Early chronic systemic inflammation and associations with cognitive performance after moderate to severe TBI

Abstract

Background Cognitive dysfunction adversely effects multiple functional outcomes and social roles after TBI. We hypothesize that chronic systemic inflammation exacerbates cognitive deficits post-injury and diminishes functional cognition and quality of life (QOL). Yet few studies have examined relationships between inflammation and cognition after TBI. Associations between early chronic serum inflammatory biomarker levels, cognitive outcomes, and QOL 6-months and 12-months after moderate-to-severe TBI were identified using unweighted (uILS) and weighted (wILS) inflammatory load score (ILS) formation. Methods Adults with moderate-to-severe TBI (n ​= ​157) completed neuropsychological testing, the Functional Impairment Measure Cognitive Subscale (FIM-Cog) and self-reported Percent Back to Normal scale 6 months (n ​= ​139) and 12 months (n ​= ​136) post-injury. Serial serum samples were collected 1–3 months post-TBI. Cognitive composite scores were created as equally weighted means of T-scores derived from a multidimensional neuropsychological test battery. Median inflammatory marker levels associated with 6-month and 12-month cognitive composite T-scores (p ​< ​0.10) were selected for ILS formation. Markers were quartiled, and quartile ranks were summed to generate an uILS. Marker-specific β-weights were derived using penalized ridge regression, multiplied by standardized marker levels, and summed to generate a wILS. ILS associations with cognitive composite scores were assessed using multivariable linear regression. Structural equation models assessed ILS influences on functional cognition and QOL using 12-month FIM-Cog and Percent Back to Normal scales. Results ILS component markers included: IL-1β, TNF-α, sIL-4R, sIL-6R, RANTES, and MIP-1β. Increased sIL-4R levels were positively associated with overall cognitive composite T-scores in bivariate analyses, while remaining ILS markers were negatively associated with cognition. Multivariable receiver operator curves (ROC) showed uILS added 14.98% and 31.93% relative improvement in variance captured compared to the covariates only base model (age, sex, education, Glasgow Coma Scale score) when predicting cognitive composite scores at 6 and 12 months, respectively; wILS added 33.99% and 36.87% relative improvement in variance captured. Cognitive composite mediated wILS associations with FIM-Cog scores at 12 months, and both cognitive composite and FIM-Cog scores mediated wILS associations with QOL. Conclusions Early chronic inflammatory burden is associated with cognitive performance post-TBI. wILS explains greater variance in cognitive composite T-scores than uILS. Linking inflammatory burden associated with cognitive deficits to functional outcome post-TBI demonstrates the potential impact of immunotherapy interventions aimed at improving cognitive recovery post-TBI.

Brain-gut axis dysfunction in the pathogenesis of traumatic brain injury

“…Higher proinflammatory burden with IL-6, relative to the antiinflammatory marker IL-10, was shown to be relevant to global TBI recovery. Moreover, the acute-phase cytokine load score predicted cognitive performance in moderate-to-severe TBI patients (66), such that IL-1β, TNF-α, sIL-6R, RANTES, and MIP-1β were negatively associated with cognition. Thus, there is a significant correlation between circulating cytokines and chemokines and worsened patient outcomes.…”

Preclinical findings reveal the pharmacological targets of ferulic acid in the treatment of traumatic brain injury

“…Ferulic acid is preclinically found in vivo with neuroprotective action, as shown in animal reports (Wang et al, 2021 ). Other pieces of evidence proved that TBI can trigger penetrating lesions in astroglia and microglia and cause inflammatory development (Milleville et al, 2020 ). Current GO findings indicated that some of the top BP categories was involved in the effective modulation of neuronal apoptosis.…”

An Initial miRNA Profile of Persons With Persisting Neurobehavioral Impairments and States of Disordered Consciousness After Severe Traumatic Brain Injury

“…Key words: biomarker, disorders of consciousness, minimally conscious state, traumatic brain injury miRNA, vegetative state P ERSONS EXPERIENCING SEVERE TRAU-MATIC BRAIN INJURY (TBI) and remaining in states of disordered consciousness (DoC), after acute medical care, are evaluated with neurobehavioral tests to distinguish between states of DoC and to inform rehabilitation management. 1 When considering the heterogeneity of primary and secondary brain damage triggered by TBI, [2][3][4][5] it becomes evident that differential DoC diagnoses, based solely on neurobehavioral testing, will result in a proportion of inaccurate diagnoses, thereby providing an inadequate empirical foundation for evidence-based neurorehabilitation. The long-standing problem of diagnostic inaccuracy 6,7 highlights the need for phenotypes of who will/will not progress from a vegetative state (VS) to the minimally conscious state (MCS) relative to emergence from MCS (eMCS).…”

“…Specifically, severe TBI triggers pathological cellular processes (eg, excitotoxicity), thought to be active through chronic recovery phases, causing excitotoxicity, apoptosis, inflammatory events, seizures, demyelination, white matter pathology, and diminished neurogenesis, all of which are correlated with persisting neurobehavioral impairments. [2][3][4][5] For clinical neurorehabilitation research and practice, miRNAs are particularly promising because humans have more than 2500 miRNAs regulating 30% to 60% of messenger RNAs. [16][17][18][19][20] In addition, 70% of miRNAs are thought to be specific to the brain, spinal cord, and nerves.…”

“…miRNAs are single-stranded, 20- to 24-nucleotide, stable RNA molecules conserved across species,12–14 and, as previously reviewed,15 the secondary damage triggered by TBI makes miRNA potentially useful as acute, subacute, and/or chronic biomarkers. Specifically, severe TBI triggers pathological cellular processes (eg, excitotoxicity), thought to be active through chronic recovery phases, causing excitotoxicity, apoptosis, inflammatory events, seizures, demyelination, white matter pathology, and diminished neurogenesis, all of which are correlated with persisting neurobehavioral impairments 2–5. For clinical neurorehabilitation research and practice, miRNAs are particularly promising because humans have more than 2500 miRNAs regulating 30% to 60% of messenger RNAs 16–20.…”