Journal of Investigative Medicine最新文献

Over the past three decades, thrombolytic therapy for acute ischaemic stroke has evolved dramatically since the landmark National Institute of Neurological Disorders and Stroke (NINDS) trial in 1995, which formally established recombinant tissue plasminogen activator as an effective treatment for stroke. This evolution has occurred along three key dimensions: (1) an expanding repertoire of thrombolytic agents, (2) a progressive broadening of the therapeutic window and (3) organisational and technological innovations aimed at minimizing prehospital and in-hospital treatment delays.In this review, we summarise the major milestones in the clinical evidence supporting thrombolytic therapy over the past 30 years, with particular emphasis on large phase III randomised clinical trials. Our goal is to delineate the trajectory of progress in stroke thrombolysis and to provide clinicians and researchers with a clear and coherent framework for understanding the field's past achievements and future directions.

Background: The heterogeneity of cerebral small vessel disease (CSVD) within community populations remains underexplored. In this study, we aimed to establish an imaging biomarker-based research paradigm to investigate CSVD heterogeneity and assess differences in progression risk among population subgroups.

Methods: This study is a population-based prospective cohort that included participants aged 50-75 years from the Polyvascular Evaluation for Cognitive Impairment and Vascular Events study. Participants underwent two follow-up evaluations, with continuous monitoring for incident vascular events and mortality. Imaging markers, including white matter hyperintensities (WMH), lacunes, enlarged perivascular spaces (EPVS) and cerebral microbleeds (CMB) were rated on cranial MRI. Automated pipelines quantified WMH volume, and cognitive function was assessed using the Montreal Cognitive Assessment. K-means clustering identified subgroups with distinct CSVD imaging features. Mixed linear regression models predicted imaging progression and cognitive decline. Internal and external validation were performed using cross-validation and outcome-based Cox proportional hazards models, respectively.

Results: Among 2332 participants, four distinct CSVD subgroups were identified. Subgroup 1 exhibited a globally high imaging burden, the greatest vascular risk factor load, and was classified as a high-risk, rapidly progressing arteriolosclerosis subtype. Subgroup 2 demonstrated a high lacune/CMB burden, moderate EPVS severity, low WMH load, few risk factors and elevated high high-density lipoprotein cholesterol levels, representing a protected, slowly progressing subtype. Subgroup 3 showed low lacune/CMB counts, moderate WMH and EPVS burden, multiple risk factors and prevalent renal impairment, forming a high-risk, rapidly progressing renal impairment subtype. Subgroup 4 presented moderate WMH burden, high lacune/CMB counts, low EPVS severity, the lowest risk profile and was identified as a global low-risk, slowly progressing subtype.

Conclusions: Cluster analysis effectively delineated heterogeneous CSVD subgroups in a community population, each exhibiting distinct progression risks. Imaging-based heterogeneity profiling may support population risk stratification and guide targeted intervention strategies.

Background: Improving the efficacy of neuroregulatory treatments for disorders of consciousness (DOCs) remains a significant challenge. Changes in brain spatiotemporal dynamics reveal the underlying mechanisms of brain networks involved in the DOC. This study explored the spatiotemporal dynamics of electroencephalography source-level microstates associated with deep brain stimulation (DBS) neuromodulation in DOC patients under different stimulation frequencies.

Methods: This study included nine patients with chronic DOC. During the DBS stimulation period, different stimulation parameter combinations were applied (stimulation frequencies of 25 Hz, 50 Hz or 100 Hz, with a stimulation voltage of 3.0 V and a pulse width of 120 μs). Changes in source-level microstate indicators were assessed to explore the spatiotemporal dynamics and underlying mechanisms of brain activity under different frequency modulations.

Results: Microstate analysis revealed seven optimal microstate types. The mean duration of microstates in the 100 Hz stimulation group was significantly longer than in the 25 Hz and 50 Hz groups, with the left sensorimotor and right temporal regions showing the most pronounced differences. The microstate syntax matrix showed that, compared with baseline, microstate transitions in the 100 Hz stimulation group occurred across a larger number of cortical areas. Additionally, compared with the 25 Hz and 50 Hz groups, microstate transitions were particularly prominent in the left sensorimotor state and right dorsal state transitioning to the right temporal state.

Conclusions: High-frequency brain stimulation elicits a pronounced transition in spatiotemporal dynamics of microstates and induces global brain dynamic alterations centred on right temporal nodes, underscoring the pivotal role of the default mode network in consciousness circuits during the DBS.

Trial registration number: ChiCTR2400085855.

Background: Remote ischaemic conditioning (RIC) is an endogenous neuroprotective strategy involving repeated, transient occlusion of a limb artery to reduce ischaemic injury at a distant site. We investigated the effects of RIC in a mouse model of focal cerebral ischaemia induced by distal transient middle cerebral artery occlusion (tMCAO). Animals were randomised into three groups: Stroke (tMCAO, 60 min), Stroke+remote ischaemic preconditioning (RIPerC) (RIC applied during ischaemia) and Stroke+remote ischaemic postconditioning (RIPostC) (RIC initiated 10 min after reperfusion). The RIC protocol consisted of three cycles of 5-minute hindlimb ischaemia followed by 5-minute reperfusion.

Results: At 72 hours postischaemia, both RIPerC and RIPostC significantly reduced the infarct volumes in male and female mice. In males, infarct size decreased from 6.31 ± 0.28% (Stroke) to 3.77 ± 0.47% (RIPerC, p<0.0025) and 4.00 ± 0.40% (RIPostC, p<0.0061). However, the RIPerC+RIPostC group significantly increased the infarct volume compared with the Stroke group (8.41± 0.72%). In females, reductions were greater: from 6.69±0.46% (Stroke) to 2.95 ± 0.34% (RIPerC, p<0.0001) and 2.96 ± 0.32% (RIPostC, p<0.0001). Functional recovery was improved, particularly with RIPostC, correlating with infarct size reduction (Pearson's r=0.5505 in males, r=0.7313 in females). Apoptosis was reduced by over 50% with both treatments, and microglial phagocytic activity (cluster of differentiation 68+/Iba1+ (ionised calcium binding adaptor molecule 1)) increased significantly.Microglial depletion using PLX3397 (71.3% reduction in Iba1+ cells) worsened ischaemic injury, yet RIC preserved its protective effects, suggesting additional microglia-independent mechanisms. Furthermore, RIC enhanced neurogenesis in the subventricular zone and infarct core (doublecortin marker+ cells doubled versus Stroke), with a marked proliferative response in female hippocampi (Ki67+ cells increased by 127%).

Conclusion: These findings reveal sex-specific efficacy of RIC, with mechanistic insights obtained in male animals suggesting a dual mode of action via modulation of microglial function and promotion of endogenous neurorepair pathways.

Over the past three decades, the development of evidence-based medicine (EBM) has brought significant opportunities to the advancement of clinical practice in stroke medicine. Substantial EBM evidence has transformed clinical practice in multiple areas, including intravenous thrombolysis, thrombectomy, antiplatelet therapy, intracranial angioplasty, carotid endarterectomy and stenting, blood pressure lowering, blood glucose control, lipid-lowering and anti-inflammation (colchicine). Yet, the current body of evidence is not enough to meet the complex and evolving needs of stroke patients. This review was based on a special lecture, 'What's Next' on the future of stroke medicine, delivered by Prof. Yongjun Wang in Beijing on 4 July 2025. The talk was attended by more than 10 recipients of the William M. Feinberg Award for Excellence in Clinical Stroke from around the world. This article reviews past achievements, highlights critical gaps in current knowledge and outlines future research priorities. By mapping out the trajectory of stroke medicine, this review aims to guide future efforts and illuminate the path forward for stroke medicine.

Stroke is a leading cause of mortality and morbidity in Bangladesh, and young adults are increasingly affected. Common risk factors include hypertension, diabetes, dyslipidaemia, obesity and smoking, whereas rare causes include haematologic disorders, premature atherosclerosis, vasculopathy and arteritis. Treatment barriers include inadequate infrastructure, a lack of trained staff and high intervention costs. Bangladesh faces a scarcity of neurologists and well-equipped hospitals, necessitating strategies to mitigate the burden of stroke among young people. This editorial summarises the current knowledge regarding the aetiology, pathophysiology and challenges in diagnosing and treating stroke in young people in Bangladesh, while addressing rare vasculopathy. Initiatives to support young stroke survivors and their families were also discussed. Prospective cohort studies, such as the Norwegian Stroke in the Young Study, provide insights into optimising prevention and early intervention by assessing family history and subclinical vascular diseases, which have also been highlighted. Recommendations include advanced neuroimaging for risk assessment, incorporating patient care and rehabilitation into medical education, conducting relevant research and promoting healthy lifestyles through campaigns and training of the healthcare staff.

Background: Acute ischaemic stroke, due to its high mortality and disability rates, imposes a significant economic and social burden worldwide. Typically, endovascular treatment within the therapeutic window is provided to salvage the ischaemic penumbra; however, even when recanalisation is successful during endovascular treatment, the clinical outcomes may still be disappointing. This highlights the necessity of further research, so as to discover better solutions to futile recanalisation and improve patient outcomes.

Objective: To investigate the efficacy and safety of Y-6 sublingual tablets (cilostazol and dexborneol) compared with a placebo in the treatment of patients with acute ischaemic stroke caused by large vessel occlusion.

Method: The efficacy and safety of Y-6 sublingual tablets in patients with acute ischaemic stroke are evaluated in a phase II, randomised, double-blind, double-dummy, placebo-controlled, parallel clinical trial. Eligible patients having provided informed consent are randomised into five groups for a 28-day treatment period. The primary outcome is the percentage of patients achieving the modified Rankin Scale score of 0-1 at 90 days.

Discussion: The EFfects of Y-6 SUblingual Tablets for PaTients with AcUte Ischemic StRokE trial assesses whether Y-6 sublingual tablets are effective and safe in improving the clinical outcomes of patients with acute ischaemic stroke caused by large vessel occlusion.

Trial registration number: NCT06138834.

Background: Inflammation and blood-brain barrier disruption may contribute to the pathogenesis of ischaemic stroke. Minocycline was shown to exert anti-inflammatory effects by attenuating microglial activation and protecting blood-brain barrier in preclinical studies. Previous small-scale clinical studies have suggested that minocycline may have a potential beneficial effect on prognosis in acute ischaemic stroke. However, the efficacy and safety of minocycline in patients with acute ischaemic stroke need to be further confirmed.

Study aims: We designed the study, Efficacy and Safety of Minocycline in Patients with Moderate to Severe Acute Ischaemic Stroke (EMPHASIS), to evaluate the effect of minocycline in improving the functional outcome and the drug safety in patients with acute ischaemic stroke.

Methods: The EMPHASIS study is a multicentre, randomised, double-blind, placebo-controlled trial aiming to recruit patients with acute ischaemic stroke. Patients who had ischaemic stroke within 72 hours of onset, a National Institutes of Health Stroke Scale score between 4 and 25 and Ia≤1 (moderate-to-severe) will be randomly allocated to either minocycline or placebo groups in a 1:1 ratio. Patients will receive minocycline (or placebo) with a loading dose of 200 mg, and subsequent 100 mg every 12 hours for 4 days. All patients will receive routine guideline-based treatment. The primary efficacy outcome is an excellent functional outcome assessed by the proportion of modified Rankin Scale score of 0-1 at 90±7 days. The main safety outcomes include the number of symptomatic intracranial haemorrhage at 24±2 hours and 6±1 days.

Discussion: The EMPHASIS trial is the first phase III trial to investigate whether minocycline is effective and safe in improving functional outcome at 90 days in patients with moderate-to-severe acute ischaemic stroke. The data generated may provide valuable evidence of a potential anti-inflammation treatment for ischaemic stroke.

Background: The prognostic significance of the affected hemisphere in haemorrhagic stroke remains uncertain. We aimed to determine the relationship between the affected hemisphere (right or left) and differences in non-motor outcomes, including mood and pain, in patients with acute, supratentorial intracerebral haemorrhage (ICH). These non-motor outcomes are often overlooked in studies following ICH but impact patient recovery and well-being.

Methods: A secondary prespecified analysis of the Minimally Invasive Surgery with Thrombolysis in Intracerebral Hemorrhage Evacuation (MISTIE) III study-a randomised, international, multicentre, placebo-controlled trial of participants with spontaneous, non-traumatic, supratentorial ICH of 30 mL or more that evaluated minimally invasive surgery with thrombolysis compared with standard medical care. Outcomes included EQ-5D three-level version (EQ-5D-3L, composite and individual non-motor components) and modified Rankin scale (mRS) scores at days 30, 180 and 365 post-ICH.

Results: A total of 493 participants were eligible for analysis at day 30 following ICH. In multivariable analyses, patients with right hemispheric ICH were more likely to report problems with pain and discomfort at days 30 (β=0.257 (95% CI 0.131, 0.383)), 180 (β=0.213 (95% CI 0.090, 0.336)) and 365 (β=0.209 (95% CI 0.090, 0.328)) post-ICH. Patients with right hemispheric ICH were also more likely to report problems with anxiety and depression at days 30 (β=0.160 (95% CI 0.030, 0.291)) and 180 (β=0.171 (95% CI 0.049, 0.293)) following ICH. There were no differences in mRS scores between patients with left or right-sided haemorrhages.

Conclusions: Right hemispheric lesions were associated with increased reports of mood-related symptoms (depression, anxiety) and pain in patients with acute ICH over time.

Trial registration number: NCT01827046.