Testing a Multivariate Proteomic Panel for Traumatic Brain Injury Biomarker Discovery: A TRACK-TBI Pilot Study

Abstract

The complex and heterogeneous nature of traumatic brain injury (TBI) has rendered the identification of diagnostic and prognostic biomarkers elusive. A single acute biomarker may not be sufficient to categorize injury severity and/or predict outcome. Using multivariate dimension reduction analyses, we tested the sensitivity and specificity of a multi-analyte panel of proteins as an ensemble biomarker for TBI. Serum was collected within 24 h of injury in a cohort of 130 patients enrolled in the multi-center prospective Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK-TBI Pilot) study and run on an array that measured 72 proteins. Using unsupervised principal components analysis, we first identified the subset of protein changes accounting for the most variance across patients. This yielded a group of 21 proteins that reflected an inverse relationship between inflammatory cytokines and regulators of anti-inflammation, and generated an individual inflammatory profile score for each patient. We then tested the association between these scores and computed tomography (CT) findings at hospital admission, as well as their prognostic association with functional recovery at 3 and 6 months (Glasgow Outcome Scale-Extended), and cognitive recovery at 6 months (California Verbal Learning Test, Second Edition) after injury. Inflammatory signatures were significantly increased in patients with positive CT findings, as well as in those who showed poor or incomplete recovery. Inflammation biomarker scores also showed significant sensitivity and specificity as a discriminator of these outcome measures (all areas under the curve [AUCs] >0.62). This proof of concept for the feasibility of multivariate biomarker identification demonstrates the prognostic validity of using a proteomic panel as a potential biomarker for TBI.

A Prospective Study of Acute Blood‐Based Biomarkers for Sport‐Related Concussion

“…ED admission levels of CRP predicted the presence of postconcussion symptoms at 3 months postinjury in a cohort of adult patients with mTBI . Inflammatory markers contributed to a multivariate predictor model for recovery at 3 and 6 months postinjury in an ED sample of mostly mTBI patients . Tumor necrosis factor levels at 1 to 4 days postconcussion were elevated in pediatric mTBI patients that developed persistent symptoms at 1 month postinjury .…”

An integrated perspective linking physiological and psychological consequences of mild traumatic brain injury

“…For example, similarities exist between post-traumatic symptomatology and cognitive or behavioral changes that arise from other inflammatory conditions, such as sepsis [40]. Interestingly, a recent study has shown that using an unsupervised multivariate approach applied to a multi-analyte proteomic panel, including several inflammatory markers, it was possible to fairly accurately predict positive CT-findings and outcome in a study sample that consisted predominantly of mild TBI patients, although 42% of these patients had lesions on CT [42].…”

iTRAQ-based proteomic profiling reveals protein alterations after traumatic brain injury and supports thyroxine as a potential treatment

“…Proteomic research on neural diseases has mainly focused on neurodegenerative diseases, such as Alzheimer’s disease and Huntington’s disease [ 34 – 36 ], epilepsy [ 37 ], narcolepsy [ 38 ], and ischemic cerebral disease [ 39 , 40 ]. As for TBI, proteomics has been primarily applied to discover new biomarkers [ 41 , 42 ]. In particular, Cheng et al found that targeted temperature management (TTM) prevented TBI-induced neuronal necrosis, neuronal death, and brain edema, and some altered proteins (i.e., plasminogen, antithrombin III, and transthyretin) were identified [ 43 ].…”