Innate immune memory after brain injury drives inflammatory cardiac dysfunction.

The medical burden of stroke extends beyond the brain injury itself and is largely determined by chronic comorbidities that develop secondarily. We hypothesized that these comorbidities might share a common immunological cause, yet chronic effects post-stroke on systemic immunity are underexplored. Here, we identify myeloid innate immune memory as a cause of remote organ dysfunction after stroke. Single-cell sequencing revealed persistent pro-inflammatory changes in monocytes/macrophages in multiple organs up to 3 months after brain injury, notably in the heart, leading to cardiac fibrosis and dysfunction in both mice and stroke patients. IL-1ß was identified as a key driver of epigenetic changes in innate immune memory. These changes could be transplanted to naive mice, inducing cardiac dysfunction. By neutralizing post-stroke IL-1ß or blocking pro-inflammatory monocyte trafficking with a CCR2/5 inhibitor, we prevented post-stroke cardiac dysfunction. Such immune-targeted therapies could potentially prevent various IL-1ß-mediated comorbidities, offering a framework for secondary prevention immunotherapy.

DNA-sensing inflammasomes cause recurrent atherosclerotic stroke.

The risk of early recurrent events after stroke remains high despite currently established secondary prevention strategies1. Risk is particularly high in patients with atherosclerosis, with more than 10% of patients experiencing early recurrent events1,2. However, despite the enormous medical burden of this clinical phenomenon, the underlying mechanisms leading to increased vascular risk and recurrent stroke are largely unknown. Here, using a novel mouse model of stroke-induced recurrent ischaemia, we show that stroke leads to activation of the AIM2 inflammasome in vulnerable atherosclerotic plaques via an increase of circulating cell-free DNA. Enhanced plaque inflammation post-stroke results in plaque destabilization and atherothrombosis, finally leading to arterioarterial embolism and recurrent stroke within days after the index stroke. We confirm key steps of plaque destabilization also after experimental myocardial infarction and in carotid artery plaque samples from patients with acute stroke. Rapid neutrophil NETosis was identified as the main source of cell-free DNA after stroke and NET-DNA as the causative agent leading to AIM2 inflammasome activation. Neutralization of cell-free DNA by DNase treatment or inhibition of inflammasome activation reduced the rate of stroke recurrence after experimental stroke. Our findings present an explanation for the high recurrence rate after incident ischaemic events in patients with atherosclerosis. The detailed mechanisms uncovered here provide clinically uncharted therapeutic targets for which we show high efficacy to prevent recurrent events. Targeting DNA-mediated inflammasome activation after remote tissue injury represents a promising avenue for further clinical development in the prevention of early recurrent events.

Cerebral Vascular Dysfunctions Detected in Human Small Vessel Disease and Implications for Preclinical Studies.

Cerebral small vessel disease (SVD) is highly prevalent and a common cause of ischemic and hemorrhagic stroke and dementia, yet the pathophysiology is poorly understood. Its clinical expression is highly varied, and prognostic implications are frequently overlooked in clinics; thus, treatment is currently confined to vascular risk factor management. Traditionally, SVD is considered the small vessel equivalent of large artery stroke (occlusion, rupture), but data emerging from human neuroimaging and genetic studies refute this, instead showing microvessel endothelial dysfunction impacting on cell-cell interactions and leading to brain damage. These dysfunctions reflect defects that appear to be inherited and secondary to environmental exposures, including vascular risk factors. Interrogation in preclinical models shows consistent and converging molecular and cellular interactions across the endothelial-glial-neural unit that increasingly explain the human macroscopic observations and identify common patterns of pathology despite different triggers. Importantly, these insights may offer new targets for therapeutic intervention focused on restoring endothelial-glial physiology.

Severity-Dependent Interhemispheric White Matter Connectivity Predicts Poststroke Neglect Recovery.

Left-sided spatial neglect is a very common and challenging issue after right-hemispheric stroke, which strongly and negatively affects daily living behavior and recovery of stroke survivors. The mechanisms underlying recovery of spatial neglect remain controversial, particularly regarding the involvement of the intact, contralesional hemisphere, with potential contributions ranging from maladaptive to compensatory. In the present prospective, observational study, we assessed neglect severity in 54 right-hemispheric stroke patients (32 male; 22 female) at admission to and discharge from inpatient neurorehabilitation. We demonstrate that the interaction of initial neglect severity and spared white matter (dis)connectivity resulting from individual lesions (as assessed by diffusion tensor imaging, DTI) explains a significant portion of the variability of poststroke neglect recovery. In mildly impaired patients, spared structural connectivity within the lesioned hemisphere is sufficient to attain good recovery. Conversely, in patients with severe impairment, successful recovery critically depends on structural connectivity within the intact hemisphere and between hemispheres. These distinct patterns, mediated by their respective white matter connections, may help to reconcile the dichotomous perspectives regarding the role of the contralesional hemisphere as exclusively compensatory or not. Instead, they suggest a unified viewpoint wherein the contralesional hemisphere can - but must not necessarily - assume a compensatory role. This would depend on initial impairment severity and on the available, spared structural connectivity. In the future, our findings could serve as a prognostic biomarker for neglect recovery and guide patient-tailored therapeutic approaches.

Focal Brain Lesions Causing Acquired Amusia Map to a Common Brain Network.

Music is a universal human attribute. The study of amusia, a neurologic music processing deficit, has increasingly elaborated our view on the neural organization of the musical brain. However, lesions causing amusia occur in multiple brain locations and often also cause aphasia, leaving the distinct neural networks for amusia unclear. Here, we utilized lesion network mapping to identify these networks. A systematic literature search was carried out to identify all published case reports of lesion-induced amusia. The reproducibility and specificity of the identified amusia network were then tested in an independent prospective cohort of 97 stroke patients (46 female and 51 male) with repeated structural brain imaging, specifically assessed for both music perception and language abilities. Lesion locations in the case reports were heterogeneous but connected to common brain regions, including bilateral temporoparietal and insular cortices, precentral gyrus, and cingulum. In the prospective cohort, lesions causing amusia mapped to a common brain network, centering on the right superior temporal cortex and clearly distinct from the network causally associated with aphasia. Lesion-induced longitudinal structural effects in the amusia circuit were confirmed as reduction of both gray and white matter volume, which correlated with the severity of amusia. We demonstrate that despite the heterogeneity of lesion locations disrupting music processing, there is a common brain network that is distinct from the language network. These results provide evidence for the distinct neural substrate of music processing, differentiating music-related functions from language, providing a testable target for noninvasive brain stimulation to treat amusia.

Arterial Thromboembolism in Patients With Atrial Fibrillation and CHA2DS2-VASc Score 1: A Nationwide Study.

BACKGROUND: Oral anticoagulation is suggested in patients with atrial fibrillation and a CHA2DS2-VASc score ≥1 (congestive heart failure, hypertension, age ≥75 years, diabetes, stroke, vascular disease, age 65-74 years, and sex score). To assess granular differences within CHA2DS2-VASc 1, the incidence of arterial thromboembolism according to CHA2DS2-VASc 1 subgroups was examined. METHODS: The Danish National Patient Registry and the Danish Prescription Registry were linked on a nationwide level to identify patients with atrial fibrillation from 2000 to 2021 without oral anticoagulation and categorized according to CHA2DS2-VASc score: CHA2DS2-VASc 0 (male and female subjects); CHA2DS2-VASc 1 (hypertension, heart failure, diabetes, vascular disease, and age 65-74 years); or CHA2DS2-VASc 2 (age ≥75 years without other risk factors). Female sex was not considered a risk factor in any risk group. The outcome was arterial thromboembolism (ischemic stroke, embolism of extremity, or transient cerebral ischemia). Study groups were compared using Cox regression analysis. RESULTS: We included 26 701 patients with a CHA2DS2-VASc 0 score; 22 915 with CHA2DS2-VASc 1 (1483 patients with heart failure, 9066 with hypertension, 843 with diabetes, 770 with vascular disease, and 10 753 who were 65 to 74 years of age); and 14 525 patients with CHA2DS2-VASc 2 (≥75 years of age without other risk factors). With a median of 1 year of observation time, the cumulative incidence of arterial thromboembolism was 0.6% (n=154 [95% CI, 0.6%-0.8%]), 1.4% (n=16 [95% CI, 0.8%-2.2%]), 1.9% (n=141 [95% CI, 1.6%-2.2%]), 1.7% (n=12 [95% CI, 0.9%-2.9%]), 2.0% (n=13 [95% CI, 1.1%-3.4%]), 2.3% (n=187 [95% CI, 2.0%-2.7%]), and 4.4% (n=533 [95% CI, 4.1%-4.8%]) for CHA2DS2-VASc 0, heart failure, hypertension, diabetes, vascular disease, age 65 to 74 years (CHA2DS2-VASc 1), and age ≥75 years (CHA2DS2-VASc 2), respectively. No statistically significant difference was identified among subgroups of CHA2DS2-VASc 1 (P=0.15 for difference). CONCLUSIONS: For patients with atrial fibrillation, all subgroups of CHA2DS2-VASc 1 were associated with lower incidence of arterial thromboembolism compared with age ≥75 years without other risk factors (ie, CHA2DS2-VASc 2) and a higher incidence compared with CHA2DS2-VASc 0. No statistically significant difference was identified between the subgroups of CHA2DS2-VASc 1. These findings support current recommendations that patients within this intermediate risk group could be identified with a similar risk of arterial thromboembolism.

Strokes Averted by Intravenous Thrombolysis: A Secondary Analysis of a Prospective, Multicenter, Controlled Trial of Mobile Stroke Units.

OBJECTIVE: This study was undertaken to examine averted stroke in optimized stroke systems. METHODS: This secondary analysis of a multicenter trial from 2014 to 2020 compared patients treated by mobile stroke unit (MSU) versus standard management. The analytical cohort consisted of participants with suspected stroke treated with intravenous thrombolysis. The main outcome was a tissue-defined averted stroke, defined as a final diagnosis of stroke with resolution of presenting symptoms/signs by 24 hours attributed to thrombolysis and no acute infarction/hemorrhage on imaging. An additional outcome was stroke with early symptom resolution, defined as a final diagnosis of stroke with resolution of presenting symptoms/signs by 24 hours attributed to thrombolysis. RESULTS: Among 1,009 patients with a median last known well to thrombolysis time of 87 minutes, 159 (16%) had tissue-defined averted stroke and 276 (27%) had stroke with early symptom resolution. Compared with standard management, MSU care was associated with more tissue-defined averted stroke (18% vs 11%, adjusted odds ratio [aOR] = 1.82, 95% confidence interval [CI] = 1.13-2.98) and stroke with early symptom resolution (31% vs 21%, aOR = 1.74, 95% CI = 1.12-2.61). The relationships between thrombolysis treatment time and averted/early recovered stroke appeared nonlinear. Most models indicated increased odds for stroke with early symptom resolution but not tissue-defined averted stroke with earlier treatment. Additionally, younger age, female gender, hyperlipidemia, lower National Institutes of Health Stroke Scale, lower blood pressure, and no large vessel occlusion were associated with both tissue-defined averted stroke and stroke with early symptom resolution. INTERPRETATION: In optimized stroke systems, 1 in 4 patients treated with thrombolysis recovered within 24 hours and 1 in 6 had no demonstrable brain injury on imaging. ANN NEUROL 2024;95:347-361.

Endovascular Thrombectomy for a Progressive Stroke Patient With a High-Burden Carotid Free-Floating Thrombus.

Carotid free-floating thrombus (FFT) is a rare cause of acute ischemic events. The optimal management of carotid FFT remains unclear. The optimal and individualized management of carotid FFT should be determined based on the underlying etiology, clinical manifestation, and imaging characteristics. we reported a case with endovascular thrombectomy for a progressive stroke patient with a high-burden carotid free-floating thrombus. ANN NEUROL 2024;95:362-364.

Association of the Timing of Atrial Fibrillation Detection and Insular Involvement With the Risk of Embolic Events After Acute Ischemic Stroke.

OBJECTIVE: Atrial fibrillation (AF) detected after insular stroke might arise from autonomic and inflammatory mechanisms triggered by insular damage, and be associated with a low embolic risk. We assessed the association of the timing of AF detection and insular involvement with the risk of embolic events after acute ischemic stroke. METHODS: Acute ischemic stroke patients with AF who underwent brain magnetic resonance imaging at baseline were enrolled. Patients were classified according to the timing of AF detection (AF detected after stroke [AFDAS] or known AF [KAF]) and insular involvement. The primary outcome was embolic events defined as recurrent ischemic stroke, transient ischemic attack, and systemic embolism within 90 days. RESULTS: Of 1,548 patients, 360 had AFDAS with insular cortex lesions (+I), 409 had AFDAS without insular cortex lesions (-I), 349 had KAF+I, and 430 had KAF-I. Cumulative incidence rates of embolic events at 90 days in patients with AFDAS+I, AFDAS-I, KAF+I, and KAF-I were 0.8%, 3.5%, 4.9%, and 3.3%, respectively. Patients with AFDAS-I (adjusted hazard ratio 5.04, 95% confidence interval 1.43-17.75), KAF+I (6.18, 1.78-21.46), and KAF-I (5.26, 1.48-18.69) had a significantly higher risk of embolic events than those with AFDAS+I. INTERPRETATION: Acute ischemic stroke patients with AFDAS and insular cortex lesions had a lower risk of embolic events than those who had AFDAS without insular cortex lesions or those with KAF, regardless of insular involvement. ANN NEUROL 2024;95:338-346.

Associations of clonal hematopoiesis with recurrent vascular events and death in patients with incident ischemic stroke.

Clonal hematopoiesis (CH) is common among older people and is associated with an increased risk of atherosclerosis, inflammation, and shorter overall survival. Age and inflammation are major risk factors for ischemic stroke, yet the association of CH with risk of secondary vascular events and death is unknown. We investigated CH in peripheral blood DNA from 581 patients with first-ever ischemic stroke from the Prospective Cohort With Incident Stroke-Berlin study using error-corrected targeted sequencing. The primary composite end point (CEP) consisted of recurrent stroke, myocardial infarction, and all-cause mortality. A total of 348 somatic mutations with a variant allele frequency ≥1% were identified in 236 of 581 patients (41%). CH was associated with large-artery atherosclerosis stroke (P = .01) and white matter lesion (P < .001). CH-positive patients showed increased levels of proinflammatory cytokines, such as interleukin-6 (IL-6), interferon gamma, high-sensitivity C-reactive protein, and vascular cell adhesion molecule 1. CH-positive patients had a higher risk for the primary CEP (hazard ratio [HR], 1.55; 95% confidence interval [CI], 1.04-2.31; P = .03), which was more pronounced in patients with larger clones. CH clone size remained an independent risk factor (HR, 1.30; 95% CI, 1.04-1.62; P = .022) in multivariable Cox regression. Although our data show that, in particular, larger and TET2- or PPM1D-mutated clones are associated with increased risk of recurrent vascular events and death, this risk is partially mitigated by a common germline variant of the IL-6 receptor (IL-6R p.D358A). The CH mutation profile is accompanied by a proinflammatory profile, opening new avenues for preventive precision medicine approaches to resolve the self-perpetuating cycle of inflammation and clonal expansion.

Silent cerebral infarction during immune TTP remission: prevalence, predictors, and impact on cognition.

Immune thrombotic thrombocytopenic purpura (iTTP) survivors have increased risk of cardiovascular disease, including strokes, and report persistent cognitive difficulties during remission. We conducted this prospective study involving iTTP survivors during clinical remission to determine the prevalence of silent cerebral infarction (SCI), defined as magnetic resonance imaging (MRI) evidence of brain infarction without corresponding overt neurodeficits. We also tested the hypothesis that SCI is associated with cognitive impairment, assessed using the National Institutes of Health ToolBox Cognition Battery. For cognitive assessments, we used fully corrected T scores adjusted for age, sex, race, and education. Based on the diagnostic and statistical manual 5 criteria, we defined mild and major cognitive impairment as T scores with a 1 or 2 standard deviation (SD) and >2 SD below the mean on at least 1 test, respectively. Forty-two patients were enrolled, with 36 completing MRIs. SCI was present in 50% of the patients (18), of which 8 (44.4%) had prior overt stroke including during acute iTTP. Patients with SCI had higher rates of cognitive impairment (66.7% vs 27.7%; P = .026), including major cognitive impairment (50% vs 5.6%; P = .010). In separate logistic regression models, SCI was associated with any (mild or major) cognitive impairment (odds ratio [OR] 10.5 [95% confidence interval (95% CI), 1.45-76.63]; P = .020) and major cognitive impairment (OR 7.98 [95% CI, 1.11-57.27]; P = .039) after adjusting for history of stroke and Beck depression inventory scores. MRI evidence of brain infarction is common in iTTP survivors; the strong association of SCI with impaired cognition suggests that these silent infarcts are neither silent nor innocuous.

Prolonged myelin deficits contribute to neuron loss and functional impairments after ischaemic stroke.

Ischaemic stroke causes neuron loss and long-term functional deficits. Unfortunately, effective approaches to preserving neurons and promoting functional recovery remain unavailable. Oligodendrocytes, the myelinating cells in the CNS, are susceptible to oxygen and nutrition deprivation and undergo degeneration after ischaemic stroke. Technically, new oligodendrocytes and myelin can be generated by the differentiation of oligodendrocyte precursor cells (OPCs). However, myelin dynamics and their functional significance after ischaemic stroke remain poorly understood. Here, we report numerous denuded axons accompanied by decreased neuron density in sections from ischaemic stroke lesions in human brain, suggesting that neuron loss correlates with myelin deficits in these lesions. To investigate the longitudinal changes in myelin dynamics after stroke, we labelled and traced pre-existing and newly-formed myelin, respectively, using cell-specific genetic approaches. Our results indicated massive oligodendrocyte death and myelin loss 2 weeks after stroke in the transient middle cerebral artery occlusion (tMCAO) mouse model. In contrast, myelin regeneration remained insufficient 4 and 8 weeks post-stroke. Notably, neuronal loss and functional impairments worsened in aged brains, and new myelin generation was diminished. To analyse the causal relationship between remyelination and neuron survival, we manipulated myelinogenesis by conditional deletion of Olig2 (a positive regulator) or muscarinic receptor 1 (M1R, a negative regulator) in OPCs. Deleting Olig2 inhibited remyelination, reducing neuron survival and functional recovery after tMCAO. Conversely, enhancing remyelination by M1R conditional knockout or treatment with the pro-myelination drug clemastine after tMCAO preserved white matter integrity and neuronal survival, accelerating functional recovery. Together, our findings demonstrate that enhancing myelinogenesis is a promising strategy to preserve neurons and promote functional recovery after ischaemic stroke.

Localization of stuttering based on causal brain lesions.

Stuttering affects approximately 1 in 100 adults and can result in significant communication problems and social anxiety. It most often occurs as a developmental disorder but can also be caused by focal brain damage. These latter cases may lend unique insight into the brain regions causing stuttering. Here, we investigated the neuroanatomical substrate of stuttering using three independent datasets: (i) case reports from the published literature of acquired neurogenic stuttering following stroke (n = 20, 14 males/six females, 16-77 years); (ii) a clinical single study cohort with acquired neurogenic stuttering following stroke (n = 20, 13 males/seven females, 45-87 years); and (iii) adults with persistent developmental stuttering (n = 20, 14 males/six females, 18-43 years). We used the first two datasets and lesion network mapping to test whether lesions causing acquired stuttering map to a common brain network. We then used the third dataset to test whether this lesion-based network was relevant to developmental stuttering. In our literature dataset, we found that lesions causing stuttering occurred in multiple heterogeneous brain regions, but these lesion locations were all functionally connected to a common network centred around the left putamen, including the claustrum, amygdalostriatal transition area and other adjacent areas. This finding was shown to be specific for stuttering (PFWE < 0.05) and reproducible in our independent clinical cohort of patients with stroke-induced stuttering (PFWE < 0.05), resulting in a common acquired stuttering network across both stroke datasets. Within the common acquired stuttering network, we found a significant association between grey matter volume and stuttering impact for adults with persistent developmental stuttering in the left posteroventral putamen, extending into the adjacent claustrum and amygdalostriatal transition area (PFWE < 0.05). We conclude that lesions causing acquired neurogenic stuttering map to a common brain network, centred to the left putamen, claustrum and amygdalostriatal transition area. The association of this lesion-based network with symptom severity in developmental stuttering suggests a shared neuroanatomy across aetiologies.

EEG microstates analysis after TMS in patients with subacute stroke during the resting state.

To investigate whether intermittent theta burst stimulation over the cerebellum induces changes in resting-state electroencephalography microstates in patients with subacute stroke and its correlation with cognitive and emotional function. Twenty-four stroke patients and 17 healthy controls were included in this study. Patients and healthy controls were assessed at baseline, including resting-state electroencephalography and neuropsychological scales. Fifteen patients received lateral cerebellar intermittent theta burst stimulation as well as routine rehabilitation training (intermittent theta burst stimulation-RRT group), whereas 9 patients received only conventional rehabilitation training (routine rehabilitation training group). After 2 wk, baseline data were recorded again in both groups. Stroke patients exhibited reduced parameters in microstate D and increased parameters in microstate C compared with healthy controls. However, after the administration of intermittent theta burst stimulation over the lateral cerebellum, significant alterations were observed in the majority of metrics for both microstates D and C. Lateral cerebellar intermittent theta burst stimulation combined with conventional rehabilitation has a stronger tendency to improve emotional and cognitive function in patients with subacute stroke than conventional rehabilitation. The improvement of mood and cognitive function was significantly associated with microstates C and D. We identified electroencephalography microstate spatiotemporal dynamics associated with clinical improvement following a course of intermittent theta burst stimulation therapy.

Common and distinct patterns underlying different linguistic tasks: multivariate disconnectome symptom mapping in poststroke patients.

Numerous studies have been devoted to neural mechanisms of a variety of linguistic tasks (e.g. speech comprehension and production). To date, however, whether and how the neural patterns underlying different linguistic tasks are similar or differ remains elusive. In this study, we compared the neural patterns underlying 3 linguistic tasks mainly concerning speech comprehension and production. To address this, multivariate regression approaches with lesion/disconnection symptom mapping were applied to data from 216 stroke patients with damage to the left hemisphere. The results showed that lesion/disconnection patterns could predict both poststroke scores of speech comprehension and production tasks; these patterns exhibited shared regions on the temporal pole of the left hemisphere as well as unique regions contributing to the prediction for each domain. Lower scores in speech comprehension tasks were associated with lesions/abnormalities in the superior temporal gyrus and middle temporal gyrus, while lower scores in speech production tasks were associated with lesions/abnormalities in the left inferior parietal lobe and frontal lobe. These results suggested an important role of the ventral and dorsal stream pathways in speech comprehension and production (i.e. supporting the dual stream model) and highlighted the applicability of the novel multivariate disconnectome-based symptom mapping in cognitive neuroscience research.

White matter fiber integrity and structural brain network topology: implications for balance function in postischemic stroke patients.

Previous studies have suggested that ischemic stroke can result in white matter fiber injury and modifications in the structural brain network. However, the relationship with balance function scores remains insufficiently explored. Therefore, this study aims to explore the alterations in the microstructural properties of brain white matter and the topological characteristics of the structural brain network in postischemic stroke patients and their potential correlations with balance function. We enrolled 21 postischemic stroke patients and 21 age, sex, and education-matched healthy controls (HC). All participants underwent balance function assessment and brain diffusion tensor imaging. Tract-based spatial statistics (TBSS) were used to compare the fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity of white matter fibers between the two groups. The white matter structural brain network was constructed based on the automated anatomical labeling atlas, and we conducted a graph theory-based analysis of its topological properties, including global network properties and local node properties. Additionally, the correlation between the significant structural differences and balance function score was analyzed. The TBSS results showed that in comparison to the HC, postischemic stroke patients exhibited extensive damage to their whole-brain white matter fiber tracts (P < 0.05). Graph theory analysis showed that in comparison to the HC, postischemic stroke patients exhibited statistically significant reductions in the values of global efficiency, local efficiency, and clustering coefficient, as well as an increase in characteristic path length (P < 0.05). In addition, the degree centrality and nodal efficiency of some nodes in postischemic stroke patients were significantly reduced (P < 0.05). The white matter fibers of the entire brain in postischemic stroke patients are extensively damaged, and the topological properties of the structural brain network are altered, which are closely related to balance function. This study is helpful in further understanding the neural mechanism of balance function after ischemic stroke from the white matter fiber and structural brain network topological properties.

Functional connectome hierarchy of thalamus impacts fatigue in acute stroke patients.

This study aimed to explore the topographic features of thalamic subregions, functional connectomes and hierarchical organizations between thalamus and cortex in poststroke fatigue patients. We consecutively recruited 121 acute ischemic stroke patients (mean age: 59 years) and 46 healthy controls matched for age, sex, and educational level. The mean age was 59 years (range 19-80) and 38% of acute stroke patients were females. Resting-state functional and structural magnetic resonance imaging were conducted on all participants. The fatigue symptoms were measured using the Fatigue Severity Scale. The thalamic functional subdivisions corresponding to the canonical functional network were defined using the winner-take-all parcellation method. Thalamic functional gradients were derived using the diffusion embedding analysis. The results suggested abnormal functional connectivity of thalamic subregions primarily located in the temporal lobe, posterior cingulate gyrus, parietal lobe, and precuneus. The thalamus showed a gradual increase from the medial to the lateral in all groups, but the right thalamus shifted more laterally in poststroke fatigue patients than in non- poststroke fatigue patients. Poststroke fatigue patients also had higher gradient scores in the somatomotor network and the right medial prefrontal and premotor thalamic regions, but lower values in the right lateral prefrontal thalamus. The findings suggested that poststroke fatigue patients had altered functional connectivity and thalamocortical hierarchical organizations, providing new insights into the neural mechanisms of the thalamus.

Suppression of neuronal CDK9/p53/VDAC signaling provides bioenergetic support and improves post-stroke neuropsychiatric outcomes.

Bioenergy decline occurs with reperfusion following acute ischemic stroke. However, the molecular mechanisms that limit energy metabolism and their impact on post-stroke cognitive and emotional complications are still unclear. In the present study, we demonstrate that the p53 transcriptional response is responsible for neuronal adenosine triphosphate (ATP) deficiency and progressively neuropsychiatric disturbances, involving the downregulation of mitochondrial voltage-dependent anion channels (VDACs). Neuronal p53 transactivated the promoter of microRNA-183 (miR-183) cluster, thereby upregulating biogenesis of miR-183-5p (miR-183), miR-96-5p (miR-96), and miR-182-5p. Both miR-183 and miR-96 directly targeted and post-transcriptionally suppressed VDACs. Neuronal ablation of p53 protected against ATP deficiency and neurological deficits, whereas post-stroke rescue of miR-183/VDAC signaling reversed these benefits. Interestingly, cyclin-dependent kinase 9 (CDK9) was found to be enriched in cortical neurons and upregulated the p53-induced transcription of the miR-183 cluster in neurons after ischemia. Post-treatment with the CDK9 inhibitor oroxylin A promoted neuronal ATP production mainly through suppressing the miR-183 cluster/VDAC axis, further improved long-term sensorimotor abilities and spatial memory, and alleviated depressive-like behaviors in mice following stroke. Our findings reveal an intrinsic CDK9/p53/VDAC pathway that drives neuronal bioenergy decline and underlies post-stroke cognitive impairment and depression, thus highlighting the therapeutic potential of oroxylin A for better outcomes.

Stroke risk in women with atrial fibrillation.

BACKGROUND AND AIMS: Female sex is associated with higher rates of stroke in atrial fibrillation (AF) after adjustment for other CHA2DS2-VASc factors. This study aimed to describe sex differences in age and cardiovascular care to examine their relationship with stroke hazard in AF. METHODS: Population-based cohort study using administrative datasets of people aged ≥66 years diagnosed with AF in Ontario between 2007 and 2019. Cause-specific hazard regression was used to estimate the adjusted hazard ratio (HR) for stroke associated with female sex over a 2-year follow-up. Model 1 included CHA2DS2-VASc factors, with age modelled as 66-74 vs. ≥ 75 years. Model 2 treated age as a continuous variable and included an age-sex interaction term. Model 3 further accounted for multimorbidity and markers of cardiovascular care. RESULTS: The cohort consisted of 354 254 individuals with AF (median age 78 years, 49.2% female). Females were more likely to be diagnosed in emergency departments and less likely to receive cardiologist assessments, statins, or LDL-C testing, with higher LDL-C levels among females than males. In Model 1, the adjusted HR for stroke associated with female sex was 1.27 (95% confidence interval 1.21-1.32). Model 2 revealed a significant age-sex interaction, such that female sex was only associated with increased stroke hazard at age >70 years. Adjusting for markers of cardiovascular care and multimorbidity further decreased the HR, so that female sex was not associated with increased stroke hazard at age ≤80 years. CONCLUSION: Older age and inequities in cardiovascular care may partly explain higher stroke rates in females with AF.

Prevention and treatment of ischaemic and haemorrhagic stroke in people with diabetes mellitus: a focus on glucose control and comorbidities.

Diabetes mellitus is a significant risk factor for both ischaemic and haemorrhagic stroke, affecting up to a third of individuals with cerebrovascular diseases. Beyond being a risk factor for stroke, diabetes and hyperglycaemia have a negative impact on outcomes after ischaemic and haemorrhagic stroke. Hyperglycaemia during the acute ischaemic stroke phase is associated with a higher risk of haemorrhagic transformation and poor functional outcome, with evidence in favour of early intervention to limit and manage severe hyperglycaemia. Similarly, intensive glucose control nested in a broader bundle of care, including blood pressure, coagulation and temperature control, can provide substantial benefit for clinical outcomes after haemorrhagic stroke. As micro- and macrovascular complications are frequent in people with diabetes, cardiovascular prevention strategies also need to consider tailored treatment. In this regard, the broader availability of sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists can allow tailored treatments, particularly for those with heart failure and chronic kidney disease as comorbidities. Here, we review the main concepts of hyperacute stroke management and CVD prevention among people with diabetes, capitalising on results from large studies and RCTs to inform clinicians on preferred treatments.