Repeated mild traumatic brain injuries induce persistent changes in plasma protein and magnetic resonance imaging biomarkers in the rat

David K Wright,Leigh A Johnston,Mujun Sun,Alaa Kamnaksh,Stuart J Mcdonald,Richelle Mychasiuk,Meng Law,Jack Trezise,Rhys D Brady,Terence J O’Brien,Sandy R Shultz,Denes V Agoston,Scott C Kolbe

doi:10.1038/s41598-019-51267-w

Abstract

A single mild traumatic brain injury (mTBI) typically causes only transient symptoms, but repeated mTBI (RmTBI) is associated with cumulative and chronic neurological abnormalities. Clinical management of mTBI is challenging due to the heterogeneous, subjective and transient nature of symptoms, and thus would be aided by objective biomarkers. Promising biomarkers including advanced magnetic resonance imaging (MRI) and plasma levels of select proteins were examined here in a rat model of RmTBI. Rats received either two mild fluid percussion or sham injuries administered five days apart. Rats underwent MRI and behavioral testing 1, 3, 5, 7, and 30 days after the second injury and blood samples were collected on days 1, 7, and 30. Structural and diffusion-weighted MRI revealed that RmTBI rats had abnormalities in the cortex and corpus callosum. Proteomic analysis of plasma found that RmTBI rats had abnormalities in markers indicating axonal and vascular injury, metabolic and mitochondrial dysfunction, and glial reactivity. These changes occurred in the presence of ongoing cognitive and sensorimotor deficits in the RmTBI rats. Our findings demonstrate that RmTBI can result in chronic neurological abnormalities, provide insight into potential contributing pathophysiological mechanisms, and supports the use of MRI and plasma protein measures as RmTBI biomarkers.

Highlights

Mild traumatic brain injuries, such as concussions, are induced by biomechanical forces acting on the brain, and are a common and significant health problem worldwide[1]
Of particular relevance to this study, we have previously found that a single mild fluid percussion injury in rats results in abnormalities detectable by both diffusion-weighted MRI (DWI) and plasma protein measures, and that these changes persisted longer than the cognitive abnormalities that recovered by day five post-mFPI12
The aim of this study was to assess the utility of magnetic resonance imaging (MRI) and select plasma protein biomarkers, as well as neurobehavior measures, to detect acute, sub-acute, and long-term changes in rats that received two mild traumatic brain injury (mTBI)

Summary

Introduction

Mild traumatic brain injuries (mTBI), such as concussions, are induced by biomechanical forces acting on the brain, and are a common and significant health problem worldwide[1]. There is growing evidence that MRI and blood-based protein measures can detect changes after a single mTBI, how RmTBI affects these measures and how they relate to the functional consequences of RmTBI remains largely unknown relative to the growing understanding of a single mTBI. This is in part due to the difficulties in rigorously studying the effects of RmTBI and characterizing biomarkers purely in the clinical setting[21,22]. Investigating the effects and evolution of clinical RmTBI present additional challenges and complexities (e.g., inter-injury time) than studies of a single mTBI. In this study we used the repeated mFPI (RmFPI) rat model to determine changes detected by MRI, select plasma protein biomarkers, and neurobehavioral measures at different recovery times after RmTBI

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Conclusion