following acute ischemic stroke. However, the molecular mechanisms that limit energy metabolism and their impact on post-stroke cognitive and emotional complications are still unclear. In the present study, we demonstrate that the p53 transcriptional response is responsible for neuronal adenosine triphosphate (ATP) deficiency and progressively neuropsychiatric disturbances, involving the downregulation of mitochondrial voltage-dependent anion channels (VDACs). Neuronal p53 transactivated the promoter of microRNA-183 (miR-183) cluster, thereby upregulating biogenesis of miR-183-5p (miR-183), miR-96-5p (miR-96), and miR-182-5p. Both miR-183 and miR-96 directly targeted and post-transcriptionally suppressed VDACs. Neuronal ablation of p53 protected against ATP deficiency and neurological deficits, whereas post-stroke rescue of miR-183/VDAC signaling reversed these benefits. Interestingly, cyclin-dependent kinase 9 (CDK9) was found to be enriched in cortical neurons and upregulated the p53-induced transcription of the miR-183 cluster in neurons after ischemia. Post-treatment with the CDK9 inhibitor oroxylin A promoted neuronal ATP production mainly through suppressing the miR-183 cluster/VDAC axis, further improved long-term sensorimotor abilities and spatial memory, and alleviated depressive-like behaviors in mice following stroke. Our findings reveal an intrinsic CDK9/p53/VDAC pathway that drives neuronal bioenergy decline and underlies post-stroke cognitive impairment and depression, thus highlighting the therapeutic potential of oroxylin A for better outcomes.

Neuropsychological and Anatomical-Functional Effects of Transcranial Magnetic Stimulation in Post-Stroke Patients with Cognitive Impairment and Aphasia: A Systematic Review.

Transcranial magnetic stimulation (TMS) has been found to be promising in the neurorehabilitation of post-stroke patients. Aphasia and cognitive impairment (CI) are prevalent post-stroke; however, there is still a lack of consensus about the characteristics of interventions based on TMS and its neuropsychological and anatomical-functional benefits. Therefore, studies that contribute to creating TMS protocols for these neurological conditions are necessary. To analyze the evidence of the neuropsychological and anatomical-functional TMS effects in post-stroke patients with CI and aphasia and determine the characteristics of the most used TMS in research practice. The present study followed the PRISMA guidelines and included articles from PubMed, Scopus, Web of Science, ScienceDirect, and EMBASE databases, published between January 2010 and March 2023. In the 15 articles reviewed, it was found that attention, memory, executive function, language comprehension, naming, and verbal fluency (semantic and phonological) are the neuropsychological domains that improved post-TMS. Moreover, TMS in aphasia and post-stroke CI contribute to greater frontal activation (in the inferior frontal gyrus, pars triangularis, and opercularis). Temporoparietal effects were also found. The observed effects occur when TMS is implemented in repetitive modality, at a frequency of 1 Hz, in sessions of 30 min, and that last more than 2 weeks in duration. The use of TMS contributes to the neurorehabilitation process in post-stroke patients with CI and aphasia. However, it is still necessary to standardize future intervention protocols based on accurate TMS characteristics.

Association between Blood Pressure and Post-Stroke Cognitive Impairment: A Meta-Analysis.

Background: Post-stroke cognitive impairment (PSCI) represents a serious post-stroke complication with poor cognitive consequences. A vascular consequence after a stroke is that the occurrence and progression of PSCI may be closely related to blood pressure (BP). Thus, we systematically reviewed and performed a meta-analysis of the literature to examine the correlations between BP and PSCI. Methods: We systematically queried databases, including PubMed, the Cochrane Library, Embase, and Scopus, and conducted meta-analyses on studies reporting odds ratios (ORs) related to the association between BP and PSCI. Two authors autonomously assessed all titles, abstracts, and full texts and extracted data following the Meta-Analysis of Observational Studies in Epidemiology guidelines. The quality of the studies was evaluated using the modified Newcastle-Ottawa scale. Results: Meta-analyses incorporated 12 articles comprising a cumulative participant cohort of 21,732 individuals. The quality assessment indicated good in five studies, fair in one study, and poor in six. Through meta-analyses, we found that hypertension, systolic or diastolic BP (SBP or DBP) was significantly associated with PSCI (OR 1.53, 95% confidence interval (CI), 1.18-1.99; p = 0.001, I 2 = 66%; OR 1.13, 95% CI, 1.05-1.23; p = 0.002, I 2 = 52%; OR 1.38, 95% CI, 1.11-1.72; p = 0.004, I 2 = 90%, respectively). In the subgroup analysis, SBP < 120 mmHg, 120-139 mmHg, 140-159 mmHg, 160-179 mmHg, and DBP ≥ 100 mmHg highly predicted the occurrence of PSCI (OR 1.15, p = 0.0003; OR 1.26, p = 0.010; OR 1.15, p = 0.05; OR 1.02, p = 0.009; OR 1.96, p < 0.00001, respectively). However, the predictive effect of BP for PSCI declines when SBP ≥ 180 mmHg and DBP ≤ 99 mmHg (p > 0.05). Statistical heterogeneity was moderate to high, and publication bias was detected in SBP for PSCI. Conclusions: Considering the multifactorial etiology of PSCI, it is difficult to conclude that BP is an independent risk factor for PSCI. Given the restricted inclusion of studies, caution is advised when interpreting the findings from this meta-analysis. Subsequent investigations with substantial sample sizes are essential to exploring BP as a prospective target for addressing PSCI. Trial Registration Number: CRD42023437783 from PROSPERO.

Neopterin, kynurenine metabolites, and indexes related to vitamin B6 are associated with post-stroke cognitive impairment: The Nor-COAST study.

BACKGROUND AND AIMS: We have previously shown that systemic inflammation was associated with post-stroke cognitive impairment (PSCI). Because neopterin, kynurenine pathway (KP) metabolites, and B6 vitamers are linked to inflammation, in our study we investigated whether those biomarkers were associated with PSCI. MATERIAL AND METHODS: The Norwegian Cognitive Impairment After Stroke study is a prospective multicenter cohort study of patients with acute stroke recruited from May 2015 through March 2017. Plasma samples of 422 participants (59 % male) with ischemic stroke from the index hospital stay and 3 months post-stroke were available for analyses of neopterin, KP metabolites, and B6 vitamers using liquid chromatography-tandem mass spectrometry. Mixed linear regression analyses adjusted for age, sex, and creatinine, were used to assess whether there were associations between those biomarkers and cognitive outcomes, measured by the Montreal Cognitive Assessment scale (MoCA) at 3-, 18-, and 36-month follow-up. RESULTS: Participants had a mean (SD) age of 72 (12) years, with a mean (SD) National Institutes of HealthStroke Scale score of 2.7 (3.6) at Day 1. Higher baseline values of quinolinic acid, PAr (i.e., an inflammatory marker based on vitamin B6 metabolites), and HKr (i.e., a marker of functional vitamin B6 status based on selected KP metabolites) were associated with lower MoCA score at 3, 18, and 36 months post-stroke (p < 0.01). Higher baseline concentrations of neopterin and 3-hydroxykynurenine were associated with lower MoCA scores at 18 and 36 months, and higher concentrations of xanthurenic acid were associated with higher MoCA score at 36 months (p < 0.01). At 3 months post-stroke, higher concentrations of neopterin and lower values of pyridoxal 5́-phosphate were associated with lower MoCA scores at 18- and 36-month follow-up, while lower concentrations of picolinic acid were associated with a lower MoCA score at 36 months (p < 0.01). CONCLUSION: Biomarkers and metabolites of systemic inflammation, including biomarkers of cellular immune activation, indexes of vitamin B6 homeostasis, and several neuroactive metabolites of the KP pathway, were associated with PSCI. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02650531.

Differentially Expressed miR-511-3p in Stroke Patients Predicts the Presence of Post-Stroke Cognitive Impairment.

INTRODUCTION: Stroke is common cerebrovascular disease in the elderly, which is characterized by neurological defects caused by cerebral vessels. Multiple studies have shown that miRNAs play important roles in stroke. In addition, a large number of evidence suggest that stroke increases the risk and severity of cognitive impairments. METHODS: miR-511-3p expression levels were detected by real-time PCR. Receiver operating characteristic (ROC) curve analysis was used to evaluate the diagnostic value of miR-511-3p in distinguishing stroke patients from healthy controls and to assess risk of post-stroke cognitive impairment (PSCI) in stroke patients. Pearson correlation coefficient was used to determine the relationship between miR-511-3p expression level and Montreal Cognitive Assessment Scale (MoCA) scores. RESULTS: Serum miR-511-3p expression levels were decreased in stroke patients, and the decrease was more significant in PSCI patients. ROC curve results showed that miR-511-3p had high diagnostic accuracy in distinguishing healthy controls from stroke patients. Moreover, the expression level of miR-511-3p can be used as an independent predictor for the occurrence of PSCI and is positively correlated with MoCA scores of PSCI patients. CONCLUSION: miR-511-3p may be involved in the occurrence and development of stroke. In addition, miR-511-3p may be a novel biomarker for predicting PSCI occurred in stroke patients. These results may help improve the quality of prognosis of stroke.

Diagnostic accuracy of the Clock Drawing Test in screening for early post-stroke neurocognitive disorder: the Nor-COAST study.

BACKGROUND: Post-stroke neurocognitive disorder, though common, is often overlooked by clinicians. Moreover, although the Montreal Cognitive Assessment (MoCA) has proven to be a valid screening test for neurocognitive disorder, even more time saving tests would be preferred. In our study, we aimed to determine the diagnostic accuracy of the Clock Drawing Test (CDT) for post-stroke neurocognitive disorder and the association between the CDT and MoCA. METHODS: This study is part of the Norwegian Cognitive Impairment After Stroke study, a multicentre prospective cohort study following patients admitted with acute stroke. At the three-month follow-up, patients were classified with normal cognition, mild neurocognitive disorder, or major neurocognitive disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria. Any neurocognitive disorder compromised both mild- and major neurocognitive disorder. The CDT at the three-month assessment was given scores ranging from 0 to 5. Patients able to complete the CDT and whose cognitive status could be classified were included in analyses. The CDT diagnostic accuracy for post-stroke neurocognitive disorder was identified using receiver operating characteristic curves, sensitivity, specificity, positive predictive value, and negative predictive value. The association between the MoCA and CDT was analysed with Spearman's rho. RESULTS: Of 554 participants, 238 (43.0%) were women. Mean (SD) age was 71.5 (11.8) years, while mean (SD) National Institutes of Health Stroke Scale score was 2.6 (3.7). The area under the receiver operating characteristic curve of the CDT for major neurocognitive disorder and any neurocognitive disorder was 0.73 (95% CI, 0.68-0.79) and 0.68 (95% CI, 0.63-0.72), respectively. A CDT cutoff of < 5 yielded 68% sensitivity and 60% specificity for any neurocognitive disorder and 78% sensitivity and 53% specificity for major neurocognitive disorder. Spearman's correlation coefficient between scores on the MoCA and CDT was 0.50 (95% CI, 0.44-0.57, p < .001). CONCLUSIONS: The CDT is not accurate enough to diagnose post-stroke neurocognitive disorder but shows acceptable accuracy in identifying major neurocognitive disorder. Performance on the CDT was associated with performance on MoCA; however, the CDT is inferior to MoCA in identifying post-stroke neurocognitive disorder. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02650531). Retrospectively registered January 8, 2016.

Computer-aided cognitive training combined with tDCS can improve post-stroke cognitive impairment and cerebral vasomotor function: a randomized controlled trial.

BACKGROUND: Post-stroke cognitive impairment (PSCI) is the focus and difficulty of poststroke rehabilitation intervention with an incidence of up to 61%, which may be related to the deterioration of cerebrovascular function. Computer-aided cognitive training (CACT) can improve cognitive function through scientific training targeting activated brain regions, becoming a popular training method in recent years. Transcranial direct current stimulation (tDCS), a non-invasive brain stimulation technique, can regulate the cerebral vascular nerve function, and has an effect on the rehabilitation of cognitive dysfunction after stroke. This study examined the effectiveness of both CACT and tDCS on cognitive and cerebrovascular function after stroke, and explored whether CACT combined with tDCS was more effective. METHODS: A total of 72 patients with PSCI were randomly divided into the conventional cognitive training (CCT) group (n = 18), tDCS group (n = 18), CACT group (n = 18), and CACT combined with tDCS group (n = 18). Patients in each group received corresponding 20-minute treatment 15 times a week for 3 consecutive weeks. Montreal Cognitive Assessment (MoCA) and the Instrumental Activities of Daily Living Scale (IADL) were used to assess patients' cognitive function and the activities of daily living ability. Transcranial Doppler ultrasound (TCD) was used to assess cerebrovascular function, including cerebral blood flow velocity (CBFV), pulse index (PI), and breath holding index (BHI). These outcome measures were measured before and after treatment. RESULTS: Compared with those at baseline, both the MoCA and IADL scores significantly increased after treatment (P < 0.01) in each group. There was no significantly difference in efficacy among CCT, CACT and tDCS groups. The CACT combined with tDCS group showed greater improvement in MoCA scores compared with the other three groups (P < 0.05), especially in the terms of visuospatial and executive. BHI significantly improved only in CACT combined with tDCS group after treatment (p ≤ 0.05) but not in the other groups. Besides, no significant difference in CBFV or PI was found before and after the treatments in all groups. CONCLUSION: Both CACT and tDCS could be used as an alternative to CCT therapy to improve cognitive function and activities of daily living ability after stroke. CACT combined with tDCS may be more effective improving cognitive function and activities of daily living ability in PSCI patients, especially visuospatial and executive abilities, which may be related to improved cerebral vasomotor function reflected by the BHI. TRIAL REGISTRATION NUMBER: The study was registered in the Chinese Registry of Clinical Trials (ChiCTR2100054063). Registration date: 12/08/2021.

Efficacy of intermittent theta burst stimulation (iTBS) on post-stroke cognitive impairment (PSCI): a systematic review and meta-analysis.

BACKGROUND: Stroke is a significant global cause of mortality and morbidity, and post-stroke cognitive impairment (PSCI) affects up to half of stroke patients. Despite the availability of pharmacological and non-pharmacological interventions, there is a lack of definitive effective treatments for PSCI. Non-invasive brain stimulation, particularly intermittent theta burst stimulation (iTBS), has emerged as a promising therapy for the treatment of PSCI. OBJECTIVE: This systematic review and meta-analysis aimed to evaluate the efficacy and safety of iTBS in enhancing cognitive function among patients with PSCI. METHODS: A comprehensive search was conducted across multiple databases, including PubMed, Web of Science, Scopus, Cochrane Library, and CNKI, to identify relevant randomized controlled trials published before April 2023. The primary outcome measured changes in global cognitive scales, while the secondary outcomes focused on improvements in attention, orientation, visual-spatial perception, and activities of daily living. RESULTS: The meta-analysis encompassed six studies involving 325 patients. The results demonstrated that iTBS led to a significant improvement in global cognitive scales (SMD = 1.12, 95% CI = [0.59 to 1.65], P < 0.0001), attention (SMD = 0.48, 95% CI [0.13 to 0.82], P = 0.007), visual perception (SMD = 0.99, 95% CI [0.13 to 1.86], P = 0.02), and activities of daily living (SMD = 0.82, 95% CI [0.55 to 1.08], P < 0.00001). However, there was no significant effect on orientation (SMD = 0.36, 95% CI [- 0.04 to 0.76], P = 0.07). Subgroup analysis based on the number of sessions was conducted, revealing a significant improvement in global cognition among patients with PSCI across the three categories (10 sessions, 20 sessions, and 30 sessions) with no between-group difference (P = 0.28). None of the included studies reported any serious adverse effects. CONCLUSION: In conclusion, iTBS appears to be a safe and effective non-invasive treatment that can enhance the cognitive abilities and daily living skills of patients with post-stroke cognitive impairment. However, our conclusion is constrained by the limited number of studies. Further high-quality, large-sample RCTs with extended follow-up periods are necessary to validate these findings. Integrating iTBS with brain imaging techniques, such as functional near-infrared spectroscopy and functional magnetic resonance, could aid in understanding the mechanism of iTBS action.

Clinical application of repetitive transcranial magnetic stimulation in improving functional impairments post-stroke: review of the current evidence and potential challenges.

In recent years, the stroke incidence has been increasing year by year, and the related sequelae after stroke, such as cognitive impairment, motor dysfunction, and post-stroke depression, seriously affect the patient's rehabilitation and daily activities. Repetitive transcranial magnetic stimulation (rTMS), as a safe, non-invasive, and effective new rehabilitation method, has been widely recognized in clinical practice. This article reviews the application and research progress of rTMS in treating different functional impairments (cognitive impairment, motor dysfunction, unilateral spatial neglect, depression) after stroke in recent years, and preliminary summarized the possible mechanisms. It has been found that the key parameters that determine the effectiveness of rTMS in improving post-stroke functional impairments include pulse number, stimulated brain areas, stimulation intensity and frequency, as well as duration. Generally, high-frequency stimulation is used to excite the ipsilateral cerebral cortex, while low-frequency stimulation is used to inhibit the contralateral cerebral cortex, thus achieving a balance of excitability between the two hemispheres. However, the specific mechanisms and the optimal stimulation mode for different functional impairments have not yet reached a consistent conclusion, and more research is needed to explore and clarify the best way to use rTMS. Furthermore, we will identify the issues and challenges in the current research, explore possible mechanisms to deepen understanding of rTMS, propose future research directions, and offer insightful insights for better clinical applications.

Using Dual-Target rTMS, Single-Target rTMS, or Sham rTMS on Post-Stroke Cognitive Impairment.

BACKGROUND: The clinical application of 10 Hz repetitive transcranil magnetic stimulation (rTMS) remains limited despite its demonstrated effectiveness in enhancing cortical excitability and improving cognitive function. The present study used a novel stimulus target [left dorsolateral prefrontal cortex + primary motor cortex] to facilitate the enhancement of cognitive function through the bidirectional promotion of cognitive and motor functions; Methods: Post-stroke cognitive impairment patients (n = 48) were randomly assigned to receive either dual-target, single-target, or sham rTMS for 4 weeks. Before and after 4 weeks of treatment, participants were asked to complete the Montreal Cognitive Assessment (MoCA) test, the Modified Barthel Index (MBI), the Trail-making Test (TMT), and the Digital Span Test (DST). In addition, the levels of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) in serum were also measured. RESULTS: After adjusting for pre-intervention (baseline) MoCA scores, the post-intervention MoCA scores varied significantly. After post-hoc analysis, differences existed between the post-treatment scores of the dual-target rTMS group and the sham rTMS group (the experimental group scores were significantly higher), and between those of the dual-target rTMS group and the single-target rTMS group (the dual-target rTMS scores were significantly higher). The serum VEGF levels of the dual-target rTMS group were significantly higher those that of the sham rTMS group. CONCLUSIONS: The present study presented data showing that a dual-target rTMS therapy is effective for Post-stroke cognitive impairment (PSCI). The stimulation exhibited remarkable efficacy, suggesting that dual-target stimulation (left dorsolateral prefrontal cortex+motor cortex (L-DLPFC+M1)) holds promise as a potential target for TMS therapy in individuals with cognitive impairment after stroke. CLINICAL TRIAL REGISTRATION: No: ChiCTR220066184. Registered 26 November, 2022, https://www.chictr.org.cn.

Web-based artificial intelligence to predict cognitive impairment following stroke: A multicenter study.

BACKGROUND AND PURPOSE: Post-stroke cognitive impairment (PSCI) is highly prevalent in modern society. However, there is limited study implying an accurate and explainable machine learning model to predict PSCI. The aim of this study is to develop and validate a web-based artificial intelligence (AI) tool for predicting PSCI. METHODS: The retrospective cohort study design was conducted to develop and validate a web-based prediction model. Adults who experienced a stroke between January 1, 2004, and September 30, 2017, were enrolled, and patients with PSCI were followed up from the stroke index date until their last follow-up. The model's performance metrics, including accuracy, area under the curve (AUC), recall, precision, and F1 score, were compared. RESULTS: A total of 3209 stroke patients were included in the study. The model demonstrated an accuracy of 0.8793, AUC of 0.9200, recall of 0.6332, precision of 0.9664, and F1 score of 0.7651. In the external validation phase, the accuracy improved to 0.9039, AUC to 0.9094, recall to 0.7457, precision to 0.9168, and F1 score to 0.8224. The final model can be accessed at https://psci-calculator.my.id/. CONCLUSION: Our results are able to produce a user-friendly interface that is useful for health practitioners to perform early prediction on PSCI. These findings also suggest that the provided AI model is reliable and can serve as a roadmap for future studies using AI models in a clinical setting.

Circulating circular RNAs as novel biomarkers and functional prediction for the early diagnosis in post-stroke cognitive impairment: A single-center prospective study in China.

BACKGROUND: Early evaluation and intervention for post-stroke cognitive impairment are crucial for improving the prognosis of acute ischemic stroke. The search for specific diagnostic markers and feasible therapeutic targets is extremely urgent.The characteristics of circular RNAs make them promising candidates. AIMS: To screen circular RNAs as novel biomarkers and therapeutic targets for post-stroke cognitive impairment in large-artery atherosclerosis anterior circulation cerebral infarction patients. METHODS: In this prospective observational study, patients with first-ever large-artery atherosclerosis anterior circulation cerebral infarction were recruited. The Montreal Cognitive Assessment was used to assess the cognitive statuses of patients. Venous blood samples were collected on the seventh day after stroke onset. A circRNA microarray was used to identify differentially expressed circular RNAs in the discovery cohort (four patients with post-stroke cognitive impairment and four patients with post-stroke cognitive normal characteristics), and validation was performed in the validation cohorts (45 patients with post-stroke cognitive impairment and 30 patients with post-stroke cognitive normal characteristics) using quantitative real-time polymerase chain reaction. Receiver operating characteristic curves of the validated circular RNAs and the NIHSS score were constructed, and the area under the curve, sensitivity, and specificity were calculated. Correlation analysis was performed to explore the relationship between the copy number of circular RNAs and the cognitive status. The functions of the differentially expressed circular RNAs were predicted using bioinformatics analysis. RESULTS: CircRNA microarray analysis revealed 189 human circular RNAs (152 upregulated and 37 downregulated) that were differentially expressed in the plasma samples of patients with post-stroke cognitive impairment and PSCN characteristics. The expression of hsa_circ_0089763, hsa_circ_0064644, and hsa_circ_0089762 was validated using quantitative real-time polymerase chain reaction. The area under the curve, sensitivity, and specificity of hsa_circ_0089762 in post-stroke cognitive impairment diagnosis were 0.993, 97.8%, and 96.7%, respectively, and the correlation coefficient between hsa_circ_0089762 expression and the Montreal Cognitive Assessment score was -0.693 (p < 0.001), which made it an ideal biomarker. Bioinformatic analysis revealed that the targeted mRNAs of the three circular RNAs were enriched in pathologically related signaling pathways of post-stroke cognitive impairment, such as the MAPK and PI3K-Akt signaling pathways. Based on the circRNA-miRNA-mRNA network, the three circular RNAs play a crucial role in numerous pathological processes of acute ischemic stroke and post-stroke cognitive impairment by sponging miRNAs such as MiR-335, MiR-424, and MiR-670. By building the protein-protein interaction network, we identified cluster 1 according to the MCODE score; cluster 1 was composed of ERBB4, FGFR1, CACNA2D1, NRG1, PPP2R5E, CACNB4, CACNB2, CCND1, NTRK2, and PTCH. CONCLUSION: Hsa_circ_0089762, hsa_circ_0064644, and hsa_circ_0089763 are potential novel biomarkers and focal points for exploring intervention targets in post-stroke cognitive impairment of large-artery atherosclerosis anterior circulation cerebral infarction patients. REGISTRATION NUMBER: ChiCTR2000035074.

High triglyceride-glucose index at admission is a predictor of post-stroke cognitive impairment in patients with acute ischemic stroke.

BACKGROUND: Post-stroke cognitive impairment (PSCI) is a very common complication of ischemic stroke (IS). Triglyceride-glucose (TyG) index was an effective alternative marker of insulin resistance (IR). This prospective study was designed to explore the correlation between TyG index and PSCI. METHODS: Between January 1 2021 to June 30 2022, consecutive patients with first onset IS were enrolled prospectively. Baseline information was collected at admission and fasting blood was drawn the next morning. Montreal Cognitive Assessment (MoCA) was used to evaluate cognitive function at three months after stroke. Multiple regression analysis was used to explore the correlation between PSCI and TyG. Receiver operating characteristic (ROC) was performed to evaluate the predictive ability. RESULTS: Ultimately, 313 patients were enrolled in this study. The TyG index was higher in patients with PSCI than those without PSCI (8.99 (8.55, 9.54) vs. 8.61(8.25, 8.87), P<0.001). The spearman correlation analysis indicated that TyG index was negatively correlated with MoCA score (r=-0.272, P<0.001). The multivariate logistic regression analysis demonstrated that TyG index was correlated with PSCI independently (P<0.001) regardless of whether the patients had diabetes or not. The area under curve (AUC) of the ROC was 0.684 (95%CI=0.635-0.768, P<0.001). The optimal cutoff value of TyG index for predicting PSCI was 8.81, with a sensitivity of 61.7% and a specificity of 73.6%. CONCLUSION: A higher TyG index level at admission was independently correlated with increased risk of PSCI three months later and could be used as a predictor.

Blood biomarkers for post-stroke cognitive impairment: A systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Post-stroke cognitive impairment (PSCI) is a frequent consequence of stroke, which affects the quality of life and prognosis of stroke survivors. Numerous studies have indicated that blood biomarkers may be the key determinants for predicting and diagnosing cognitive impairment, but the results remain varied. Therefore, this meta-analysis aims to summarize potential biomarkers associated with PSCI. METHODS: PubMed, Web of Science, Embase, and Cochrane Library were comprehensively searched for studies exploring blood biomarkers associated with PSCI from inception to 15 April 2022. RESULTS: 63 studies were selected from 4,047 references, which involves 95 blood biomarkers associated with the PSCI. We meta-analyzed 20 potential blood biomarker candidates, the results shown that the homocysteine (Hcy) (SMD = 0.35; 95 %CI: 0.20-0.49; P < 0.00001), c-reactive protein (CRP) (SMD = 0.49; 95 %CI: 0.20-0.78; P = 0.0008), uric acid (UA) (SMD = 0.41; 95 %CI: 0.06-0.76; P = 0.02), interleukin 6 (IL-6) (SMD = 0.92; 95 % CI: 0.27-1.57; P = 0.005), cystatin C (Cys-C) (SMD = 0.58; 95 %CI: 0.28-0.87; P = 0.0001), creatinine (SMD = 0.39; 95 %CI: 0.23-0.55; P < 0.00001) and tumor necrosis factor alpha (TNF-α) (SMD = 0.45; 95 %CI: 0.08-0.82; P = 0.02) levels were significantly higher in patients with PSCI than in the non-PSCI group. CONCLUSION: Based on our findings, we recommend that paramedics focus on the blood biomarkers levels of Hcy, CRP, UA, IL-6, Cys-C, creatinine and TNF-α in conjunction with neuroimaging and neuropsychological assessment to assess the risk of PSCI, which may help with early detection and timely preventive measures. At the same time, other potential blood biomarkers should be further validated in future studies.

Incidence and influencing factors of post-stroke cognitive impairment in convalescent young patients with first-ever stroke.

OBJECTIVE: To investigate the occurrence of post-stroke cognitive impairment (PSCI) and its influencing factors in convalescent young patients with first-ever stroke. METHODS: A total of 300 first-ever young stroke patients (age ≤45 years) were collected. The Mini-Mental State Examination (MMSE) was used to assess the cognitive status. The sociodemographic data, clinical symptoms, social environment, and behavior-related information were collected and analyzed. RESULTS: The incidence of PSCI in young stroke patients was 62.33 %. Through univariate analysis, there were statistical differences in different levels of education, smoking status and hypertension (P < 0.05). With subsequently multivariate logistic regression analysis, it was found that junior high school (OR=8.58,95 %CI:2.25∼32.70) and high school (OR=10.50,95 %CI:2.69∼41.00) education levels, lesion volume >3.00 cm3 (OR=8.03,95 %CI:2.28∼28.36), stroke in the frontal-parietal-temporal region (OR=7.26,95 %CI:1.58∼33.40) and the basal ganglia area (OR=6.13,95 %CI:1.24∼30.43), high NIHSS score (OR=1.17,95 %CI: 1.06∼1.29), and high diastolic blood pressure variability coefficient (OR=1.43,95 %CI: 1.02∼2.01) were risk factors for PSCI. Meanwhile, 24≤BMI<28 (OR=0.06,95 %CI:0.02∼0.23) and BMI<24 (OR=0.18,95 %CI:0.06∼0.53), hospitalization cost >20,000/month (OR=0.22,95 %CI:0.09∼0.56), and stroke onset in spring and summer (OR=0.37,95 %CI:0.14∼0.96) were protective factors. CONCLUSION: The incidence of PSCI is relatively high in young stroke patients. Junior high and high school education, stroke lesions >3.00cm3, strokes in the frontal-parietal-temporal and basal ganglia regions, high NIHSS scores, and high DBPV are risk factors for PSCI in young stroke patients. Meanwhile, BMI<28, treatment cost >20,000/month, and stroke onset in spring and summer are protective factors for PSCI in young stroke patients.

[Effects of epimedium total flavone capsules on post-stroke cognitive impairment in rats].

To investigate the effect of epimedium total flavone capsules on post-stroke cognitive impairment(PSCI) in rats. The transient middle cerebral artery occlusion(tMCAO) model was constructed on selected rats, and rats with impaired neurological function were randomly divided into the model group, low, middle, and high dose groups of epimedium total flavone capsules, and nimodipine tablet group. The cognitive function of rats was measured after administration. Pathological changes in brain tissue were observed after hematoxylin-eosin staining(HE). Neuronal nuclei(NeuN) and glial fibrillary acidic protein(GFAP) distribution in brain tissue were tested by immunofluorescent staining. The level of amyloid beta 1-42(Aß_(1-42)), neuron specific enolase(NSE), acetylcholine(ACH), dopamine(DA), 5-hydroxytryptamine(5-HT), norepinephrine(NE), interleukin-1ß(IL-1ß), tumor necrosis factor-α(TNF-α), and hypersensitive C-reactive protein(hs-CRP) in rat serum was tested. Moreover, Western blot was utilized to test the expression of nuclear factor-kappaB(NF-κB), p-NF-κB, alpha inhibitor of NF-κB(IκBα) protein, and p-IκBα protein in the hippocampus. The experimental results showed that epimedium total flavone capsules can improve the cognitive function of model rats, and the mechanism may be related to the regulation of the expression of p-IκBα and p-NF-κB proteins, so as to inhibit inflammatory response induced by ischemia-reperfusion.

A Review of Post-Stroke Cognitive Impairment and the Potential Benefits of Stingless Bee Honey Supplementation.

Post-stroke cognitive impairment (PSCI) is a common decline in cognitive abilities that occurs within 3 months after a stroke. During recovery, stroke survivors often experience varying degrees of cognitive decline, with some patients experiencing permanent cognitive deficits. Thus, it is crucial to prioritise recovery and rehabilitation after a stroke to promote optimal protection of and improvement in cognitive function. Honey derived from stingless bees has been linked to various therapeutic properties, including neuroprotective effects. However, scientific evidence for the mechanisms through which these honey supplements enhance cognitive function remains limited. This narrative review aims to provide an overview of the causes of PSCI, current treatments, the biomarkers influencing cognition in post-stroke patients and the potential of stingless bee honey (SBH) as a neuroprotective agent against the progression of PSCI.

Effects of Ischemic Stroke on Interstitial Fluid Clearance in Mouse Brain: a Bead Study.

The clearance of brain interstitial fluid (ISF) is important in maintaining brain homeostasis. ISF clearance impairment leads to toxic material accumulation in the brain, and ischemic stroke could impair ISF clearance. The present study investigates ISF clearance under normal and ischemic conditions. The carboxylate-modified FluoSpheres beads (0.04 µm in diameter) were injected into the striatum. Sham or transient middle cerebral artery occlusion surgeries were performed on the mice. The brain sections were immunostained with cell markers, and bead distribution at various time points was examined with a confocal microscope. Primary mouse neuronal cultures were incubated with the beads to explore in vitro endocytosis.  Two physiological routes for ISF clearance were identified. The main one was to the lateral ventricle (LV) through the cleft between the striatum and the corpus callosum (CC)/external capsule (EC), where some beads were captured by the ependymal macrophages and choroid plexus. An alternative and minor route was to the subarachnoid space through the CC/EC and the cortex, where some of the beads were endocytosed by neurons. After ischemic stroke, a significant decrease in the main route and an increase in the minor route were observed. Additionally, microglia/macrophages engulfed the beads in the infarction. In conclusion, we report that the physiological clearance of ISF and beads mainly passes through the cleft between the CC/EC and striatum into the LV, or alternatively through the cortex into the subarachnoid space. Stroke delays the main route but enhances the minor route, and microglia/macrophages engulf the beads in the infarction. Ischemic stroke impairs the clearance of brain interstitial fluid/beads. Under physiological conditions, the main route ( ① ) of interstitial fluid clearance is to the lateral ventricle, and the minor one ( ② ) is to the subarachnoid space. Ischemic stroke weakens the main route ( ① ), enhances the minor one ( ② ), and leads to microglial/macrophage phagocytosis within the infarction ( ③ ).

Intestinal epithelial stem cell transplants as a novel therapy for cerebrovascular stroke.

Almost 2/3rds of stroke survivors exhibit vascular cognitive impairment and a third of stroke patients will develop dementia 1-3 years after stroke. These dire consequences underscore the need for effective stroke therapies. In addition to its damaging effects on the brain, stroke rapidly dysregulates the intestinal epithelium, resulting in elevated blood levels of inflammatory cytokines and toxic gut metabolites due to a 'leaky' gut. We tested whether repairing the gut via intestinal epithelial stem cell (IESC) transplants would also improve stroke recovery. Organoids containing IESCs derived from young rats transplanted into older rats after stroke were incorporated into the gut, restored stroke-induced gut dysmorphology and decreased gut permeability, and reduced circulating levels of endotoxin LPS and the inflammatory cytokine IL-17A. Remarkably, IESC transplants also improved stroke-induced acute (4d) sensory-motor disability and chronic (30d) cognitive-affective function. Moreover, IESCs from older animals displayed senescent features and were not therapeutic for stroke. These data underscore the gut as a critical therapeutic target for stroke and demonstrate the effectiveness of gut stem cell therapy.

Effects of moxibustion on cognition and activities of daily living in post-stroke cognitive impairment: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Post-stroke cognitive impairment (PSCI) imposes a huge burden on patients and society as a whole; however, unequivocally effective treatments for PSCI are still lacking. Therefore, the exploration of effective and safe non-pharmacological treatment modalities for PSCI is a key imperative. Moxibustion has been widely used for cognitive rehabilitation; however, there is a paucity of systematic reviews of the available evidence. Therefore, we conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) that investigated the effectiveness of moxibustion for treatment of PSCI to provide evidence base for the treatment of PSCI with moxibustion. OBJECTIVE: To evaluate the efficacy of moxibustion in improving cognitive function and activities of daily living (ADLs) in patients with PSCI. DESIGN: Systematic review and meta-analysis of RCTs. PARTICIPANTS: Patients with a clinical diagnosis of PSCI. REVIEW METHODS: Relevant studies published in English or Chinese were retrieved from ten databases until December 2021. RCTs that assessed the efficacy of moxibustion on cognitive functioning and ADL in patients with PSCI were included. Two reviewers independently identified the trials and extracted the data. Risk-of-bias was assessed using the Cochrane Risk of Bias Tool. Cochrane's Review Manager (RevMan 5.4) software was used for the meta-analysis. RESULTS: Eighteen RCTs (1290 participants) qualified the inclusion criteria and were included. Compared with the control group, the addition of moxibustion significantly improved the cognitive function, evaluated using the Montreal Cognitive Assessment (MoCA) [pooled mean difference (MD): 2.27, 95% CI: 1.98, 2.55, I2  = 22%]. The pooled MD of Mini-Mental State Examination (MMSE) score was 1.85 (95% CI: 1.56, 2.15, I2  = 26%), and the pooled odds ratios (OR) total effective rate was 4.74 (95% CI: 2.55, 8.80, I2  = 0%) (p < 0.05 for all). Moxibustion also significantly improved ADL, assessed using Modified Barthel Index (MBI) (pooled MD = 4.10, 95% CI: 2.10 to 6.10, I2  = 0%) and Barthel Index (pooled MD: 8.63, 95% CI: 7.47, 9.79, I2  = 5%) (p < 0.05 for all). CONCLUSIONS: Compared with control group, the addition of moxibustion significantly improved the cognition and ADL of patients with PSCI. CLINICAL RELEVANCE: Nurses can incorporate moxibustion into the rehabilitation nursing of PSCI.