Diagnosis of traumatic brain injury using miRNA signatures in nanomagnetically isolated brain-derived extracellular vesicles.

The accurate diagnosis and clinical management of traumatic brain injury (TBI) is currently limited by the lack of accessible molecular biomarkers that reflect the pathophysiology of this heterogeneous disease. To address this challenge, we developed a microchip diagnostic that can characterize TBI more comprehensively using the RNA found in brain-derived extracellular vesicles (EVs). Our approach measures a panel of EV miRNAs, processed with machine learning algorithms to capture the state of the injured and recovering brain. Our diagnostic combines surface marker-specific nanomagnetic isolation of brain-derived EVs, biomarker discovery using RNA sequencing, and machine learning processing of the EV miRNA cargo to minimally invasively measure the state of TBI. We achieved an accuracy of 99% identifying the signature of injured vs. sham control mice using an independent blinded test set (N = 77), where the injured group consists of heterogeneous populations (injury intensity, elapsed time since injury) to model the variability present in clinical samples. Moreover, we successfully predicted the intensity of the injury, the elapsed time since injury, and the presence of a prior injury using independent blinded test sets (N = 82). We demonstrated the translatability in a blinded test set by identifying TBI patients from healthy controls (AUC = 0.9, N = 60). This approach, which can detect signatures of injury that persist across a variety of injury types and individual responses to injury, more accurately reflects the heterogeneity of human TBI injury and recovery than conventional diagnostics, opening new opportunities to improve treatment of traumatic brain injuries.

Red Blood Cell Distribution Width is Associated with Poor Clinical Outcome After Subarachnoid Hemorrhage: A Pilot Study.

INTRODUCTION: The red cell distribution width (RDW) is a biomarker strongly associated with poor outcome in inflammatory and thrombotic diseases. Subarachnoid hemorrhage (SAH) is both an inflammatory and thrombotic state in which many biomarkers have been studied. In this exploratory pilot study, we sought to determine whether RDW predicts poor outcome in patients with SAH. METHODS: Patients with moderate-to-severe SAH were prospectively enrolled in an observational study of biomarkers and outcome. CBC, ESR, high sensitivity CRP, D-dimer, and fibrinogen were obtained on post-bleed days (PBD) 1, 3, 5, 7, and 10. Poor outcome was defined as a modified Rankin score of 3-6 at 90-days. RESULTS: Of 40 patients, 5 (12.5%) died and 19 (47.5%) had a poor outcome. RDW (p = 0.046) when measured serially over the study period, was significantly higher among patients with poor outcome. Maximum RDW (OR 2.3 95% CI 1.2-3.6; p = 0.014) and maximum WBC count (OR 1.29 95% CI 1.04-1.60; p = 0.018) were associated with poor outcome. Stepwise addition of maximum ESR, CRP, D-dimer, and fibrinogen yielded a model with RDW (OR 2.54 95% CI 1.21-5.35; p = 0.014) and fibrinogen (OR 1.01 95% CI 1.002-1.01; p = 0.004) predicting outcome. With addition of age and Hunt and Hess grade, RDW, fibrinogen, and high-grade status remained significantly associated with poor outcome. Use of PBD1 RDW in lieu of maximum RDW, resulted in a similar model. CONCLUSIONS: An elevated RDW is associated with poor outcome in SAH patients. RDW may be a useful predictor of outcomes after SAH.

Mammalian target of rapamycin: master regulator of cell growth in the nervous system.

The mammalian target of rapamycin (mTOR) is a highly conserved serine/threonine protein kinase that regulates a number of diverse biologic processes important for cell growth and proliferation, including ribosomal biogenesis and protein translation. In this regard, hyperactivation of the mTOR signaling pathway has been demonstrated in numerous human cancers, including a number of inherited cancer syndromes in which individuals have an increased risk of developing benign and malignant tumors. Three of these inherited cancer syndromes (Lhermitte-Duclos disease, neurofibromatosis type 1, and tuberous sclerosis complex) are characterized by significant central nervous system dysfunction and brain tumor formation. Each of these disorders is caused by a genetic mutation that disrupts the expression of proteins which negatively regulate mTOR signaling, indicating that the mTOR signaling pathway is critical for appropriate brain development and function. In this review, we discuss our current understanding of the mTOR signaling pathway and its role in promoting ribosome biogenesis and cell growth. We suggest that studies of this pathway may prove useful in identifying molecular targets for biologically-based therapies of brain tumors associated with these inherited cancer syndromes as well as sporadic central nervous system tumors.