Brain injury exosomal proteins are promising blood biomarker candidates in traumatic brain injury (TBI). A better understanding of their role in the diagnosis, characterization, and management of TBI is essential for upcoming clinical implementation. In the current investigation, we aimed to explore longitudinal trajectories of brain injury exosomal proteins in blood of patients with moderate-to-severe TBI, and to evaluate the relation with the free-circulating counterpart and patient imaging and clinical parameters. Exosomal levels of glial (glial fibrillary acidic protein (GFAP)) and neuronal/axonal (ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), neurofilament light chain (NFL), and total-tau (t-tau)) proteins were measured in serum of 21 patients for up 5 days after injury using single molecule array (Simoa) technology. Group-based trajectory analysis was used to generate distinct temporal exosomal biomarker profiles. We found altered profiles of serum brain injury exosomal proteins following injury. The dynamics and levels of exosomal and related free-circulating markers, although correlated, showed differences. Patients with diffuse injury displayed higher acute exosomal NFL and GFAP concentrations in serum than those with focal lesions. Exosomal UCH-L1 profile characterized by acutely elevated values and a secondary steep rise was associated with early mortality (n = 2) with a sensitivity and specificity of 100%. Serum brain injury exosomal proteins yielded important diagnostic and prognostic information and represent a novel means to unveil underlying pathophysiology in patients with moderate-to-severe TBI. Our findings support their utility as potential tools to improve patient phenotyping in clinical practice and therapeutic trials.

Traumatic brain injury (TBI) induces blood-brain barrier (BBB) disruption, which contributes to secondary injury of brain tissue and development of chronic cognitive decline. However, single mild (m)TBI, the most frequent form of brain trauma disrupts the BBB only transiently. We hypothesized, that co-morbid conditions exacerbate persistent BBB disruption after mTBI leading to long term cognitive dysfunction. Since hypertension is the most important cerebrovascular risk factor in populations prone to mild brain trauma, we induced mTBI in normotensive Wistar and spontaneously hypertensive rats (SHR) and we assessed BBB permeability, extravasation of blood-borne substances, neuroinflammation and cognitive function two weeks after trauma. We found that mTBI induced a significant BBB disruption two weeks after trauma in SHRs but not in normotensive Wistar rats, which was associated with a significant accumulation of fibrin and increased neuronal expression of inflammatory cytokines TNFα, IL-1β and IL-6 in the cortex and hippocampus. SHRs showed impaired learning and memory two weeks after mild TBI, whereas cognitive function of normotensive Wistar rats remained intact. Future studies should establish the mechanisms through which hypertension and mild TBI interact to promote persistent BBB disruption, neuroinflammation and cognitive decline to provide neuroprotection and improve cognitive function in patients with mTBI.

Traumatic brain injury (TBI) induces cerebrovascular oxidative stress, which is associated with neurovascular uncoupling, autoregulatory dysfunction, and persisting cognitive decline in both pre-clinical models and patients. However, single mild TBI (mTBI), the most frequent form of brain trauma, increases cerebral generation of reactive oxygen species (ROS) only transiently. We hypothesized that comorbid conditions might exacerbate long-term ROS generation in cerebral arteries after mTBI. Because hypertension is the most important cerebrovascular risk factor in populations prone to mild brain trauma, we induced mTBI in normotensive and spontaneously hypertensive rats (SHR) and assessed changes in cytoplasmic and mitochondrial superoxide (O ₂ -) production by confocal microscopy in isolated middle cerebral arteries (MCA) 2 weeks after mTBI using dihydroethidine (DHE) and the mitochondria-targeted redox-sensitive fluorescent indicator dye MitoSox. We found that mTBI induced a significant increase in long-term cytoplasmic and mitochondrial O ₂ - production in MCAs of SHRs and increased expression of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit Nox4, which were reversed to the normal level by treating the animals with the cell-permeable, mitochondria-targeted antioxidant peptide SS-31 (5.7 mg kg ⁻¹ day ⁻¹ , i.p.). Persistent mTBI-induced oxidative stress in MCAs of SHRs was significantly decreased by inhibiting vascular NADPH oxidase (apocyinin). We propose that hypertension- and mTBI-induced cerebrovascular oxidative stress likely lead to persistent dysregulation of cerebral blood flow (CBF) and cognitive dysfunction, which might be reversed by SS-31 treatment.

Post-traumatic hypopituitarism (PTHP) is a significant, but often neglected consequence of traumatic brain injury (TBI). We aimed to provide a comprehensive overview of epidemiology, pathophysiology, clinical features and diagnostic approaches of PTHP. MEDLINE, EMBASE, Cochrane Library and Web of Science were searched. 45 articles of human studies evaluating acute endocrine changes following mild, moderate and severe TBI were selected. Severity of TBI seems to be the most important risk factor of PTHP. Adrenal insufficiency (AI) was present in 10% of TBI patients (prevalence can be as high as 50% after severe TBI), and hypocortisolemia is a predictor of mortality and long-term hypopituitarism. Suppression of the thyroid axis in 2–33% of TBI patients may be an independent predictor of adverse neurological outcome, as well. 9–36% of patients with severe TBI exhibit decreased function of the somatotrophic axis with a divergent effect on the central nervous system. Arginine-Vasopressin (AVP) deficiency is present in 15–51% of patients, associated with increased mortality and unfavorable outcome. Due to shear and injury of the stalk hyperprolactinemia is relatively common (2–50%), but it bears little clinical significance. Sex hormone levels remain within normal values. PTHP occurs frequently after TBI, affecting various axis and determining patients’ outcome. However, evidence is scarce regarding exact epidemiology, diagnosis, and effective clinical application of hormone substitution. Future studies are needed to identify patients at-risk, determine the optimal timing for endocrine testing, and refine diagnostic and treatment approaches to improve outcome.

Purpose Stereo vision tests are widely used in the clinical practice for screening amblyopia and amblyogenic conditions. According to literature, none of these tests seems to be suitable to be used alone as a simple and reliable tool. There has been a growing interest in developing new types of stereo vision tests, with sufficient sensitivity to detect amblyopia. This new generation of assessment tools should be computer based, and their reliability must be statistically warranted. The present study reports the clinical evaluation of a screening system based on random dot stereograms using a tablet as display. Specifically, a dynamic random dot stereotest with binocularly detectable Snellen-E optotype (DRDSE) was used and compared with the Lang II stereotest. Methods A total of 141 children (aged 4–14, mean age 8.9) were examined in a field study at the Department of Ophthalmology, Pécs, Hungary. Inclusion criteria consisted of diagnoses of amblyopia, anisometropia, convergent strabismus, and hyperopia. Children with no ophthalmic pathologies were also enrolled as controls. All subjects went through a regular pediatric ophthalmological examination before proceeding to the DRDSE and Lang II tests. Results DRDSE and Lang II tests were compared in terms of sensitivity and specificity for different conditions. DRDSE had a 100% sensitivity both for amblyopia (n = 11) and convergent strabismus (n = 21), as well as a 75% sensitivity for hyperopia (n = 36). However, the performance of DRDSE was not statistically significant when screening for anisometropia. On the other hand, Lang II proved to have 81.8% sensitivity for amblyopia, 80.9% for strabismus, and only 52.8% for hyperopia. The specificity of DRDSE was 61.2% for amblyopia, 67.3% for strabismus, and 68.6% for hyperopia, respectively. Conversely, Lang II showed about 10% better specificity, 73.8% for amblyopia, 79.2% for strabismus, and 77.9% for hyperopia. Conclusions The DRDSE test has a better sensitivity for the detection of conditions such as amblyopia or convergent strabismus compared with Lang II, although with slightly lower specificity. If the specificity could be further improved by optimization of the stimulus parameters, while keeping the sensitivity high, DRDSE would be a promising stereo vision test for screening of amblyopia.