APOE2 protects against Aß pathology by improving neuronal mitochondrial function through ERRα signaling.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disease and apolipoprotein E (APOE) genotypes (APOE2, APOE3, and APOE4) show different AD susceptibility. Previous studies indicated that individuals carrying the APOE2 allele reduce the risk of developing AD, which may be attributed to the potential neuroprotective role of APOE2. However, the mechanisms underlying the protective effects of APOE2 is still unclear. METHODS: We analyzed single-nucleus RNA sequencing and bulk RNA sequencing data of APOE2 and APOE3 carriers from the Religious Orders Study and Memory and Aging Project (ROSMAP) cohort. We validated the findings in SH-SY5Y cells and AD model mice by evaluating mitochondrial functions and cognitive behaviors respectively. RESULTS: The pathway analysis of six major cell types revealed a strong association between APOE2 and cellular stress and energy metabolism, particularly in excitatory and inhibitory neurons, which was found to be more pronounced in the presence of beta-amyloid (Aß). Moreover, APOE2 overexpression alleviates Aß1-42-induced mitochondrial dysfunction and reduces the generation of reactive oxygen species in SH-SY5Y cells. These protective effects may be due to ApoE2 interacting with estrogen-related receptor alpha (ERRα). ERRα overexpression by plasmids or activation by agonist was also found to show similar mitochondrial protective effects in Aß1-42-stimulated SH-SY5Y cells. Additionally, ERRα agonist treatment improve the cognitive performance of Aß injected mice in both Y maze and novel object recognition tests. ERRα agonist treatment increased PSD95 expression in the cortex of agonist-treated-AD mice. CONCLUSIONS: APOE2 appears to enhance neural mitochondrial function via the activation of ERRα signaling, which may be the protective effect of APOE2 to treat AD.

Radiation-induced chronic pain plagues head and neck cancer survivors: A cross-sectional analysis from the Cohort in Radiotherapy-related Nervous System Complications.

The epidemiology and prognosis of radiation-induced chronic pain, especially chronic neuropathic pain (CNP), are the understudied domain among head and neck cancer (HNC) survivors after radiotherapy (RT). This study aimed to estimate the prevalence of such chronic pain, and explore their correlations with mental health, sleep disorders, cognitive function, and quality of life (QOL) within these patients. This research encompassed HNC survivors post-RT. The determination of radiation-induced chronic pain and CNP adhered to the guidelines outlined by the International Association for the Study of Pain (IASP). Multivariable regression analyses were employed to explore the relationship between pain and anxiety, depression, sleep disturbances, cognitive function, and QOL. A total of 1071 HNC survivors post-RT were included in this study. The prevalence of radiation-induced chronic pain was 67.1%, and the prevalence of RT-associated CNP was 38.3%,. Compared with those reporting no pain, patients with radiation-induced chronic pain had a significantly increased risk of anxiety, depression and sleep disorders (all p < 0.001). And there was a significantly negative association between chronic pain and QOL across physiological (p < 0.001), psychological (p < 0.001), social relationships (p = 0.001) and environmental (p = 0.009) domains. Compared with non-CNP, patients with RT-related CNP had a higher risk of anxiety (p= 0.027) and sleep disorders (p= 0.013). The significantly negative associations were found between CNP and the physiological (p = 0.001), psychological (p = 0.012) and social score (p = 0.035) in WHOQOL-BREF. This study underscores the substantial prevalence of chronic pain, particularly CNP, and their potential impact on the mental health, sleep, and QOL among HNC survivors post-RT. PERSPECTIVE: This study highlights the high prevalence of radiation-induced chronic pain and CNP, and their potential impacts on anxiety, depression, sleep and QOL among the HNC survivors. Clinically, these findings have important implications for improving the care and outcomes of HNC survivors.

Terminally differentiated cytotoxic CD4+ T cells were clonally expanded in the brain lesion of radiation-induced brain injury.

BACKGROUND: Accumulating evidence supports the involvement of adaptive immunity in the development of radiation-induced brain injury (RIBI). Our previous work has emphasized the cytotoxic function of CD8+ T cells in RIBI. In this study, we aimed to investigate the presence and potential roles of cytotoxic CD4+ T cells (CD4+ CTLs) in RIBI to gain a more comprehensive understanding of adaptive immunity in this context. MAIN TEXT: Utilizing single-cell RNA sequencing (scRNA-seq), we analyzed 3934 CD4+ T cells from the brain lesions of four RIBI patients and identified six subclusters within this population. A notable subset, the cytotoxic CD4+ T cells (CD4+ CTLs), was marked with high expression of cytotoxicity-related genes (NKG7, GZMH, GNLY, FGFBP2, and GZMB) and several chemokine and chemokine receptors (CCL5, CX3CR1, and CCL4L2). Through in-depth pseudotime analysis, which simulates the development of CD4+ T cells, we observed that the CD4+ CTLs exhibited signatures of terminal differentiation. Their functions were enriched in protein serine/threonine kinase activity, GTPase regulator activity, phosphoprotein phosphatase activity, and cysteine-type endopeptidase activity involved in the apoptotic signaling pathway. Correspondingly, mice subjected to gamma knife irradiation on the brain showed a time-dependent infiltration of CD4+ T cells, an increase of MHCII+ cells, and the existence of CD4+ CTLs in lesions, along with an elevation of apoptotic-related proteins. Finally, and most crucially, single-cell T-cell receptor sequencing (scTCR-seq) analysis at the patient level determined a large clonal expansion of CD4+ CTLs in lesion tissues of RIBI. Transcriptional factor-encoding genes TBX21, RORB, and EOMES showed positive correlations with the cytotoxic functions of CD4+ T cells, suggesting their potential to distinguish RIBI-related CD4+ CTLs from other subsets. CONCLUSION: The present study enriches the understanding of the transcriptional landscape of adaptive immune cells in RIBI patients. It provides the first description of a clonally expanded CD4+ CTL subset in RIBI lesions, which may illuminate new mechanisms in the development of RIBI and offer potential biomarkers or therapeutic targets for the disease.

Progression rate of radiation-induced carotid stenosis in head and neck cancer survivors after statin treatment: a retrospective cohort study.

BACKGROUND AND AIMS: Whether statin treatment is effective in retarding the progression of radiation-induced carotid stenosis (RICS) in head and neck cancer (HNC) survivors has not been well studied. The purpose of this study was to assess the association of statin treatment with RICS progression rate in HNC survivors after radiotherapy. METHODS: We conducted a retrospective cohort study at Sun Yat-sen Memorial Hospital, Sun Yat-sen University in Guangzhou, China. Between January 2010 and December 2021, we screened HNC survivors whose carotid ultrasound scans had shown stenosis of the common and/or internal carotid arteries. The primary outcome was the RICS progression rate. We compared eligible patients treated with statins with those who did not in multivariable Cox regression models. RESULTS: A total of 200 patients were included in this study, of whom 108 received statin treatment and 92 did not. Over a mean follow-up time of 1.5 years, 56 (28.0%) patients showed RICS progression, 24 (42.9%) and 32 (57.1%) in the statin and control groups, respectively. The statin group showed less RICS progression than the control group (adjusted-HR 0.49, 95% CI 0.30-0.80, P = 0.005). In the subgroup analysis, there was no significant interaction in the effect of statins on lowering RICS progression rate in the subgroups stratified by baseline low-density lipoprotein cholesterol (LDL-C) levels (P for interaction = 0.53) or baseline degrees of stenosis (P for interaction = 0.50). CONCLUSIONS: Statin treatment was associated with a lower risk of RICS progression in patients with HNC after radiotherapy, regardless of baseline LDL-C level and baseline stenosis degrees.

Blockage of VEGF function by bevacizumab alleviates early-stage cerebrovascular dysfunction and improves cognitive function in a mouse model of Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder and the predominant type of dementia worldwide. It is characterized by the progressive and irreversible decline of cognitive functions. In addition to the pathological beta-amyloid (Aß) deposition, glial activation, and neuronal injury in the postmortem brains of AD patients, increasing evidence suggests that the often overlooked vascular dysfunction is an important early event in AD pathophysiology. Vascular endothelial growth factor (VEGF) plays a critical role in regulating physiological functions and pathological changes in blood vessels, but whether VEGF is involved in the early stage of vascular pathology in AD remains unclear. METHODS: We used an antiangiogenic agent for clinical cancer treatment, the humanized monoclonal anti-VEGF antibody bevacizumab, to block VEGF binding to its receptors in the 5×FAD mouse model at an early age. After treatment, memory performance was evaluated by a novel object recognition test, and cerebral vascular permeability and perfusion were examined by an Evans blue assay and blood flow scanning imaging analysis. Immunofluorescence staining was used to measure glial activation and Aß deposits. VEGF and its receptors were analyzed by enzyme-linked immunosorbent assay and immunoblotting. RNA sequencing was performed to elucidate bevacizumab-associated transcriptional signatures in the hippocampus of 5×FAD mice. RESULTS: Bevacizumab treatment administered from 4 months of age dramatically improved cerebrovascular functions, reduced glial activation, and restored long-term memory in both sexes of 5×FAD mice. Notably, a sex-specific change in different VEGF receptors was identified in the cortex and hippocampus of 5×FAD mice. Soluble VEGFR1 was decreased in female mice, while full-length VEGFR2 was increased in male mice. Bevacizumab treatment reversed the altered expression of receptors to be comparable to the level in the wild-type mice. Gene Set Enrichment Analysis of transcriptomic changes revealed that bevacizumab effectively reversed the changes in the gene sets associated with blood-brain barrier integrity and vascular smooth muscle contraction in 5×FAD mice. CONCLUSIONS: Our study demonstrated the mechanistic roles of VEGF at the early stage of amyloidopathy and the protective effects of bevacizumab on cerebrovascular function and memory performance in 5×FAD mice. These findings also suggest the therapeutic potential of bevacizumab for the early intervention of AD.

Progression of cognitive dysfunction in NPC survivors with radiation-induced brain necrosis: A prospective cohort.

BACKGROUND AND PURPOSE: The evidence of longitudinal changes in cognition in nasopharyngeal carcinoma (NPC) survivors with radiation-induced brain necrosis (RIBN) after radiotherapy (RT) remained insufficient. We aimed to estimate the clinical progression rate of cognitive decline and identify patients with differential decline rates. MATERIALS AND METHODS: Based on an ongoing prospective cohort study, NPC patients aged ≥18 years old and diagnosed with RIBN were included in this current analysis if they finished the time frame of 3-year follow-up and had at least twice cognition assessments. The Chinese version of the Montreal Cognitive Assessment (MoCA) was used to assess the cognitive state. Linear mixed-effect models were used to analyze the annual progression rates of MoCA total and seven sub-items scores. RESULTS: Among 134 patients in this study, the transition probability from normal to mild/moderate cognitive dysfunction were 14.2 % (19/134) and 1.49 % (2/134) respectively during the median follow-up time of 2.35 years. The total MoCA score declined by -0.569 (SE 0.208) points annually (p = 0.008). Patients with ≤6 years of duration from RT to RIBN have higher annual progression rate of total scores [-0.851 (SE 0.321), p = 0.013; p for interaction = 0.041]. CONCLUSION: Our findings of the annual decline rate of cognition in NPC patients with RIBN from a 3-year longitudinal data, particularly for those who developed RIBN rapidly after RT, have important implications for the upcoming clinical trials designed to prevent or decrease cognitive decline in NPC patients with RIBN, regarding the selection of study patients and the calculation of sample size.

Brain perivascular macrophages: current understanding and future prospects.

Brain perivascular macrophages are specialized populations of macrophages that reside in the space around cerebral vessels, such as penetrating arteries and venules. With the help of cutting-edge technologies, such as cell fate mapping and single-cell multi-omics, their multifaceted, pivotal roles in phagocytosis, antigen presentation, vascular integrity maintenance and metabolic regulation have more recently been further revealed under physiological conditions. Accumulating evidence also implies that perivascular macrophages are involved in the pathogenesis of neurodegenerative disease, cerebrovascular dysfunction, autoimmune disease, traumatic brain injury and epilepsy. They can act in either protective or detrimental ways depending on the disease course and stage. However, the underlying mechanisms of perivascular macrophages remain largely unknown. Therefore, we highlight potential future directions in research on perivascular macrophages, including the utilization of genetic mice and novel therapeutic strategies that target these unique immune cells for neuroprotective purposes. In conclusion, this review provides a comprehensive update on the current knowledge of brain perivascular macrophages, shedding light on their pivotal roles in central nervous system health and disease.

Cluster-based radiomics reveal spatial heterogeneity of bevacizumab response for treatment of radiotherapy-induced cerebral necrosis.

Background: Bevacizumab is used in the treatment of radiation necrosis (RN), which is a debilitating toxicity following head and neck radiotherapy. However, there is no biomarker to predict if a patient would respond to bevacizumab. Purpose: We aimed to develop a cluster-based radiomics approach to characterize the spatial heterogeneity of RN and map their responses to bevacizumab. Methods: 118 consecutive nasopharyngeal carcinoma patients diagnosed with RN were enrolled. We divided 152 lesions from the patients into 101 for training, and 51 for validation. We extracted voxel-level radiomics features from each lesion segmented on T1-weighted+contrast and T2 FLAIR sequences of pre- and post-bevacizumab magnetic resonance images, followed by a three-step analysis involving individual- and population-level clustering, before delta-radiomics to derive five radiomics clusters within the lesions. We tested the association of each cluster with response to bevacizumab and developed a clinico-radiomics model using clinical predictors and cluster-specific features. Results: 71 (70.3%) and 34 (66.7%) lesions had responded to bevacizumab in the training and validation datasets, respectively. Two radiomics clusters were spatially mapped to the edema region, and the volume changes were significantly associated with bevacizumab response (OR:11.12 [95% CI: 2.54-73.47], P = 0.004; and 1.63[1.07-2.78], P = 0.042). The combined clinico-radiomics model based on textural features extracted from the most significant cluster improved the prediction of bevacizumab response, compared with a clinical-only model (AUC:0.755 [0.645-0.865] to 0.852 [0.764-0.940], training; 0.708 [0.554-0.861] to 0.816 [0.699-0.933], validation). Conclusion: Our radiomics approach yielded intralesional resolution, enabling a more refined feature selection for predicting bevacizumab efficacy in the treatment of RN.

A Synthetic Steroid 5α-Androst-3ß, 5, 6ß-triol Alleviates Radiation-Induced Brain Injury in Mice via Inhibiting GBP5/NF-κB/NLRP3 Signal Axis.

Radiotherapy for head and neck tumors can lead to a severe complication known as radiation-induced brain injury (RIBI). However, the underlying mechanism of RIBI development remains unclear, and limited prevention and treatment options are available. Neuroactive steroids have shown potential in treating neurological disorders. 5α-Androst-3ß, 5, 6ß-triol (TRIOL), a synthetic neuroprotective steroid, holds promise as a treatment candidate for RIBI patients. However, the neuroprotective effects and underlying mechanism of TRIOL on RIBI treatment are yet to be elucidated. In the present study, our findings demonstrate TRIOL's potential as a neuroprotective agent against RIBI. In gamma knife irradiation mouse model, TRIOL treatment significantly reduced brain necrosis volume, microglial activation, and neuronal loss. RNA-sequencing, immunofluorescence, real-time quantitative polymerase chain reaction, siRNA transfection, and western blotting techniques revealed that TRIOL effectively decreased microglial activation, proinflammatory cytokine release, neuron loss, and guanylate-binding protein 5 (GBP5) expression, along with its downstream signaling pathways NF-κB and NLRP3 activation in vitro. In summary, TRIOL effectively alleviate RIBI by inhibiting the GBP5/NF-κB/NLRP3 signal axis, reducing microglia activation and pro-inflammation cytokines release, rescuing neuron loss. This study highlights the potential of TRIOL as a novel and promising therapy drug for RIBI treatment.

Efficacy of transcutaneous auricular vagus nerve stimulation on radiotherapy-related neuropathic pain in patients with head and neck cancers (RELAX): protocol for a multicentre, randomised, double-blind, sham-controlled trial.

INTRODUCTION: Radiotherapy-related neuropathic pain (RRNP) is one of the most distressing complications after radiotherapy for head and neck cancers. Drug therapy is not sufficiently effective and has limitations in terms of dose titration period and side effects. Transcutaneous auricular vagus nerve stimulation (taVNS), which stimulates the auricular branches of the vagus nerve through electrical impulses, has been proven to have analgesic effects in certain diseases. However, it is unknown whether taVNS can relieve RRNP. METHODS AND ANALYSIS: This is a multicentre, randomised, double-blind, parallel, sham-controlled trial. We will include adult patients newly diagnosed with neuropathic pain after radiotherapy for head and neck cancers. One hundred and sixteen individuals will be recruited and randomly assigned in a 1:1 ratio to receive taVNS or sham stimulation. The interventions will last for 7 days, twice daily for 30 min each. The primary efficacy outcome is pain reduction on day 7. The secondary outcomes are changes in functional interference, psychological distress, fatigue, quality of life and serum inflammatory factors. The study may provide a new early intervention strategy for RRNP among patients with head and neck cancers. ETHICS AND DISSEMINATION: This study has been approved by the Medical Research Ethics Committee of Sun Yat-sen University (SYSKY-2022-109-01) and will be conducted in strict accordance with the Declaration of Helsinki. Ethical approvals will be obtained separately for all centres involved in the study. Study results will be published in peer-reviewed academic journals. The database of the study will be available from the corresponding author on reasonable request. TRIAL REGISTRATION NUMBER: NCT05543239.

H2O2/O2 self-supply and Ca2+ overloading MOF-based nanoplatform for cascade-amplified chemodynamic and photodynamic therapy.

Introduction: Reactive oxygen species (ROS)-mediated therapies have typically been considered as noninvasive tumor treatments owing to their high selectivity and efficiency. However, the harsh tumor microenvironment severely impairs their efficiency. Methods: Herein, the biodegradable Cu-doped zeolitic imidazolate framework-8 (ZIF-8) was synthesized for loading photosensitizer Chlorin e6 (Ce6) and CaO2 nanoparticles, followed by surface decoration by hyaluronic acid (HA), obtaining HA/CaO2-Ce6@Cu-ZIF nano platform. Results and Discussion: Once HA/CaO2-Ce6@Cu-ZIF targets tumor sites, the degradation of Ce6 and CaO2 release from the HA/CaO2-Ce6@Cu-ZIF in response to the acid environment, while the Cu2+ active sites on Cu-ZIF are exposed. The released CaO2 decompose to generate hydrogen peroxide (H2O2) and oxygen (O2), which alleviate the insufficiency of intracellular H2O2 and hypoxia in tumor microenvironment (TME), effectively enhancing the production of hydroxyl radical (•OH) and singlet oxygen (1O2) in Cu2+-mediated chemodynamic therapy (CDT) and Ce6-induced photodynamic therapy (PDT), respectively. Importantly, Ca2+ originating from CaO2 could further enhance oxidative stress and result in mitochondrial dysfunction induced by Ca2+ overloading. Conclusion: Thus, the H2O2/O2 self-supplying and Ca2+ overloading ZIF-based nanoplatform for cascade-amplified CDT/PDT synergistic strategy is promising for highly efficient anticancer therapy.

Prognostic Value of Nutritional Assessments on Overall Survival in Head and Neck Cancer Survivors with Radiation-Induced Brain Necrosis.

Malnutrition is related to worsened prognosis, but the association between nutritional risk status and overall survival in radiation-induced brain necrosis (RN) has never been studied. We included consecutive patients who had received radiotherapy for head and neck cancer (HNC) and subsequently developed RN from 8 January 2005 through to 19 January 2020. The primary outcome was overall survival. We utilized three commonly-used nutritional assessments: the Geriatric Nutritional Risk Index (GNRI), Prognostic Nutritional Index (PNI), and the COntrolling NUTritional Status (CONUT) measure, to quantify the baseline nutritional risk. A total of 398 eligible patients were included. During a median follow-up of 2.3 years, 42 (10.6%) patients died of any cause. Malnutrition at admission was associated with an increased risk of future death, as assessed by the GNRI (per 1-point decreased, HR 1.05, 95%CI 1.02-1.09, p = 0.001), the PNI (per 1-point decreased, HR 1.07, 95%CI 1.03-1.12, p = 0.002), and the CONUT (per 1-point increased, HR 1.22, 95%CI 1.08-1.37, p = 0.001). There were no nonlinear correlations between all three indices and post-RN survival. Among HNC survivors with RN, the assessment of nutritional risk by composite indices upon admission could help identify patients who might be at high risk of future death and deliver better nutritional management.

A radiomics model for predicting the response to methylprednisolone in brain necrosis after radiotherapy for nasopharyngeal carcinoma.

BACKGROUND: Methylprednisolone is recommended as the front-line therapy for radiation-induced brain necrosis (RN) after radiotherapy for nasopharyngeal carcinoma. However, some patients fail to benefit from methylprednisolone or even progress. This study aimed to develop and validate a radiomic model to predict the response to methylprednisolone in RN. METHODS: Sixty-six patients receiving methylprednisolone were enrolled. In total, 961 radiomic features were extracted from the pre-treatment magnetic resonance imagings of the brain. Least absolute shrinkage and selection operator regression was then applied to construct the radiomics signature. Combined with independent clinical predictors, a radiomics model was built with multivariate logistic regression analysis. Discrimination, calibration and clinical usefulness of the model were assessed. The model was internally validated using 10-fold cross-validation. RESULTS: The radiomics signature consisted of 16 selected features and achieved favorable discrimination performance. The radiomics model incorporating the radiomics signature and the duration between radiotherapy and RN diagnosis, yielded an AUC of 0.966 and an optimism-corrected AUC of 0.967 via 10-fold cross-validation, which also revealed good discrimination. Calibration curves showed good agreement. Decision curve analysis confirmed the clinical utility of the model. CONCLUSIONS: The presented radiomics model can be conveniently used to facilitate individualized prediction of the response to methylprednisolone in patients with RN.

Amifostine-Loaded Nanocarrier Traverses the Blood-Brain Barrier and Prevents Radiation-Induced Brain Injury.

Radiation-induced brain injury (RIBI) is a severe, irreversible, or even life-threatening cerebral complication of radiotherapy in patients with head and neck tumors, and there is no satisfying prevention and effective treatment available for these patients. Amifostine (AMF) is a well-known free radical scavenger with demonstrated effectiveness in preventing radiation-induced toxicity. However, the limited permeability of AMF across the blood-brain barrier (BBB) when administered intravenously reduces the effectiveness of AMF in preventing RIBI. Herein, we construct a nanoparticle (NP) platform for BBB delivery of AMF. AMF is conjugated with 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-n-[poly(ethylene glycol)]-hydroxy succinamide [DSPE-PEG-NHS, PEG M 2000], and the product is DSPE-PEG-AMF. Then, the nanoparticles (DAPP NPs) were formed by self-assembly of poly(lactic-co-glycolic acid) (PLGA), DSPE-PEG-AMF, and polysorbate 80 (PS 80). PEG shields the nanoparticles from blood clearance by the reticuloendothelial system and lengthens the drug circulation time. PS 80 is used to encapsulate nanoparticles for medication delivery to the brain. The results of our study showed that DAPP NPs were able to effectively penetrate the blood-brain barrier (BBB) in healthy C57BL/6 mice. Furthermore, in a well-established mouse model of X-knife-induced brain injury, treatment with DAPP NPs (corresponding to 250 mg/kg AMF) was found to significantly reduce the volume of brain necrosis compared to mice treated with AMF (250 mg/kg). Importantly, the use of DAPP NPs was also shown to significantly mitigate the effects of radiation-induced neuronal damage and glial activation. This work presents a convenient brain-targeted AMF delivery system to achieve effective radioprotection for the brain, providing a promising strategy with tremendous clinical translation potential.

A phase 2 study of thalidomide for the treatment of radiation-induced blood-brain barrier injury.

Radiation-induced brain injury (RIBI) is a debilitating sequela after radiotherapy to treat head and neck cancer, and 20 to 30% of patients with RIBI fail to respond to or have contraindications to the first-line treatments of bevacizumab and corticosteroids. Here, we reported a Simon's minmax two-stage, single-arm, phase 2 clinical trial (NCT03208413) to assess the efficacy of thalidomide in patients with RIBI who were unresponsive to or had contraindications to bevacizumab and corticosteroid therapies. The trial met its primary endpoint, with 27 of 58 patients enrolled showing ≥25% reduction in the volume of cerebral edema on fluid-attenuated inversion recovery-magnetic resonance imaging (FLAIR-MRI) after treatment (overall response rate, 46.6%; 95% CI, 33.3 to 60.1%). Twenty-five (43.1%) patients demonstrated a clinical improvement based on the Late Effects Normal Tissues-Subjective, Objective, Management, Analytic (LENT/SOMA) scale, and 36 (62.1%) experienced cognitive improvement based on the Montreal Cognitive Assessment (MoCA) scores. In a mouse model of RIBI, thalidomide restored the blood-brain barrier and cerebral perfusion, which were attributed to the functional rescue of pericytes secondary to elevation of platelet-derived growth factor receptor ß (PDGFRß) expression by thalidomide. Our data thus demonstrate the therapeutic potential of thalidomide for the treatment of radiation-induced cerebral vasculature impairment.

Microglia drive transient insult-induced brain injury by chemotactic recruitment of CD8+ T lymphocytes.

The crosstalk between the nervous and immune systems has gained increasing attention for its emerging role in neurological diseases. Radiation-induced brain injury (RIBI) remains the most common medical complication of cranial radiotherapy, and its pathological mechanisms have yet to be elucidated. Here, using single-cell RNA and T cell receptor sequencing, we found infiltration and clonal expansion of CD8+ T lymphocytes in the lesioned brain tissues of RIBI patients. Furthermore, by strategies of genetic or pharmacologic interruption, we identified a chemotactic action of microglia-derived CCL2/CCL8 chemokines in mediating the infiltration of CCR2+/CCR5+ CD8+ T cells and tissue damage in RIBI mice. Such a chemotactic axis also participated in the progression of cerebral infarction in the mouse model of ischemic injury. Our findings therefore highlight the critical role of microglia in mediating the dysregulation of adaptive immune responses and reveal a potential therapeutic strategy for non-infectious brain diseases.

Association of shift work with incident dementia: a community-based cohort study.

BACKGROUND: Some observational studies had found that shift work would increase risks of metabolic disorders, cancers, and cardiovascular diseases, but there was no homogeneous evidence of such an association between shift work and incident dementia. This study aimed to investigate whether shift work would increase the risk of dementia in a general population. METHODS: One hundred seventy thousand seven hundred twenty-two employed participants without cognitive impairment or dementia at baseline recruited between 2006 and 2010 were selected from the UK Biobank cohort study. Follow-up occurred through June 2021. Shift work status at baseline was self-reported by participants and they were categorized as non-shift workers or shift workers. Among shift workers, participants were further categorized as night shift workers or shift but non-night shift workers. The primary outcome was all-cause dementia in a time-to-event analysis, and the secondary outcomes were subtypes of dementia, including Alzheimer's disease, vascular dementia, and other types of dementia. RESULTS: In total, 716 dementia cases were observed among 170,722 participants over a median follow-up period of 12.4 years. Shift workers had an increased risk of all-cause dementia as compared with non-shift workers after multivariable adjustment (hazard ratio [HR], 1.30, 95% confidence interval [CI], 1.08-1.58); however, among shift workers, night shift work was not associated with the risk of dementia (HR, 1.04, 95% CI, 0.73-1.47). We found no significant interaction between shift work and genetic predisposition to dementia on the primary outcome (P for interaction = 0.77). CONCLUSIONS: Shift work at baseline was associated with an increased risk of all-cause dementia. Among shift workers, there was no significant association between night shift work and the risk of dementia. The increased incidence of dementia in shift workers did not differ between participants in different genetic risk strata for dementia.

Motor neuron survival is associated with reduced neuroinflammation and increased autophagy after brachial plexus avulsion injury in aldose reductase-deficient mice.

Brachial plexus root avulsion (BPRA) is frequently caused by high-energy trauma including traffic accident and birth trauma, which will induces massive motoneurons (MNs) death as well as loss of motor and sensory function in the upper limb. The death of MNs is attributed to energy deficiency, neuroinflammation and oxidative stress at the injured ventral horn of spinal cord triggered by BPRA injury. It has been reported which aldose reductase (AR), an endogenous enzyme that catalyzes fructose synthesis, positively correlates with the poor prognosis following cerebral ischemic injury, diabetic retinopathy and diabetic peripheral neuropathy. However, the role of AR in BPRA remains unknown. Herein, we used a mouse model and found that in the spinal cord of BPRA mice, the upregulation of AR correlated significantly with (1) an inactivated SIRT1-AMPK-mTOR pathway and disrupted autophagy; (2) increased byproducts accumulation of lipid peroxidation metabolism and neuroinflammation; and (3) increased MNs death. Furthermore, our results demonstrated the role of AR in BPRA injury whereby the absence of AR (AR knockout mice, AR-/-) prevented the hyper-neuroinflammation and disrupted autophagy as well as motor neuron death caused by BPRA injury. Finally, we further demonstrate that AR inhibitor epalrestat is neuroprotective against BPRA injury by increasing autophagy level, alleviating neuroinflammation and rescuing MNs death in mice. Collectively, our data demonstrate that the AR upregulation in the spinal cord is an important factor contributing to autophagy disruption, neuroinflammation and MNs death following brachial plexus roots avulsion in mice. Our study also provides a promising therapy drug to assist re-implantation surgery for the treatment of BPRA.

Notch Signaling Mediates Radiation-Induced Smooth Muscle Cell Hypermuscularization and Cerebral Vasculopathy.

BACKGROUND: Emerging evidence highlighted vascular injury in aggravating radiation-induced brain injury (RIBI), a common complication of radiotherapy. This study aimed to delineate the pathological feature of cerebral small vessel and investigate the functional roles of Notch signaling in RIBI. METHODS: Brain tissue and functional MRI from RIBI patients were collected and analyzed for radiation-induced vasculopathy. A RIBI mouse model was induced by a single dose of 30-Gy cranial irradiation. Vascular morphology, pulsatility, and reactivity to pharmacological interventions, such as nimodipine and 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid, were monitored by 2-photon imaging in mice at 6 weeks postirradiation. Western blot, real-time quantitative PCR, immunofluorescence staining, and behavioral tests were performed. The effect of N-[N-(3, 5-difluorophenacetyl)-l-alanyl]-s-phenylglycinet-butyl ester, a Notch inhibitor, was used to investigate the vascular pathogenesis of RIBI mouse model. RESULTS: Morphologically, radiation resulted in vascular malformation featured by focal contractile rings together with general stenosis. Functionally, radiation also led to hypoperfusion, attenuated vascular pulsatility, and decreased dilation to nimodipine and 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid. Mechanically, Notch activation and increased expression of α-SMA protein were found in both surgical specimens of RIBI patients and the irradiated mice. Importantly, Notch inhibition by N-[N-(3, 5-difluorophenacetyl)-l-alanyl]-s-phenylglycinet-butyl ester significantly alleviated cerebral hypoperfusion, vasculopathy, and cognitive deficits in the RIBI mouse model. CONCLUSIONS: Radiation-induced cerebral vasculopathy showed bead-like shape and increased contractile state. Inhibition of Notch signaling by N-[N-(3, 5-difluorophenacetyl)-l-alanyl]-s-phenylglycinet-butyl ester effectively attenuated vasculopathy and relieved cognitive impairment, suggesting Notch signaling as a therapeutic target for the treatment of RIBI.

Pregabalin mitigates microglial activation and neuronal injury by inhibiting HMGB1 signaling pathway in radiation-induced brain injury.

BACKGROUND: Radiation-induced brain injury (RIBI) is the most serious complication of radiotherapy in patients with head and neck tumors, which seriously affects the quality of life. Currently, there is no effective treatment for patients with RIBI, and identifying new treatment that targets the pathological mechanisms of RIBI is urgently needed. METHODS: Immunofluorescence staining, western blotting, quantitative real-time polymerase chain reaction (Q-PCR), co-culture of primary neurons and microglia, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay, enzyme-linked immunosorbent assay (ELISA), and CRISPR-Cas9-mediated gene editing techniques were employed to investigate the protective effects and underlying mechanisms of pregabalin that ameliorate microglial activation and neuronal injury in the RIBI mouse model. RESULTS: Our findings showed that pregabalin effectively repressed microglial activation, thereby reducing neuronal damage in the RIBI mouse model. Pregabalin mitigated inflammatory responses by directly inhibiting cytoplasmic translocation of high-mobility group box 1 (HMGB1), a pivotal protein released by irradiated neurons which induced subsequent activation of microglia and inflammatory cytokine expression. Knocking out neuronal HMGB1 or microglial TLR2/TLR4/RAGE by CRISPR/Cas9 technique significantly inhibited radiation-induced NF-κB activation and pro-inflammatory transition of microglia. CONCLUSIONS: Our findings indicate the protective mechanism of pregabalin in mitigating microglial activation and neuronal injury in RIBI. It also provides a therapeutic strategy by targeting HMGB1-TLR2/TLR4/RAGE signaling pathway in the microglia for the treatment of RIBI.