Repetitive mild traumatic brain injury (rmTBI) is considered to be an important risk factor for long-term neurodegenerative disorders such as Alzheimer's disease, which is characterized by b-amyloid abnormalities and impaired cognitive function. Microglial exosomes have been reported to be involved in the transportation, distribution, and clearance of b-amyloid in Alzheimer's disease. However, their impacts on the development of neurodegeneration after rmTBI are not yet known. The role of miRNAs in microglial exosomes on regulating post-traumatic neurodegeneration was investigated in the present study. We demonstrated that miR-124-3p level in microglial exosomes from injured brain was significantly altered in the acute, sub-acute, and chronic phases after rmTBI. In in vitro experiments, microglial exosomes with upregulated miR-124-3p (EXO-124) alleviated neurodegeneration in repetitive scratch-injured neurons. The effects were exerted by miR-124-3p targeting Rela, an inhibitory transcription factor of ApoE that promotes the b-amyloid proteolytic breakdown, thereby inhibiting b-amyloid abnormalities. In mice with rmTBI, the intravenously injected microglial exosomes were taken up by neurons in injured brain. Besides, miR-124-3p in the exosomes was transferred into hippocampal neurons and alleviated neurodegeneration by targeting the Rela/ApoE signaling pathway. Consequently, EXO-124 treatments improved the cognitive outcome after rmTBI, suggesting a promising therapeutic strategy for future clinical translation.

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Mild traumatic brain injury (mTBI) has a relatively higher incidence in aging people due to walking problems. Cranial computed tomography and magnetic resonance imaging provide the standard diagnostic tool to identify intracranial complications in patients with mTBI. However, it is still necessary to further explore blood biomarkers for evaluating the deterioration risk at the early stage of mTBI to improve medical decision-making in the emergency department. The activation of the inflammatory response is one of the main pathological mechanisms leading to unfavorable outcomes of mTBI. As complete blood count (CBC) analysis is the most extensively used laboratory test in practice, we extracted clinical data of 994 patients with mTBI from two large clinical cohorts (MIMIC-IV and eICU-CRD) and selected inflammation-related indicators from CBC analysis to investigate their relationship with the deterioration after mTBI. The combinatorial indices neutrophil-to-lymphocyte ratio (NLR), red cell distribution width-to-platelet ratio (RPR), and NLR times RPR (NLTRP) were supposed to be potential risk predictors, and the data from the above cohorts were integratively analyzed using our previously reported method named MeDICS. We found that NLR, RPR, and NLTRP levels were higher among deteriorated patients than non-deteriorated patients with mTBI. Besides, high NLTRP was associated with increased deterioration risk, with the odds ratio increasing from NLTRP of 1–2 (2.69, 1.48–4.89) to > 2 (4.44, 1.51–13.08), using NLTRP of 0–1 as the reference. NLTRP had a moderately good prognostic performance with an area under the ROC curve of 0.7554 and a higher prediction value than both NLR and RPR, indicated by the integrated discrimination improvement index. The decision curve analysis also showed greater clinical benefits of NLTRP than NLR and RPR in a large range of threshold probabilities. Subgroup analysis further suggested that NLTRP is an independent risk factor for the deterioration after mTBI. In addition, in vivo experiments confirmed the association between NLTRP and neural/systemic inflammatory response after mTBI, which emphasized the importance of controlling inflammation in clinical treatment. Consequently, NLTRP is a promising biomarker for the deterioration risk of mTBI. It can be used in resource-limited settings, thus being proposed as a routinely available tool at all levels of the medical system.

Background: Outcome prediction is crucial for the effective treatment of patients with acute traumatic brain injury (TBI). However, there is still a lack of reliable and routinely available blood predictors with sufficient clinical evidence till now. This research is designed to investigate the association between red cell distribution width to platelet count ratio (RPR) and mortality risk of TBI patients, thereby providing a promising indicator for prognosis evaluation of TBI.Methods: Clinical data of 2,220 patients with TBI that extracted from two large ICU cohorts (MIMIC-III database and eICU Collaborative Research Database), were integratively analyzed using our developed method named MeDICS. The association between RPR and hospital mortality was determined using the logistic regression model and Lowess Smoothing technique. Multivariable logistic regression analyses were used to control for confounders. The receiver-operating characteristic (ROC) curve was depicted to show the prognostic performance. The stepwise backward elimination method was performed to develop a nomogram, where tenfold cross-validation was used to protect it against overfitting. Results: Higher RPR can be observed among non-survivors than survivors with TBI (p < 0.001). Besides, high RPR was associated with increased mortality, with the odds ratio (OR) increasing from RPR of 0.074-0.098 (OR: 2.13, 95% CI 1.39 to 3.28, p = 0.001) to > 0.098 (OR: 3.82, 95% CI 2.55 to 5.72, p < 0.001), using RPR of < 0.057 as the reference. RPR had a moderately good prognostic performance with an area under ROC Curve (AUC) of 0.7367, which was greater than that of Glasgow Coma Scale (GCS, AUC = 0.6022). The nomogram consisting of RPR, GCS and other risk factors can further improve the prognostic value of RPR (Harrell’s C-index = 0.8582, p value of Hosmer-Lemeshow test = 0.3159). In addition, in-vivo experiments indicated that the continuous change in RPR after TBI was attributed to the development of inflammatory response.Conclusions: As an easily accessible index, RPR is a promising predictor of mortality for acute TBI. The nomogram generated from RPR can be used in resource-limited settings, thus be proposed as a prognosis evaluation aid for patients with TBI in all levels of medical system.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts, which is susceptible in elderly people with declined mobility, athletes of full contact sports, military personnel and victims of domestic violence. It has been pathologically diagnosed in brain donors with a history of repetitive mild traumatic brain injury (rmTBI), but cannot be clinically diagnosed for a long time. By the continuous efforts by neuropathologists, neurologists and neuroscientists in recent 10 years, an expert consensus for the diagnostic framework of CTE was proposed in 2021 funded by the National Institute of Neurological Disorders and Stroke. The new consensus contributes to facilitating research in the field. However, it still needs to incorporate in vivo biomarkers to further refine and validate the clinical diagnostic criteria. From this, a single-center, observational cohort study has been being conducted by Tianjin Medical University General Hospital since 2021. As a pilot study of this clinical trial, the present research recruited 12 pairs of gender- and age-matched rmTBI patients with healthy subjects. Their blood samples were collected for exosome isolation, and multi-omics screening to explore potential diagnostic biomarkers in blood and its exosomes. The expression level of CHL1 protein, KIF2A mRNA, LIN7C mRNA, miR-297, and miR-1183 in serum and exosomes were found to be differentially expressed between groups. Besides, serum and exosomal CHL1, KIF2A, and miR-1183, as well as exosomal miR-297 were further verified as potential biomarkers for CTE by low-throughput assays. They are expected to contribute to establishing a novel set of CTE diagnostic signatures with classic neurodegenerative indicators in our future study, thereby updating the consensus diagnostic criteria for CTE by incorporating new evidence of the in vivo biomarkers.

Tumor necrosis factor-α (TNF-α) antagonists, the first biologics approved for treating patients with inflammatory bowel disease (IBD), are effective for the induction and maintenance of remission and significantly improving prognosis. However, up to one-third of treated patients show primary nonresponse (PNR) to anti-TNF-α therapies, and 23%-50% of IBD patients experience loss of response (LOR) to these biologics during subsequent treatment. There is still no recognized predictor for evaluating the efficacy of anti-TNF drugs. This review summarizes the existing predictors of PNR and LOR to anti-TNF in IBD patients. Most predictors remain controversial, and only previous surgical history, disease manifestations, drug concentrations, antidrug antibodies, serum albumin, some biologic markers, and some genetic markers may be potentially predictive. In addition, we also discuss the next steps of treatment for patients with PNR or LOR to TNF antagonists. Therapeutic drug monitoring plays an important role in treatment selection. Dose escalation, combination therapy, switching to a different anti-TNF drug, or switching to a biologic with a different mechanism of action can be selected based on the concentration of the drug and/or antidrug antibodies.