Circulating Brain Injury Exosomal Proteins following Moderate-to-Severe Traumatic Brain Injury: Temporal Profile, Outcome Prediction and Therapy Implications

Mondello, Stefania; Guedes, Vivian A.; Lai, Chen; Czeiter, Endre; Amrein, Krisztina; Kobeissy, Firas; Mechref, Yehia; Jeromin, Andreas; Mithani, Sara; Martín, Carina Aguilar; Wagner, Chelsea; Czigler, Andras; Toth, Luca; Fazekas, Bálint; Büki, András; Gill, Jessica

doi:10.3390/cells9040977

Cited by 53 publications

(65 citation statements)

References 38 publications

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“…Elevated GFAP is considered an indicator of astrocytic cell impairment following TBI 16 , 17 , and elevated NfL is suggestive of neuroaxonal damage 18 – 20 . Levels of NfL in exosomes and other EVs following TBI have been evaluated in few studies, with variable results 9 , 21 – 23 . A recent study has shown an association between GFAP levels in EVs, but not free-circulating GFAP, and presence of diffuse injury as compared to other lesion types 23 .…”

Section: Discussionmentioning

confidence: 99%

“…Levels of NfL in exosomes and other EVs following TBI have been evaluated in few studies, with variable results 9 , 21 – 23 . A recent study has shown an association between GFAP levels in EVs, but not free-circulating GFAP, and presence of diffuse injury as compared to other lesion types 23 . Additional studies are needed to elucidate the mechanisms leading to chronic elevations of these biomarkers and to determine their effects.…”

Section: Discussionmentioning

confidence: 99%

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Extracellular vesicle concentrations of glial fibrillary acidic protein and neurofilament light measured 1 year after traumatic brain injury

Flynn

Leete

Shahim

et al. 2021

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Traumatic brain injury (TBI) is linked to long-term symptoms in a sub-set of patients who sustain an injury, but this risk is not universal, leading us and others to question the nature of individual variability in recovery trajectories. Extracellular vesicles (EVs) are a promising, novel avenue to identify blood-based biomarkers for TBI. Here, our aim was to determine if glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) measured 1-year postinjury in EVs could distinguish patients from controls, and whether these biomarkers relate to TBI severity or recovery outcomes. EV GFAP and EV NfL were measured using an ultrasensitive assay in 72 TBI patients and 20 controls. EV GFAP concentrations were elevated in moderate and severe TBI compared to controls (p’s < 0.001) and could distinguish controls from moderate (AUC = 0.86) or severe TBI (AUC = 0.88). Increased EV GFAP and EV NfL levels were associated with lower 1-year Glasgow Outcome Scale–Extended (GOS-E) score (p’s < 0.05). These findings suggest that blood-derived EV concentrations of GFAP and NfL drawn even 1 year after injury are higher in TBI patients compared to controls, and are related to injury severity and poor recovery outcomes, suggesting that TBIs alter the activity of these biomarkers, likely contributing to individual variability in recovery.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Extracellular vesicle concentrations of glial fibrillary acidic protein and neurofilament light measured 1 year after traumatic brain injury

Flynn

Leete

Shahim

et al. 2021

Sci Rep

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“…The UCH-L1 serum biomarker levels, however, may not be as reliable in this pig models of diffuse TBI as was highlighted in our previous study ( 25 ). The addition of a pathobiologically diverse set of biomarkers, including their exosomal component, may substantially improve the current approach, enabling us to reflect and gauge the response to therapy more effectively ( 38 – 41 ). However, blood-based brain injury biomarker research in large animal models is in its infancy, and the majority of the assays have been not specifically tested and validated in pigs, thereby limiting their reliability and application and requiring further study ( 42 ).…”

Section: Discussionmentioning

confidence: 99%

Operation Brain Trauma Therapy: An Exploratory Study of Levetiracetam Treatment Following Mild Traumatic Brain Injury in the Micro Pig

et al. 2021

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Operation brain trauma therapy (OBTT) is a drug- and biomarker-screening consortium intended to improve the quality of preclinical studies and provide a rigorous framework to increase the translational potential of experimental traumatic brain injury (TBI) treatments. Levetiracetam (LEV) is an antiepileptic agent that was the fifth drug tested by OBTT in three independent rodent models of moderate to severe TBI. To date, LEV has been the most promising drug tested by OBTT and was therefore advanced to testing in the pig. Adult male micro pigs were subjected to a mild central fluid percussion brain injury followed by a post-injury intravenous infusion of either 170 mg/kg LEV or vehicle. Systemic physiology was assessed throughout the post-injury period. Serial serum samples were obtained pre-injury as well as at 1 min, 30 min, 1 h, 3 h, and 6 h post-injury for a detailed analysis of the astroglial biomarker glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1. Tissue was collected 6 h following injury for histological assessment of diffuse axonal injury using antibodies against the amyloid precursor protein (APP). The animals showed significant increases in circulating GFAP levels from baseline to 6 h post-injury; however, LEV treatment was associated with greater GFAP increases compared to the vehicle. There were no differences in the numbers of APP+ axonal swellings within the pig thalamus with LEV treatment; however, significant alterations in the morphological properties of the APP+ axonal swellings, including reduced swelling area and increased swelling roundness, were observed. Additionally, expression of the neurite outgrowth marker, growth-associated protein 43, was reduced in axonal swellings following LEV treatment, suggesting potential effects on axonal outgrowth that warrant further investigation.

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“…The TRAJ procedure determines patterns in longitudinal biomarker data by assuming that the population is composed of distinct subgroups containing their own unique biomarker profiles and can handle data that is missing completely at random ( 19 , 20 ). The trajectories are identified on a likelihood basis using methods previously described ( 21 – 23 ). A censored normal model was used given the minimal detectable limit for each biomarker and the skewed distribution.…”

Section: Methodsmentioning

confidence: 99%

Sex Differences in Circulating T-Tau Trajectories After Sports-Concussion and Correlation With Outcome

et al. 2020

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Sex differences in molecular biomarkers after sports-related concussion (SRC) could steadily advance our understanding of injury heterogeneity and complexity, and help capture phenotypic characteristics, by unveiling sex-dependent pathobiological processes and disease mechanisms. Such knowledge will help improve diagnosis, clinical management, and prognosis. Total-tau (t-tau) has recently emerged as a promising blood marker showing sex-associated differences in neurodegenerative diseases. Nonetheless, to date, little is known about the potential influence of sex on its injury-related concentration and dynamics after SRC. We hypothesized that measurements of circulating levels of t-tau over time would reflect a differential vulnerability signature, providing insights into the sex-related phenotypes and their relationship with clinical outcomes. To test this hypothesis, plasma levels of t-tau were measured using an ultrasensitive immunoassay up to 7 days after injury, in 46 concussed athletes (20 males, 26 females). We used trajectory analysis to generate two distinct temporal profiles of t-tau, which were then compared with gender and return to play (RTP). The majority of subjects (∼63%) started with low t-tau concentrations that further declined within the first 48 h; while the remaining ("maximal decliners") started with concentrations comparable to the baseline levels that also fell over time, but persisting markedly higher compared with the first profile. The maximal decliner group was primarily composed of female subjects (p = 0.007) and was significantly associated with poor outcome (RTP ≥ 10 days after concussion) (p = 0.011). Taken together, our data provide evidence for the existence of sex-related biosignatures following sports-related concussions, possibly indicating a differential effect as a result of distinct brain vulnerability and inherent injury response. Future studies will be required to further elucidate underlying sex-based biological and pathophysiological mechanisms, and determine the value of t-tau signatures for management and therapeutic decision-making in sports-related concussions.

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Circulating Brain Injury Exosomal Proteins following Moderate-to-Severe Traumatic Brain Injury: Temporal Profile, Outcome Prediction and Therapy Implications

Cited by 53 publications

References 38 publications

Extracellular vesicle concentrations of glial fibrillary acidic protein and neurofilament light measured 1 year after traumatic brain injury

Extracellular vesicle concentrations of glial fibrillary acidic protein and neurofilament light measured 1 year after traumatic brain injury

Operation Brain Trauma Therapy: An Exploratory Study of Levetiracetam Treatment Following Mild Traumatic Brain Injury in the Micro Pig

Sex Differences in Circulating T-Tau Trajectories After Sports-Concussion and Correlation With Outcome

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