Exosomal microRNA Differential Expression in Plasma of Young Adults with Chronic Mild Traumatic Brain Injury and Healthy Control.
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ABSTRACT:
SUBMITTER: Vorn R
PROVIDER: S-EPMC8773035 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Blast-related mild traumatic brain injury (mTBI) is considered the "signature" injury of the wars in Iraq and Afghanistan. Identifying biomarkers that could aid in diagnosis and assessment of chronic mTBI are urgently needed, as little progress has been made toward identifying blood-based biomarkers of repetitive mTBI in the chronic state. Addressing this knowledge gap is especially important in the population of military veterans who are receiving assessment and care often years after their last exposure. Circulating microRNAs (miRNAs), especially those encapsulated in extracellular vesicles (EVs), have gained interest as a source of biomarkers for neurological conditions. To identify biomarkers for chronic mTBI, we used next generation sequencing (NGS) to analyze miRNAs in plasma and plasma-derived EVs from 27 Iraq and Afghanistan war veterans with blast-related chronic mTBI, 11 deployed veteran non-TBI controls, and 31 civilian controls. We identified 32 miRNAs in plasma and 45 miRNAs in EVs that significantly changed in the chronic mTBI cohort compared with control groups. These miRNAs were predominantly associated with pathways involved in neuronal function, vascular remodeling, blood-brain barrier integrity, and neuroinflammation. In addition, the plasma proteome was analyzed and showed that the concentrations of C-reactive protein (CRP) and membrane metalloendopeptidase (MME) were elevated in chronic mTBI samples. These plasma miRNAs and proteins could potentially be used as biomarkers and provide insights into the molecular processes associated with the long-term health outcomes associated with blast-related chronic mTBI.
| S-EPMC7249467 | biostudies-literature
Project description:Circulating microRNAs (miRNAs) present in the serum/plasma are characteristically altered in many pathological conditions, and have been employed as diagnostic markers for specific diseases. We examined if plasma miRNA levels are altered in patients with traumatic brain injury (TBI) relative to matched healthy volunteers, and explored their potential for use as diagnostic TBI biomarkers. The plasma miRNA profiles from severe TBI patients (Glasgow Coma Scale [GCS] score ≤8) and age-, gender-, and race-matched healthy volunteers were compared by microarray analysis. Of the 108 miRNAs identified in healthy volunteer plasma, 52 were altered after severe TBI, including 33 with decreased and 19 with increased relative abundance. An additional 8 miRNAs were detected only in the TBI plasma. We used quantitative RT-PCR to determine if plasma miRNAs could identify TBI patients within the first 24 h post-injury. Receiver operating characteristic curve analysis indicated that miR-16, miR-92a, and miR-765 were good markers of severe TBI (0.89, 0.82, and 0.86 AUC values, respectively). Multiple logistic regression analysis revealed that combining these miRNAs markedly increased diagnostic accuracy (100% specificity and 100% sensitivity), compared to either healthy volunteers or orthopedic injury patients. In mild TBI patients (GCS score > 12), miR-765 levels were unchanged, while the plasma levels of miR-92a and miR-16 were significantly increased within the first 24 h of injury compared to healthy volunteers, and had AUC values of 0.78 and 0.82, respectively. Our results demonstrate that circulating miRNA levels are altered after TBI, providing a rich new source of potential molecular biomarkers. Plasma-derived miRNA biomarkers, used in combination with established clinical practices such as imaging, neurocognitive, and motor examinations, have the potential to improve TBI patient classification and possibly management.
| S-EPMC6468948 | biostudies-literature
Project description:To assess (1) whether visual disturbances can be demonstrated with objective measures more often in patients with mild traumatic brain injury (mTBI) than in orthopaedic controls and non-injured controls, (2) whether such objectively demonstrated disturbances change over time and (3) whether self-reported visual symptoms after mTBI correlate with objectively measurable changes in visuomotor performance.A prospective, controlled, observational study, with assessments planned 7-10 and 75-100 days after injury.Emergency department of a general hospital in Sweden.15 patients with mTBI, 15 patients with minor orthopaedic injury, 15 non-injured controls, aged 18-40 years.Visual examination, including assessment of visual acuity, accommodation, eye alignment, saccades and stereoacuity. Symptom assessment using Convergence Insufficiency Symptoms Survey (CISS) and Rivermead PostConcussion Symptoms Questionnaire.Assessments were performed 4-13 and 81-322 days after injury (extended time frames for logistical reasons). No statistically significant difference was found between the mTBI and control groups regarding saccade performance and stereoacuity at any time point. The accommodative amplitude was significantly lower in the mTBI group compared with non-injured controls at baseline. 6 out of 13 patients with mTBI had accommodative insufficiency at follow-up. Near point of convergence in the mTBI group was receded at baseline and improved statistically significantly at follow-up. At baseline, patients with mTBI had significantly higher CISS score than orthopaedic and non-injured controls. For patients with mTBI, the CISS score correlated with fusional vergence.There were some transient measurable visual changes regarding convergence in patients with mTBI during the subacute period after the injury. Our findings of persistence of accommodative insufficiency in a considerable proportion of patients with mTBI suggest that this visual function should not be overlooked in clinical assessment.
| S-EPMC5829871 | biostudies-other
Project description:Concussion is a heterogeneous injury that relies predominantly on subjective symptom reports for patient assessment and treatment. Developing an objective, biological test could aid phenotypic categorization of concussion patients, leading to advances in personalized treatment. This prospective multi-center study employed saliva micro-ribonucleic acid (miRNA) levels to stratify 251 individuals with concussion into biological subgroups. Using miRNA biological clusters, our objective was to assess for differences in medical/demographic characteristics, symptoms, and functional measures of balance and cognition. The miRNAs that best defined each cluster were used to identify physiological pathways that characterized each cluster. The 251 participants (mean age: 18 ± 7 years; 57% male) were optimally grouped into 10 clusters based on 22 miRNA levels. The clusters differed in age (χ2 = 19.1, p = 0.024), days post-injury at the time of saliva collection (χ2 = 22.6; p = 0.007), and number of prior concussions (χ2 = 17.6, p = 0.040). The clusters also differed in symptom reports for fatigue (χ2 = 17.7; p = 0.039), confusion (χ2 = 22.3; p = 0.008), difficulty remembering (χ2 = 22.0; p = 0.009), and trouble falling asleep (χ2 = 17.2; p = 0.046), but not objective balance or cognitive performance (p > 0.05). The miRNAs that defined concussion clusters regulate 16 physiological pathways, including adrenergic signaling, estrogen signaling, fatty acid metabolism, GABAergic signaling, synaptic vesicle cycling, and transforming growth factor (TGF)-β signaling. These results show that saliva miRNA levels may stratify individuals with concussion based on underlying biological perturbations that are relevant to both symptomology and pharmacological targets. If validated in a larger cohort, miRNA assessment could aid individualized, biology-driven concussion treatment.
| S-EPMC9248343 | biostudies-literature
Project description:We report the microRNA expression in patients with multiple myeloma and healthy adults. RNA sequencing was performed for circulating exosomes obtained from the serum of 10 MM patients and 5 healthy individuals.
2017-08-22 | GSE94564 | GEO
Project description:To acquire the time profiling of miRNA levels in microglial exosomes from injured brain after rmTBI, we employed a developed rmTBI mice model, and harvested the microglial exosomes at 1, 3, 7, 14, 21, 28, 35 and 42 DPI. The exosomes were first identified by TEM scanning, NTA measurement and Western Blot. miRNA microArray was performed to detect the miRNA levels in microglial exosomes after rmTBI. 3, 14 and 42 DPI were selected to respectively represents the time-point of acute phase, sub-acute phase and chronic phase after rmTBI. 10 miRNAs had an expression change of more than two-folds (up- or down-regualted) with a P value less than 0.05 at the 3 time-points. Among them, the expression changes of miR-124-3p were particularly evident. In addition, miR-124-3p was the only miRNA that up-regulated at 3 and 14 DPI, and down-regulated (reversely expressed) at 42 DPI, suggesting that its low expression in the chronic phase after rmTBI may exert a reverse impact on neural pathology, compared with that in the acute and sub-acute phase.
2019-07-10 | GSE133997 | GEO
Project description:Past and recent attempts at devising objective biomarkers for traumatic brain injury (TBI) in both blood and cerebrospinal fluid have focused on abundance measures of time-dependent proteins. Similar independent determinants would be most welcome in diagnosing the most common form of TBI, mild TBI (mTBI), which remains difficult to define and confirm based solely on clinical criteria. There are currently no consensus diagnostic measures that objectively define individuals as having sustained an acute mTBI. Plasma metabolomic analyses have recently evolved to offer an alternative to proteomic analyses, offering an orthogonal diagnostic measure to what is currently available. The purpose of this study was to determine whether a developed set of metabolomic biomarkers is able to objectively classify college athletes sustaining mTBI from non-injured teammates, within 6 hours of trauma and whether such a biomarker panel could be effectively applied to an independent cohort of TBI and control subjects. A 6-metabolite panel was developed from biomarkers that had their identities confirmed using tandem mass spectrometry (MS/MS) in our Athlete cohort. These biomarkers were defined at ?6 hours following mTBI and objectively classified mTBI athletes from teammate controls, and provided similar classification of these groups at the 2, 3, and 7 days post-mTBI. The same 6-metabolite panel, when applied to a separate, independent cohort provided statistically similar results despite major differences between the two cohorts. Our confirmed plasma biomarker panel objectively classifies acute mTBI cases from controls within 6 hours of injury in our two independent cohorts. While encouraged by our initial results, we expect future studies to expand on these initial observations.
| S-EPMC5909890 | biostudies-literature
Project description:Introduction: Risk factors for young adults with mTBI are not well understood. Improved understanding of age and sex as risk factors for impaired six-month outcomes in young adults is needed. Methods: Young adult mTBI subjects aged 18-39 years (18-29y; 30-39y) with six-month outcomes were extracted from the Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK-TBI Pilot) study. Multivariable regressions were performed for outcomes with age, sex, and the interaction factor age-group*sex as variables of interest, controlling for demographic and injury variables. Mean-differences (B) and 95% CIs are reported. Results: One hundred mTBI subjects (18-29y, 70%; 30-39y, 30%; male, 71%; female, 29%) met inclusion criteria. On multivariable analysis, age-group*sex was associated with six-month post-traumatic stress disorder (PTSD; PTSD Checklist-Civilian version); compared with female 30-39y, female 18-29y (B= -19.55 [-26.54, -4.45]), male 18-29y (B= -19.70 [-30.07, -9.33]), and male 30-39y (B= -15.49 [-26.54, -4.45]) were associated with decreased PTSD symptomatology. Female sex was associated with decreased six-month functional outcome (Glasgow Outcome Scale-Extended (GOSE): B= -0.6 [1.0, -0.1]). Comparatively, 30-39y scored higher on six-month nonverbal processing speed (Wechsler Adult Intelligence Scale-Processing Speed Index (WAIS-PSI); B= 11.88, 95% CI [1.66, 22.09]). Conclusions: Following mTBI, young adults aged 18-29y and 30-39y may have different risks for impairment. Sex may interact with age for PTSD symptomatology, with females 30-39y at highest risk. These results may be attributable to cortical maturation, biological response, social modifiers, and/or differential self-report. Confirmation in larger samples is needed; however, prevention and rehabilitation/counseling strategies after mTBI should likely be tailored for age and sex.
| S-EPMC6571056 | biostudies-literature
Project description:Wars in Iraq and Afghanistan have highlighted the problems of diagnosis and treatment of mild traumatic brain injury (mTBI). MTBI is a heterogeneous injury that may lead to the development of neurological and behavioral disorders. In the absence of specific diagnostic markers, mTBI is often unnoticed or misdiagnosed. In this study, mice were induced with increasing levels of mTBI and microRNA (miRNA) changes in the serum were determined. MTBI was induced by varying weight and fall height of the impactor rod resulting in four different severity grades of the mTBI. Injuries were characterized as mild by assessing with the neurobehavioral severity scale-revised (NSS-R) at day 1 post injury. Open field locomotion and acoustic startle response showed behavioral and sensory motor deficits in 3 of the 4 injury groups at day 1 post injury. All of the animals recovered after day 1 with no significant neurobehavioral alteration by day 30 post injury. Serum microRNA (miRNA) profiles clearly differentiated injured from uninjured animals. Overall, the number of miRNAs that were significantly modulated in injured animals over the sham controls increased with the severity of the injury. Thirteen miRNAs were found to identify mTBI regardless of its severity within the mild spectrum of injury. Bioinformatics analyses revealed that the more severe brain injuries were associated with a greater number of miRNAs involved in brain related functions. The evaluation of serum miRNA may help to identify the severity of brain injury and the risk of developing adverse effects after TBI.
| S-EPMC4224512 | biostudies-literature
Project description:BackgroundIt is known that blood levels of neurofilament light (NF-L) and diffusion-weighted magnetic resonance imaging (DW-MRI) are both associated with outcome of patients with mild traumatic brain injury (mTBI). Here, we sought to examine the association between admission levels of plasma NF-L and white matter (WM) integrity in post-acute stage DW-MRI in patients with mTBI.MethodsNinety-three patients with mTBI (GCS ≥ 13), blood sample for NF-L within 24 h of admission, and DW-MRI ≥ 90 days post-injury (median = 229) were included. Mean fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were calculated from the skeletonized WM tracts of the whole brain. Outcome was assessed using the Extended Glasgow Outcome Scale (GOSE) at the time of imaging. Patients were divided into CT-positive and -negative, and complete (GOSE = 8) and incomplete recovery (GOSE < 8) groups.ResultsThe levels of NF-L and FA correlated negatively in the whole cohort (p = 0.002), in CT-positive patients (p = 0.016), and in those with incomplete recovery (p = 0.005). The same groups showed a positive correlation with mean MD, AD, and RD (p < 0.001-p = 0.011). In CT-negative patients or in patients with full recovery, significant correlations were not found.ConclusionIn patients with mTBI, the significant correlation between NF-L levels at admission and diffusion tensor imaging (DTI) measurements of diffuse axonal injury (DAI) over more than 3 months suggests that the early levels of plasma NF-L may associate with the presence of DAI at a later phase of TBI.
| S-EPMC10426141 | biostudies-literature