Browsing by Author "Wellington, Cheryl"

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    Effects of Interval Exercise on Commonly Studied Fluid Biomarkers for Sport-related Concussion in Serum and Plasma
    (2022-06) Penner, Linden; Smirl, Jonathan; Emery, Carolyn; Debert, Chantel; Wellington, Cheryl; Fraser, Douglas
    High intensity interval exercise has been shown to increase blood levels of commonly studied fluid biomarkers for SRC. If true, the potential diagnostic or prognostic applications of these markers for SRC may be limited due to exercise being implicit in sport. This thesis examines the effects of interval exercise on serially collected plasma levels of t-tau, GFAP, NFL, and UCH-L1 in healthy young adults (7 females; 3 males), and differences in biomarker levels between plasma and serum matrices. The first study showed small and short-lived decreases in plasma NFL and GFAP immediately following interval exercise. The second study demonstrated differences between plasma and serum concentrations of t-tau, NFL, and GFAP. Together, these results suggest exercise should be considered prior to the clinical validation of these biomarkers for diagnosis or prognosis of SRC and highlights the need to harmonize analytical methodologies across research investigations aiming to develop objective measures of SRC.
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    Plasma Biomarkers Associated with Sport-Related Concussion in Adolescents: Age and Sex Matter
    (2023-04-13) Tabor, Jason Benjamin; Emery, Carolyn; Debert, Chantel; Yeates, Keith; Esser, Michael; Wellington, Cheryl
    Adolescent sport-related concussion (SRC) is a growing public health concern. Relative to adult SRC, there exists a large gap in the literature concerning adolescents, with few studies focusing on blood biomarkers relevant to SRC. Multiple studies in this thesis aim to increase our understanding of how blood biomarkers associated with SRC may present in athletic adolescents. This thesis begins by reviewing the current landscape of SRC biomarkers (i.e., glial fibrillary acidic protein [GFAP], ubiquitin-c-terminal hydrolase L1 [UCH-L1], neurofilament light [NF-L], and tau) and their possible roles in clinical management. Limitations to the SRC biomarker literature precluding their progress towards clinical validation are also highlighted. The neuroinflammatory response to concussion is then discussed in more detail, emphasizing potential covariables that may influence SRC biomarkers. Plasma biomarker levels [GFAP, UCH-L1, NF-L, total tau (T-tau), and P-tau-181] are then characterized with respect to age, sex, and previous concussion in healthy adolescents. This thesis then discusses the impact of replicate error in biomarker measurements at low concentrations and explores multiple biostatistical approaches to optimizing statistical precision in biomarker data analysis. Finally, the associations between SRC and plasma biomarker levels are examined in adolescent sport participants to investigate whether biomarkers are sensitive to SRC at various timepoints throughout recovery. The collective work of this thesis demonstrates that multiple confounding variables may influence GFAP, UCH-L1, NF-L, and tau in adolescents. First, in healthy individuals, UCH-L1 and P-tau-181 differed by sex, and age was negatively associated with GFAP. Secondly, this thesis showed that varying levels of agreement in these biomarkers samples from these healthy adolescents warranted a multilevel modelling approach using both replicates in analysis (as opposed to excluding sample duplicates based on arbitrary variation thresholds) to produce optimally precise estimates of association. Lastly, the work herein provides evidence suggesting GFAP, UCH-L1, NF-L, and T-tau are sensitive to SRC at various times throughout recovery in adolescents. Furthermore, results emphasize the importance of analyzing these biomarkers with respect to age and sex. The findings presented in this thesis make a significant contribution to the field of adolescent SRC biomarkers and support their continued use for investigating adolescent SRC neuropathophysiology.
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    Using metabolomics to predict severe traumatic brain injury outcome (GOSE) at 3 and 12 months
    (2023-07-22) Banoei, Mohammad M.; Lee, Chel H.; Hutchison, James; Panenka, William; Wellington, Cheryl; Wishart, David S.; Winston, Brent W.
    Abstract Background Prognostication is very important to clinicians and families during the early management of severe traumatic brain injury (sTBI), however, there are no gold standard biomarkers to determine prognosis in sTBI. As has been demonstrated in several diseases, early measurement of serum metabolomic profiles can be used as sensitive and specific biomarkers to predict outcomes. Methods We prospectively enrolled 59 adults with sTBI (Glasgow coma scale, GCS ≤ 8) in a multicenter Canadian TBI (CanTBI) study. Serum samples were drawn for metabolomic profiling on the 1st and 4th days following injury. The Glasgow outcome scale extended (GOSE) was collected at 3- and 12-months post-injury. Targeted direct infusion liquid chromatography-tandem mass spectrometry (DI/LC–MS/MS) and untargeted proton nuclear magnetic resonance spectroscopy (1H-NMR) were used to profile serum metabolites. Multivariate analysis was used to determine the association between serum metabolomics and GOSE, dichotomized into favorable (GOSE 5–8) and unfavorable (GOSE 1–4), outcomes. Results Serum metabolic profiles on days 1 and 4 post-injury were highly predictive (Q2 > 0.4–0.5) and highly accurate (AUC > 0.99) to predict GOSE outcome at 3- and 12-months post-injury and mortality at 3 months. The metabolic profiles on day 4 were more predictive (Q2 > 0.55) than those measured on day 1 post-injury. Unfavorable outcomes were associated with considerable metabolite changes from day 1 to day 4 compared to favorable outcomes. Increased lysophosphatidylcholines, acylcarnitines, energy-related metabolites (glucose, lactate), aromatic amino acids, and glutamate were associated with poor outcomes and mortality. Discussion Metabolomic profiles were strongly associated with the prognosis of GOSE outcome at 3 and 12 months and mortality following sTBI in adults. The metabolic phenotypes on day 4 post-injury were more predictive and significant for predicting the sTBI outcome compared to the day 1 sample. This may reflect the larger contribution of secondary brain injury (day 4) to sTBI outcome. Patients with unfavorable outcomes demonstrated more metabolite changes from day 1 to day 4 post-injury. These findings highlighted increased concentration of neurobiomarkers such as N-acetylaspartate (NAA) and tyrosine, decreased concentrations of ketone bodies, and decreased urea cycle metabolites on day 4 presenting potential metabolites to predict the outcome. The current findings strongly support the use of serum metabolomics, that are shown to be better than clinical data, in determining prognosis in adults with sTBI in the early days post-injury. Our findings, however, require validation in a larger cohort of adults with sTBI to be used for clinical practice.