Comparing Outcomes of Thrombectomy Versus Intravenous Thrombolysis Based on Middle Cerebral Artery M2 Occlusion Features.

BACKGROUND: Current evidence provides limited support for the superiority of endovascular thrombectomy (EVT) in patients with M2 segment middle cerebral artery occlusion. We aim to investigate whether imaging features of M2 segment occlusion impact the effectiveness of EVT. METHODS: We conducted a retrospective cohort study from January 2017 to January 2022, drawing data from the CASE II registry (Computer-Based Online Database of Acute Stroke Patients for Stroke Management Quality Evaluation), which specifically documented patients with acute ischemic stroke presenting with M2 segment occlusion undergoing reperfusion therapy. Patients were stratified into the intravenous thrombolysis (IVT) group (IVT alone) and EVT group (IVT plus EVT or EVT alone). The primary outcome was a modified Rankin Scale score 0 to 2 at 90 days. Secondary outcomes included additional thresholds and distribution of modified Rankin Scale scores, 24-hour recanalization, early neurological deterioration, and relevant complications during hospitalization. Safety outcomes encompassed intracranial hemorrhagic events at 24 hours and mortality at 90 days. Binary logistic regression analyses with propensity score matching were used. Subgroup analyses were performed based on the anatomic site of occlusion, including right versus left, proximal versus distal, dominant/co-dominant versus nondominant, single versus double/triple branch(es), and anterior versus central/posterior branch. RESULTS: Among 734 patients (43.3% were females; median age, 73 years) with M2 segment occlusion, 342 (46.6%) were in the EVT group. Propensity score matching analysis revealed no statistical difference in the primary outcome (odds ratio, 0.860 [95% CI, 0.611-1.209]; P=0.385) between the EVT group and IVT group. However, EVT was associated with a higher incidence of subarachnoid hemorrhage (odds ratio, 6.655 [95% CI, 1.487-29.788]; P=0.004) and pneumonia (odds ratio, 2.015 [95% CI, 1.364-2.977]; P<0.001). Subgroup analyses indicated that patients in the IVT group achieved better outcomes when presenting with right, distal, or nondominant branch occlusion (Pall interaction<0.05). CONCLUSIONS: Our study showed similar efficiency of EVT versus IVT alone in acute M2 segment middle cerebral artery occlusion. This suggested that only specific patient subpopulations might have a potentially higher benefit of EVT over IVT alone. REGISTRATION: URL: https://clinicaltrials.gov; Unique identifier: NCT04487340.

Choroid Plexus Enlargement Exacerbates White Matter Hyperintensity Growth through Glymphatic Impairment.

OBJECTIVE: Choroid plexus (CP) is a key regulator in cerebrospinal fluid production, but its contribution to glymphatic clearance function and association with white matter hyperintensity (WMH) remains unclear. METHODS: This retrospective study included 2 prospective 3.0-T magnetic resonance imaging (MRI) cohorts. In cohort 1, patients with indications for lumbar puncture underwent 3-dimensional T1-weighted sequence (3D-T1) before and at 39 hours after intrathecal administration of contrast agent (glymphatic MRI). In cohort 2, patients with WMH were enrolled from the CIRCLE study and had a median follow-up time of 1.4 years. WMH and CP of the lateral ventricles were automatically segmented on T2 fluid-attenuated inversion recovery (FLAIR) and 3D-T1, respectively. CP volume was expressed as a ratio to intracranial volume. Glymphatic clearance was measured as signal percentage change from baseline to 39 hours at 8 brain locations based on glymphatic MRI in the first cohort, or as noninvasive diffusion tensor image analysis along the perivascular space (DTI-ALPS) index based on DTI in the second cohort. RESULTS: In cohort 1, a total of 52 patients were included. Higher CP volume was correlated with slower glymphatic clearance rate in all brain locations. In cohort 2, a total of 197 patients were included. Baseline CP volume was positively associated with WMH volume and its growth. Furthermore, DTI-ALPS index partially mediated the association of CP with both WMH load and growth. INTERPRETATIONS: Enlarged CP volume could be an indicator for larger growth of WMH, potentially involving impaired glymphatic clearance function. The exploration of CP may provide a novel perspective to clarify the mechanism of WMH pathogenesis, as well as other glymphatic-related disorders. ANN NEUROL 2023;94:182-195.

Effect of computed tomography vs. computed tomography perfusion on mechanical thrombectomy outcomes within 6 hours.

OBJECTIVES: It is unclear which selection strategy, plain CT vs. CT perfusion (CTP), is more powerful in predicting outcome after mechanical thrombectomy (MT). We aimed to compare the effect of plain CT and CTP in predicting outcome after MT within 6 h. METHODS: We conducted a prospective analysis of a retrospective cohort from our single-center study, which had occlusion of the internal carotid artery and middle cerebral artery up to the proximal M2 segment and received MT within 6 h. According to the Alberta Stroke Program Early CT Score (ASPECTS), patients were divided into a high-ASPECTS group (≥ 6) and a low ASPECTS group (< 6). Similarly, patients were divided into mismatch and no-mismatch groups according to the DEFUSE3 criteria for CTP. A good outcome was defined as a 90-day modified Rankin Scale (mRS) score of ≤ 3. Univariate and binary logistic regression analyses were used to investigate the association between different imaging modality and 90-day mRS score, and mortalities, respectively. RESULTS: The high ASPECTS group included 307 patients (89.2%). The mismatch group included 189 (54.9%) patients meeting the DEFUSE3 criterion. Compared to the low ASPECTS group, the high ASPECTS group had a good outcome (odds ratio (OR), 2.285; [95% confidence interval (CI) (1.106, 4.723)], p = 0.026) and lower mortality (OR, 0.350; [95% CI (0.163, 0.752)], p = 0.007). However, there were no significant differences in good outcomes and mortality between the mismatch and no-mismatch groups. CONCLUSIONS: Compared with plain CT, CTP does not provide additional benefits in the selection of patients suitable for MT within 6 h. CLINICAL RELEVANCE STATEMENT: CT perfusion is not superior to plain CT for the prediction of clinical outcomes when selecting patients for mechanical thrombectomy in the first 6 h. In that clinical setting, plain CT may be safe in the absence of perfusion data. KEY POINTS: • The advantage of CT perfusion (CTP) over CT in pre-mechanical thrombectomy (MT) screening has not been proven for patients with a large infarct core. • CTP is not better than plain CT in predicting good outcome following MT within 6 h. • Plain CT is sufficient for selecting patients suitable for MT within 6 h of large artery occlusion.

Brain region-specific synaptic function of FUS underlies the FTLD-linked behavioural disinhibition.

Synaptic dysfunction is one of the earliest pathological processes that contribute to the development of many neurological disorders, including Alzheimer's disease and frontotemporal lobar degeneration. However, the synaptic function of many disease-causative genes and their contribution to the pathogenesis of the related diseases remain unclear. In this study, we investigated the synaptic role of fused in sarcoma, an RNA-binding protein linked to frontotemporal lobar degeneration and amyotrophic lateral sclerosis, and its potential pathological role in frontotemporal lobar degeneration using pyramidal neuron-specific conditional knockout mice (FuscKO). We found that FUS regulates the expression of many genes associated with synaptic function in a hippocampal subregion-specific manner, concomitant with the frontotemporal lobar degeneration-linked behavioural disinhibition. Electrophysiological study and molecular pathway analyses further reveal that fused in sarcoma differentially regulates synaptic and neuronal properties in the ventral hippocampus and medial prefrontal cortex, respectively. Moreover, fused in sarcoma selectively modulates the ventral hippocampus-prefrontal cortex projection, which is known to mediate the anxiety-like behaviour. Our findings unveil the brain region- and synapse-specific role of fused in sarcoma, whose impairment might lead to the emotional symptoms associated with frontotemporal lobar degeneration.

Influencing factors of futile recanalization after endovascular intervention in patients with acute basilar artery occlusion. / æ€¥æ€§åŸºåº•åŠ¨è„‰é—­å¡žæ‚£è€ è¡€ç®¡å† æ²»ç–—åŽå‘ç”Ÿæ— æ•ˆå†é€šçš„å½±å“å› ç´ .

OBJECTIVES: To explore the influence factors for futile recanalization following endovascular treatment (EVT) in patients with acute basilar artery occlusion (BAO). METHODS: Clinical data of patients with acute BAO, who underwent endovascular treatment within 24 h of onset from January 2017 to November 2022, were retrospectively analyzed. The futile recanalization was defined as modified thrombolysis in cerebral infarction (mTICI) grade ≥2b or 3 after successful reperfusion, but the modified Rankin Scale score >2 at 3 months after EVT. Binary logistic regression model was used to analyze the influencing factors of futile recanalization. RESULTS: A total of 471 patients with a median age of 68 (57, 74) years were included and 68.9% were males, among whom 298 (63.27%) experienced futile recanalization. Multivariate analysis revealed that concomitant atrial fibrillation (OR=0.456, 95%CI: 0.282-0.737, P<0.01), bridging thrombolysis (OR=0.640, 95%CI: 0.416-0.985, P<0.05), achieving mTICI grade 3 (OR=0.554, 95%CI: 0.334-0.918, P<0.05), arterial occlusive lesion (AOL) grade 3 (OR=0.521, 95%CI: 0.326-0.834, P<0.01), and early postoperative statin therapy (OR=0.509, 95%CI: 0.273-0.948, P<0.05) were protective factors for futile recanalization after EVT in acute BAO patients. High baseline National Institutes of Health Stroke Scale (NIHSS) score (OR=1.068, 95%CI: 1.049-1.087, P<0.01), coexisting hypertension (OR=1.571, 95%CI: 1.017-2.427, P<0.05), multiple retrieval attempts (OR=1.237, 95%CI: 1.029-1.488, P<0.05) and postoperative hemorrhagic transformation (OR=8.497, 95%CI: 2.879-25.076, P<0.01) were risk factors. For trial of ORG 10172 in acute stroke treatment (TOAST) classification, cardiogenic embolism (OR=0.321, 95%CI: 0.193-0.534, P<0.01) and other types (OR=0.499, 95%CI: 0.260-0.961, P<0.05) were related to lower incidence of futile recanalization. CONCLUSIONS: The incidence of futile recanalization after EVT in patients with acute BAO is high. Bridging venous thrombolysis before operation and an early postoperative statin therapy may reduce the incidence of futile recanalization.

Association between baseline hemoglobin level and early neurological deterioration after intravenous thrombolysis in patients with acute ischemic stroke. / åŸºçº¿è¡€çº¢è›‹ç™½æ°´å¹³å¯¹æ€¥æ€§ç¼ºè¡€æ€§è„‘å’ä¸­æ‚£è€ é™è„‰æº¶æ “åŽæ—©æœŸç¥žç»åŠŸèƒ½æ¶åŒ–çš„å½±å“.

OBJECTIVES: To investigate the association between baseline hemoglobin level and early neurologic deterioration (END) after intravenous thrombolysis in patients with acute ischemic stroke (AIS). METHODS: Data of AIS patients who received intravenous thrombolytic therapy at multiple hospitals across the country between January 2017 and July 2020 were collected from the online database Acute Stroke Patients for Stroke Management Quality Evaluation (CASE-Ⅱ, NCT04487340). Binary logistic regression analysis was used to study the factors affecting the occurrence of END after intravenous thrombolytic therapy, and the correlation between baseline hemoglobin level and END was investigated by limiting cubic spline curve analysis. RESULTS: A total of 8162 patients were included. Patients with END had lower baseline hemoglobin levels (136 and 140 g/L, P<0.01) and higher rates of anemia (24.2% and 16.9%, P<0.01) compared with non-END patients. Binary logistic regression analysis showed that baseline hemoglobin level (OR=0.995, 95%CI: 0.991-0.999, P<0.05) and anemia (OR=1.238, 95%CI: 1.055-1.454, P<0.01) were independently correlated with the occurrence of END after intravenous thrombolysis in AIS patients. Restricted cubic spline regression showed that there was a U-shaped relationship between hemoglobin level and the risk of END after intravenous thrombolysis in AIS patients (P<0.01), although this relationship was only significant in male patients (P<0.05) and not in female patients (P>0.05). CONCLUSIONS: There is a correlation between baseline hemoglobin level and the risk of END in AIS patients after intravenous thrombolysis, especially in male patients, in whom both lower and higher hemoglobin level may increase the risk of END.

Effect of anesthesia mode during endovascular treatment on neurological functional outcomes in patients with acute posterior circulation stroke. / éº»é†‰æ–¹å¼å¯¹æ€¥æ€§åŽå¾ªçŽ¯è„‘å’ä¸­è¡€ç®¡å† æ²»ç–—æ‚£è€ ç¥žç»åŠŸèƒ½ç»“å±€çš„å½±å“.

OBJECTIVES: To compare the effect of anesthesia mode on the neurological functional outcomes in patients undergoing endovascular treatment for acute posterior circulation ischemic stroke. METHODS: Clinical data of 656 patients undergoing intravascular therapy for acute posterior circulation ischemic stroke registered in online Acute Stroke Patients for Stroke Management Quality Evaluation Database from January 2017 to December 2022 were retrospectively analyzed. The data included 163 cases with conscious sedation and 493 cases with general anesthesia during the procedure. After propensity score matching, 428 patients were included in the analysis, including 155 cases in the conscious sedation group and 273 cases in the general anesthesia group. The differences of operation mode, etiology type, vascular recanalization, hemorrhagic transformation at 24 h, modified Rankin Scale (mRS) score at 3 months and mortality within 3 months were compared between the two groups. Binary logistic regression was used to explore the effect of different anesthesia mode on neurological functional outcomes. RESULTS: There was a significant difference in operation mode between the two groups (P<0.01), while there were no significant differences in etiology type, vascular recanalization, hemorrhagic transformation at 24 h, mRS score at 3 months or mortality within 3 months (all P>0.05). Binary logistic regression analysis revealed that anesthesia modes were not significantly associated with functional outcomes of patients (OR=1.151, 95%CI: 0.751-1.765, P>0.05). CONCLUSIONS: Anesthesia mode (conscious sedation or general anesthesia) will not affect the neurological functional outcomes in patients with acute posterior circulation ischemic stroke undergoing endovascular treatment.

Safety of early antiplatelet therapy for non-cardioembolic mild stroke patients with thrombocytopenia. / åˆå¹¶è¡€å°æ¿å‡å°‘ç—‡çš„éžå¿ƒæºæ€§è½»åž‹è„‘å’ä¸­æ‚£è€ æ—©æœŸæŠ—è¡€å°æ¿æ²»ç–—çš„å®‰å ¨æ€§ç ”ç©¶.

OBJECTIVES: To investigate the safety of early antiplatelet therapy for non-cardioembolic mild stroke patients with thrombocytopenia. METHODS: Data of acute ischemic stroke patients with baseline National Institutes of Health Stroke Scale (NIHSS) score ≤3 and a platelet count <100×109/L were obtained from a multicenter register. Those who required anticoagulation or had other contraindications to antiplatelet therapy were excluded. Short-term safety outcomes were in-hospital bleeding events, while the long-term safety outcome was a 1-year all-cause death. The short-term neurological outcomes were evaluated by modified Rankin scale (mRS) score at discharge. RESULTS: A total of 1868 non-cardioembolic mild stroke patients with thrombocytopenia were enrolled. Multivariate regression analyses showed that mono-antiplatelet therapy significantly increased the proportion of mRS score of 0-1 at discharge (OR=1.657, 95%CI: 1.253-2.192, P<0.01) and did not increase the risk of intracranial hemorrhage (OR=2.359, 95%CI: 0.301-18.503, P>0.05), compared with those without antiplatelet therapy. However, dual-antiplatelet therapy did not bring more neurological benefits (OR=0.923, 95%CI: 0.690-1.234, P>0.05), but increased the risk of gastrointestinal bleeding (OR=2.837, 95%CI: 1.311-6.136, P<0.01) compared with those with mono-antiplatelet therapy. For patients with platelet counts ≤75×109/L and >90×109/L, antiplatelet therapy significantly improved neurological functional outcomes (both P<0.05). For those with platelet counts (>75-90)×109/L, antiplatelet therapy resulted in a significant improvement of 1-year survival (P<0.05). For patients even with concurrent coagulation abnormalities, mono-antiplatelet therapy did not increase the risk of various types of bleeding (all P>0.05) but improved neurological functional outcomes (all P<0.01). There was no significant difference in the occurrence of bleeding events, 1-year all-cause mortality risk, and neurological functional outcomes between aspirin and clopidogrel (all P>0.05). CONCLUSIONS: For non-cardioembolic mild stroke patients with thrombocytopenia, antiplatelet therapy remains a reasonable choice. Mono-antiplatelet therapy has the same efficiency as dual-antiplatelet therapy in neurological outcome improvement with lower risk of gastrointestinal bleeding.

Reperfusion Injury Is Associated With Poor Outcome in Patients With Recanalization After Thrombectomy.

BACKGROUND: The existence of cerebral reperfusion injury in human beings remains controversial. Thus, we aimed to explore the presence of reperfusion injury in acute ischemic stroke patients with recanalization after mechanical thrombectomy and analyzed its impact on neurological outcome. METHODS: We reviewed our prospectively collected database CIPPIS (Comparison Influence to Prognosis of CTP and MRP in AIS Patients, NCT03367286), and enrolled anterior circulation large artery occlusion patients with recanalization after mechanical thrombectomy who underwent (1) computed tomography (CT) perfusion on admission and immediately after recanalization to determine reperfusion region, and (2) CT and/or magnetic resonance imaging (MRI) immediately and 24 hours after recanalization to determine lesion areas. The expansion of lesion between recanalization and 24 hours within reperfusion region was potentially caused by reperfusion, thus termed as radiological observed reperfusion injury (RORI). Based on the imaging modality immediately after recanalization, RORI was further divided into RORICT and RORIMRI. We first included a small cohort who had performed both CT and MRI immediately after recanalization to validate the consistency between RORICT and RORIMRI (Study 1). Then the association with RORICT and poor outcome, defined as 3-month modified Rankin Scale score of 3 to 6, was explored in a larger cohort (Study 2). RESULTS: Study 1 included 23 patients and good consistency was found between RORICT and RORIMRI (intraclass correlation=0.97, P<0.001). Among 226 patients included in Study 2, a total of 106 (46.9%) were identified with RORI. The ratio of RORI to reperfusion region was 30.1 (16.2, 51.0)% and was independently associated with poor outcome (odds ratio=1.55 per 10% [95% CI' 1.30-1.84]; P<0.001). CONCLUSIONS: Our findings suggested that RORI was relatively frequent in stroke patients with recanalization after mechanical thrombectomy and associated with poor outcome despite successful recanalization. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03367286.

Endovascular Thrombectomy with or without Intravenous Alteplase in Acute Stroke.

BACKGROUND: In acute ischemic stroke, there is uncertainty regarding the benefit and risk of administering intravenous alteplase before endovascular thrombectomy. METHODS: We conducted a trial at 41 academic tertiary care centers in China to evaluate endovascular thrombectomy with or without intravenous alteplase in patients with acute ischemic stroke. Patients with acute ischemic stroke from large-vessel occlusion in the anterior circulation were randomly assigned in a 1:1 ratio to undergo endovascular thrombectomy alone (thrombectomy-alone group) or endovascular thrombectomy preceded by intravenous alteplase, at a dose of 0.9 mg per kilogram of body weight, administered within 4.5 hours after symptom onset (combination-therapy group). The primary analysis for noninferiority assessed the between-group difference in the distribution of the modified Rankin scale scores (range, 0 [no symptoms] to 6 [death]) at 90 days on the basis of a lower boundary of the 95% confidence interval of the adjusted common odds ratio equal to or larger than 0.8. We assessed various secondary outcomes, including death and reperfusion of the ischemic area. RESULTS: Of 1586 patients screened, 656 were enrolled, with 327 patients assigned to the thrombectomy-alone group and 329 assigned to the combination-therapy group. Endovascular thrombectomy alone was noninferior to combined intravenous alteplase and endovascular thrombectomy with regard to the primary outcome (adjusted common odds ratio, 1.07; 95% confidence interval, 0.81 to 1.40; P = 0.04 for noninferiority) but was associated with lower percentages of patients with successful reperfusion before thrombectomy (2.4% vs. 7.0%) and overall successful reperfusion (79.4% vs. 84.5%). Mortality at 90 days was 17.7% in the thrombectomy-alone group and 18.8% in the combination-therapy group. CONCLUSIONS: In Chinese patients with acute ischemic stroke from large-vessel occlusion, endovascular thrombectomy alone was noninferior with regard to functional outcome, within a 20% margin of confidence, to endovascular thrombectomy preceded by intravenous alteplase administered within 4.5 hours after symptom onset. (Funded by the Stroke Prevention Project of the National Health Commission of the People's Republic of China and the Wu Jieping Medical Foundation; DIRECT-MT ClinicalTrials.gov number, NCT03469206.).

Effect of Imaging Markers on Reperfusion Therapy in Basilar Artery Occlusion.

OBJECTIVE: We aimed to investigate the effectiveness of endovascular therapy (EVT) versus intravenous thrombolysis (IVT) in patients with basilar artery occlusion (BAO), based on the information of advanced imaging. METHODS: We analyzed data of stroke patients with radiologically confirmed BAO within 24 hours. BAO subjects were categorized into "top-of-the-basilar" syndrome (TOBS) and other types. An initial infarct size of <70ml and a ratio of ischemic tissue to infarct volume of ≥1.8 was defined as "target mismatch." The primary outcome was a good outcome, defined as a modified Rankin Scale score of 0 to 3 at 3 months. Propensity score adjustment and inverse probability of treatment weighting (IPTW) propensity score methods were used. RESULTS: Among 474 BAO patients, 93 (19.6%) were treated with IVT prior to EVT, 91 (19.2%) were treated with IVT alone, 95 (20.0%) were treated with EVT alone, and 195 (41.1%) were treated with antithrombotic therapy. In IPTW analyses, we found no benefit of EVT over IVT for good outcome in either TOBS patients (odds ratio = 1.08, 95% confidence interval [CI] = 0.88-1.31) or those with other types (odds ratio = 1.13, 95% CI = 0.94-1.36). However, in patients with other types, if there existed a target mismatch, EVT was independently related to good outcome (odds ratio = 1.46, 95% CI = 1.17-1.81). INTERPRETATION: The "target mismatch profile" seems to be a possible candidate selection standard of EVT for those with other types of BAO. Future studies should separate TOBS from other types of BAO, and try to use advanced imaging. ANN NEUROL 2022;92:97-106.

Predictors of malignant middle cerebral artery infarction after endovascular thrombectomy: results of DIRECT-MT trial.

OBJECTIVES: Predictors of malignant middle cerebral artery infarction (mMCAi) in patients after intravenous thrombolysis were well documented, but the risk factors of mMCAi after endovascular thrombectomy (EVT) were not fully explored. Therefore, the present study aimed to investigate the predictors of mMCAi after EVT in stroke patients. METHODS: This was a secondary analysis of the DIRECT-MT trial. Patients who underwent EVT for the occlusions of MCA and/or intracranial internal carotid artery were analyzed. Primary outcome was the occurrence of mMCAi after EVT. Demographic, clinical, imaging, and treatment data were recorded, and multivariate logistic regression analysis was used to identify independent predictors. All of the candidate predictors were included, and forward elimination was applied to establish the most effective predictive model. Predictive ability and calibration of the model were assessed using the area under the receiver operating characteristic curve (AUC) and Hosmer-Lemeshow test, respectively. RESULTS: Of 559 enrolled patients, 74 (13.2%) patients developed mMCAi. Predictors of mMCAi included unsuccessful reperfusion, higher serum glucose, lower Alberta Stroke Project Early Computed Tomography Change Score (ASPECTS), higher clot burden score (CBS), lower collateral score, and higher pass number of thrombectomy device. AUC of predictive model integrating all independent variables was 0.836. The Hosmer-Lemeshow test showed appropriate calibration (p = 0.859). CONCLUSIONS: Reperfusion, serum glucose, ASPECTS, CBS, collateral, and pass number of thrombectomy device were associated with the occurrence of mMCAi in stroke patients after EVT, while alteplase treatment was not. Our findings might facilitate the early identification and management of stroke patients at a high risk of mMCAi. KEY POINTS: • A total of 13.2% of stroke patients with large vessel occlusion of anterior circulation developed mMCAi after EVT. • The occurrence of mMCAi had a definite negative impact on the outcome for stroke patients. • Reperfusion, serum glucose, ASPECTS, CBS, collateral score, and the pass number of thrombectomy device were associated with the occurrence of mMCAi after EVT in stroke patients.

Glymphatic function plays a protective role in ageing-related cognitive decline.

OBJECTIVE: The glymphatic pathway, characterised as a cerebral drainage system, influences cognitive function in neurodegenerative diseases; however, evidence is limited in a normal ageing population. The aim of this study was to investigate the effect of glymphatic function on ageing-related cognitive decline. METHODS: We retrospectively reviewed the Cognitive Impairment, Retinopathy, and Cerebrovascular Lesions in the Elderly (CIRCLE) study, and participants with multi-model magnetic resonance imaging (MRI) scans and Mini-Mental State Examinations (MMSE) were enrolled. Glymphatic function was evaluated via the diffusion tensor imaging along the perivascular space (DTI-ALPS) index. Regression models were used to estimate the impact of the DTI-ALPS index on cognitive decline cross-sectionally and longitudinally. We further analysed the mediation effect of the DTI-ALPS on age and cognitive function. RESULTS: A total of 633 participants were included in this study (48.2% female; mean age, 62.8 ± 8.9 years). The DTI-ALPS index was positively associated with cognitive function cross-sectionally (ß = 0.108, P = 0.003), and was an independent protective factor for cognitive decline longitudinally (odds ratio (OR) = 0.029, P = 0.007). The DTI-ALPS index declined progressively with ageing (r = -0.319, P <0.001), and the decrease was more pronounced after 65 years of age. Furthermore, the DTI-ALPS index mediated the relationship between age and MMSE score (ß = -0.016, P <0.001). The mediation effect accounted for 21.3%, which was higher in subjects aged over 65 years (25.3%) compared with those aged under 65 years (5.3%). CONCLUSION: Glymphatic function played a protective role in normal ageing-related cognitive decline, which may serve as a potential therapeutic target against cognitive decline in future.

Prevalent stroke, age of its onset, and post-stroke lifestyle in relation to dementia: A prospective cohort study.

INTRODUCTION: The association of age at stroke onset with dementia and the role of post-stroke lifestyle on dementia risk remains unclear. METHODS: We leveraged data of 496,251 dementia-free participants from UK Biobank and explored the relationship between age at stroke onset and incident dementia. Among 8328 participants with stroke history, we further investigated the association of a healthy lifestyle with risk of dementia. RESULTS: Participants with stroke history had a higher risk of dementia (hazard ratio [HR], 2.02). The association was stronger among participants with stroke onset at a younger age (≤50: HR, 2.63) compared with those at the age > 50 years (50-60: HR, 2.17; ≥60: HR, 1.58). Among participants with stroke history, a favorable lifestyle was associated with a lower risk of incident dementia. DISCUSSION: Stroke onset in earlier life stage predicted a higher risk for dementia, but a favorable post-stroke lifestyle may protect against dementia.

Clinical and Imaging Indicators of Hemorrhagic Transformation in Acute Ischemic Stroke After Endovascular Thrombectomy.

BACKGROUND: Prior studies have investigated the clinical and imaging factors for hemorrhagic transformation (HT), especially symptomatic intracranial hemorrhage (sICH); however, whether alteplase increases the risk of HT after endovascular thrombectomy (EVT) is unknown. This study aimed to assess clinical and imaging features associated with HT, sICH, and parenchymal hematoma (PH) in patients with acute ischemic stroke after EVT, with and without intravenous alteplase in DIRECT-MT (Direct Intraarterial Thrombectomy to Revascularize Acute Ischemic Stroke Patients with Large Vessel Occlusion Efficiently in Chinese Tertiary Hospitals: a Multicenter Randomized Clinical Trial). METHODS: The DIRECT-MT trial is a randomized trial of EVT alone versus intravenous thrombolysis combined with EVT. HT, sICH, and PH was evaluated on follow-up computed tomography. Multivariable ordinal logistic regression analysis was used to test the association of stepwise selected determinants with HT, sICH, and PH. RESULTS: In total, 633 patients were analyzed; 261 (41.2%) had HT; 34 (5.4%) had sICH; and 85 (13.4%) had PH. The median age was 69, and 56.7% were men. The median National Institutes of Health Stroke Scale score was 18, and 320 patients were in combination-therapy group. Symptomatic intracranial hemorrhage was associated with higher baseline National Institutes of Health Stroke Scale score (adjusted odds ratio [OR], 1.06 [95% CI, 1.10-1.12]) and higher glucose level at hospital arrival (adjusted OR, 1.14 [95% CI, 1.00-1.29]). No association was found between alteplase treatment and HT, sICH, or PH. The independent predictor of sICH was higher baseline National Institutes of Health Stroke Scale score (adjusted OR, 1.09 [95% CI, 1.01-1.18]) in EVT alone group, and history of anticoagulant drugs (adjusted OR, 3.75 [95% CI, 1.07-13.06]), higher glucose level at hospital arrival (adjusted OR, 1.19 [95% CI, 1.03-1.38]), >3 passes of device (adjusted OR, 4.42 [95% CI, 1.36-14.32]) in combination-therapy group. CONCLUSIONS: In DIRECT-MT, independent predictors of sICH were baseline National Institutes of Health Stroke Scale score and glucose level at hospital arrival. Alteplase treatment did not increase the risk of HT, sICH, or PH after EVT. The independent predictor of sICH was different in EVT alone group and combination-therapy group. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03469206.

Evaluation of a multicomponent intervention to shorten thrombolytic door-to-needle time in stroke patients in China (MISSION): A cluster-randomized controlled trial.

BACKGROUND: Rapid intravenous thrombolysis (IVT) for acute ischemic stroke (AIS) is crucial for improving outcomes. However, few randomized trials of interventions aimed at reducing in-hospital delay have been carried out in China. We aimed to evaluate the effect of a multicomponent intervention on thrombolytic door-to-needle time (DNT) of AIS patients via video teleconference based on the Behavior Change Wheel (BCW) method. METHODS AND FINDINGS: This cluster-randomized trial, conducted between January 1, 2019 and December 31, 2019, randomly allocated 22 hospitals equally to PEITEM (Persuasion Environment reconstruction Incentivization Training Education Modeling) intervention or routine care plus stroke registry and subsequently enrolled 1,634 AIS patients receiving IVT within 4.5 hours upon stroke onset from participant hospitals. The PEITEM group received a 1-year PEITEM 6-component intervention based on the behavioral theory monthly via video teleconference. The primary outcome was the proportion of patients with a DNT of 60 minutes or less. A total of 987 patients participated in the PEITEM group (mean age, 69 years; female, 411 [41.6%]) and 647 patients in the control group (mean age, 70 years; female, 238 [36.8%]). Of all participants, the proportion of DNT ≤60 minutes in the PEITEM group was higher than in the control group (82.0% versus 73.3%; adjusted odds ratio, 1.77; 95% confidence interval (CI), 1.17 to 2.70; ICC, 0.04; P = 0.007). Among secondary outcomes, the average DNT was 43 minutes in the PEITEM group and 50 minutes in the control group (adjusted mean difference: -8.83; 95% CI, -14.03 to -3.64; ICC, 0.12; P = 0.001). Favorable functional outcome (score of 0 to 1 on the modified Rankin scale (mRS)) was achieved in 55.6% patients of the PEITEM group and 50.4% of the control group (adjusted odds ratio, 1.38; 95% CI, 1.00 to 1.90; ICC, 0.01; P = 0.049). Main study limitations include non-blinding of clinicians, and that specific interventions component responsible for the observed changes could not be determined. CONCLUSIONS: The teleconference-delivered PEITEM intervention resulted in a moderate but clinically relevant shorter DNT and better functional outcome in AIS patients receiving IVT. TRIAL REGISTRATION: Clinicaltrials.gov NCT03317639.

Superficial white matter microstructure affects processing speed in cerebral small vessel disease.

White matter hyperintensities (WMH) are a typical feature of cerebral small vessel disease (CSVD), which contributes to about 50% of dementias worldwide. Microstructural alterations in deep white matter (DWM) have been widely examined in CSVD. However, little is known about abnormalities in superficial white matter (SWM) and their relevance for processing speed, the main cognitive deficit in CSVD. In 141 CSVD patients, processing speed was assessed using Trail Making Test Part A. White matter abnormalities were assessed by WMH burden (volume on T2-FLAIR) and diffusion MRI measures. SWM imaging measures had a large contribution to processing speed, despite a relatively low SWM WMH burden. Across all imaging measures, SWM free water (FW) had the strongest association with processing speed, followed by SWM mean diffusivity (MD). SWM FW was the only marker to significantly increase between two subgroups with the lowest WMH burdens. When comparing two subgroups with the highest WMH burdens, the involvement of WMH in the SWM was accompanied by significant differences in processing speed and white matter microstructure. Mediation analysis revealed that SWM FW fully mediated the association between WMH volume and processing speed, while no mediation effect of MD or DWM FW was observed. Overall, results suggest that the SWM has an important contribution to processing speed, while SWM FW is a sensitive imaging marker associated with cognition in CSVD. This study extends the current understanding of CSVD-related dysfunction and suggests that the SWM, as an understudied region, can be a potential target for monitoring pathophysiological processes.

Stroke outcome of early antiplatelet in post-thrombolysis haemorrhagic infarction.

BACKGROUND AND PURPOSE: Initiation of early antiplatelet (EA) therapy after acute ischaemic stroke (AIS) is essential. We aimed to investigate the safety and effectiveness of EA therapy in patients who had an AIS with haemorrhagic infarction (HI) after intravenous thrombolysis (IVT). METHODS: Based on a multicentre stroke registry database, patients who had an AIS with post-thrombolysis HI at 24 hours were identified. EA users and non-EA users were defined as patients with HI who received or did not receive antiplatelet therapy between 24 and 48 hours after IVT. Primary outcome was favourable outcome defined as modified Rankin Scale scores 0-2 at 3 months. Secondary outcomes were early neurological deterioration (END) and haemorrhagic transformation expansion. RESULTS: A total of 842 patients with HI were identified from 24 061 thrombolytic patients within 4.5 hours, and 341 (40.5%) received EA therapy. EA users were more likely to have a favourable outcome (55.7% vs 39.5%, OR 1.565; 95% CI 1.122 to 2.182; p=0.008) and lower rate of END (12.6% vs 21.4%, OR 0.585; 95% CI 0.391 to 0.875; p=0.009) compared with non-EA users. EA therapy was not associated with haemorrhagic transformation expansion (p=0.125). After propensity score matching, EA therapy was still independently associated with favourable outcome (54.3% vs 46.3%, OR 1.495; 95% CI 1.031 to 2.167; p=0.038) and lower risk of END (13.5% vs 21.2%, OR 0.544; 95% CI 0.350 to 0.845; p=0.007). CONCLUSIONS: Antiplatelet therapy can be safely used between 24 and 48 hours when HI occurs after IVT, and such therapy is associated with reduced risk of END and improved neurological outcome in patients who had an AIS.

Effect of baseline infarct size on endovascular thrombectomy with or without intravenous alteplase in stroke patients: A subgroup analysis of a randomized trial (DIRECT-MT).

BACKGROUND AND PURPOSE: DIRECT-MT showed that endovascular thrombectomy was noninferior to thrombectomy preceded by intravenous alteplase with regard to functional outcome in patients with acute ischemic stroke. In this post hoc analysis, we examined whether infarct size modified the effect of alteplase. METHODS: All patients with baseline Alberta Stroke Program Early Computed Tomography Score (ASPECTS) grades were included. The primary outcome was the 90-day modified Rankin Scale (mRS) score. Multivariate ordinal logistic regression analysis was used to calculate the adjusted common odds ratio (OR) for better functional outcome based on the mRS for thrombectomy alone versus combination therapy. An interaction term was entered to test for an interaction with baseline ASPECTS subgroups: 0-4 versus 5-7 versus 8-10. RESULTS: Of 649 patients, 323 (49.8%) were in the thrombectomy-alone group and 326 (50.2%) in the combination-therapy group. There was no significant treatment-by-trichotomized ASPECTS interaction with alteplase prior to endovascular treatment for the primary endpoint of ordinal mRS (p-value interaction term relative to ASPECTS 8-10: ASPECTS 0-4, p = 0.386; ASPECTS 5-7, p = 0.936). Adjusted common ORs for improvement in the 90-day mRS with thrombectomy alone compared with combination therapy were 1.99 (95% confidence interval = 0.72-5.46) for ASPECTS 0-4, 1.07 (0.62-1.86) for ASPECTS 5-7, and 1.03 (0.74-1.45) for ASPECTS 8-10. There was no significant difference in the safety outcomes between the two groups. CONCLUSIONS: Baseline infarct size may not modify the effect of alteplase prior to endovascular thrombectomy with regard to favorable functional outcomes and adverse events.

Pyrroloquinoline quinone ameliorates diabetic cardiomyopathy by inhibiting the pyroptosis signaling pathway in C57BL/6 mice and AC16 cells.

PURPOSE: Diabetic cardiomyopathy (DCM), a common complication of diabetes mellitus and is characterized by myocardial hypertrophy and myocardial fibrosis. Pyrroloquinoline quinone (PQQ), a natural nutrient, exerts strong protection against various myocardial diseases. Pyroptosis, a type of inflammation-related programmed cell death, is vital to the development of DCM. However, the protective effects of PQQ against DCM and the associated mechanisms are not clear. This study aimed to investigate whether PQQ protected against DCM and to determine the underlying molecular mechanism. METHODS: Diabetes was induced in mice by intraperitoneal injection of streptozotocin, after which the mice were administered PQQ orally (10, 20, or 40 mg/kg body weight/day) for 12 weeks. AC16 human myocardial cells were divided into the following groups and treated accordingly: control (5.5 mmol/L glucose), high glucose (35 mmol/L glucose), and HG + PQQ groups (1 and 10 nmol/L PQQ). Cells were treated for 24 h. RESULTS: PQQ reduced myocardial hypertrophy and the area of myocardial fibrosis, which was accompanied by an increase in antioxidant function and a decrease in inflammatory cytokine levels. Moreover, myocardial hypertrophy-(ANP and BNP), myocardial fibrosis-(collagen I and TGF-ß1), and pyroptosis-related protein levels decreased in the PQQ treatment groups. Furthermore, PQQ abolished mitochondrial dysfunction and the activation of NF-κB/IκB, and decreased NLRP3 inflammation-mediated pyroptosis in AC16 cells under high-glucose conditions. CONCLUSION: PQQ improved DCM in diabetic mice by inhibiting NF-κB/NLRP3 inflammasome-mediated cell pyroptosis. Long-term dietary supplementation with PQQ may be greatly beneficial for the treatment of DCM. Diagram of the underlying mechanism of the effects of PQQ on DCM. PQQ inhibits ROS generation and NF-κB activation, which stimulates activation of the NLRP3 inflammasome and regulates the expression of caspase-1, IL-1ß, and IL-18. The up-regulated inflammatory cytokines trigger myocardial hypertrophy and cardiac fibrosis and promote the pathological process of DCM.