Inhibition of ANGPTL8 protects against diabetes-associated cognitive dysfunction by reducing synaptic loss via the PirB signaling pathway.

BACKGROUND: Type 2 diabetes mellitus (T2D) is associated with an increased risk of cognitive dysfunction. Angiopoietin-like protein 8 (ANGPTL8) is an important regulator in T2D, but the role of ANGPTL8 in diabetes-associated cognitive dysfunction remains unknown. Here, we explored the role of ANGPTL8 in diabetes-associated cognitive dysfunction through its interaction with paired immunoglobulin-like receptor B (PirB) in the central nervous system. METHODS: The levels of ANGPTL8 in type 2 diabetic patients with cognitive dysfunction and control individuals were measured. Mouse models of diabetes-associated cognitive dysfunction were constructed to investigate the role of ANGPTL8 in cognitive function. The cognitive function of the mice was assessed by the Barnes Maze test and the novel object recognition test, and levels of ANGPTL8, synaptic and axonal markers, and pro-inflammatory cytokines were measured. Primary neurons and microglia were treated with recombinant ANGPTL8 protein (rA8), and subsequent changes were examined. In addition, the changes induced by ANGPTL8 were validated after blocking PirB and its downstream pathways. Finally, mice with central nervous system-specific knockout of Angptl8 and PirB-/- mice were generated, and relevant in vivo experiments were performed. RESULTS: Here, we demonstrated that in the diabetic brain, ANGPTL8 was secreted by neurons into the hippocampus, resulting in neuroinflammation and impairment of synaptic plasticity. Moreover, neuron-specific Angptl8 knockout prevented diabetes-associated cognitive dysfunction and neuroinflammation. Mechanistically, ANGPTL8 acted in parallel to neurons and microglia via its receptor PirB, manifesting as downregulation of synaptic and axonal markers in neurons and upregulation of proinflammatory cytokine expression in microglia. In vivo, PirB-/- mice exhibited resistance to ANGPTL8-induced neuroinflammation and synaptic damage. CONCLUSION: Taken together, our findings reveal the role of ANGPTL8 in the pathogenesis of diabetes-associated cognitive dysfunction and identify the ANGPTL8-PirB signaling pathway as a potential target for the management of this condition.

Incremental Value of Stroke-Induced Structural Disconnection in Predicting Global Cognitive Impairment After Stroke.

BACKGROUND: Poststroke cognitive impairment (PSCI) is highly prevalent in stroke survivors and correlated with unfavorable clinical outcomes. This study aimed to identify the neural substrate of PSCI using atlas-based disconnectome analysis and assess the value of disconnection score, a baseline measure for stroke-induced structural disconnection, in PSCI prediction. METHODS: A multicenter prospective cohort of 676 first-ever patients with acute ischemic stroke was enrolled from 3 independent hospitals in China. Sociodemographic, clinical, and neuroimaging data were collected at acute stage of stroke. Cognitive assessment was performed at 3 months after stroke. Voxel-wise and tract-wise disconnectome analysis were performed to uncover the strategic structural disconnection pattern for global PSCI. Disconnection score was calculated for each participant in leave-one-dataset-out cross-validation. Multivariable logistic regression was performed for the association between disconnection score and PSCI. Prediction models with and without disconnection score were developed, cross-validated, and compared in terms of discrimination and goodness-of-fit. RESULTS: Compared with lesions of non-PSCI, those of PSCI were more likely to have fiber connections with left prefrontal cortex and left deep structures (thalamus and basal ganglia). Disconnection score could predict the risk and severity of PSCI during cross-validation, and was independently associated with PSCI after controlling for all baseline covariates (odds ratio, 1.38 [95% CI, 1.17-1.64]; P<0.001). Incorporating disconnection score into a reference model with 6 known predictors resulted in significant improvement in both discrimination and goodness-of-fit throughout cross-validation. CONCLUSIONS: A strategic structural disconnection pattern centered on left prefrontal cortex, thalamus, and basal ganglia is identified for global PSCI using indirect disconnectome analysis. The baseline disconnection score is independently predictive of PSCI and has significant incremental value to preexisting sociodemographic, clinical, and neuroimaging predictors. REGISTRATION: URL: http://www.chictr.org.cn/enIndex.aspx; Unique identifier: ChiCTR-ROC-17013993.

Development and validation of a novel radiomics-clinical model for predicting post-stroke epilepsy after first-ever intracerebral haemorrhage.

OBJECTIVES: Post-stroke epilepsy (PSE) is associated with increased morbidity and mortality. This study aimed to develop and validate a novel prediction model combining clinical factors and radiomics features to accurately identify patients at high risk of developing PSE after intracerebral haemorrhage (ICH). METHODS: Researchers performed a retrospective medical chart review to extract derivation and validation cohorts of patients with first-ever ICH that attended two tertiary hospitals in China between 2010 and 2020. Clinical data were extracted from electronic medical records and supplemented by tele-interview. Predictive clinical variables were selected by multivariable logistic regression to build the clinical model. Predictive radiomics features were identified, and a Rad-score was calculated according to the coefficient of the selected feature. Both clinical variables and radiomic features were combined to build the radiomics-clinical model. Performances of the clinical, Rad-score, and combined models were compared. RESULTS: A total of 1571 patients were included in the analysis. Cortical involvement, early seizures within 7 days of ICH, NIHSS score, and ICH volume were included in the clinical model. Rad-score, instead of ICH volume, was included in the combined model. The combined model exhibited better discrimination ability and achieved an overall better benefit against threshold probability than the clinical model in the decision curve analysis (DCA). CONCLUSIONS: The combined radiomics-clinical model was better able to predict ICH-associated PSE compared to the clinical model. This can help clinicians better predict an individual patient's risk of PSE following a first-ever ICH and facilitate earlier PSE diagnosis and treatment. KEY POINTS: • Radiomics has not been used in predicting the risk of developing PSE. • Higher Rad-scores were associated with higher risk of developing PSE. • The combined model showed better performance of PSE prediction ability.

A 6-month prognostic nomogram incorporating hemoglobin level for intracerebral hemorrhage in younger adults.

OBJECTIVE: Intracerebral hemorrhage (ICH) is the second most common subtype of stroke, with high mortality and morbidity. At present, there are no effective 6-month prognostic markers, particularly for younger patients. The aim of this research was to construct a new valuable prognostic nomogram model incorporating haemoglobin levels for adult patients with ICH. METHODS: Patients aged between 18 and 50 presenting with intracerebral haemorrhage at the Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology between January 1st 2012 and December 31st 2018 were included in this retrospective study. Independent factors of prognosis were identified by univariate and multivariate logistic regression analyses, and a new nomogram model was constructed and validated. The clinical value of the nomogram model was subsequently explored utilizing decision curve analysis and clinical impact curves. RESULTS: In total, 565 patients were enrolled in this study, 117 (20.7%) of whom developed an unfavourable prognosis. Infratentorial lesion (adjusted odds ratio [aOR] = 3.708, 95% confidence interval [CI], 1.490-9.227; P = 0.005) was the most significant unfavourable outcome. Age ([aOR] = 1.054; 95% CI, 1.014-1.096; P = 0.008), hematoma volume (aOR = 1.014, 95% CI, 1.002-1.027; P = 0.024), haemoglobin (aOR = 0.981, 95% CI, 0.969-0.993; P = 0.002), blood glucose (aOR = 1.135, 95% CI, 1.037-1.241; P = 0.005) and NIHSS (aOR = 1.105, 95% CI, 1.069-1.141; P < 0.001) were independent risk factors. Based on these 6 factors, the nomogram can be employed to predict early functional prognosis with high accuracy (AUC 0.791). Decision curve analysis and clinical impact curves showed an increased net benefit for utilizing the nomogram. CONCLUSION: The haemoglobin level at admission may be an easily overlooked factor in clinical work. This new nomogram model could be a promising and convenient tool to predict the early functional prognosis of adults with ICH. More prospective multicentre studies are needed to validate these findings.

External validation and comparison of clinical scores for predicting late seizures after intracerebral hemorrhage in Chinese patients.

PURPOSE: Clinical scores have been established to predict the probability of late seizures following intracerebral hemorrhage (ICH) for individual patients, including the CAVE, CAVS and LANE scores. The purpose of this study was to compare these prediction scores in the Chinese population and undertake an independent external validation on them. METHODS: At one tertiary hospital in China, we retrospectively recruited consecutive inpatients who had been diagnosed with ICH. Medical records and tele interviews with a modified standardized questionnaire were used to identify late seizures. All the predictors of the prediction scores were collected from patient charts and databases by a standardized data collection protocol. The external validation of the prediction scores was quantified by the area under the curve (AUC), sensitivity, specificity, Youden index (YI), positive predictive value (PPV), and negative predictive value (NPV). RESULTS: 69 (5.4%) of 1276 patients experienced late seizures after ICH. There was no significant difference in the CAVE, CAVS, and LANE scores, which had AUCs of 0.75 (95% CI = 0.70-0.81), 0.74 (95% CI = 0.68-0.80), and 0.76 (95% CI = 0.70-0.82), respectively. At the optimal cutoff score, the LANE score had a lower sensitivity but a higher specificity than the CAVE and CAVS scores. Among the three prediction scores, the LANE score had a higher PPV than the others (0.145 vs. 0.088, 0.083), while the NPV was similar among the three prediction scores (0.989, 0.989, and 0.972). CONCLUSION: Our study showed that the CAVE, CAVS and LANE scores had similar AUCs for the occurrence of late seizures, but the LANE score had a relatively high PPV at the optimal cutoff score. Due to low evidence for using prophylactic antiseizure medications (ASM) in patients with ICH and poor availability of specialist stroke care in China, the LANE score with a cutoff score of 3 could be an applicable prediction tool in Chinese patients with ICH.

Catatonia in adult anti-NMDAR encephalitis: an observational cohort study.

BACKGROUND: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is one of the most prevalent autoimmune encephalitis and is closely related to catatonia. This study aimed to investigate the clinical features and disease outcomes of adult catatonic anti-NMDAR encephalitis patients. METHODS: Adult patients diagnosed with anti-NMDAR encephalitis between January 2013 and October 2021 were retrospectively enrolled in this study. According to the Bush Francis Catatonia screening instrument (BFCSI), patients were divided into two groups: those with catatonia and those without catatonia. The modified Rankin scale (mRS), Clinical Assessment Scale for Autoimmune Encephalitis (CASE), Neuropsychiatric Inventory (NPI), Patient Health Questionnaire-9 (PHQ-9) and 7-item Generalized Anxiety Disorder Questionnaire (GAD-7) scores were assessed at follow-up. The Mann-Whitney U test (nonparametric), Student's t test (parametric), and chi-squared test were used to analyse the differences between the two groups. RESULTS: Eighty-four patients were recruited, including twenty-five catatonic patients and fifty-nine noncatatonic patients. Among them, 28 had positive antibody only in cerebrospinal fluid (CSF), 4 had positive antibody only in serum and 52 had positive antibody both in CSF and serum. Catatonic patients experienced more disturbance of consciousness (p = 0.01), aggression (p = 0.046) and affective disorders (p = 0.043) than noncatatonic patients. The mRS scores of the catatonia group assessed at admission (p = 0.045) were worse than those of the non-catatonia group. Catatonic patients were more inclined to develop deep vein thrombosis (p = 0.003), decubitus (p = 0.046), pneumonia (p = 0.025), and to be admitted to the intensive care unit (ICU) (p = 0.011) than noncatatonic patients. All patients in the catatonia group received first-line immunotherapy. At the 24-month follow-up, 2 patients in the catatonia group did not achieve good outcomes. At the last follow-up, the catatonia group had more relapses (p = 0.014) and more neuropsychiatric problems (p = 0.035). CONCLUSIONS: Adult anti-NMDAR encephalitis patients with catatonia present distinct clinical features in disease course and are prone to experience more relapses and long-term neuropsychiatric problems than those without catatonia.

Psychopathological network for early-onset post-stroke depression symptoms.

BACKGROUND: Post-stroke depression (PSD) can be conceptualized as a complex network where PSD symptoms (PSDS) interact with each other. The neural mechanism of PSD and interactions among PSDS remain to be elucidated. This study aimed to investigate the neuroanatomical substrates of, as well as the interactions between, individual PSDS to better understand the pathogenesis of early-onset PSD. METHODS: A total of 861 first-ever stroke patients admitted within 7 days poststroke were consecutively recruited from three independent hospitals in China. Sociodemographic, clinical and neuroimaging data were collected upon admission. PSDS assessment with Hamilton Depression Rating Scale was performed at 2 weeks after stroke. Thirteen PSDS were included to develop a psychopathological network in which central symptoms (i.e. symptoms most strongly correlated with other PSDS) were identified. Voxel-based lesion-symptom mapping (VLSM) was performed to uncover the lesion locations associated with overall PSDS severity and severities of individual PSDS, in order to test the hypothesis that strategic lesion locations for central symptoms could significantly contribute to higher overall PSDS severity. RESULTS: Depressed mood, Psychiatric anxiety and Loss of interest in work and activities were identified as central PSDS at the early stage of stroke in our relatively stable PSDS network. Lesions in bilateral (especially the right) basal ganglia and capsular regions were found significantly associated with higher overall PSDS severity. Most of the above regions were also correlated with higher severities of 3 central PSDS. The other 10 PSDS could not be mapped to any certain brain region. CONCLUSIONS: There are stable interactions among early-onset PSDS with Depressed mood, Psychiatric anxiety and Loss of interest as central symptoms. The strategic lesion locations for central symptoms may indirectly induce other PSDS via the symptom network, resulting in higher overall PSDS severity. TRIAL REGISTRATION: URL: http://www.chictr.org.cn/enIndex.aspx ; Unique identifier: ChiCTR-ROC-17013993.

Direct bilirubin: A predictor of hematoma expansion after intracerebral hemorrhage.

BACKGROUND: Previous evidence demonstrated that several biomarkers involved in the pathological process of coagulation/hemostasis dysfunction, impairment of brain vascular integrity and inflammation are associated with hematoma expansion (HE) after intracerebral hemorrhage (ICH). We aimed to explore whether there were unreported laboratory biomarkers associated with HE that were readily and commonly available in clinical practice. METHODS: We retrospectively analyzed consecutive acute ICH patients from 2012 to 2020 with admission laboratory tests and baseline and follow-up computed tomography (CT) scans. Univariate and multivariate regression analyses were used to evaluate associations between conventional laboratory indicators and HE. The results were verified in a prospective validation cohort. The relationship of candidate biomarker and 3-month outcomes was also investigated and mediation analysis was undertaken to determine causal associations among candidate biomarker, HE and outcome. RESULTS: Of 734 ICH patients, 163 (22.2%) presented HE. Among the included laboratory indicators, higher direct bilirubin (DBil) was associated with HE (adjusted odds ratio [OR] of per 1.0 µmol/L change 1.082; 95% confidence interval [CI] 1.011-1.158). DBil >5.65 µmol/L was a predictor of HE in validation cohort. Higher DBil was also associated with poor 3-month outcomes. The mediation analysis indicated that the association of higher DBil and poor outcomes was partially mediated by HE. CONCLUSIONS: DBil is a predictor of HE and poor 3-month outcomes after ICH. DBil's metabolic process and involvement in the pathological mechanism of HE are likely to contribute to the association between DBil and HE. Interventions targeting DBil to improve post-ICH prognosis may be meaningful and worthy of further exploration.

Good functional outcome following bilateral external capsule hemorrhage mimicking bilateral basal ganglia hemorrhage in a coma patient.

Simultaneous spontaneous bilateral external capsule hemorrhage is a rare clinical entity with extremely poor outcome. However, knowledge on the effective management of this fatal disease is limited. Herein,we described a case of a 42-year-old man with acute coma and quadriplegia as well as respiratory failure related to the disease. The patient underwent minimally invasive surgery plus local thrombolysis. Consequently, he recovered with satisfactory neurological function recovery on the 180th day of follow-up.

Comparative study on acute management of intracerebral haematoma using local thrombolysis in moyamoya and non-moyamoya patients: a single institution experience.

PURPOSE: Spontaneous intracerebral haemorrhage (ICH) is the main presentation in adults with moyamoya disease (MMD), an unusual clinical entity with a poor prognosis. However, optimal management in the acute stage of ICH in patients with MMD remains a challenge. Since minimally invasive surgery (MIS) plus local thrombolysis has emerged as a promising strategy for ICH, we aimed to describe our experience of performing this procedure in this special population in the acute phase, while focusing on its efficacy and safety. MATERIALS AND METHODS: The medical data of patients with ICH treated with MIS and local thrombolysis between November 2013 and December 2017 were retrospectively reviewed at our institution. MMD was identified based on the angiographic images. The primary outcome was postoperative intracranial rebleeding. The secondary outcomes were 30-day mortality and 6-month outcome graded using the modified Rankin scale (mRS). Logistic regression was applied to explore independent risk factors for the above outcomes. RESULTS: A cohort of consecutive 337 ICH patients was analysed, of whom 14 (4.15%) were diagnosed with MMD. In total, 36 (11.46%) patients experienced postoperative intracranial rehaemorrhage, of which one patient had MMD. No significant difference was found between the patients with and without MMD regarding postoperative rebleeding (9.09% vs. 11.55%, p = 1.000). Additionally, the 30-day mortality of patients with MMD was 21.42% (3/14), which was not significantly different from that of non-MMD patients (10.83%; p = 0.201). Moreover, 53.8% of patients had poor outcomes at the 6-month follow-up among MMD patients, similar to 43.9% of patients without MMD (p = 0.573). The coexistence of MMD failed to show a significant association with postoperative intracranial rebleeding (p = 0.348), 30-day mortality (p = 0.211), or poor outcome at the 6-month follow-up (p = 0.450). CONCLUSION: Our findings suggest that coexistent MMD is not associated with an increased risk of postoperative rebleeding or poor outcome after local thrombolysis for ICH.

The asymmetry of glymphatic system dysfunction in patients with temporal lobe epilepsy: A DTI-ALPS study.

BACKGROUND AND PURPOSE: While the occurrence of glymphatic system dysfunction has been observed in temporal lobe epilepsy (TLE), the potential asymmetry of this system has yet to be investigated in the TLE context. We aimed to investigate the glymphatic system function in both hemispheres and to analyze asymmetric features of the glymphatic system in TLE patients using diffusion tensor image analysis along the perivascular space (DTI-ALPS) method. MATERIALS AND METHODS: 43 patients (left TLE (LTLE), n = 20; right TLE (RTLE), n = 23) and 39 healthy controls (HC) were enrolled in this study. The DTI-ALPS index was calculated for the left (left ALPS index) and right (right ALPS index) hemispheres respectively. An asymmetry index (AI) was calculated by AI = (Right - Left)/ [(Right + Left)/2] to represent the asymmetric pattern. Independent two sample t-test, two-sample paired t-test or one-way ANOVA with Bonferroni correction were conducted to compare the differences in ALPS indices and AI among the groups. RESULTS: Both left ALPS index (p = 0.040) and right ALPS index (p = 0.001) of RTLE patients were significantly decreased, while only left ALPS index of LTLE patients (p = 0.005) was reduced. Compared to contralateral ALPS index, the ipsilateral ALPS index was significantly decreased in TLE (p = 0.008) and RTLE (p = 0.009) patients. Leftward asymmetry of the glymphatic system was found in HC (p = 0.045) and RTLE (p = 0.009) patients. The LTLE patients presented reduced asymmetric traits when compared to RTLE patients (p = 0.029). CONCLUSION: The TLE patients exhibited altered ALPS indices, which could be triggered by glymphatic system dysfunction. Altered ALPS indices were more severe in ipsilateral than in the contralateral hemisphere. Moreover, LTLE and RTLE patients exhibited different change patterns of the glymphatic system. In addition, glymphatic system function presented asymmetric patterns in both normal adult brain and RTLE patients.

Systemic low-grade inflammation and depressive symptomology at chronic phase of ischemic stroke: The chain mediating role of fibrinogen and neutrophil counts.

BACKGROUND: Post-stroke depression (PSD) is the most common psychological consequence of stroke. Increased inflammatory markers resulting from ischemic stroke may played an important role in the pathogenesis of depressive symptomology. The present study was conducted to further elucidate the relationship between stroke severity, systemic low-grade inflammation and chronic phase post-stroke depressive symptomology (CP-PSDS). METHODS: A total of 897 stroke patients were consecutively recruited in this multicenter prospective cohort study and followed up for 1 year. The analytical sample consisted of 436 patients with ischemic stroke (23.4% female, median age = 57 years) from this cohort. Serum concentrations of inflammatory markers were measured in all 436 patients with ischemic stroke, from fasting morning venous blood samples on admission. Stroke severity was evaluated using the National Institutes of Health Stroke Scale (NIHSS) on admission and post-stroke depressive symptomology (PSDS) was evaluated by 17-item Hamilton Rating Scale for Depression (HRSD). RESULTS: In the fully adjusted models, we observed that 1) NIHSS (Model 2: ß = 0.200, 95%CI, 0.057 ∼ 0.332), fibrinogen (Model 2: ß = 0.828, 95%CI, 0.269 ∼ 1.435), white blood cell counts (WBC, model 2: ß = 0.354, 95%CI, 0.122 ∼ 0.577) and neutrophil counts (Model 2: ß = 0.401, 95%CI, 0.126 ∼ 0.655) can independently predict the CP-PSDS after ischemic stroke onset; 2) fibrinogen (Indirect effect = 0.027, 95%CI, 0.007 ∼ 0.063, 13.4% mediated), WBC (Indirect effect = 0.024, 95%CI, 0.005 ∼ 0.058, 11.8% mediated) and neutrophil counts (Indirect effect = 0.030, 95%CI, 0.006 ∼ 0.069, 14.8% mediated) could partially mediate the association between stroke severity and CP-PSDS, and 3) stroke severity might cause CP-PSDS partly through the chain-mediating role of both fibrinogen and neutrophil counts (chain mediated effect = 0.003, 95%CI, 0.000 ∼ 0.011, p = 0.025, 1.6% mediated). CONCLUSIONS: Findings revealed that fibrinogen, WBC and neutrophil counts may be independent predictors of CP-PSDS and partial mediators of the relationship between stroke severity and CP-PSDS among patients with ischemic stroke. In addition, the chain mediating effect of fibrinogen and neutrophil counts might play an important role in the occurrence of CP-PSDS. However, no inflammatory markers were associated with CP-PSDS in females.

SMASH-U aetiological classification: A predictor of long-term functional outcome after intracerebral haemorrhage.

BACKGROUND: SMASH-U is a systematic aetiological classification system for intracerebral haemorrhage (ICH) proven to be a predictor of post-ICH haematoma expansion and mortality. However, its role in predicting functional outcome remains elusive. Therefore, we aimed to investigate whether SMASH-U is associated with long-term functional outcome after ICH and improves the accuracy of prediction when added to max-ICH score. METHODS: Consecutive acute ICH patients from 2012 to 2018 from the neurology department of Tongji Hospital were enrolled. ICH aetiology was classified according to the SMASH-U system. The association of SMASH-U with 12-month functional outcome after ICH and the predictive value were evaluated. RESULTS: Of 1938 ICH patients, the aetiology of 1295 (66.8%) patients were classified as hypertension, followed by amyloid angiopathy (n = 250, 12.9%), undetermined (n = 159, 8.2%), structural lesions (n = 149, 7.7%), systemic disease (n = 74, 3.8%) and medication (n = 11, 0.6%). The baseline characteristics were different among the six aetiologies. In multivariate analysis, SMASH-U was proven to be a predictor of 12-month unfavourable functional outcome. When adding the SMASH-U system, the predictive performance of max-ICH score was improved (area under the receiver operating characteristic curve from 0.802 to 0.812, p = 0.010) and the predictive accuracy was enhanced (integrated discrimination improvement [IDI]: 1.60%, p < 0.001; continuous net reclassification improvement [NRI]: 28.16%, p < 0.001; categorical NRI: 3.34%, p = 0.004). CONCLUSIONS: SMASH-U predicted long-term unfavourable functional outcomes after acute ICH and improved the accuracy of prediction when added to max-ICH score. Integrating the aetiology to a score model to predict the post-ICH outcome may be meaningful and worthy of further exploration.

Explore the influencing factors and construct random forest models of post-stroke depression at 3 months in males and females.

BACKGROUND: Post-stroke depression (PSD) is one of the most common neuropsychiatric complications after stroke. The occurrence, development and prognosis of PSD have long been different between males and females. The main purpose of this study was to explore the influencing factors of PSD at 3 months in males and females, and construct random forest (RF) models to rank the influencing factors. METHODS: This is a prospective multicenter cohort study (Registration number: ChiCTR-ROC-17013993). Stroke patients hospitalized in the department of Neurology of three hospitals in Wuhan were enrolled from May 2018 to August 2019. Scale assessments were performed 24 hours after admission and 3 months after stroke onset. Binary logistic regression analysis was used for univariate and multivariate (stepwise backward method) analysis, when p was less than 0.05, the difference between groups was considered statistically significant. Lastly, the RF models were constructed according to the results of multivariate regression analysis. RESULTS: This study found that several baseline variables were associated with PSD at 3 months in males and females. RF model ranked them as stroke severity (OR [odds ratio] =1.17, p < 0.001, 95%CI [confidence interval]:1.11-1.24), neuroticism dimension (OR = 1.06, p = 0.002, 95%CI:1.02-1.10), physical exercise (OR = 0.62, p = 0.007, 95%CI:0.44-0.88), sleeping time < 5 h (OR = 1.91, p = 0.006, 95% CI:1.20-3.04) and atrial fibrillation (OR = 4.18, p = 0.012, 95%CI:1.38-12.68) in males. In females, RF model ranked them as psychological resilience (OR = 0.98, p = 0.015, 95%CI:0.96-1.00), ability of daily living (OR = 0.98, p = 0.001, 95%CI:0.97-0.99), neuroticism dimension (OR = 1.11, p = 0.002, 95%CI:1.04-1.18) and subjective support (OR = 1.11, p < 0.001, 95%CI:1.05-1.78). CONCLUSION: The study found influencing factors of PSD at 3 months were different in males and females, and construct RF models to rank them according to their importance. This suggests that clinicians should focus their interventions on sex-specific influencing factors in order to improve the prognosis of PSD patients. TRIAL REGISTRATION: ChiCTR-ROC-17013993.

Blood biomarkers of post-stroke depression after minor stroke at three months in males and females.

BACKGROUND: Post-stroke depression (PSD) is one of the most common neuropsychiatric complications after stroke. Studies on the underlying mechanisms and biological markers of sex differences in PSD are of great significance, but there are still few such studies. Therefore, the main objective of this study was to investigate the association of biomarkers with PSD at 3 months after minor stroke in men and women. METHODS: This was a prospective multicenter cohort study that enrolled 530 patients with minor stroke (males, 415; females, 115). Demographic information and blood samples of patients were collected within 24 h of admission, and followed up at 3 months after stroke onset. PSD was defined as a depressive disorder due to another medical condition with depressive features, major depressive-like episode, or mixed-mood features according to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-V). Univariate analysis was performed using the chi-square test, Mann-Whitney U test, or t-test. Partial least-squares discriminant analysis (PLS-DA) was used to distinguish between patients with and without PSD. Factors with variable importance for projection (VIP) > 1.0 were classified as the most important factors in the model segregation. RESULTS: The PLS-DA model mainly included component 1 and component 2 for males and females. For males, the model could explain 13% and 16.9% of the variables, respectively, and 29.9% of the variables in total; the most meaningful predictors were exercise habit and fibrinogen level. For females, the model could explain 15.7% and 10.5% of the variables, respectively, and 26.2% of the variables in total; the most meaningful predictors in the model were brain-derived neurotrophic factor (BDNF), magnesium and free T3. Fibrinogen was positively correlated with the Hamilton Depression Scale-17 items (HAMD-17) score. BDNF, magnesium, and free T3 levels were negatively correlated with the HAMD-17 score. CONCLUSIONS: This was a prospective cohort study. The most important markers found to be affecting PSD at 3 months were fibrinogen in males, and free T3, magnesium, and BDNF in females. TRIAL REGISTRATION: ChiCTR-ROC-17013993 .

Age-dependent aggregation of α-synuclein in the nervous system of gut-brain axis is associated with caspase-1 activation.

α-Synuclein (α-Syn) plays a key role in the development of Parkinson' desease (PD). As aging is acknowledged to be the greatest risk factor for PD, here we investigated α-Syn expression in the ileum, thoracic spinal cord, and midbrain of young (1-month-old), middle-aged (6-, 12-month-old) to old (18-month-old) mice. We demonstrated that both the levels of α-Syn monomers, oligomers and ratios of oligomers to monomers were increased with aging in the ileum, thoracic spinal cord, and midbrain. Whereas, the expression of tyrosine hydroxylase (TH), the rate-limiting enzyme for dopamine synthesis, was decreased with aging in the midbrain. We failed to find corresponding α-Syn mRNA increase with aging. However, we found an increased expression of caspase-1 in the ileum, thoracic spinal cord, and midbrain. A specific caspase-1 inhibitor VX765 significantly reduced levels of both the α-Syn monomers and oligomers triggered by the rotenone in vitro. Taken together, the increase in α-Syn aggregation with aging might not occur first in the gut, but simultaneously in the nervous system of gut-brain axis. The mechanism of the age-dependent aggregation of α-Syn in nervous system is likely triggered by the aging-related caspase-1 activation.

Apolipoprotein E genotype predicts subarachnoid extension in spontaneous intracerebral haemorrhage.

BACKGROUND AND PURPOSE: Spontaneous intracerebral haemorrhage (ICH) with subarachnoid extension (SAHE) predicts poor outcomes and haematoma expansion in spontaneous ICH and is also a potential predictor of the severity of vascular amyloid deposition. The biological underpinnings of SAHE remain elusive. A study was conducted to identify risk factors associated with SAHE. METHODS: A retrospective analysis was performed of an ongoing prospective cohort of primary spontaneous supratentorial ICH patients admitted to Tongji Hospital. SAHE was rated on baseline noncontrast computed tomography images by investigators blinded to the clinical data. RESULTS: A total of 189 patients were enrolled. Apolipoprotein E (APOE) ε2 copies (p = 0.020), but not APOE ε4 copies (p > 0.2), were more common in patients with SAHE in univariate analysis. After controlling for confounding factors in multiple logistic regression, lobar haematoma (odds ratio [OR] 14.21, 95% confidence interval [CI] 5.89-34.33; p < 0.001), large haematoma volume (OR 1.04, 95% CI 1.02-1.06; p < 0.001) and APOE ε2 copies (OR 3.07, 95% CI 1.05-8.97; p = 0.041) were three independent predictors of SAHE. For subgroup analysis stratified by location, APOE ε2 showed a possible association with SAHE in lobar ICH (p = 0.026) but not in deep ICH (p > 0.2). No significant association was found between APOE ε4 copies and either lobar (p > 0.2) or deep ICH (p > 0.2). CONCLUSIONS: The APOE ε2 allele predicts SAHE in spontaneous supratentorial ICH. The association may predominantly apply to lobar ICH. Given the established relationship between the APOE ε2 allele and pathological cerebrovascular changes, our findings suggest that SAHE involves genetically driven vessel pathology.

Long QT syndrome with potassium voltage-gated channel subfamily H member 2 gene mutation mimicking refractory epilepsy: case report.

BACKGROUND: Epileptic seizures can be difficult to distinguish from other etiologies that cause cerebral hypoxia, especially cardiac diseases. Long QT syndrome (LQTS), especially LQTS type 2 (LQT2), frequently masquerades as seizures because of the transient cerebral hypoxia caused by ventricular arrhythmia. The high rate of sudden death in LQTS highlights the importance of accurate and early diagnosis; correct diagnosis of LQTS also prevents inappropriate treatment with anti-epileptic drugs (AEDs). CASE PRESENTATION: We report a case of congenital LQT2 with potassium voltage-gated channel subfamily H member 2 gene (KCNH2) mutation misdiagnosed as refractory epilepsy and treated with various AEDs for 22 years. The possibility of cardiac arrhythmia was suspected after the patient presented to the emergency room and the electrocardiograph (ECG) monitor showed paroxysmal ventricular tachycardia during attacks. Atypical seizure like attacks with prodromal uncomfortable chest sensation and palpitation, triggered by auditory stimulation, and typical ventricular tachycardia monitored by ECG raised suspicion for LQT2, which was confirmed by exome sequencing and epileptic seizure was ruled out by 24-h EEG monitoring. Although the patient rejected implantation of an implantable cardioverter defibrillator, ß blocker was given and the syncope only attacked 1-2 per year when there was an incentive during the 5 years follow up. CONCLUSIONS: Our case illustrates how long LQTS can masquerade convincingly as epilepsy and can be treated wrongly with AEDs, putting the patient at high risk of sudden cardiac death. Careful ECG evaluation is recommend for both patients with first seizure and those with refractory epilepsy.

Higher fasting C-peptide is associated with post-stroke depression: a multicenter prospective cohort study.

BACKGROUND: Fasting C-peptide (FCP) has been shown to play an important role in the pathophysiology of mood disorders including depression and schizophrenia, but it is unknown whether it also predicts post-stroke depression (PSD). This study examined the association between FCP and PSD at 6 months after acute ischemic-stroke onset among Chinese subjects. METHODS: A total of 656 stroke patients were consecutively recruited from three hospitals of Wuhan city, Hubei province. Clinical and laboratory data were collected on admission. PSD status was evaluated by DSM-V criteria and 17-item Hamilton Rating Scale for Depression (HAMD-17) at 6 months after acute ischemic stroke. The χ2-test, Mann-Whitney U-test, and t-test were used to check for statistical significance. Multivariate logistic regression model was used to explore independent predictor of PSD. RESULTS: In the univariate analysis, significant differences were found between the PSD and non-PSD groups in terms of FCP level (p = 0.009). After multivariate adjustments, FCP remained a significant independent predictor of PSD, with an adjusted odds ratio of 1.179 (95%CI: 1.040-1.337, p = 0.010). CONCLUSIONS: Higher FCP levels on admission were found to be associated with PSD at 6 months after acute ischemic-stroke onset. For stroke patients, doctors should pay attention to the baseline FCP for screening high-risk PSD in clinical practice.

The impact of social factors, especially psychological worries on anxiety and depression in patients with epilepsy.

BACKGROUND: Social factors are believed to affect mental health in patients with epilepsy (PWE). However, there is still a lack of sufficient manifest proof, given the difficulty of exposing PWE to relatively consistent natural social environments with a low or high level of social interaction to study their significant role. METHODS: This single-center, longitudinal study was conducted via online questionnaires during the coronavirus disease 2019. PWE were recruited from downtown Wuhan and surrounding areas. The Patient Health Questionnaire-9 and Generalized Anxiety Disorder-7 were used to assess psychological status. RESULTS: We analyzed 588 questionnaires completed by 294 PWE who participated in the dual survey. Under lockdown and reopening, the prevalence of anxiety was 13.6%/22.5%, and the prevalence of depression was 19.4%/34.0%. Raising children and seizure-related characteristics, including uncontrolled seizures, seizure exacerbation, seizure frequency ≥ 2/m, and changes in drug regimen, were risk factors in the first and second surveys. A high education level (OR = 1.946, 95% CI = 1.191-3.182), low life satisfaction (OR = 1.940, 95% CI = 1.007-3.737), worry about unanticipated seizures (OR = 2.147, 95% CI = 1.049-4.309), and worry about purchasing medication outside (OR = 2.063, 95% CI = 1.060-4.016) were risk factors for higher scores after reopening. Worry about unanticipated seizures (OR = 3.012, 95% CI = 1.302-6.965) and in-person medical consultation (OR = 2.319, 95% CI = 1.262-4.261) were related to newly diagnosed patients with psychological disorder after reopening. CONCLUSIONS: We identified an association between social variables and epileptic psychiatric comorbidities.