Blood-derived factors to brain communication in brain diseases.

Brain diseases, mainly including acute brain injuries, neurodegenerative diseases, and mental disorders, have posed a significant threat to human health worldwide. Due to the limited regenerative capability and the existence of the blood-brain barrier, the brain was previously thought to be separated from the rest of the body. Currently, various cross-talks between the central nervous system (CNS) and peripheral organs have been widely described, including the brain-gut axis, the brain-liver axis, the brain-skeletal muscle axis, and the brain-bone axis. Moreover, several lines of evidence indicate that leveraging systemic biology intervention approaches, including but not limited to lifestyle interventions, exercise, diet, blood administration, and peripheral immune responses, have demonstrated a significant influence on the progress and prognosis of brain diseases. The advancement of innovative proteomic and transcriptomic technologies has enriched our understanding of the nuanced interplay between peripheral organs and brain diseases. An array of novel or previously underappreciated blood-derived factors have been identified to play pivotal roles in mediating these communications. In this review, we provide a comprehensive summary of blood-to-brain communication following brain diseases. Special attention is given to the instrumental role of blood-derived signals, positing them as significant contributors to the complex process of brain diseases. The insights presented here aim to bridge the current knowledge gaps and inspire novel therapeutic strategies for brain diseases.

Neuroprotection on ischemic brain injury by Mg2+/H2 released from endovascular Mg implant.

Most acute ischemic stroke patients with large vessel occlusion require stent implantation for complete recanalization. Yet, due to ischemia-reperfusion injury, over half of these patients still experience poor prognoses. Thus, neuroprotective treatment is imperative to alleviate the ischemic brain injury, and a proof-of-concept study was conducted on "biodegradable neuroprotective stent". This concept is premised on the hypothesis that locally released Mg2+/H2 from Mg metal within the bloodstream could offer synergistic neuroprotection against reperfusion injury in distant cerebral ischemic tissues. Initially, the study evaluated pure Mg's neuroactive potential using oxygen-glucose deprivation/reoxygenation (OGD/R) injured neuron cells. Subsequently, a pure Mg wire was implanted into the common carotid artery of the transient middle cerebral artery occlusion (MCAO) rat model to simulate human brain ischemia/reperfusion injury. In vitro analyses revealed that pure Mg extract aided mouse hippocampal neuronal cell (HT-22) in defending against OGD/R injury. Additionally, the protective effects of the Mg wire on behavioral abnormalities, neural injury, blood-brain barrier disruption, and cerebral blood flow reduction in MCAO rats were verified. Conclusively, Mg-based biodegradable neuroprotective implants could serve as an effective local Mg2+/H2 delivery system for treating distant cerebral ischemic diseases.

Model-predicted brain temperature computational imaging by multimodal noninvasive functional neuromonitoring of cerebral oxygen metabolism and hemodynamics: MRI-derived and clinical validation.

Brain temperature, a crucial yet under-researched neurophysiological parameter, is governed by the equilibrium between cerebral oxygen metabolism and hemodynamics. Therapeutic hypothermia has been demonstrated as an effective intervention for acute brain injuries, enhancing survival rates and prognosis. The success of this treatment hinges on the precise regulation of brain temperature. However, the absence of comprehensive brain temperature monitoring methods during therapy, combined with a limited understanding of human brain heat transmission mechanisms, significantly hampers the advancement of hypothermia-based neuroprotective therapies. Leveraging the principles of bioheat transfer and MRI technology, this study conducted quantitative analyses of brain heat transfer during mild hypothermia therapy. Utilizing MRI, we reconstructed brain structures, estimated cerebral blood flow and oxygen consumption parameters, and developed a brain temperature calculation model founded on bioheat transfer theory. Employing computational cerebral hemodynamic simulation analysis, we established an intracranial arterial fluid dynamics model to predict brain temperature variations across different therapeutic hypothermia modalities. We introduce a noninvasive, spatially resolved, and optimized mathematical bio-heat model that synergizes model-predicted and MRI-derived data for brain temperature prediction and imaging. Our findings reveal that the brain temperature images generated by our model reflect distinct spatial variations across individual participants, aligning with experimentally observed temperatures.

Mild hypothermia therapy attenuates early BBB leakage in acute ischaemic stroke.

Reperfusion therapy inevitably leads to brain-blood barrier (BBB) disruption and promotes damage despite its benefits for acute ischaemic stroke (AIS). An effective brain cytoprotective treatment is still needed as an adjunct to reperfusion therapy. Here, we explore the potential benefits of therapeutic hypothermia (HT) in attenuating early BBB leakage and improving neurological outcomes. Mild HT was induced during the early and peri-recanalization stages in a mouse model of transient middle cerebral artery occlusion and reperfusion (tMCAO/R). The results showed that mild HT attenuated early BBB leakage in AIS, decreased the infarction volume, and improved functional outcomes. RNA sequencing data of the microvessels indicated that HT decreased the transcription of the actin polymerization-related pathway. We further discovered that HT attenuated the ROCK1/MLC pathway, leading to a decrease in the polymerization of G-actin to F-actin. Arachidonic acid (AA), a known structural ROCK agonist, partially counteracted the protective effects of HT in the tMCAO/R model. Our study highlights the importance of early vascular protection during reperfusion and provides a new strategy for attenuating early BBB leakage by HT treatment for ischaemic stroke.

Subpixel motion artifacts correction and motion estimation for 3D-OCT.

A number of hardware-based and software-based strategies have been suggested to eliminate motion artifacts for improvement of 3D-optical coherence tomography (OCT) image quality. However, the hardware-based strategies have to employ additional hardware to record motion compensation information. Many software-based strategies have to need additional scanning for motion correction at the expense of longer acquisition time. To address this issue, we propose a motion artifacts correction and motion estimation method for OCT volumetric imaging of anterior segment, without requirements of additional hardware and redundant scanning. The motion correction effect with subpixel accuracy for in vivo 3D-OCT has been demonstrated in experiments. Moreover, the physiological information of imaging object, including respiratory curve and respiratory rate, has been experimentally extracted using the proposed method. The proposed method offers a powerful tool for scientific research and clinical diagnosis in ophthalmology and may be further extended for other biomedical volumetric imaging applications.

Trends and hotspots of the neuroprotection of hypothermia treatment: A bibliometric and visualized analysis of research from 1992 to 2023.

AIM: Recent studies have extensively investigated hypothermia as a therapeutic approach for mitigating neural damage. Despite this, bibliometric analyses specifically focusing on this area remain scarce. Consequently, this study aims to comprehensively outline the historical framework of research and to pinpoint future research directions and trends. METHODS: Articles spanning from 2003 to 2023, relevant to both "neuroprotection" and "hypothermia", were sourced from the Web of Science Core Collection. The CiteSpace software facilitated a comprehensive evaluation and analysis of these publications. This analysis included examining the annual productivity, collaboration among nations, institutions, and authors, as well as the network of co-cited references, authors and journals, and the co-occurrence of keywords, and their respective clusters and trends, all of which were visualized. RESULTS: This study included 2103 articles on the neuroprotection effects of hypothermia, noting a consistent increase in publications since 1992. The United States, the University of California System, and Ji Xunming emerged as the most productive nation, institution, and author, respectively. Analysis of the top 10 co-cited publications revealed that seven articles focused on the effects of hypothermia in infants with hypoxic-ischemic encephalopathy, while three studies addressed cardiac arrest. Shankaran S and the journal Stroke were the most frequently co-cited author and journal, respectively. Keyword cluster analysis identified ischemic stroke as the primary focus of hypothermia therapy historically, with cardiac arrest and neonatal hypoxic-ischemic encephalopathy emerging as current research foci. CONCLUSIONS: Recent studies on the neuroprotective effects of hypothermia in cardiac arrest and neonatal hypoxic-ischemic encephalopathy suggest that hypothermia may mitigate neural damage associated with these conditions. However, the application of hypothermia in the treatment of ischemic stroke remains confined to animal models and in vitro studies, with a notable absence of evidence from multicenter randomized controlled trials (RCTs). Further research is required to address this gap.

A narrative review of intravascular catheters in therapeutic hypothermia.

Therapeutic hypothermia (TH) has been regarded as a promising neuroprotective method for acute ischemic stroke (AIS) for decades. During the development of TH, most researchers focused on improving hypothermic benefits by optimizing treatment processes and conditions. Intravenous thrombolysis and endovascular thrombectomy, for instance, have been introduced into AIS treatment. However, the lack of specialized intervention consumables, especially intervention catheter, led to inaccurate and uncontrolled hypothermic temperature, limited the efficacy of TH. In this review, intervention catheters as well as accessory equipment utilized in TH treatment has been summarized. Hopefully, this review may inspire the future development of TH specialized intervention catheter, enhance the outcome of TH, and neuroprotective efficacy in AIS.

Research hotpots and frontier trends of neuroprotective effects of magnesium from 1999 to 2023: A bibliometric analysis.

BACKGROUND: The neuroprotective effect of magnesium has been widely discussed, and its effectiveness has been confirmed by animal and clinical trials. However, there are still difficulties in clinical translation in diseases such as cerebral ischemia and subarachnoid hemorrhage. Therefore, it is necessary to analyze the literatures about neuroprotection of magnesium to reveal a more comprehensive knowledge framework, research hotspots and trends in the future. METHODS: Original articles and reviews related to neuroprotective effects of magnesium from 1999 to 2022 were retrieved from the Web of Science Core Collection (WoSCC). The bibliometrics CiteSpace 6.2.R4 software was used to conduct co-occurrence/co-citation network analysis and plot knowledge visualization maps. RESULTS: A total of 762 articles from 216 institutions in 64 countries were included in this study. The United States had the largest number of publications, followed by China and Canada. The University of California, UDICE-French Research Universities, and the University of Adelaide were the top three institutions in publication volume. Crowther Caroline A was the most published and cited author. Among the top 10 cited articles, there were seven articles on neuroprotection in preterm infants and three on acute stroke. Keyword cluster analysis obtained 11 clusters, showing that current research hotspots focused on magnesium therapy in neurovascular diseases such as cerebral ischemia, spinal cord injury, subarachnoid hemorrhage, and emerging treatment strategies. CONCLUSION: The neuroprotective effects of magnesium in preterm infants have been extensively studied and adequately confirmed. The therapeutic effects of magnesium on cerebral ischemia and subarachnoid hemorrhage have been demonstrated in animal models. However, the results of clinical studies were not satisfactory, and exploring new therapeutic strategies may be the solution. Recently, the combination of magnesium and hypothermia had great potential in neuroprotective therapy and may become a development trend and hotspot in the future.

"No-reflow" phenomenon in acute ischemic stroke.

Acute ischemic stroke (AIS) afflicts millions of individuals worldwide. Despite the advancements in thrombolysis and thrombectomy facilitating proximal large artery recanalization, the resultant distal hypoperfusion, referred to "no-reflow" phenomenon, often impedes the neurological function restoration in patients. Over half a century of scientific inquiry has validated the existence of cerebral "no-reflow" in both animal models and human subjects. Furthermore, the correlation between "no-reflow" and adverse clinical outcomes underscores the necessity to address this phenomenon as a pivotal strategy for enhancing AIS prognoses. The underlying mechanisms of "no-reflow" are multifaceted, encompassing the formation of microemboli, microvascular compression and contraction. Moreover, a myriad of complex mechanisms warrant further investigation. Insights gleaned from mechanistic exploration have prompted advancements in "no-reflow" treatment, including microthrombosis therapy, which has demonstrated clinical efficacy in improving patient prognoses. The stagnation in current "no-reflow" diagnostic methods imposes limitations on the timely application of combined therapy on "no-reflow" post-recanalization. This narrative review will traverse the historical journey of the "no-reflow" phenomenon, delve into its underpinnings in AIS, and elucidate potential therapeutic and diagnostic strategies. Our aim is to equip readers with a swift comprehension of the "no-reflow" phenomenon and highlight critical points for future research endeavors.

Causal Effect of Lipoprotein-Associated Phospholipase A2 Activity on Ischemic Stroke: A Mendelian Randomization Study.

BACKGROUND: The relationship between ischemic stroke (IS) and lipoprotein-associated phospholipase A2 (Lp-PLA2) activity is still unclear, and there is a dearth of stratified research on the relationship between Lp-PLA2 activity and different IS subtypes. Therefore, Mendelian randomization (MR) was used in this study to examine the relationship between genetically proxied Lp-PLA2 activity and the risks of IS and its subtypes. METHODS: Based on information from a meta-analysis of genome-wide association studies, which included 13,664 European people, five single nucleotide polymorphisms related to Lp-PLA2 activity were chosen as instrumental variables. Summary statistics information about the MEGESTROKE consortium with the European group (40,585 cases and 406,111 controls) include any IS (AIS; n = 34,217), large-artery stroke (LAS; n = 4,373), cardioembolic stroke (CES; n = 7,193), and small-vessel stroke (SVS; n = 5,386). In order to determine the causal relationships between Lp-PLA2 activity and IS as well as its subtypes, the inverse-variance-weighted (IVW) approach was chosen as the primary analysis. Significant estimates were then tested by sensitivity analysis to rule out heterogeneity and pleiotropy. RESULTS: IVW showed that Lp-PLA2 activity was causally associated with LAS (odds ratio = 3.25, 95% confidence interval = 1.65-6.41, p = 0.0007) but not with other subtypes of stroke. Sensitivity analysis for causal estimates between Lp-PLA2 activity and LAS showed no significant heterogeneity or pleiotropy. CONCLUSIONS: These MR analyses support a causal effect of Lp-PLA2 activity on LAS but not on AIS, CES, or SVS, which suggests that serum Lp-PLA2 activity might be a biomarker for prediction of LAS.

Hemolysis performance analysis and a novel estimation model of roller pump system.

OBJECTIVE: Hemolysis performance is a crucial criterion for roller pumps utilized in life supporting system. In this study, the factor of hemolysis for roller pumps was selected as the target, and an estimation formulation was built to evaluate its hemolysis. METHODS: Several models were proposed and then simulated with the assistant of Computational fluid dynamics (CFD) framework. The hemolysis performance was calculated using the power law model based on CFD and the estimation model in accordance with geometry parameters proposed in this study. The results of the in vitro experiments were compared with the simulation results. Power law model with the lowest error was utilized in following analysis. RESULTS: As indicated by the simulation result, the rotary speed most significantly affected the hemolysis performance of roller blood pumps, followed by roller number and diameter of tube. The index of hemolysis (IH) for roller blood pumps at a rotary speed of 20-100 rpm ranged from 8.73E-7 to 8.07E-5. The relative error of the estimation model (4.93%) was lower than of the power law model (6.78%). CONCLUSION: The IH led by pumps shows a significant, nonlinear relationship with the rotary speed. The design of multiple rollers design is harmful for hemolysis performance and larger diameter of tube exhibits decreased hemolysis at constant flow rate. An estimation formula was proposed with lower relative error for roller pump with the same shell set, which exhibited reduced computation and elevated convenience. And it can be utilized in hemolysis estimation of roller pumps potentially.

Dual-sized hollow particle incorporated fibroin thermal insulating coatings on catheter for cerebral therapeutic hypothermia.

Selective endovascular hypothermia has been used to provide cooling-induced cerebral neuroprotection, but current catheters do not support thermally-insulated transfer of cold infusate, which results in an increased exit temperature, causes hemodilution, and limits its cooling efficiency. Herein, air-sprayed fibroin/silica-based coatings combined with chemical vapor deposited parylene-C capping film was prepared on catheter. This coating features in dual-sized-hollow-microparticle incorporated structures with low thermal conductivity. The infusate exit temperature is tunable by adjusting the coating thickness and infusion rate. No peeling or cracking was observed on the coatings under bending and rotational scenarios in the vascular models. Its efficiency was verified in a swine model, and the outlet temperature of coated catheter (75 µm thickness) was 1.8-2.0 °C lower than that of the uncoated one. This pioneering work on catheter thermal insulation coatings may facilitate the clinical translation of selective endovascular hypothermia for neuroprotection in patients with acute ischemic stroke.

Branched-chain amino acids and risk of stroke: A Mendelian randomization study.

Background: The causality between plasma branched-chain amino acids (BCAAs) levels and stroke remains uncertain and the stratified research on the association between BCAAs levels and subtypes of stroke is not well studied. Therefore, the association of genetically proxied circulating BCAA levels with the risks of stroke and its subtypes was explored by Mendelian randomization (MR) in this study. Methods: Summary-level data derived from the published genome-wide association studies (GWAS) were employed for analyses. Data for plasma BCAA levels (n = 16,596) were obtained from a meta-analysis of GWAS. The MEGASTROKE consortium provided data for ischemic stroke (n = 440,328) and its subtypes and data for hemorrhagic stroke were available from 2 meta-analyses of GWAS of European-ancestry groups (intracerebral hemorrhage, n = 3,026; subarachnoid hemorrhage, n = 77,074). The inverse variance weighted (IVW) method was selected as the primary MR analysis. Supplementary analysis used included the weighted median, MR-Egger regression, Cochran's Q statistic, MR Pleiotropy Residual Sum and Outlier global test, and leave-one-out analysis method. Results: According to IVW analysis, 1-SD increment in genetically determined circulating isoleucine was associated with increased risks of cardioembolic stroke (CES) (OR: 1.56, 95% CI: 1.21-2.20, P = 0.0007), but not with risks of other stroke subtypes. We could not discover any proof that leucine and valine levels could increase risk of any stroke subtype. All heterogeneity tests produced stable findings, and there was no concrete evidence to indicate the perturbation of horizontal multiplicity. Conclusion: Increasing plasma isoleucine level had a causal effect on the risk of CES but not on the risk of other stroke subtypes. Further research is needed to identify the mechanisms of the causal associations between BCAAs and stroke subtypes.

The intra-arterial selective cooling infusion system: A mathematical temperature analysis and in vitro experiments for acute ischemic stroke therapy.

INTRODUCTION: The neuroprotection of acute ischemic stroke patients can be achieved by intra-arterial selective cooling infusion using cold saline, which can decrease brain temperature without influencing the body core temperature. This approach can lead to high burdens on the heart and decreased hematocrit in the scenario of loading a high amount of liquid for longtime usage. Therefore, autologous blood is utilized as perfusate to circumvent those side effects. METHODS: In this study, a prototype instrument with an autologous blood cooling system was developed and further evaluated by a mathematical model for brain temperature estimation. RESULTS: Hypothermia could be achieved due to the adequate cooling capacity of the prototype system, which could provide the lowest cooling temperature into the blood vessel of 10.5°C at 25 rpm (209.7 ± 0.8 ml/min). And, the core body temperature did not alter significantly (-0.7 ~ -0.2°C) after 1-h perfusion. The cooling rate and temperature distributions of the brain were analyzed, which showed a 2°C decrease within the initial 5 min infusion by 44 ml/min and 13.7°C perfusate. CONCLUSION: This prototype instrument system could safely cool simulated blood in vitro and reperfuse it to the target cerebral blood vessel. This technique could promote the clinical application of an autologous blood perfusion system for stroke therapy.

The blood heat exchanger in intra-arterial selective cooling infusion for acute ischemic stroke: A computational fluid-thermodynamics performance, experimental assessment and evaluation on the brain temperature.

Intra-arterial selective cooling infusion with the autologous blood (IA-SCAI) is a promising therapeutic hypothermia induction method for conferring neuroprotection to acute ischemic stroke (AIS) patients. The blood heat exchanger (BHE) plays a crucial role in IA-SCAI's cooling capacity. However, there are no BHEs currently available that are specifically designed for the IA-SCAI, which requires a low blood flow to be compatible with cerebral hemodynamics. In an effort to develop a BHE for AIS patients, a prototype of a commercial BHE, Medtronic MYOtherm XP®, was mathematically modeled; specifically, computational fluid dynamics (CFD) was used to analyze its hemo- and thermo-dynamic characteristics under low blood flow including temperature distribution, velocity field and shear stress. Our numerical model predicted the hemolysis index to be 0.0041%-0.0581% inside the BHE with blood flows rates of 10 ml min-1-50 ml min-1. The in vitro heat transfer experiment showed that the BHE efficiently cooled the simulated blood from the initial 37 °C-5.8 °C within 150 s by using cold water (200 ml·min-1, 0 °C). The cooled simulated blood was able to cool the simulated blood in the middle cerebral artery of an artificial circulating system from 37 °C to 16.8 °C-33.7 °C depending on the blood perfusion rate (10-50 ml/min). A biological heat transfer mathematical model showed that brain tissue could be cooled by 2 °C within the initial 1min of infusion. This study verified the feasibility of using a commercial BHE for IA-SCAI and provided insights into its cooling capacity for therapeutic hypothermia.

Design and evaluation of an air-insulated catheter for intra-arterial selective cooling infusion from numerical simulation and in vitro experiment.

Intra-arterial selective cooling infusion (IA-SCI) is a promising method for neuroprotection of patients with acute ischemic stroke. One shortcoming of IA-SCI is the elevated delivery temperature caused by the cold perfusate warming along the catheter pathway. Therefore, increasing the thermal resistance of the catheter is of significant importance. In this manuscript, an air-insulated catheter was designed and manufactured through extrusion molding technique. The computational fluid dynamics (CFD)-based thermo-/hemo-dynamics models were exploited to evaluate the thermal conductivity of the catheter. Compared with commercially available endovascular catheters, its thermal insulation property was analyzed through an in vitro experiment. The temperature of the 4°C perfusate (20 ml/min) increased to 14.2°C ± 0.2°C after being transferred to the distal tip of the air-insulated catheter, which was significantly lower than that (30°C) of commercially available alternatives. Moreover, the simulated blood (56% glycerin and 44% bi-distilled water, 37°C) in the middle cerebral artery of the artificial circulating system was cooled down to 29.7°C ± 0.1°C by this perfusate. The cooling process of the brain tissue was also estimated by a biological heat-transfer mathematical model, which showed a 2°C decrease within the initial 1 min infusion. This study demonstrated that the air-insulated catheter for IA-SCI was promising in vitro in terms of its high cooling efficiency and could be a competitive intervention catheter for therapeutic hypothermia.

Current status and outlook of biodegradable metals in neuroscience and their potential applications as cerebral vascular stent materials.

Over the past two decades, biodegradable metals (BMs) have emerged as promising materials to fabricate temporary biomedical devices, with the purpose of avoiding potential side effects of permanent implants. In this review, we first surveyed the current status of BMs in neuroscience, and briefly summarized the representative stents for treating vascular stenosis. Then, inspired by the convincing clinical evidence on the in vivo safety of Mg alloys as cardiovascular stents, we analyzed the possibility of producing biodegradable cerebrovascular Mg alloy stents for treating ischemic stroke. For these novel applications, some key factors should also be considered in designing BM brain stents, including the anatomic features of the cerebral vasculature, hemodynamic influences, neuro-cytocompatibility and selection of alloying elements. This work may provide insights into the future design and fabrication of BM neurological devices, especially for brain stents.