Post-stroke Functional Recovery Research Articles

Blocking cGAS-STING pathway promotes post-stroke functional recovery in an extended treatment window via facilitating remyelination

Ischemic stroke is a major cause of worldwide death and disability, with recombinant tissue plasminogen activator being the sole effective treatment, albeit with a limited treatment window. The cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) pathway is emerging as the major DNA-sensing pathway to invoke immune responses in neuroinflammatory disorders. By performing a series of neurobehavioral assessments, electrophysiological analysis, high-throughput sequencing, and cell-based assays based on the transient middle cerebral artery occlusion (tMCAO) mouse stroke model, we examined the effects and underlying mechanisms of genetic and pharmacological inhibition of the cGAS-STING pathway on long-term post-stroke neurological functional outcomes. Blocking the cGAS-STING pathway, even 3days after tMCAO, significantly promoted functional recovery in terms of white matter structural and functional integrity as well as sensorimotor and cognitive functions. Mechanistically, the neuroprotective effects via inhibiting the cGAS-STING pathway were contributed not only by inflammation repression at the early stage of tMCAO but also by modifying the cell state of phagocytes to facilitate remyelination at the sub-acute phase. The activation of the cGAS-STING pathway significantly impeded post-stroke remyelination through restraining myelin debris uptake and degradation and hindering oligodendrocyte differentiation and maturation. Manipulating the cGAS-STING pathway has an extended treatment window in promoting long-term post-stroke functional recovery via facilitating remyelination in a mouse stroke model. Our results highlight the roles of the cGAS-STING pathway in aggregating stroke pathology and propose a new way for improving functional recovery after ischemic stroke. This work was primarily funded by the National Key R&D Program of China.

Trunk control and acute-phase multifactorial predictors of community mobility after stroke: a longitudinal observational study.

Stroke is a detrimental condition associated with long-term functional impairments that restrict community reintegration, which is an indicator of successful post-stroke functional recovery and rehabilitation. Additionally, trunk control is an understudied factor that may contribute to community mobility and participation after stroke. This study aimed to identify predictors of community mobility among stroke survivors in the acute phase, with a primary focus on trunk control, in addition to exploring the mediating and moderating role of predictive factors. A longitudinal observational study included 61 participants with acute stroke. Trunk control test (TCT) during sitting, stroke severity, quality of life, fear of falls, depression, and age was assessed during the acute phase as potential predictors. The community mobility outcome measure was assessed 3 months after baseline using the Reintegration to Normal Living Index (RNLI). Statistical analyses included correlation, linear regression, mediation, and moderation analyses. Trunk control test was the strongest predictor of RNLI among all factors (β = 0.72; 95%CI = 0.004-0.007; p ≤ 0.0001). Stroke severity, quality of life, fear of falls, and age significantly predicted RNLI (p < 0.01). Higher age was a significant moderator of the relationship between TCT and RNLI (β = 0.002; p < 0.001; 95% CI = 0.0001-0.0003). The findings highlight sitting trunk control impairment during the acute stage as a crucial predictor of reduced community mobility after stroke, where age over 60 years can moderate this relationship. The study emphasizes that addressing trunk control during early stroke rehabilitation may enhance community reintegration prospects.

STING inhibition suppresses microglia-mediated synapses engulfment and alleviates motor functional deficits after stroke

Ischemic stroke is the leading cause of adult disability. Ischemia leads to progressive neuronal death and synapse loss. The engulfment of stressed synapses by microglia further contributes to the disruption of the surviving neuronal network and related brain function. Unfortunately, there is currently no effective target for suppressing the microglia-mediated synapse engulfment. Stimulator of interferon genes (STING) is an important participant in innate immune response. In the brain, microglia are the primary cell type that mediate immune response after brain insult. The intimate relationship between STING and microglia-mediated neuroinflammation has been gradually established. However, whether STING affects other functions of microglia remains elusive. In this study, we found that STING regulated microglial phagocytosis of synapses after photothrombotic stroke. The treatment of STING inhibitor H151 significantly improved the behavioral performance of injured mice in grid-walking test, cylinder test, and adhesive removal test after stroke. Moreover, the puncta number of engulfed SYP or PSD95 in microglia was reduced after consecutive H151 administration. Further analysis showed that the mRNA levels of several complement components and phagocytotic receptors were decreased after STING inhibition. Transcriptional factor STAT1 is known for regulating most of the decreased molecules. After STING inhibition, the nucleus translocation of phosphorylated STAT1 was also suppressed in microglia. Our data uncovered the novel regulatory effects of STING in microglial phagocytosis after stroke, and further emphasized STING as a potential drug-able target for post-stroke functional recovery.

Chemogenetic activation of astrocytic Gi signaling promotes spinogenesis and motor functional recovery after stroke.

Ischemic stroke is the leading cause of adult disability. The rewiring of surviving neurons is the fundamental process for functional recovery. Accumulating evidence implicates astrocytes in synapses and neural circuits formation, but few studies have further studied how to enhance the effects of astrocytes on synapse and circuits after stroke and its impacts on post-stroke functional recovery. In this study, we made use of chemogenetics to specifically activate astrocytic Gi signaling in the peri-infarcted sensorimotor cortex at different time epochs in a mouse model of photothrombotic stroke. We found that early activation of astrocytic hM4Di after stroke by CNO modulates astrocyte activity and upregulates synaptogenic molecules including thrombospondin-1 (TSP1) as revealed by bulk RNA-sequencing, but no significant improvement was observed in dendritic spine density and behavioral performance in grid walking test. Interestingly, when the manipulation was initiated at the subacute phase of stroke, the recovery of spine density and motor function could be effectively promoted, accompanied by increased TSP1 expression. Our data highlight the important role of astrocytes in synapse remodeling during the repair phase of stroke and suggest astrocytic Gi signaling activation as a potential strategy for synapse regeneration, circuit rewiring, and functional recovery.

The SGLT2 inhibitor Empagliflozin promotes post-stroke functional recovery in diabetic mice

Type-2 diabetes (T2D) worsens stroke recovery, amplifying post-stroke disabilities. Currently, there are no therapies targeting this important clinical problem. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are potent anti-diabetic drugs that also efficiently reduce cardiovascular death and heart failure. In addition, SGLT2i facilitate several processes implicated in stroke recovery. However, the potential efficacy of SGLT2i to improve stroke recovery in T2D has not been investigated. Therefore, we determined whether a post-stroke intervention with the SGLT2i Empagliflozin could improve stroke recovery in T2D mice. T2D was induced in C57BL6J mice by 8 months of high-fat diet feeding. Hereafter, animals were subjected to transient middle cerebral artery occlusion and treated with vehicle or the SGLTi Empagliflozin (10 mg/kg/day) starting from 3 days after stroke. A similar study in non diabetic mice was also conducted. Stroke recovery was assessed using the forepaw grip strength test. To identify potential mechanisms involved in the Empagliflozin-mediated effects, several metabolic parameters were assessed. Additionally, neuronal survival, neuroinflammation, neurogenesis and cerebral vascularization were analyzed using immunohistochemistry/quantitative microscopy. Empagliflozin significantly improved stroke recovery in T2D but not in non-diabetic mice. Improvement of functional recovery was associated with lowered glycemia, increased serum levels of fibroblast growth factor-21 (FGF-21), and the normalization of T2D-induced aberration of parenchymal pericyte density. The global T2D-epidemic and the fact that T2D is a major risk factor for stroke are drastically increasing the number of people in need of efficacious therapies to improve stroke recovery. Our data provide a strong incentive for the potential use of SGLT2i for the treatment of post-stroke sequelae in T2D.

Abstract TMP113: RNA Sequencing Reveals Novel Pericytic MiR-15a/16-1 Targets in Post-Stroke Cerebral Angiogenesis

Introduction: Angiogenesis actively contributes to post-stroke functional recovery and improves long-term survival in stroke patients. Previously, we demonstrated that endothelium-targeted deletion of miR-15a/16-1 promotes post-stroke angiogenesis by enhancing classic pro-angiogenic factors and their receptors, and genetic deletion of miR-15a/16-1 in pericytes likewise promotes post-stroke functional recovery by stimulating cerebral angiogenesis. Here, we further investigate the underlying mechanisms and downstream targets of pericytic miR-15a/16-1 in cerebral angiogenesis after ischemic stroke. Methods: Pericyte-miR15a/16-1 conditional knockout mice (Pericyte-miR-15a/16-1 cKO) and wild-type (WT) controls were subjected to 1h MCAO followed by 7d reperfusion. Cerebral microvessels were extracted and subjected to RNA-seq to identify the significant differentially expressed genes (DEGs) that related to miR-15a/16-1 and angiogenesis among experimental groups. TargetScan and miRDB were used to predict potential miR-15a/16-1 downstream targets. Primary mouse brain vascular pericytes (mBVPs) were treated with lentivirus to achieve loss- or gain-of-miR-15a/16-1 function, and subjected to OGD 8h and reperfusion 24h. Pro-angiogenic factors were further verified by dual-luciferase reporter assay, qPCR, and western blotting. Results: RNA-seq analysis showed 289 upregulated genes (P &lt; 0.05 &amp; at least one CPM &gt; 1) and 399 upregulated genes from 100 positive enriched gene sets (GESA) in cerebral microvessels of pericyte-miR-15a/16-1 cKO mice compared to WT controls 7d after MCAO. By comparing to miR-15a/16-1 potential target database from TargetScan and miRDB, 9 angiogenic genes were identified. Further biochemical analysis revealed that Pappa2, Fgf9, Islr, and Ccr2 mRNA and protein expression are significantly increased in cerebral microvessels of cKO mice and mBVPs with loss-of-miR-15a/16-1 function. Furthermore, dual-luciferase assay results verified that loss- or gain-of-miR-15a/16-1 function significantly increased or decreased luciferase reporter activity of these four genes, respectively. Conclusion: Our findings reveal novel pericytic miR-15a/16-1 mediated angiogenic targets in ischemic stroke.

Genetics in Ischemic Stroke: Current Perspectives and Future Directions.

Ischemic stroke is a heterogeneous condition influenced by a combination of genetic and environmental factors. Recent advancements have explored genetics in relation to various aspects of ischemic stroke, including the alteration of individual stroke occurrence risk, modulation of treatment response, and effectiveness of post-stroke functional recovery. This article aims to review the recent findings from genetic studies related to various clinical and molecular aspects of ischemic stroke. The potential clinical applications of these genetic insights in stratifying stroke risk, guiding personalized therapy, and identifying new therapeutic targets are discussed herein.

The Promotoer, a brain-computer interface-assisted intervention to promote upper limb functional motor recovery after stroke: a statistical analysis plan for a randomized controlled trial

BackgroundElectroencephalography (EEG)-based brain-computer interfaces (BCIs) allow to modulate the sensorimotor rhythms and are emerging technologies for promoting post-stroke motor function recovery. The Promotoer study aims to assess the short and long-term efficacy of the Promotoer system, an EEG-based BCI assisting motor imagery (MI) practice, in enhancing post-stroke functional hand motor recovery. This paper details the statistical analysis plan of the Promotoer study.MethodsThe Promotoer study is a randomized, controlled, assessor-blinded, single-centre, superiority trial, with two parallel groups and a 1:1 allocation ratio. Subacute stroke patients are randomized to EEG-based BCI-assisted MI training or to MI training alone (i.e. no BCI). An internal pilot study for sample size re-assessment is planned. The primary outcome is the effectiveness of the Upper Extremity Fugl-Meyer Assessment (UE-FMA) score. Secondary outcomes include clinical, functional, and user experience scores assessed at the end of intervention and at follow-up. Neurophysiological assessments are also planned. Effectiveness formulas have been specified, and intention-to-treat and per-protocol populations have been defined. Statistical methods for comparisons of groups and for development of a predictive score of significant improvement are described. Explorative subgroup analyses and methodology to handle missing data are considered.DiscussionThe Promotoer study will provide robust evidence for the short/long-term efficacy of the Promotoer system in subacute stroke patients undergoing a rehabilitation program. Moreover, the development of a predictive score of response will allow transferring of the Promotoer system to optimal clinical practice. By carefully describing the statistical principles and procedures, the statistical analysis plan provides transparency in the analysis of data.Trial registrationClinicalTrials.gov NCT04353297. Registered on April 15, 2020.

Post-stroke brain can be protected by modulating the lncRNA FosDT

We previously showed that knockdown or deletion of Fos downstream transcript (FosDT; a stroke-induced brain-specific long noncoding RNA) is neuroprotective. We presently tested the therapeutic potential of FosDT siRNA in rodents subjected to transient middle cerebral artery occlusion (MCAO) using the Stroke Treatment Academic Industry Roundtable criteria, including sex, age, species, and comorbidity. FosDT siRNA (IV) given at 30 min of reperfusion significantly improved motor function recovery (rotarod test, beam walk test, and adhesive removal test) and reduced infarct size in adult and aged spontaneously hypertensive rats of both sexes. FosDT siRNA administered in a delayed fashion (3.5 h of reperfusion following 1 h transient MCAO) also significantly improved motor function recovery and decreased infarct volume. Furthermore, FosDT siRNA enhanced post-stroke functional recovery in normal and diabetic mice. Mechanistically, FosDT triggered post-ischemic neuronal damage via the transcription factor REST as REST siRNA mitigated the enhanced functional outcome in FosDT−/− rats. Additionally, NF-κB regulated FosDT expression as NF-κB inhibitor BAY 11-7082 significantly decreased post-ischemic FosDT induction. Thus, FosDT is a promising target with a favorable therapeutic window to mitigate secondary brain damage and facilitate recovery after stroke regardless of sex, age, species, and comorbidity.

Suppression of DAPK1 reduces ischemic brain injury through inhibiting cell death signaling and promoting neural remodeling

The role of death-associated protein kinase1 (DAPK1) in post-stroke functional recovery is controversial, as is its mechanism of action and any neural remodeling effect after ischemia. To assess the debatable role of DAPK1, we established the middle cerebral artery occlusion (MCAo) model in DAPK1 knockout mice and Sprague-Dawley (SD) rats. We identified that the genetic deletion of the DAPK1 as well as pharmacological inhibition of DAPK1 showed reduced brain infarct volume and neurological deficit. We report that DAPK1 inhibition (DI) reduces post-stroke neuronal death by inhibiting BAX/BCL2 and LC3/Beclin1 mediated apoptosis and autophagy, respectively. Histological analysis displayed a reduction in nuclear condensation, neuronal dissociation, and degraded cytoplasm in the DI group. The DI treatment showed enhanced dendrite spine density and neurite outgrowth, upregulated neural proliferation marker proteins like brain-derived neurotrophic factor, and reduced structural abnormalities of the cortical pyramidal neurons. This research shows that DAPK1 drives cell death, its activation exacerbates functional recovery after cerebral ischemia and shows that oxazolone-based DI could be an excellent candidate for stroke and ischemic injury intervention.

Caregiver burden and its associated factors among primary caregivers of stroke survivors at Amhara regional state tertiary hospitals: a multicenter study

BackgroundCaregivers of stroke survivors play a crucial role in post-stroke functional recovery and the prevention of complications. Although the situation is incredibly stressful and intimidating and the caregiver burden is high, there is little evidence in the local Ethiopian context of the extent of the burden among caregivers of stroke survivors. Therefore, the aim of this study was to assess the level of caregiver burden and its associated factors among primary caregivers of stroke survivors in Ethiopia.MethodsA cross-sectional study was conducted in Amhara regional state tertiary hospitals from April to June 2022. A standardized questionnaire was used to record factors associated with caregiver burden, including sociodemographic, clinical, and care situation factors. The Zarit caregiver burden interview (short form) was used to assess the level of caregiver burden. A systematic random sampling method was employed to select the study participants. Multinomial logistic regression was employed to identify the potential factors associated with the level of caregiver burden.ResultsThe overall prevalence burden among primary caregivers of stroke survivors was 67%. 61.1% had a mild to moderate burden, while 5.9% had a severe burden. In multivariable multinomial logistic regression analysis, sex, household income, duration of care, and duration of caregiving hours per day were factors significantly associated with the level of burden among caregivers of stroke survivors.ConclusionsBeing female, having a low household income, caring for more than 3 months, and caring for more than 6 h per day were factors significantly associated with the burdens of the primary caregivers of stroke survivors. It is better: health care providers must recognize and screen for burdens and provide special attention.

Responsiveness of Section GG Scores in Tracking Post-Stroke Functional Recovery From Inpatient Rehabilitation Admission to 90-Day Follow-Up

ObjectiveTo evaluate the responsiveness and scale-to-sample targeting of Section GG of the Inpatient Rehabilitation Facility-Patient Assessment Instrument in measuring the trajectory of functional recovery in patients with stroke from inpatient rehabilitation admission to 90 days after discharge. DesignRetrospective cohort study. Setting150-bed inpatient rehabilitation facility. ParticipantsPatients with stroke (N=1087) discharged between December 2019 to April 2021. InterventionNot applicable. Main Outcome MeasuresAdmission and discharge self-care and mobility scores from Section GG were analyzed for the Inpatient Only group (n= 817). Admission, discharge and 90-day post-discharge Section GG scores from telephone interviews with patients or caregivers were analyzed for the Follow-Up group (n=270). Standardized response means (SRM) determined responsiveness of the tool for each group and time interval. Score means, standard deviations, and floor/ceiling effects illustrated scale-to-sample targeting of the tool. ResultsSelf-care and mobility scores improved significantly from admission to discharge (P<.001) for both groups and from discharge to 90 days (P<.001) for the Follow-Up group. Large SRM existed from admission to discharge for self-care and mobility scores in both groups. ​A small-to-moderate SRM was seen from discharge to 90 days for self-care (0.46) and a moderate SRM was observed for mobility (0.68). Overall floor effects were minor at admission for self-care (9.8%) and mobility (7.2.%). Overall ceiling effects were minor at discharge for self-care (11.2%) and mobility (4.6%)​ and significant at follow-up for both self-care (45.2%) and mobility (32.2%). ConclusionsSection GG is responsive to change and appropriately measures patients’ functional ability during inpatient rehabilitation. More study is required for telephone follow-up after discharge from inpatient rehabilitation.

A U-shaped relationship between body mass index and functional recovery in older Japanese stroke survivors undergoing hospital rehabilitation

ObjectiveA relationship between body mass index and functional recovery in older survivors of stroke is unclear. Therefore, this study aimed to investigate the association of body mass index with post-stroke functional recovery in older Japanese stroke survivors undergoing hospital rehabilitation. MethodsThis was a multicenter retrospective observational study of 757 older survivors of stroke, from six convalescent rehabilitation hospitals in Japan. The participants were classified into seven categories according to body mass index at admission. The measurements included outcomes of the absolute gain in the motor subscale of the Functional Independence Measure. Poor functional recovery was defined as gain < 17 points. Multivariate logistic regression analysis was performed to examine the impact of these body mass index categories on poor functional recovery. ResultsThe mean motor gains were highest in the 23.5–25.4 kg/m2 group (28.1 points), and lowest in the < 17.5 kg/m2 group (220.0 points). The results of the multivariate regression analyses (reference; 23.5–25.4 kg/m2 group) showed that the < 17.5 kg/m2 group (odds ratios 4.30; 95 % confidence intervals 2.09–8.87), the 17.5–19.4 kg/m2 group (1.99; 1.03–3.87), the 19.5–21.4 kg/m2 group (1.93; 1.05–3.54), and the ≥ 27.5 kg/m2 group (3.34; 1.33–8.42) were significantly associated with poor functional recovery, but not in the other groups. ConclusionsOlder survivors of stroke with high-normal weight had the most favorable functional recovery among the seven groups. Meanwhile, both low and extremely high body mass indexes were associated with poor functional recovery.

Quantitative EEG Based on Direct Recording and Source Localization Estimation in Repetitive Hand Motor Activity

Electroencephalography (EEG) has been widely used in clinical practice as a tool to guide an efficient post-stroke functional recovery program and adjust the rehabilitation training program. EEG has some advantages in temporal resolution, portability, and relatively low cost. Motor-related brain activities can be quantified by measuring the mu rhythm’s event-related desynchronization (ERD), acquired from a direct surface EEG recording. The common problem of direct surface EEG is the crosstalk between brain regions that are unrelated to the sensorimotor cortex. This problem can be solved through the EEG source localization technique. Essentially, the idea of source reconstruction is to estimate the primary cortical current densities during the given EEG recording across the head surface. The recent work aims to compare EEG power spectral density (PSD) analysis and source localization. Modification of exact-Low Resolution Brain Electromagnetic Tomography (eLORETA) was used as an EEG source localization method. EEG data recording was performed on a healthy, able-bodied male subject using 21 electrodes based on the case study’s 10-20 electrode placement system. The subject was asked to perform basic hand movements, i.e., grasping with and without hand load. Mu power was calculated from the electrodes that are located around the motor cortex (C3 and C4), while the average current density was calculated from the Brodmann Area (BA) 4 and 6, both during grasping and relaxation (baseline). The comparison showed that during grasping, there was a decrease in aver-age current density around BA-4 and BA-6 and a decrease in mu power at C3 and C4 when compared to baseline. These results indicate: (1) the activity of mu rhythm’s ERD around the sensorimotor cortex during hand movement; and (2) the possibility of using the EEG source localization method as an alternative biofeedback modality.

Abstract WP55: Development Of Comprehensive Post-Acute Stroke Program Standards

Introduction: Evidence-based rehabilitation and secondary prevention interventions improve post-stroke functional recovery and reduce secondary complications. However, stroke rehabilitation expertise, processes of care, and educational resources vary among sites where post-acute care (PAC) is delivered. Purpose: The American Heart Association (AHA) developed quality standards based on the AHA 2016 Guidelines for Adult Stroke Rehabilitation and Recovery to address these gaps. Methods: An interdisciplinary PAC standards writing committee identified key areas for PAC: quality improvement, medical management, care coordination, patient/caregiver and personnel education, and program management. Subgroups developed draft standards, combining results from a national landscape survey of PAC sites with clinical practice guidelines. The committee then refined the draft standards using a consensus-based process. AHA staff and PAC sites in Montana (MT) convened a learning collaborative to gather feedback and provide gap analyses of the standards relative to current practices. Qualitative input from beta testing in MT, and quantitative results from the nationwide survey and MT sites were analyzed and used to refine the standards further. Results: The national landscape survey demonstrated that most sites do not meet the proposed standards: stroke program oversight structure (78% fall short), stroke rehabilitation leadership (70%), stroke-specific order sets/protocols (61%), and policies requiring staff stroke education (66%). Regarding MT findings, 41% of the PAC sites have no mechanisms to identify areas of quality improvement specific to their stroke rehabilitation programs, and 59% do not use standardized tools to ensure performance improvement initiatives are followed. However, with adequate support and resources, most MT sites stated they would be able to meet the proposed standards. Conclusions: The Stroke PAC Program Standards are applicable in diverse PAC settings and provide a pathway to improving access to high-quality care for stroke survivors. Outcome studies are needed to confirm anticipated improvements in medical and functional outcomes.

Abstract TMP118: Brain Derived Neurotrophic Factor Secretion From Lungs Mediate The Post-stroke Functional Recovery After Systemic Administration Of MSCs

Background: Bone marrow derived mesenchymal stromal cells (MSCs) have been actively tested in clinical trials. After intravenous (IV) administration, vast majority of them are trapped in lung vasculature, with only few reaching brain. Even though MSCs are short-lived in the lungs, their beneficial effects on post-stroke recovery extends for weeks, suggesting a paracrine mechanism of action. Integrins expression on MSCs is known to mediate the lung entrapment by binding to ICAM1-expressing endothelial cells (ECs). Furthermore, ECs can perform paracrine functions by releasing neurotrophins, such as brain derived neurotrophic factor (BDNF). We explored EC-MSC interaction in lungs, and its effect on BDNF release from lung ECs, in an experimental stroke model. Methods: Human lung ECs (Cell Biologics) were cultured at P3. Human MSCs were isolated from bone marrow of healthy donor and P3 MSCs were used for experiments. Serum from stroke patients with NIH Stroke Scale (NIHSS) severity ranging from 0 to 10 was collected at 24 hours after stroke. Co-culture experiments were done in trans-well plates. BDNF mRNA was isolated using Qiagen RNeasy kit. Middle Cerebral Artery Occlusion model (filament model) was used in C57BL/6 mice. Modified Neurological Severity Score (mNSS) was used for functional assessment in mice stroke model. Results: Human primary lung ECs exposed to plasma from stroke patients as well as recombinant TNF-α showed robust increase in BDNF secretion, with MSCs enhancing the secretion furthermore. BDNF mRNA was robustly increased in whole mouse lungs as well as lung ECs. IV MSC administration robustly increased plasma BDNF and BDNF mRNA expression in mouse lung ECs. Furthermore, IV MSCs provided better functional recovery as compared to IV BDNF. Conclusion: BDNF is already known to be neuroprotective. Our results show that BDNF secretions increase from lung ECs after IV MSC administration, which could mediate functional recovery in mice after stroke.

Extracellular Vesicles as Delivery Shippers for Noncoding RNA-Based Modulation of Angiogenesis: Insights from Ischemic Stroke and Cancer.

Ischemic stroke and systemic cancer are two of the leading causes of mortality. Hypoxia is a central pathophysiological component in ischemic stroke and cancer, representing a joint medical function. This function includes angiogenesis regulation. Vascular remodeling coupled with axonal outgrowth following cerebral ischemia is critical in improving poststroke neurological functional recovery. Antiangiogenic strategies can inhibit cancer vascularization and play a vital role in impeding cancer growth, invasion, and metastasis. Although there are significant differences in the cause of angiogenesis across both pathophysiological conditions, emerging evidence states that common signaling structures, such as extracellular vesicles (EVs) and noncoding RNAs (ncRNAs), are involved in this context. EVs, heterogeneous membrane vesicles encapsulating proteomic genetic information from parental cells, act as multifunctional regulators of intercellular communication. Among the multifaceted roles in modulating biological responses, exhaustive evidence shows that ncRNAs are selectively sorted into EVs, modulating common specific aspects of cancer development and stroke prognosis, namely, angiogenesis. This review will discuss recent advancements in the EV-facilitated/inhibited progression of specific elements of angiogenesis with a particular concern about ncRNAs within these vesicles. The review is concluded by underlining the clinical opportunities of EV-derived ncRNAs as diagnostic, prognostic, and therapeutic agents.

Connectome-based predictive modeling for functional recovery of acute ischemic stroke

Patients of acute ischemic stroke possess considerable chance of recovery of various levels in the first several weeks after stroke onset. Prognosis of functional recovery is important for decision-making in poststroke patient care and placement. Poststroke functional recovery has conventionally been based on demographic and clinical variables such as age, gender, and severity of stroke impairment. On the other hand, the concept of connectome has become a basis of interpreting the functional impairment and recovery of stroke patients. In this research, the connectome-based predictive modeling was used to provide predictive models for prognosing poststroke functional recovery. Predictive models were developed to use the brain connectivity at stroke onset to predict functional assessment scores at one or three months later, or to use the brain connectivity one-month poststroke to predict functional assessment scores at three months after stroke onset. The brain connectivity was computed from the resting-state fMRI signals. The functional assessment scores used in this research included modified Rankin Scale (mRS) and Barthel Index (BI). This research found significant models that used the brain connectivity at onset to predict the mRS one-month poststroke and to predict the BI three-month poststroke for patients with supratentorial infarction, as well as predictive models that used the brain connectivity one-month poststroke to predict the mRS three-month poststroke for patients with supratentorial infarction in the right hemisphere. The connectome-based predictive modeling could provide clinical value in prognosis of acute ischemic stroke.

Middle Cerebral Artery Occlusion in Aged Animal Model.

Stroke is a devastating brain injury resulting in high mortality and substantial loss of function, affecting >15 million people worldwide annually; the majority of which are over 65 years old (Feigin et al., Lancet 383:245-254, 2014; Feigin et al., Lancet Neurol 2:43-53, 2003; Benjamin et al., Circulation 135:e146-e603, 2017; Writing Group et al., Circulation 133:447-454, 2016; Roy-O'Reilly, McCullough, Endocrinology 159:3120-3131, 2018). Aging is a significant risk factor for stroke, and older patients have higher mortality and poorer functional recovery after stroke compared with younger patients (Arboix et al., J Am Geriatr Soc 48:36-41, 2000; Rojas et al., Eur J Neurol 14:895-899, 2007). Despite the importance of aging in the pathophysiology of stroke, the vast majority of preclinical studies have only used young animals. Understanding the mechanisms underlying stroke-induced brain damage and post-stroke functional recovery in aged animals is an urgent need. This step is essential to the development of therapeutics for treating stroke patients, most of whom are elderly. To understand the pathophysiology of ischemic injury induced by middle cerebral artery occlusion (MCAO), one of the most common type of stroke seen clinically (Writing Group et al., Circulation 133:e38-360, 2016), it is imperative to include older animals in preclinical testing. The purpose of this chapter is to provide insight on successfully reproducing MCAO injury in translationally relevant aged animals.

Mechanism of Post-stroke Axonal Outgrowth and Functional Recovery

Mechanism of Post-stroke Axonal Outgrowth and Functional Recovery