Stroke最新文献

Background: Stroke remains a leading cause of death and disability, underscoring the urgent need for treatments that enhance recovery. Growth Differentiation Factor 11 (GDF11), a member of the TGF-β superfamily, is a circulating protein involved in cellular development and tissue repair. GDF11 has gained attention for its potential regenerative properties in aging and disease contexts, making it a candidate for stroke recovery therapies. Methods: The therapeutic benefits of recombinant GDF11 (rGDF11) were evaluated using a rat ischemic stroke model, in which focal cerebral infarcts were induced in 8 -10 week-old young adult male Sprague-Dawley rats by permanently occluding the proximal right middle cerebral artery. Rats received single or multiple doses of rGDF11 (0.1-4 mg/kg) or vehicle 24-72 hours post-injury. Sensorimotor functions were evaluated, and brain and serum samples were examined to determine mechanism of action and identify biomarkers, using immunofluorescence, target-specific ELISAs, and an aptamer-based proteomics platform. Results: We confirmed rGDF11 activity in vitro and in established in vivo mouse models of cardiac hypertrophy and glucose metabolism and assessed the efficacy of rGDF11 treatment in six preclinical stroke studies, using independent Contract Research Organizations with all study animals and treatment groups blinded. All six studies revealed consistent improvement of sensorimotor outcomes with rGDF11. rGDF11-treated rats showed increased cortical vascularization and radial glia in the ventricular zone. Serum analysis revealed rGDF11 dose-dependent decreases in C-reactive protein and identified novel pharmacodynamic biomarkers and pathways associated with potential mechanisms of action of rGDF11. Conclusion: These results demonstrate that systemically delivered rGDF11 enhances neovascularization, reduces inflammation, promotes neurogenesis, and improves sensorimotor function post-injury in a rat model of ischemic stroke. More importantly, these data define an optimized and clinically-feasible rGDF11 dosing regimen for therapeutic development in ischemic stroke and identify a panel of candidate pharmacodynamic and mechanistic biomarkers to support clinical translation.

Background: Cardiac computed tomography (CT) is increasingly used to search for cardioembolic sources of acute ischemic stroke (AIS). We assessed the association between high-risk cardioembolic sources on cardiac CT and AIS.

Methods: We performed a case-control study using data from a prospective cohort including consecutive adult patients with suspected stroke who underwent cardiac CT acquired during the initial stroke imaging protocol between 2018 and 2020. Cases were patients with a final diagnosis of AIS. Controls were patients with a stroke mimic (SMi). We excluded patients with a transient ischemic attack. Diagnoses were established by an adjudication committee. Cardiac radiologists assessed the presence of structural high-risk sources of cardioembolism according to predefined criteria. We used the Firth penalized likelihood method to perform a logistic regression, adjusted for age, sex, and history of myocardial infarction to determine the association between high-risk embolic sources and AIS. For the primary analysis, we excluded patients with a history of atrial fibrillation. In a secondary analysis, patients with known atrial fibrillation were included.

Results: Of 774 patients, we excluded 167 patients due to no written informed consent or the diagnosis of transient ischemic attack. Of 607 patients, 107 patients had known atrial fibrillation and were excluded from the primary analysis. Of 500 included patients, 375 had AIS (75%, median age 70, 61% male) and 125 SMi (25%, median age 69, 42% male). A high-risk cardioembolic source was found on CT in 32/375 (8.5%) patients with AIS and 0/125 (0%) patients with SMi (adjusted odds ratio, 23.8 [95% CI, 3.3-3032.5]). Cardiac thrombi were the most commonly observed abnormality, present in 23 (6.1%) patients with AIS and 0 (0%) patients with SMi.

Conclusions: A high-risk source of cardioembolism was detected on cardiac CT more frequently in patients with AIS than in patients with SMi. These data substantiate the clinical relevance of cardioembolic sources detected on acute cardiac CT in patients with ischemic stroke.

Background: Ischemic stroke is a leading cause of death and disability. Society guidelines recommend pharmacotherapies for secondary stroke prevention. However, the role of sex differences in prescription and adherence to guideline-directed medical therapies (GDMT) after ischemic stroke remains understudied. The aim of this study was to examine sex differences in prescription patterns and adherence to GDMT at 1 year after ischemic stroke in a cohort of commercially insured patients.

Methods: Using the Truven Health MarketScan database from 2016 to 2020, we identified patients admitted with ischemic stroke. GDMT was defined as any statin, antihypertensive agents, or oral anticoagulant prescription within 30 days after discharge. Medication adherence was estimated using the proportion of days covered at 1 year. The proportion of days covered <0.80 was used to define nonadherence. A multivariable model adjusting for covariates was performed to identify the factors associated with nonadherence at 1 year. This analysis was restricted to new users of GDMT.

Results: Among 155 220 patients admitted with acute ischemic stroke during the study period, 15 919 met the inclusion criteria. The mean age was 55.7 years, and 8218 (51.7%) were women. Women were less likely to be prescribed statins (58.0% versus 71.8%) and antihypertensive agents (27.7% versus 41.8%). In this subset of patients with atrial flutter/fibrillation, women were also less likely to be prescribed oral anticoagulants (41.2% versus 45.0%). Women were more likely to be nonadherent (ie, proportion of days covered <0.80) to statins (47.3% versus 41.6%; P<0.0001), antihypertensives (33.3% versus 32.2%; P=0.005), and the combination of both (49.6% versus 45.0%; P=0.003). On multivariable analysis, women were likely to be nonadherent to statins and antihypertensive agents at 1 year (odds ratio, 1.23 [95% CI, 1.08-1.41]).

Conclusions: In this real-world analysis of commercially insured patients with ischemic stroke, women were less likely initiated on GDMT within 30 days after discharge. Women were more likely to be nonadherent to statins and antihypertensive agents at 1 year. Future efforts and novel interventions are needed to understand the reasons and minimize these disparities.

Background: Sex critically determines stroke pathophysiology and recovery. To reveal potential gaps in stroke care, we analyzed sex-specific differences in the stroke patient hospital admission and treatment process.

Methods: In this single-center retrospective analysis, we screened all patients referred to our stroke center between 2014 and 2020 with suspicion of stroke (n=7112). Patients with different cerebrovascular events and stroke mimics were included. We collected demographic hospitalization and 90-day follow-up data and stratified results according to sex. In a logistic regression analysis for 90-day functional outcome, we estimated the effect of sex corrected for the clinically most relevant confounders.

Results: Of 7102 patients, 56.7% were male and 43.3% female. Women were older (median, 76.3 years; interquartile range (IQR), 64-84, versus 70.7; IQR, 59-79; P<0.001), and lived more often in nursing homes before the event (10.5% versus 3.8%; P<0.001). Among patients with acute ischemic stroke (n=4515), women had more often a large vessel occlusion (38.6% versus 34.8%; P=0.015), a higher stroke severity (National Institutes of Health Stroke Scale score, 4; IQR, 1-12 versus 3; IQR, 1-8; P<0.001), and were treated more often with endovascular treatment (21.4% versus 17.3%; P=0.001). Onset-to-door, onset-to-treatment, and door-to-treatment times were significantly longer in women. A favorable 90-day functional outcome (modified Rankin Scale score 0-2) occurred more often in men (73.9% versus 64.9%; P<0.001). When correcting for confounders in a multivariable logistic regression, age, admission National Institutes of Health Stroke Scale, and prestroke modified Rankin Scale remained highly (P<0.001), large vessel occlusion and arterial hypertension moderately significant predictors for 90-day functional outcome (P<0.05), whereas female sex was not. This could be confirmed when analyzing different patient age groups separately in multivariable logistic regression subgroup analyses. An interaction-term analysis revealed no additional association between age and female sex (OR, 0.99; P=0.815).

Conclusions: Although treatment and outcome parameters seem to be in favor of men, most can be explained by older age, poorer prestroke independence, higher stroke severity, and more large vessel occlusion in women. Sex was not independently associated with worse 90-day functional outcome in women.

Several trials of endovascular treatment for patients with large-core acute ischemic stroke have been completed. Whereas future stroke clinical guidelines will provide specific recommendations, this advisory aims to summarize the results of these trials, analyze the commonalities and differences among the studies, and discuss the clinical implications of these new results.

Background: Recent studies suggest that the use of adjunctive intraarterial alteplase after mechanical thrombectomy (MT) may improve outcomes; however, there are limited data on the use of intraarterial tenecteplase, a newer-generation lytic, in this acute ischemic stroke patient population. Here, we evaluate the use of intraarterial tenecteplase in the ALLY pilot study (Adjunctive Intraarterial Tenecteplase Following Mechanical Thrombectomy).

Methods: ALLY was a prospective, single-center, nonrandomized pilot study assessing the feasibility and safety of intraarterial tenecteplase up to 4.5 mg in acute ischemic stroke-large vessel occlusion MT patients with incomplete recanalization. The primary safety end point was any intracranial hemorrhage and neurological worsening by ≥4 points on the National Institutes of Health Stroke Scale within 24 hours of treatment with intraarterial tenecteplase. A post hoc analysis was performed with a control cohort of MT patients (ALLY MT) not receiving intraarterial tenecteplase.

Results: From April 2022 to July 2023, 218 MTs were performed at ProMedica Hospital (Toledo, OH), of which 20 patients were enrolled in ALLY. The mean age was 66.1±13.8 years, with 35% women. Median baseline National Institutes of Health Stroke Scale scores and Alberta Stroke Program Early CT Scores were 13 (interquartile range, 9-18.8) and 10 (interquartile range, 9-10), respectively. IV thrombolysis was administered in 55%. Most patients presented with middle cerebral artery occlusion (90%). Post-MT modified Treatment in Cerebral Ischemia grade was 2b and 2c in 11 and 9 patients, respectively. Final modified Treatment in Cerebral Ischemia 2b, 2c, and 3 was achieved in 55% (11/20), 35% (7/20), and 10% (2/20), respectively. Any intracranial hemorrhage was observed in 11 patients; however, only 1 patient had symptomatic intracranial hemorrhage. A favorable functional outcome (modified Rankin Scale score, 0-2) at 90 days was achieved in 50%. No difference in intracranial hemorrhage rates was observed between the ALLY and ALLY MT cohorts.

Conclusions: The use of adjunctive intraarterial tenecteplase up to 4.5 mg in patients with acute ischemic stroke with incomplete reperfusion post-MT is feasible and was not associated with increased rates of hemorrhage. Larger, randomized studies are needed to assess the safety and efficacy of intraarterial tenecteplase in this population.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05172934.

Background: Activating glutamatergic neurons in the ipsilesional motor cortex can promote functional recovery after stroke. However, the underlying molecular mechanisms remain unclear. Clarifying key molecular mechanisms involved in recovery could help understand the development of neuromodulation strategies after stroke.

Methods: Adeno-associated virus 2/9-CamKIIa-hM3Dq-mCherry was injected into ipsilesional motor cortex by stereotaxic in the photothrombotic stroke model. Starting from the third day after the stroke, male mice were injected intraperitoneally with clozapine-N-oxide every day to activate excitatory neurons. C1q-blocking antibody and annexin V were used to inhibit C1q and exposed phosphatidylserine (EPS), respectively. The cylinder test and grid-walking test were performed to evaluate functional recovery. The potential molecular mechanisms of excitatory neuronal activation on microglia-mediated synaptic pruning after stroke by immunofluorescence, real-time polymerase chain reaction, Western blotting, and RNA sequencing.

Results: Activating excitatory neurons significantly promoted functional recovery and inhibited microglia-mediated synaptic pruning after stroke. Furthermore, it decreased EPS and C1q levels in synapses. On the contrary, inhibiting excitatory neurons aggravated functional defects, promoted microglia-mediated synaptic pruning, and increased EPS and C1q levels in synapses. Selective blocking of EPS repressed C1q tagging of synapses and microglia-mediated synaptic pruning and improved functional recovery. Meanwhile, blocking EPS markedly rescued synaptic density, and motor function deteriorated by chemogenetic inhibition. In addition, C1q-blocking antibody prevented phosphatidylserine engulfment by microglia.

Conclusions: Together, these data provide mechanistic insight into microglia-mediated synapse pruning after neuronal activation after stroke and identify the role of C1q binding to EPS in stroke treatment during the repair phase.