Journal of Investigative Medicine最新文献

Background: Minimally invasive surgery (MIS) for spontaneous supratentorial intracerebral haemorrhage (ICH) is controversial but may be beneficial if end-of-treatment (EOT) haematoma volume is reduced to ≤15 mL. We explored whether MRI findings of cerebral small vessel disease (CSVD) modify the effect of MIS on long-term outcomes.

Methods: Prespecified blinded subgroup analysis of 288 subjects with qualified imaging sequences from the phase 3 Minimally Invasive Surgery Plus Alteplase for Intracerebral Haemorrhage Evacuation (MISTIE) trial. We tested for heterogeneity in the effects of MIS and MIS+EOT volume ≤15 mL on the trial's primary outcome of good versus poor function at 1 year by the presence of single CSVD features and CSVD scores using multivariable models.

Results: Of 499 patients enrolled in MISTIE III, 288 patients had MRI, 149 (51.7%) randomised to MIS and 139 (48.3%) to standard medical care (SMC). Median (IQR) ICH volume was 42 (30-53) mL. In the full MRI cohort, there was no statistically significant heterogeneity in the effects of MIS versus SMC on 1-year outcomes by any specific CSVD feature or by CSVD scores (all P_interaction >0.05). In 94 MIS patients with EOT ICH volume ≤15 mL, significant reduction in odds of poor outcome was found with cerebral amyloid angiopathy score <2 (OR, 0.14 (0.05-0.42); P_interaction=0.006), absence of lacunes (OR, 0.37 (0.18-0.80); P_interaction=0.02) and absence of severe white matter hyperintensities (WMHs) (OR, 0.22 (0.08-0.58); P_interaction=0.03).

Conclusions: Following successful haematoma reduction by MIS, we found significantly lower odds of poor functional outcome with lower total burden of CSVD in addition to absence of lacunes and severe WMHs. CSVD features may have utility for prognostication and patient selection in clinical trials of MIS.

Background: Ischaemic stroke triggers neuronal mitophagy, while the involvement of mitophagy receptors in ischaemia/reperfusion (I/R) injury-induced neuronal mitophagy remain not fully elucidated. Here, we aimed to investigate the involvement of mitophagy receptor FUN14 domain-containing 1 (FUNDC1) and its modulation in neuronal mitophagy induced by I/R injury.

Methods: Wild-type and FUNDC1 knockout mice were generated to establish models of neuronal I/R injury, including transient middle cerebral artery occlusion (tMCAO) in vivo and oxygen glucose deprivation/reperfusion in vitro. Stroke outcomes of mice with two genotypes were assessed. Neuronal mitophagy was analysed both in vivo and in vitro. Activities of FUNDC1 and its regulator Src were evaluated. The impact of Src on FUNDC1-mediated mitophagy was assessed through administration of Src antagonist PP1.

Results: To our surprise, FUNDC1 knockout mice subjected to tMCAO showed stroke outcomes comparable to those of their wild-type littermates. Although neuronal mitophagy could be activated by I/R injury, FUNDC1 deletion did not disrupt neuronal mitophagy. Transient activation of FUNDC1, represented by dephosphorylation of Tyr18, was detected in the early stages (within 3 hours) of neuronal I/R injury; however, phosphorylated Tyr18 reappeared and even surpassed baseline levels in later stages (after 6 hours), accompanied by a decrease in FUNDC1-light chain 3 interactions. Spontaneous inactivation of FUNDC1 was associated with Src activation, represented by phosphorylation of Tyr416, which changed in parallel with the level of phosphorylated FUNDC1 (Tyr18) during neuronal I/R injury. Finally, FUNDC1-mediated mitophagy in neurons under I/R conditions can be rescued by pharmacological inhibition of Src.

Conclusions: FUNDC1 is inactivated by Src during the later stage (after 6 hours) of neuronal I/R injury, and rescue of FUNDC1-mediated mitophagy may serve as a potential therapeutic strategy for treating ischaemic stroke.

Background: This is the first real-world study to estimate the direct costs and indirect costs of first-ever ischaemic stroke with 1-year follow-up in China, based on a nationally representative sample.

Methods: Patients were chosen from 20 geographically diverse sites from the nationally representative database China National Stroke Registry-III (CNSR-III). The inclusion criteria were surviving patients who were hospitalised with first-ever ischaemic stroke from February 2017 to February 2018 (the index event); aged 18-80 during the index event; no history of other stroke types. The primary endpoints were direct medical costs, direct non-medical costs, indirect costs and total cost (ie, the sum of all cost components). Patient characteristics and clinical data were extracted from CNSR-III. Stroke-related in-hospital direct medical costs were collected from hospital electronic medical records. The patient survey collected data related to out-of-hospital direct medical costs, direct non-medical costs and indirect costs. The secondary objective was to explore clinical factors associated with cost outcomes through univariate analysis and multiple regression.

Results: The study enrolled 520 patients. The total cost was 57 567.48 CNY, with 26 612.67 CNY direct medical costs, 2 787.56 CNY direct non-medical costs and 28 167.25 CNY indirect costs. Univariate analysis showed that longer lengths of stay during the index event, higher National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale scores were associated with higher costs in all categories. Conversely, EuroQol 5 Dimension utility scores were associated with decreased costs except direct non-medical costs. Multiple regressions showed that higher admission NIHSS scores were independently associated with higher direct medical costs, indirect costs and total cost. Higher 3-month utilities were associated with lower total cost.

Conclusion: This real-world study showed substantial 1-year economic burden following first-ever ischaemic stroke in China, and that indirect costs are a non-negligible driver of costs.

Introduction: Evidence supporting cardiovascular diseases could increase the risk of dementia remains fragmented. A comprehensive study to illuminate the distinctive associations across different dementia types is still lacking. This study is sought to: (1) determine the clinical validity of Framingham General Cardiovascular Risk Score (FGCRS) for dementia assessment and (2) examine the associations between cardiovascular diseases and the risk of dementia.

Methods: A total of 432 079 dementia-free individuals at baseline from UK Biobank were included. Multivariable Cox proportional hazard models were used to investigate the prospective associations for FGCRS and a series of cardiovascular diseases with all-cause dementia (ACD) and its major components, Alzheimer's disease (AD) and vascular dementia (VaD).

Results: During a median follow-up of 110.1 months, 4711 individuals were diagnosed with dementia. FGCRS was associated with increased risks across the dementia spectrum. In stratification analysis, high-risk groups have demonstrated the greatest dementia burdens, particularly to VaD. Over 74 traits, 9 adverse associations, such as chronic ischaemic heart disease (ACD: HR=1.354; AD: HR=1.269; VaD: HR=1.768), atrioventricular block (ACD: HR=1.562; AD: HR=1.556; VaD: HR=2.069), heart failure (ACD: HR=1.639; AD: HR=1.543; VaD: HR=2.141) and hypotension (ACD: HR=2.912; AD: HR=2.361; VaD: HR=3.315) were observed. Several distinctions were also found, with atrial fibrillation, cerebral infarction, and haemorrhage only associated with greater risks of ACD and VaD.

Discussion: By identifying distinctive associations between cardiovascular diseases and dementia, this study has established a comprehensive 'mapping' that may untangle the long-standing discrepancy. FGCRS has demonstrated its predictivity beyond cardiovascular diseases burdens, suggesting potential opportunities for implantation.

Background and purpose: Cortical superficial siderosis (cSS) and cerebral microbleed (CMB) have distinct effects on intracerebral haemorrhage (ICH). We aim to investigate the combined effect of cSS and CMB on outcomes after ICH.

Methods: Based on a single-centre stroke registry database, patients with spontaneous ICH who had CT scan within 48 hours after ictus and MRI subsequently were identified. Eligible patients were divided into four groups (cSS-CMB-, cSS-CMB+, cSS+CMB-, cSS+CMB+) according to cSS and CMB on susceptibility-weighted image of MRI. Primary outcomes were haematoma volume on admission and unfavourable outcome defined as modified Rankin Scale scores ≥3 at 3 months. Secondary outcomes were all-cause death, recurrence of stroke and ICH during follow-up (median follow-up 2.0 years, IQR 1.0-3.0 years).

Results: A total of 673 patients were identified from 1044 patients with spontaneous ICH. 131 (19.5%) had cSS and 468 (69.5%) had CMB. Patients with cSS+CMB+ had the highest rate of poor outcome at 3 months, as well as all-cause death, recurrent stroke and ICH during follow-up. In cSS- patients, CMB was associated with smaller haematoma (β -0.13; 95% CI -0.22 to -0.03; p=0.009), but it still increased risks of recurrent ICH (OR 4.6; 95% CI 1.3 to 15.6; p=0.015) and stroke (OR 2.0; 95% CI 1.0 to 4.0; p=0.049). These effects of CMB became unremarkable in the context of cSS+.

Conclusions: Patients with different combinations of cSS and CMB have distinct patterns of short-term and long-term outcomes. Although CMB is related to restrained haematoma, it does not improve long-term outcomes.

Trial registration number: NCT04803292.

At present, due to the rapid progress of treatment technology in the acute phase of ischaemic stroke, the mortality of patients has been greatly reduced but the number of disabled survivors is increasing, and most of them are elderly patients. Physicians and rehabilitation therapists pay attention to develop all kinds of therapist techniques including physical therapy techniques, robot-assisted technology and artificial intelligence technology, and study the molecular, cellular or synergistic mechanisms of rehabilitation therapies to promote the effect of rehabilitation therapy. Here, we discussed different animal and in vitro models of ischaemic stroke for rehabilitation studies; the compound concept and technology of neurological rehabilitation; all kinds of biological mechanisms of physical therapy; the significance, assessment and efficacy of neurological rehabilitation; the application of brain-computer interface, rehabilitation robotic and non-invasive brain stimulation technology in stroke rehabilitation.

Background: Cerebral aneurysms are life-threatening cerebrovascular disorders. Currently, there are no effective treatments for preventing disease progression. Mendelian randomisation (MR) is widely used to repurify licensed drugs and identify new therapeutic targets. Therefore, this study aims to investigate effective drug targets for preventing the formation and rupture of cerebral aneurysms and analyse their potential mechanisms.

Methods: We performed a comprehensive study integrating two-sample MR analysis, colocalisation analysis and summary data-based Mendelian randomisation (SMR) to assess the causal effects of blood and brain druggable cis-expression quantitative trait loci (cis-eQTLs) on intracranial aneurysm (IA), unruptured intracranial aneurysm (UIA) and subarachnoid haemorrhage of IA rupture (SAH). Druggable genes were obtained from the study by Chris Finan et al, cis-eQTLs from the eQTLGen and PsychENCODE consortia. Results were validated using proteomic and transcriptomic data. Single-gene functional analyses probed potential mechanisms, culminating in the construction of a drug-gene regulation network.

Results: Through the MR analysis, we identified four potential drug targets in the blood, including prolylcarboxypeptidase (PRCP), proteasome 20S subunit alpha 4 (PSMA4), LTBP4 and GPR160 for SAH. Furthermore, two potential drug targets (PSMA4 and SLC22A4) were identified for IA and one potential drug target (KL) for UIA after accounting for multiple testing (P(inverse-variance weighted)<8.28e-6). Strong evidence of colocalisation and SMR analysis confirmed the relevance of PSMA4 and PRCP in outcomes. Elevated PRCP circulating proteins correlated with a lower SAH risk. PRCP gene expression was significantly downregulated in the disease cohort.

Conclusions: This study supports that elevated PRCP gene expression in blood is causally associated with the decreased risk of IA rupture. Conversely, increased PSMA4 expression in the blood is causally related to an increased risk of IA rupture and formation.

Background: Approximately 20% of all transient ischaemic attacks (TIAs) and ischaemic strokes occur within the posterior circulation, with vertebrobasilar stenosis identified as the cause in roughly 25% of the cases. Studies have shown that about a quarter of these patients have atherosclerotic stenosis of at least 50% of the vertebrobasilar artery. Stenosis has been shown to be associated with an increased risk of 90-day recurrent vertebrobasilar stroke, particularly in the first few weeks, which is significantly higher when compared with patients with stenosis of the anterior circulation. Therefore, aggressive treatment is important for the patient's prognosis. Stenting is emerging as a promising therapeutic strategy for persistent ischaemia events that do not respond to the best medical treatment, but it is not without complications. We systematically reviewed the literature on percutaneous transluminal angioplasty and stenting (PTAS) for intracranial vertebrobasilar artery stenosis (IVBS).

Methods: PubMed, Web-of-Science and Scopus were searched upon the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to include prospective/retrospective cohort, randomised/non-randomised clinical trials and case series studies describing PTAS for IVBS. Pooled rates of intervention-related complications and outcomes were analysed with random-effect model meta-analysis using StataMP V.18.0 software.

Results: 31 studies were found eligible which included 1928 cases. 1103 basilar artery stenosis cases were reported in 27 studies 0.65 (95% CI 0.53, 0.76), I²: 99.72%. 648 vertebral cases were reported in 18 studies 0.60 (95% CI 0.49, 0.70), I²: 97.49%. In four studies, the rate of vertebrobasilar stenosis cases calculated as a proportion of the total sample size was 0.10 (95% CI 0.05, 0. 15). Mean stenosis in 21 included studies was found to be 0.83 (95% CI 0.79, 0.88), I²: 0.00%, which shows variation of baseline stenosis between studies was minimal. 51 deaths were recorded in 24 studies. Meta-analysis of mortality showed the overall rate of mortality was 0.03 (95% CI 0.02, 0.05), I²: 44.90%. In 14 studies, symptomatic intracranial haemorrhage events were recorded at an overall rate of 0.01 (95% CI 0.00, 0.02), I²: 0.00%. Generally, a follow-up period of at least 3 months was reported in the included studies. Furthermore, procedural stroke/TIA was evaluated in seven studies, four of which reported no events (0.03 (95% CI 0.00, 0.08), I²: 20.38%). Mean time from initial symptoms to recanalisation was 23.98 (95% CI 18.56, 29.40), I²=98.8%, p=0.00 days.

Conclusion: In certain individuals with medically unresolved, severe, symptomatic and non-acute IVBS, elective vertebrobasilar PTAS appears to be both safe and effective. Various stent designs and angioplasty-assisted techniq

Background: Previous studies have shown contradictory results between early application of antiplatelet therapy and intravenous thrombolysis (IVT) for mild acute ischaemic stroke (AIS), with National Institutes of Health Stroke Scale score 0-5.

Objective: To compare the benefits and risks of antiplatelet therapy and IVT in patients with mild AIS.

Methods: A systematic search of MEDLINE, Embase and Cochrane Library was conducted from database inception until July 2023, without language restriction. Randomised clinical trials (RCTs) or observational studies were selected. The primary outcomes were 90-day functional outcomes, measured by the modified Rankin Scale (mRS) score. The protocol has been registered before data collection.

Results: Two RCTs and four observational studies with relatively low risk of bias that enrolled 3975 patients were analysed (2454 in antiplatelet therapy and 1521 in IVT therapy). There were no significant differences between antiplatelet therapy and IVT in 90-day functional outcomes (mRS 0-1, OR 1.08 (95% CI 0.73 to 1.58); mRS 0-2, OR, 1.04 (95% CI 0.63 to 1.73)), death (OR, 0.64 (95% CI 0.19 to 2.13)) and stroke recurrence (OR, 0.71 (95% CI 0.28 to 1.79)). Antiplatelet therapy was associated with a reduced risk of symptomatic intracranial haemorrhage (sICH) compared with IVT (OR, 0.20 (95% CI 0.06 to 0.69)).

Conclusions: Among patients with mild AIS, compared with IVT, early application of antiplatelet therapy was not significantly associated with improved functional outcomes, reduced death or stroke recurrence, but was significantly associated with a reduced risk of sICH.

Prospero registration number: CRD42023447862.

Background: The impact of lowering systolic blood pressure (SBP) following endovascular treatment (EVT) in acute large vessel occlusion stroke (LVOS) patients remains unclear. We aimed to explore the effect of the magnitude of SBP reduction (SBPr) after EVT on outcomes in LVOS patients.

Methods: We consecutively registered patients at three comprehensive stroke centres who had experienced EVT as a result of acute anterior circulation LVOS. SBPr was calculated as follows: (baseline SBP-mean SBP/baseline SBP)×100%. The 90-day modified Rankin Scale score ranging from 0 to 2 was defined as a favourable functional outcome. Based on CT scans obtained within 24 hours after procedure, symptomatic intracranial haemorrhage (sICH) was assessed according to the criteria of the European Cooperative Acute Stroke Study III.

Results: We enrolled 1080 patients, of which 908 (84.1%) had successful recanalisation. In the overall cohort, SBPr was correlated with lower odds of sICH (SBPr±10% as a reference, 20%-30%: OR 0.460; 95% CI: 0.245 to 0.864; p=0.016; >30%: OR 0.304; 95% CI 0.123 to 0.749; p=0.010). In patients who achieved successful reperfusion, SBPr>30% was correlated with higher odds of a poor outcome (SBPr±10% as a reference, OR 2.150; 95% CI 1.268 to 3.645; p=0.004) and SBPr has a similar tendency towards reducing the incidence of sICH. In the subgroup analyses, baseline Alberta Stroke Programme Early CT (ASPECT) score (p_interact=0.024) modified the effect of SBPr on the 90-day outcome.

Conclusion: Among patients with EVT, a significant drop in SBP may be related to a poor functional outcome and a reduced incidence of sICH. Baseline ASPECT score may be an important interacting factor in the association of SBPr with the 90-day outcome. This study provides new insights for individualised BP management in patients with EVT.