Mild Traumatic Brain Injury and Neuroinflammation

Abstract

Despite being a common problem, there are many gaps in the understanding of mild traumatic brain injury (mTBI). Its pathophysiology is unclear, diagnostic criteria are variable, and the associated symptomatology is non-specific. As a result, there are challenges associated with precise mTBI diagnosis and treatment. The dissertation seeks to identify distinctive features, both clinical and pathophysiological, exclusively associated with mTBI. In addition, the neuroinflammatory component of mTBI is explored in detail in the context of inflammatory cytokines’ potential use as prognostic biomarkers and development of a targeted treatment. Three studies were conducted to explore mTBI.

We conducted a retrospective chart review to identify the clinical presentation exclusively associated with mTBI that sets it apart from other similar conditions. This was accomplished through symptomatology comparison between the patients with head injuries that meet the ACRM (1993) criteria for mTBI diagnosis vs. those who do not. The results of this study showed that 20.5% of patients with chronic post-concussive symptoms do not meet the ACRM (1993) criteria of mTBI despite sustaining a head injury. In addition, no symptom specific differences were found between the two populations.

A detailed systematic review and meta-analysis were also conducted to identify the common inflammatory cytokines associated with mTBI and to explore their potential use as prognostic biomarkers. The results show significantly elevated blood IL-6, IL-1RA, IFN-γ (at <24 hrs.) and MCP-1/CCL2 (within a week) levels in patients with mTBI compared to healthy controls in majority of the included studies. A meta-analysis was further conducted that supported these findings by showing significantly elevated IL-6, MCP-1/CCL2, and IL-1β levels in patients with mTBI in the acute stages (<7 days). In addition, elevated IL-6, TNF-α, IL-1RA, IL-10, and MCP-1/CCL2 levels were associated with poor prognosis in patients with mTBI.

In addition, a systematic review was conducted to identify the inflammatory cytokines associated with adverse psychological outcome in population with mTBI. The results show that IL-6, TNF-α, IL-10, and CRP are associated with PTSD and/or depression in the population with mTBI, particularly in the chronic stages.

Collectively, these studies show that all symptomatic patients with head trauma, whether or not they meet the subjective criteria of mTBI, should be managed and offered early rehabilitation to avoid long tern adverse consequences. In addition, this thesis supports the neuro-inflammatory hypothesis of mTBI and identifies inflammatory cytokines that could be potentially utilized as prognostic biomarkers and for the development of mTBI treatment.