Cannabidiol Alleviates Neurological Deficits After Traumatic Brain Injury by Improving Intracranial Lymphatic Drainage.

Traumatic brain injury (TBI) persists as a substantial clinical dilemma, largely because of the absence of effective treatments. This challenge is exacerbated by the hindered clearance of intracranial metabolic byproducts and the continual accrual of deleterious proteins. The glymphatic system (GS) and meningeal lymphatic vessels (MLVs), key elements of the intracranial lymphatic network, play critical roles in the clearance of harmful substances. Cannabidiol (CBD) has shown promise in reducing metabolite overload and bolstering cognitive performance in various neurodegenerative diseases. The precise mechanisms attributing to its beneficial effects in TBI scenarios, however, are yet to be distinctly understood. Utilizing a fluid percussion injury paradigm, our research adopted a multifaceted approach, encompassing behavioral testing, immunofluorescence and immunohistochemical analyses, laser speckle imaging, western blot techniques, and bilateral cervical efferent lymphatic ligation. This methodology aimed to discern the influence of CBD on both neurological outcomes and intracranial lymphatic clearance in a murine TBI model. We observed that CBD administration notably ameliorated motor, memory, and cognitive functions, concurrently with a significant reduction in the concentration of phosphorylated tau protein and amyloid-ß. In addition, CBD expedited the turnover and elimination of intracranial tracers, increased cerebral blood flow, and enhanced the efficacy of fluorescent tracer migration from MLVs to deep cervical lymph nodes (dCLNs). Remarkably, CBD treatment also induced a reversion in aquaporin-4 (AQP-4) polarization and curtailed neuroinflammatory indices. A pivotal discovery was that the surgical interruption of efferent lymphatic conduits in the neck nullified CBD's positive contributions to intracranial waste disposal and cognitive improvement, yet the anti-neuroinflammatory actions remained unaffected. These insights suggest that CBD may enhance intracranial metabolite clearance, potentially via the regulation of the intracranial lymphatic system, thereby offering neurofunctional prognostic improvement in TBI models. Our findings underscore the potential therapeutic applicability of CBD in TBI interventions, necessitating further comprehensive investigations and clinical validations to substantiate these initial conclusions.

The value of computed tomography texture analysis in identifying chronic subdural hematoma patients with a good response to polytherapy.

This study aimed to investigate the predictive factors of therapeutic efficacy for chronic subdural hematoma (CSDH) patients receiving atorvastatin combined with dexamethasone therapy by using clinical imaging characteristics in conjunction with computed tomography (CT) texture analysis (CTTA). Clinical imaging characteristics and CT texture parameters at admission were retrospectively investigated in 141 CSDH patients who received atorvastatin combined with dexamethasone therapy from June 2019 to December 2022. The patients were divided into a training set (n = 81) and a validation set (n = 60). Patients in the training data were divided into two groups based on the effectiveness of the treatment. Univariate and multivariate analyses were performed to assess the potential factors that could indicate the prognosis of CSDH patients in the training set. The receiver operating characteristic (ROC) curve was used to analyze the predictive efficacy of the significant factors in predicting the prognosis of CSDH patients and was validated using a validation set. The multivariate analysis showed that the hematoma density to brain parenchyma density ratio, singal min (minimum) and singal standard deviation of the pixel distribution histogram, and inhomogeneity were independent predictors for the prognosis of CSDH patients based on atorvastatin and dexamethasone therapy. The area under the ROC curve between the two groups was between 0.716 and 0.806. As determined by significant factors, the validation's accuracy range was 0.816 to 0.952. Clinical imaging characteristics in conjunction with CTTA could aid in distinguishing patients with CSDH who responded well to atorvastatin combined with dexamethasone.

Multimodality management for chronic subdural hematoma in China: protocol and characteristics of an ambidirectional, nationwide, multicenter registry study.

BACKGROUND: Despite its prevalence, there is ongoing debate regarding the optimal management strategy for chronic subdural hematoma (CSDH), reflecting the variability in clinical presentation and treatment outcomes. This ambidirectional, nationwide, multicenter registry study aims to assess the efficacy and safety of multimodality treatment approaches for CSDH in the Chinese population. METHODS/DESIGN: A multicenter cohort of CSDH patients from 59 participating hospitals in mainland China was enrolled in this study. The treatment modalities encompassed a range of options and baseline demographics, clinical characteristics, radiographic findings, and surgical techniques were documented. Clinical outcomes, including hematoma resolution, recurrence rates, neurological status, and complications, were assessed at regular intervals during treatment, 3 months, 6 months, 1 year, and 2 years follow-up. RESULT: Between March 2022 and August 2023, a comprehensive cohort comprising 2173 individuals who met the criterion was assembled across 59 participating clinical sites. Of those patients, 81.1% were male, exhibiting an average age of 70.12 ± 14.53 years. A historical record of trauma was documented in 48.0% of cases, while headache constituted the predominant clinical presentation in 58.1% of patients. The foremost surgical modality employed was the burr hole (61.3%), with conservative management accounting for 25.6% of cases. Notably, a favorable clinical prognosis was observed in 88.9% of CSDH patients at 3 months, and the recurrence rate was found to be 2.4%. CONCLUSION: This registry study provides critical insights into the multimodality treatment of CSDH in China, offering a foundation for advancing clinical practices, optimizing patient management, and ultimately, improving the quality of life for individuals suffering from this challenging neurosurgical condition. TRIAL REGISTRATION: ChiCTR2200057179.

Cerebral glucagon-like peptide-1 receptor activation alleviates traumatic brain injury by glymphatic system regulation in mice.

AIM: We aimed to assess the effects of cerebral glucagon-like peptide-1 receptor (GLP-1R) activation on the glymphatic system and whether this effect was therapeutic for traumatic brain injury (TBI). METHODS: Immunofluorescence was employed to evaluate glymphatic system function. The blood-brain barrier (BBB) permeability, microvascular basement membrane, and tight junction expression were assessed using Evans blue extravasation, immunofluorescence, and western blot. Immunohistochemistry was performed to assess axonal damage. Neuronal apoptosis was evaluated using Nissl staining, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, and western blot. Cognitive function was assessed using behavioral tests. RESULTS: Cerebral GLP-1R activation restored glymphatic transport following TBI, alleviating BBB disruption and neuronal apoptosis, thereby improving cognitive function following TBI. Glymphatic function suppression by treatment using aquaporin 4 inhibitor TGN-020 abolished the protective effect of the GLP-1R agonist against cognitive impairment. CONCLUSION: Cerebral GLP-1R activation can effectively ameliorate neuropathological changes and cognitive impairment following TBI; the underlying mechanism could involve the repair of the glymphatic system damaged by TBI.

Exogenous interleukin 33 enhances the brain's lymphatic drainage and toxic protein clearance in acute traumatic brain injury mice.

The persistent dysregulation and accumulation of poisonous proteins from destructive neural tissues and cells activate pathological mechanisms after traumatic brain injury (TBI). The lymphatic drainage system of the brain, composed of the glymphatic system and meningeal lymphatic vessels (MLVs), plays an essential role in the clearance of toxic waste after brain injury. The neuroprotective effect of interleukin 33 (IL-33) in TBI mice has been demonstrated; however, its impact on brain lymphatic drainage is unclear. Here, we established a fluid percussion injury model to examine the IL-33 administration effects on neurological function and lymphatic drainage in the acute brain of TBI mice. We verified that exogenous IL-33 could improve the motor and memory skills of TBI mice and demonstrated that in the acute phase, it increased the exchange of cerebrospinal and interstitial fluid, reversed the dysregulation and depolarization of aquaporin-4 in the cortex and hippocampus, improved the drainage of MLVs to deep cervical lymph nodes, and reduced tau accumulation and glial activation. We speculate that the protective effect of exogenous IL-33 on TBI mice's motor and cognitive functions is related to the enhancement of brain lymphatic drainage and toxic metabolite clearance from the cortex and hippocampus in the acute stage. These data further support the notion that IL-33 therapy may be an effective treatment strategy for alleviating acute brain injury after TBI.

The accuracy of different mismatch negativity amplitude representations in predicting the levels of consciousness in patients with disorders of consciousness.

Introduction: The mismatch negativity (MMN) index has been used to evaluate consciousness levels in patients with disorders of consciousness (DoC). Indeed, MMN has been validated for the diagnosis of vegetative state/unresponsive wakefulness syndrome (VS/UWS) and minimally conscious state (MCS). In this study, we evaluated the accuracy of different MMN amplitude representations in predicting levels of consciousness. Methods: Task-state electroencephalography (EEG) data were obtained from 67 patients with DoC (35 VS and 32 MCS). We performed a microstate analysis of the task-state EEG and used four different representations (the peak amplitude of MMN at electrode Fz (Peak), the average amplitude within a time window -25- 25 ms entered on the latency of peak MMN component (Avg for peak ± 25 ms), the average amplitude of averaged difference wave for 100-250 ms (Avg for 100-250 ms), and the average amplitude difference between the standard stimulus ("S") and the deviant stimulus ("D") at the time corresponding to Microstate 1 (MS1) (Avg for MS1) of the MMN amplitude to predict the levels of consciousness. Results: The results showed that among the four microstates clustered, MS1 showed statistical significance in terms of time proportion during the 100-250 ms period. Our results confirmed the activation patterns of MMN through functional connectivity analysis. Among the four MMN amplitude representations, the microstate-based representation showed the highest accuracy in distinguishing different levels of consciousness in patients with DoC (AUC = 0.89). Conclusion: We discovered a prediction model based on microstate calculation of MMN amplitude can accurately distinguish between MCS and VS states. And the functional connection of the MS1 is consistent with the activation mode of MMN.

Effects of increased intracranial pressure on cerebrospinal fluid influx, cerebral vascular hemodynamic indexes, and cerebrospinal fluid lymphatic efflux.

The glymphatic-lymphatic fluid transport system (GLFTS) consists of glymphatic pathway and cerebrospinal fluid (CSF) lymphatic outflow routes, allowing biological liquids from the brain parenchyma to access the CSF along with perivascular space and to be cleaned out of the skull through lymphatic vessels. It is known that increased local pressure due to physical compression of tissue improves lymphatic transport in peripheral organs, but little is known about the exact relationship between increased intracranial pressure (IICP) and GLFTS. In this study, we verify our hypothesis that IICP significantly impacts GLFTS, and this effect depends on severity of the IICP. Using a previously developed inflating balloon model to induce IICP and inject fluorescent tracers into the cisterna magna, we found significant impairment of the glymphatic circulation after IICP. We further found that cerebrovascular occlusion occurred, and cerebrovascular pulsation decreased after IICP. IICP also interrupted the drainage of deep cervical lymph nodes and dorsal meningeal lymphatic function, enhancing spinal lymphatic outflow to the sacral lymph nodes. Notably, these effects were associated with the severity of IICP. Thus, our findings proved that the intensity of IICP significantly impacts GLFTS. This may have translational applications for preventing and treating related neurological disorders.

Multidimensional Assessment of Electroencephalography in the Neuromodulation of Disorders of Consciousness.

In the present study, we aimed to elucidate changes in electroencephalography (EEG) metrics during recovery of consciousness and to identify possible clinical markers thereof. More specifically, in order to assess changes in multidimensional EEG metrics during neuromodulation, we performed repeated stimulation using a high-density transcranial direct current stimulation (HD-tDCS) protocol in 42 patients with disorders of consciousness (DOC). Coma Recovery Scale-Revised (CRS-R) scores and EEG metrics [brain network indicators, spectral energy, and normalized spatial complexity (NSC)] were obtained before as well as fourteen days after undergoing HD-tDCS stimulation. CRS-R scores increased in the responders (R +) group after HD-tDCS stimulation. The R + group also showed increased spectral energy in the alpha2 and beta1 bands, mainly at the frontal and parietal electrodes. Increased graphical metrics in the alpha1, alpha2, and beta1 bands combined with increased NSC in the beta2 band in the R + group suggested that improved consciousness was associated with a tendency toward stronger integration in the alpha1 band and greater isolation in the beta2 band. Following this, using NSC as a feature to predict responsiveness through machine learning, which yielded a prediction accuracy of 0.929, demonstrated that the NSC of the alpha and gamma bands at baseline successfully predicted improvement in consciousness. According to our findings reported herein, we conclude that neuromodulation of the posterior lobe can lead to an EEG response related to consciousness in DOC, and that the posterior cortex may be one of the key brain areas involved in the formation or maintenance of consciousness.

Evaluation of the prognosis of acute subdural hematoma according to the density differences between gray and white matter.

Objective: Acute subdural hematoma (ASDH) is a common neurological emergency, and its appearance on head-computed tomographic (CT) imaging helps guide clinical treatment. To provide a basis for clinical decision-making, we analyzed that the density difference between the gray and white matter of the CT image is associated with the prognosis of patients with ASDH. Methods: We analyzed the data of 194 patients who had ASDH as a result of closed traumatic brain injury (TBI) between 2018 and 2021. The patients were subdivided into surgical and non-surgical groups, and the non-surgical group was further subdivided into "diffused [hematoma]" and "non-diffused" groups. The control group's CT scans were normal. The 3D Slicer software was used to quantitatively analyze the density of gray and white matter depicted in the CT images. Results: Imaging evaluation showed that the median difference in density between the gray and white matter on the injured side was 4.12 HU (IQR, 3.91-4.22 HU; p < 0.001) and on the non-injured side was 4.07 HU (IQR, 3.90-4.19 HU; p < 0.001), and the hematoma needs to be surgically removed. The median density difference value of the gray and white matter on the injured side was 3.74 HU (IQR, 3.53-4.01 HU; p < 0.001) and on the non-injured side was 3.71 HU (IQR, 3.69-3.73 HU; p < 0.001), and the hematoma could diffuse in a short time. Conclusion: Quantitative analysis of the density differences in the gray and white matter of the CT images can be used to evaluate the clinical prognosis of patients with ASDH.

Dual functional nanoparticles efficiently across the blood-brain barrier to combat glioblastoma via simultaneously inhibit the PI3K pathway and NKG2A axis.

The blood-brain barrier (BBB) and complex tumour immunosuppressive micro-environment posed austere challenges for combatting brain tumours such as the glioblastoma. In this study, we have developed a novel dual functional dendrimer drug delivery system (DDS) by the PAMAM and loaded with siLSINCT5 (NP- siRNA) for efficiently across the BBB to inhibit glioblastoma. To achieve the goal of BBB crossing, on the surface of NP-siRNA was decorated with the cell penetrating peptides tLyp-1 (tLypNP-siRNA). Moreover, to overcome the immunosuppressive microenvironment within the glioblastoma (GBM) tissues, a checkpoint inhibitor named as anti-NKG2A monoclonal antibody (aNKG2A), which was able of promoting anti-tumour immunity by unleashing both T and NK Cells, was further conjugated on the surface of siLSINCT5-loaded nanoparticles via the pH-sensitive linkage. Therefore, the developed dual functional and siLSINCT5-loaded dendrimer nanoparticles (tLyp/aNKNP-siRNA) was supposed to have the ability to efficiently cross the BBB and inhibit GBM by simultaneously inhibit the LSINCT5-activated signalling pathways and activate the anti-tumour immunity. The hypothesis was thoroughly confirmed by in vitro cellular and in vivo animal experiments, and provided a novel strategy for combating glioblastoma.

Long Non-Coding RNA PART1 Exerts Tumor Suppressive Functions in Glioma via Sponging miR-190a-3p and Inactivation of PTEN/AKT Pathway.

BACKGROUND: Glioma is the most commonly diagnosed primary brain tumor. Dysregulation of long non-coding RNA (lncRNA) is associated with initiation and development of various cancer types including glioma. METHODS: The relative expression of lncRNA was analyzed by real time-quantitative polymerase chain reaction (RT-qPCR). Cell counting kit (CCK-8) and flow cytometry analysis were applied to explore the role of prostate androgen-regulated transcript 1 (PART1) in glioma cell lines. Luciferase reporter assay, Western blotting and RT-qPCR were used to investigate the association between PART1, miR-190a-3p and phosphatase and tensin homolog deleted on chromosome ten (PTEN) in glioma cell lines. RESULTS: In the present study, we elucidated a pivotal role and molecular mechanism of lncRNA PART1 in glioma cell lines. It was found that PART1 was significantly downregulated in glioma tissues compared to normal tissues according to TCGA data and our RT-qPCR results. The cell-based assays showed that PART1 suppressed cell proliferation and triggered cell apoptosis in glioma cell lines. PART1 inactivated PI3K/AKT cascade in glioma cell lines. Transfection of constitutively activated AKT (Myr-AKT) reversed PART1 induced cell apoptosis and cell growth arrest. The bioinformatic analysis suggested that miR-190a-3p might bind to PART1. In the dual luciferase reporter assay, we validated that PART1 directly bound to miR-190a-3p in glioma cell lines. Furthermore, there was a reciprocal repression between PART1 and miR-190-3p. In addition, PART1 upregulated PTEN and inactivated PI3K/AKT pathway in glioma cell lines. Moreover, silencing of PTEN reversed PART1 overexpression induced cell growth arrest and apoptosis. In glioma tissues, the Pearson Correlation analysis showed that there was a strong-positive correlation between PART1 level and PTEN mRNA level. CONCLUSION: Taken together, the current study revealed a PART1/miR-190a-3p/PTEN/PI3K/AKT axis in glioma and provided novel insights for understanding the complex lncRNA-miRNA network in glioma.