Stroke最新文献

Novel strategies are needed for the treatment of acute ischemic stroke when revascularization therapies are not clinically appropriate or are unsuccessful. rKLK1 (recombinant human tissue kallikrein-1), a bradykinin-producing enzyme, offers a promising potential solution. In animal studies of acute stroke, there is a marked 36-fold increase in bradykinin B2 receptor on brain endothelial cells of the ischemic region. Due to this environment, rKLK1-generated bradykinin will exert a potent local vasodilation and increase brain perfusion via 3 synergistic signaling pathways downstream to the B2 receptor. Because of its preferential effect on ischemic tissue, systemic adverse effects such as hypotension are avoided with proper dosing. In addition, with initial vasodilation through recruitment of preexisting collaterals, rKLK1 promotes long-term benefit of brain perfusion by promoting new collateral formation. With an extended course of therapy for weeks after acute ischemic stroke, these multifaceted effects may also reduce the risk of stroke recurrence. A prior phase II trial demonstrated a favorable impact on clinical outcomes and recurrent strokes, particularly among patients who were not eligible for mechanical thrombectomy. A phase II/III trial has launched in this population, though opportunities for combination revascularization therapies deserve further investigation.

Background: Several social and biological factors are shown to differentially affect stroke outcomes between men and women. We evaluated whether clinical outcomes and endovascular thrombectomy (EVT) treatment effects differed between the sexes in patients presenting with large ischemic stroke.

Methods: The SELECT2 trial (A Randomized Controlled Trial to Optimize Patient's Selection for Endovascular Treatment in Acute Ischemic Stroke) was a randomized controlled trial assessing the efficacy and safety of EVT in patients with large strokes across the United States, Canada, Europe, Australia, and New Zealand between October 2019 and September 2022. In this subanalysis, baseline characteristics and clinical and imaging outcomes were compared between women and men, each further divided into cohorts receiving medical treatment without and with EVT. Functional outcomes at 90-day and 1-year follow-ups were assessed using regression models, adjusting for potential confounders. Sex-related effect modification was examined.

Results: Women accounted for 145 (41%) of 352 patients enrolled in the SELECT2 trial. Seventy-one (49%) of 145 women and 109 (53%) of 207 men underwent EVT. Endovascular intervention was associated with better functional outcomes (women: adjusted generalized odds ratio, 1.73 [1.22-2.45]; men: adjusted generalized odds ratio, 1.66 [1.24-2.23]; P-int: 0.94), functional independence (women: EVT, 20% versus medical management, 4%; adjusted risk ratio [aRR], 5.04 [1.59-16.02]; men: EVT, 20% versus medical management, 9%; aRR, 1.99 [0.99-4.02]; P-int: 0.20), and independent ambulation (women: EVT, 39% versus medical management, 16%; aRR, 2.44 [1.40-4.24]; men: EVT, 38% versus medical management, 20%; aRR, 1.98 [1.29-3.03]; P-int: 0.67) in both men and women at 90-day follow-up, without significant heterogeneity. Similar results were observed at 1-year follow-up. In women, as age increased (aRR, 0.97 [95% CI, 0.95-0.99]; P=0.004 per year) and core volume estimates increased (aRR, 0.99 [95% CI, 0.98-1.00]; P=0.015 per mL increase), the rate of independent ambulation after EVT decreased. A similar association of age and core volume was seen in men.

Conclusions: EVT treatment benefit was maintained in both women and men, with higher rates of functional independence and independent ambulation as compared with medical management. Age and estimated core infarct volume were independently associated with independent ambulation in both male and female patients. EVT should be equally considered for patients of both sexes meeting large core eligibility criteria.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03876457.

Clinical trials of treatments for stroke have generally utilized 2-arm, randomized designs to evaluate a single intervention against a control. Running separate clinical trials, with each addressing a single therapeutic question, is resource intensive and slows evidence generation, especially in a field with rapidly expanding treatment options and evolving practices. Platform trials-randomized clinical trials designed to evaluate multiple interventions that may enter and exit the ongoing platform based on a master protocol-accelerate the investigation of multiple therapeutic options within a single infrastructure. This in turn has the potential to accelerate access to new interventions for patients with stroke that can save lives and improve outcomes. In the context of acute ischemic stroke, 2 new platform trials have been established, the STEP trial (StrokeNet Thrombectomy Endovascular Platform) and ACT-GLOBAL (A Multi-Factorial, Multi-Arm, Multi-Stage, Randomised, Global Adaptive Platform Trial for Stroke), to address multiple therapeutic questions simultaneously using a multifactorial design including Bayesian modeling and other adaptive features. These trials are designed to maximize the information obtained from each participant, to align clinical research more closely with the complexities of clinical care, and to accelerate the identification of effective therapies. This article explores conceptual, practical, and statistical considerations in the design and implementation of adaptive platform trials and highlights their potential to accelerate the identification of new therapies, management, and rehabilitation in stroke.

Background: Although the presence of amyloid deposits is associated with a more severe cognitive status in patients with stroke at baseline, its influence on the subsequent cognitive outcome has not been extensively assessed. The primary objective of the present study of the IDEA3 (Imagerie des dépôts amyloïdes cérébraux par florbetapir AV-45 et diagnostic des déficits cognitifs et démence post Accident Vasculaire Cérébral) cohort was to determine the influence of amyloid positron emission tomography (PET) status on the 5-year cognitive outcome.

Methods: This longitudinal study performed in Amiens University Hospital (inclusions: October 2014 to October 2019; last visits: October 2018 to February 2023) has included 91 patients with stroke (ischemic stroke, 89%; hemorrhagic stroke, 11%) with florbetapir PET data at baseline (positive, n=14). Patients underwent annually comprehensive clinical and cognitive assessments for 5 years after the PET scan. The primary outcome was incident dementia; secondary outcomes were incident cognitive impairment, total prevalence of cognitive impairment, and modified Rankin Scale score.

Results: A survival analysis (mean poststroke follow-up, 80.4±27 months) showed that the incidence of incident dementia was higher in the PET-positive patients (odds ratio, 9.6 [95% CI, 2.5-36.9]; P=0.001), as was the incidence of incident cognitive impairment (odds ratio, 10 [95% CI, 1.9-52.3]; P=0.003). A Cox regression analysis showed that the association between amyloid status and the incidences of dementia (P=0.001) and cognitive impairment (P=0.007) was still significant after adjustment for age, education, prestroke modified Rankin Scale score and cognitive impairment, stroke type, and the PET status×stroke type interaction. Considering the overall prevalence at the last follow-up in the whole study population (n=91 patients), PET positivity was associated with an elevated risk of dementia (odds ratio, 6 [95% CI, 1.76-20.5]; P=0.002) and poststroke cognitive impairment (odds ratio, 6.25 [95% CI, 1.77-22]; P=0.002). The final modified Rankin Scale score did not differ (P=0.3) according to PET status.

Conclusions: Our results demonstrate the major impact of amyloid deposition on the stroke outcome and emphasized the need for comprehensive etiologic workup in patients with poststroke cognitive impairment.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02813434.

Background: A potential benefit of mechanical thrombectomy for patients with distal medium vessel occlusions is currently being investigated in randomized trials. Computed tomography perfusion imaging has not yet been tested as a method to guide mechanical thrombectomy for distal medium vessel occlusions. The purpose of this study was to assess penumbral imaging as an imaging-based method for triaging patients with ischemic stroke and acute M2-middle cerebral artery occlusion.

Methods: This observational retrospective study of M2-middle cerebral artery patients with ischemic stroke triaged by multimodal computed tomography undergoing mechanical thrombectomy at a high-volume stroke center between January 2015 and January 2023. The effect of recanalization was analyzed according to computed tomography perfusion-derived lesion volumes (defined using relative cerebral blood flow <30% and T_max >6 seconds) using logistic regression analysis, and interaction terms between the independent variables and recanalization were tested. The primary end point was functional independence at day 90, defined using modified Rankin Scale scores of 0 to 2.

Results: A total of 140 patients with M2-middle cerebral artery occlusion were included. In multivariable logistic regression analysis, recanalization was not associated with better functional outcome (adjusted odds ratio, 1.85 [95% CI, 0.87-3.90]; P=0.11). After including interaction terms, a significant treatment effect between recanalization and computed tomography perfusion-derived lesion volumes was observed in patients with >150 mL hypoperfusion volume (adjusted odds ratio, 1.02 [95% CI, 1.00-1.03]; P=0.007) or >125 mL penumbral volumes (adjusted odds ratio, 1.02 [95% CI, 1.01-1.03]; P=0.005), as well as for baseline ischemic core volume within the range of 15 to 40 mL (adjusted odds ratio, 1.11 [95% CI, 1.01-1.22]; P=0.03).

Conclusions: Penumbral imaging might serve as a useful tool for treatment decision-making in distal medium vessel occlusions, particularly in cases of suspected non- or codominant M2-middle cerebral artery vessel occlusions. A hypoperfusion volume threshold of >150 mL emphasizes the potential value of computed tomography perfusion as a standardized tool directly showing the volumetric relevance in distal medium vessel occlusion cases.

Background: Ischemic stroke is a common cause of death worldwide and a main cause of morbidity. Presently, laser speckle contrast imaging, x-ray computed tomography, and magnetic resonance imaging are the mainstay for stroke diagnosis and therapeutic monitoring in preclinical studies. These modalities are often limited in terms of their ability to map brain perfusion with sufficient spatial and temporal resolution, thus calling for development of new brain perfusion techniques featuring rapid imaging speed, cost-effectiveness, and ease of use.

Methods: We report on a new preclinical high-resolution angiography technique for murine ischemic stroke imaging based on large-field high-speed multifocal illumination fluorescence microscopy. We subsequently showcase the proposed method by monitoring therapeutic effects of thrombolysis in stroke (n=6), further performing cross-strain comparison of perfusion dynamics (n=6) and monitoring the therapeutic effects of sensory stimulation-based treatment (n=11).

Results: Quantitative readings of hemodynamic and structural changes in cerebral vascular network and pial vessels were attained with 14.4-µm spatial resolution at 80-Hz frame rate fully transcranially. The in vivo perfusion maps accurately delineated the ischemic core and penumbra, further exhibiting a strong correlation (86.1±4.5%) with ex vivo triphenyl tetrazolium chloride staining, significantly higher than for the conventional laser speckle contrast imaging method. Monitoring of therapeutic effects of thrombolysis confirmed that early recanalization could effectively save the penumbra while reducing the infarct area. Cross-strain comparison of perfusion dynamics affirmed that C57BL/6 mice feature a larger penumbra and smaller infarct core as compared with BALB/c mice, which have few or no collaterals. Sensory stimulation-based treatment could effectively enhance blood flow and abolish perfusion deficits in the ischemic core and penumbra regions.

Conclusions: A high-speed fluorescence-based angiography method for transcranial stroke imaging in mice is introduced, which is capable of localizing brain perfusion changes and accurately assessing the ischemic penumbra. Compared with the whole-brain x-ray computed tomography and magnetic resonance imaging methods, which are conventionally used for stroke diagnosis and therapeutic monitoring, the new approach is simple and cost-effective, further offering high resolution and speed for in vivo studies. It thus opens new venues for brain perfusion research under various disease conditions such as stroke, neurodegeneration, or epileptic seizures.

Background: Socioeconomic disparities exist in acute stroke care as well as in long-term stroke outcomes. We aimed to investigate whether socioeconomic status was associated with the rate of poststroke dementia (PSD).

Methods: This was a nationwide register-based cohort study including all patients with incident ischemic or hemorrhagic stroke in Denmark from 2010 to 2020. Socioeconomic status was defined by prestroke income, education, and employment. PSD was defined as a dementia diagnosis in the National Patient Registry or a dispensed prescription of dementia medication after a stroke. PSD incidence rates were compared between socioeconomic status groups using Poisson regression.

Results: A total of 98 489 patients with incident stroke without a diagnosis of prestroke dementia were identified and followed for a median (IQR) of 4.2 (IQR, 2.1-7.3) years. Median age was 72 (62-80) years, 56% were male, 5.1% were immigrants, and 86% had ischemic stroke. Dementia was diagnosed in 5680 patients at a median of 2.4 (IQR, 0.9-4.8) years after stroke (incidence rate=12.1/1000 person-years). After adjusting for age, sex, and immigrant status, PSD rates were 1.24 (1.15-1.34) times higher for low income compared with high income, 1.11 (1.03-1.20) times higher for low education compared with high education, and 1.57 (1.38-1.77) times higher for patients without employment compared with patients with employment. Further adjustments for stroke severity, cohabitation, and comorbidities showed similar results. Stratified analyses showed that the socioeconomic disparities in PSD rates were more pronounced among women, immigrants, and patients <70 years of age.

Conclusions: Low socioeconomic status measured by prestroke income, education, and employment status was associated with higher rates of PSD. These socioeconomic disparities extended beyond what could be explained by common PSD risk factors.