Journal of Investigative Medicine最新文献

Background: The p.R4810K founder mutation in the RNF213 gene confers susceptibility to moyamoya disease (MMD) and non-MMD intracranial artery disease. However, penetrance is incomplete, and the underlying molecular mechanism remains unknown.

Methods and results: Transcriptome analysis of peripheral blood was conducted with nine MMD patients and five unaffected mutation carriers from four familial MMD pedigrees. Bayesian network analysis identified upregulated gene modules associated with lipid metabolism and leucocyte development (including GATA2 and SLC45A3), and epidermal growth factor receptor (EGFR) signalling (UBTD1). It also identified downregulated gene modules related to mitochondrial ribosomal proteins (RPS3A and RPL26), and cytotoxic T cell immunity (GZMA and TRGC1). The GATA2 network was replicated through weighted gene co-expression network analysis and further examined in a case-control study, comprising 43 MMD patients, 16 non-MMD patients, 19 unaffected carriers and 35 healthy controls. GATA2 exhibited a significant linear correlation with SLC45A3 and was significantly higher in MMD patients compared with age-matched and sex-matched unaffected carriers or wild-type controls. Among patients with the p.R4810K mutation, higher GATA2 expression was associated with an earlier age of onset, bilateral involvement and symptomatic disease onset.

Conclusions: Peripheral blood GATA2 expression was associated with increased penetrance of the RNF213 mutation and more severe clinical manifestations in MMD.

Background: Advances in endovascular thrombectomy (EVT) and extended treatment criteria have improved outcomes in acute ischaemic stroke (AIS). However, contrast staining (CS) on postoperative CT complicates clinical decision-making and outcome evaluation. We investigated the association between postoperative CS and 90-day clinical outcomes in AIS patients.

Methods: In this multicentre observational study, we enrolled AIS patients treated with EVT who underwent non-contrast CT (NCCT) within 2 hours postprocedure. Patients were stratified into two groups based on the presence or absence of CS to further explore the relationship between CS characteristics and clinical outcomes. The primary outcome was poor functional outcome, defined as a modified Rankin Scale score ≥3 at 90 days, evaluated with the logistic regression analysis adjusted for age, sex and other clinical features.

Results: Among the 420 patients (mean age 63 years; 74.3% male), CS was observed in 250 (59.5%) following EVT. Logistic regression analysis showed that CS was strongly associated with poor functional outcomes. At 3 months, the proportion of patients with functional dependence was significantly higher in the CS group (76.8%) compared with the non-CS group (62.4%). In addition, the CS group exhibited a higher death rate compared with the non-CS group (p=0.028). Our study found that CS in the pons, as well as larger and denser staining volumes, was often indicative of poor prognosis.

Conclusion: In around half of AIS patients with EVT, CS can be observed and independently associate with poor clinical outcomes, primarily related to the location and density of CS.

Background: Whether mean arterial pressure (MAP) and pulse pressure (PP), two indicators of cerebral perfusion, could guide the selection of anti-hypertensive strategies after acute ischaemic stroke remains uncertain. Our study was to explore the impact of early anti-hypertensive intervention on adverse clinical outcomes following ischaemic stroke stratified by the levels of MAP and PP based on the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS).

Methods: The trial randomised 4071 acute ischaemic stroke patients with elevated systolic blood pressure (SBP) to receive anti-hypertensive treatment (targeting a 10%-25% reduction in SBP during the 24 hours postrandomisation, reaching a BP level <140/90 mm Hg in 7 days, further keeping these levels throughout hospitalisation) or discontinue anti-hypertensive treatment during hospitalisation. The primary outcome was death or major disability at 14 days or hospital discharge. Study outcomes were analysed by comparing the BP-lowering intervention group and control group, stratified by tertiles of MAP or PP levels.

Results: No significant difference was observed in the primary outcome between the intervention and control groups across all MAP (p=0.69 for homogeneity) and PP (p=0.78 for homogeneity) categories. The corresponding odds ratios (95% CIs) were 1.08 (0.85-1.36), 0.92 (0.74-1.15) and 1.00 (0.81-1.25) for participants with low, intermediate, and high MAP and were 0.99 (0.79-1.25), 1.06 (0.84-1.34) and 0.95 (0.77-1.18) for participants in PP subgroups, respectively. Furthermore, early anti-hypertensive intervention was not associated with secondary outcomes (including neurological deterioration, recurrent stroke, vascular events and all-cause mortality) by MAP and PP (all p>0.05).

Conclusions: Early anti-hypertensive therapy neither decreased nor increased the odds of major disability, mortality, recurrent stroke or vascular events in patients with acute ischaemic stroke regardless of different MAP and PP levels.

Trial registration number: ClinicalTrials.gov identifier: NCT01840072.

Background: Mechanical thrombectomy (MT) improves outcomes in patients who had an acute ischaemic stroke due to large vessel occlusion (LVO). However, socioeconomic status (SES) can influence recovery and prognosis. This study investigated the effect of SES, assessed via the Index of Multiple Deprivation (IMD), on MT outcomes in a multicentre London cohort.

Methods: This retrospective study included patients with anterior circulation LVO treated with MT between 2021 and 2023 at three London hospitals. Patients were grouped into IMD_1-5 (more deprived) and IMD_6-10 (less deprived). Inverse probability weighting balanced baseline characteristics. Primary outcomes were 90-day functional independence (modified Rankin Scale (mRS) 0-2) and 90-day mRS shift. Secondary outcomes included recanalisation, early neurological changes, 90-day mortality, symptomatic intracerebral haemorrhage (sICH) and haemorrhagic transformation (HT). Subgroup analyses explored interactions between IMD and demographic or clinical factors. LASSO (Least Absolute Shrinkage and Selection Operator) regression identified predictors of functional independence, while receiver operating characteristic analysis evaluated IMD's predictive value.

Results: Among 1219 patients with acute LVO ischemic stroke treated with MT, 533 (43.7%) were in IMD_1-5 and 686 (56.3%) in IMD_6-10. IMD_1-5 patients had lower odds of functional independence at 90 days (RR 0.79, 95% CI 0.70 to 0.90) and worse mRS shift (OR 1.29, 95% CI 1.06 to 1.58). They also had higher risks of sICH (RR 2.07, 95% CI 1.54 to 2.67) and HT (Risk Ratio 1.47, 95% CI 1.21 to 1.80). Subgroup analysis highlighted IMD's predictive importance in Asian or mixed ethnicity groups. A model incorporating IMD, age, sex, hypertension and National Institutes of Health Stroke Scale (area under the curve 0.656) demonstrated predictive accuracy for 90-day functional independence.

Conclusions: Lower SES correlates with worse outcomes and higher complications post-MT, even within a universal healthcare system. Addressing SES disparities could improve stroke care equity.

Objective: Single-stage surgery combining embolisation and microsurgery has been increasingly used as a stand-alone procedure to cure complex AVMs. This study aimed to investigate the learning curve and embolisation strategy for single-stage surgery for AVMs.

Methods: This prospective cohort study used data from the nationwide Multimodality Treatment for Brain Arteriovenous Malformations (MATCH) registry in China, conducted between August 2011 and December 2023. A total of 213 complex AVMs were divided into two groups. Group 1 included the first 25 patients. The 188 cases in group 2 included patients numbered 26-213. A case-crossover design was employed to evaluate the influence of complications, unfavourable outcomes and worsening modified Rankin Scale (mRS) score. Cumulative summation analysis was performed to assess the learning curve.

Results: The rate of major complications decreased from 52.00% in group 1 to 34.57% in group 2 (p=0.089), while the rate of unfavourable outcomes decreased from 44.00% in group 1 to 18.62% in group 2 (p=0.004). The distribution of the three preoperative embolisation strategies was as follows: curative: 72.00% and 19.15%, palliative: 24.00% and 67.55%, and targeted: 4.00% and 13.30%, respectively (p<0.001). Multivariable regression analysis showed that surgeon experience was associated with a lower rate of unfavourable outcomes (p=0.022, OR=0.333). The mean follow-up duration was 49.90±20.54 months. The follow-up mRS score of 5-6 decreased from 9.09% in group 1 to 0.8% in group 2 (p=0.035).

Conclusions: Performing single-stage combined surgery in 25 AVM cases is necessary to achieve reproducibility. Rates of major complications and unfavourable outcomes decreased significantly after the first 50 procedures. Palliative and targeted embolisation strategies are associated with a lower rate of unfavourable outcomes.

Trial registration number: NCT04572568.

Background: Cerebral ischemia-reperfusion injury (CIRI) leads to cognitive dysfunction, neuronal death, and inflammation. Understanding the molecular mechanisms underlying CIRI is crucial for developing effective therapeutic strategies.

Objective: This study aims to investigate the roles of activating transcription factor 3 (Atf3) and lon protease homolog 1 (Lonp1) in CIRI, particularly focusing on how Atf3 regulates Lonp1 expression and its effects on mitochondrial function.

Methods: Single-cell transcriptomics and proteomic analyses were employed to explore Atf3's influence on Lonp1 and its subsequent impact on neuronal survival and apoptosis.

Results: The findings indicate that Atf3 plays a crucial role in modulating Lonp1 expression, which in turn affects mitochondrial function, neuronal survival, and apoptotic pathways.

Conclusion: This study provides new insights into the regulatory mechanisms of Atf3 and Lonp1 in CIRI, identifying potential therapeutic targets for managing ischemic brain injury and neurodegenerative diseases.

Background: Dual-energy CT (DECT) provides several novel methods to assess thrombus perviousness. We aimed to evaluate whether the novel thrombus perviousness measured with DECT is associated with improved recanalisation and better functional outcomes in acute ischaemic stroke (AIS) patients with endovascular thrombectomy (EVT).

Methods: 108 AIS patients with middle cerebral artery occlusion who underwent DECT angiography on admission and received EVT treatment between April 2020 and September 2023 were retrospectively analysed. Thrombus attenuation increase (TAI) was evaluated on routine CT angiography and non-contrast CT, and DECT quantitative parameters of thrombus, including iodine concentration (IC) and normalised IC (NIC) were measured. Multivariable logistic regression analysis was used to evaluate the association of thrombus characteristics with arterial occlusive lesion scale and 90-day modified Rankin Scale.

Results: NIC was significantly associated with successful recanalisation (OR 1.372 (95% CI 1.194 to 1.625); p<0.001) and good functional outcome (OR 1.252 (95% CI 1.114 to 1.446); p<0.001). NIC yielded higher performance, with area under curve (AUC) of 0.789 and 0.740, in the prediction of recanalisation and functional outcome than TAI (AUCs=0.635 and 0.592). Compared with low-level NIC thrombus, high-level NIC was associated with 11.4 and 15.4 times higher likelihood of successful recanalisation and good functional outcome. Moreover, NIC was a significant indicator to differentiate large artery atherosclerosis from cardioembolism stroke with high specificity and positive predictive value.

Conclusions: Higher DECT-derived NIC is associated with increased odds of successful recanalisation and good functional outcome for EVT patients, and it yielded higher prediction performance than TAI.

Background: We aim to comprehensively assess and compare the predictive performance of haematoma expansion (HE) scores in a homogeneous cohort of acute intracerebral haemorrhage (ICH) patients.

Methods: Existing scores for predicting HE in acute ICH patients were included and categorised by imaging modality: non-contrast CT (NCCT), single-phase CT angiography (sCTA) and multiphase CTA (mCTA). The predictive performance of the scores was evaluated with the c-statistic in a population of consecutive adult patients with acute ICH admitted to a tertiary care centre in Southern Alberta, Canada, between February 2012 and May 2020, investigated with a multimodal imaging protocol (NCCT, sCTA and mCTA). The primary outcome was HE (ICH volume growth ≥6 mL or ≥33%), and the secondary outcome was severe HE (ICH volume growth ≥12.5 mL or ≥66%). The DeLong test compared the best-performing scores from each imaging category.

Results: 16 HE scores were assessed (NCCT=8, sCTA=6 and mCTA=2) in 217 patients with a median age of 70 years (IQR=60-80), and 86 (39.6%) were females. 51 (23.5%) patients experienced HE and 35 (16.1%) had severe HE. The c-statistic for predicting HE ranged from 0.516 to 0.674 for NCCT-based scores, 0.627 to 0.725 for sCTA-based scores and 0.800 to 0.814 for mCTA-based score. The c-statistic for predicting severe HE ranged from 0.505 to 0.666 for NCCT scores, 0.651 to 0.740 for sCTA scores and 0.813 to 0.828 for mCTA scores. A statistically significant difference favouring mCTA over other imaging modalities in predicting both HE and severe HE was observed.

Conclusions: Advanced imaging demonstrated a stepwise improvement in the predictive performance of HE scores. However, no existing score achieved excellent predictive performance (c-statistics ≥0.90) in our cohort, highlighting the need for further refinement.

Background and purpose: Approximately 25% of acute large vessel occlusive (LVO) ischaemic strokes are of unknown thrombotic origin, and there is a need to establish the aetiology to guide subsequent preventative measures. The aim of this study was to quantify thrombus composition in patients with LVO and explore associations between thrombus composition and stroke aetiology.

Methods: Thrombi were extracted from 132 patients with acute ischaemic stroke. Erythrocytes, leucocytes and F+P (fibrin+platelet) proportions were assessed in tissue sections stained with H&E, while CD3⁺ T cells and neutrophil extracellular traps (NETs) were quantified in immunohistochemistry-stained sections. Thrombus components, clinical parameters and interventional variables were compared between different stroke subtypes defined by Trial of ORG 10172 in Acute Stroke Treatment criteria.

Results: F+P composition was significantly higher (p<0.001) and erythrocyte proportions were significantly lower (p<0.001) in cardioembolic thrombi than in large artery atherosclerosis thrombi. The composition of thrombi from undetermined aetiology strokes resembled that from cardioembolic strokes. CD3⁺ T cell and NET proportions were not significantly different between stroke subtypes. CD3⁺ density per unit area was associated with the occlusive site, being significantly higher in the anterior circulation than the posterior circulation (p=0.004). Cardioembolic strokes were more common in the anterior circulation than large artery atherosclerosis strokes (p=0.002). Recanalisation time was significantly longer for large artery atherosclerosis emboli than for cardioembolic emboli (p=0.032).

Conclusion: There is significant heterogeneity in thrombus composition among different stroke subtypes. The quantitative assessment of thrombus composition may be a useful biomarker of stroke aetiology, and strokes of undetermined aetiology may be more likely to have a cardioembolic origin.

Background: Whether intravenous thrombolysis (IVT) should be administered prior to endovascular therapy (EVT) in patients with atherothrombotic stroke-related large vessel occlusion (AT-LVO) remains unclear. This study aimed to assess the efficacy and safety of IVT administered before EVT in this patient population.

Methods: We analysed the data from a multicentre registry of patients who underwent EVT for AT-LVO. Patients were categorised based on presumed mechanism of occlusion: in situ occlusion (intracranial group) or embolism from cervical artery occlusion/stenosis (tandem group). We compared the efficacy and safety of IVT before EVT in patients who received IVT (IVT stratum) and those who did not (non-IVT stratum). The primary outcome was a modified Rankin Scale score of 0-2 at 90 days.

Results: Among the 336 patients in the intracranial group, 99 patients underwent IVT. The rate of favourable functional outcomes did not differ between IVT and non-IVT strata (51.1% vs 47.6%; adjusted ORs (aORs) (95% CI), 1.18 (0.66 to 2.09)); whereas any intracranial haemorrhage (ICH) (10.1% vs 3.8%; aOR, 2.98 (1.01 to 9.26)) and mortality at 90 days (6.4% vs 1.3%; aOR, 4.66 (1.02 to 26.73)) were significantly higher in the IVT stratum. Among the 233 patients in the tandem group, 88 patients underwent IVT, with no significant differences in efficacy or safety outcomes between the strata.

Conclusion: In patients with AT-LVO, IVT before EVT did not improve outcomes and was associated with increased risk of ICH and mortality in those with in situ intracranial occlusion. IVT before EVT may not be recommended in patients with atherosclerotic intracranial occlusions.