Aldehydic load as an objective imaging biomarker of mild traumatic brain injury

Abstract

Concussion is a mild traumatic brain injury (mTBI) defined as complex neurological impairment induced by biomechanical forces without structural brain damage. There does not yet exist an objective diagnostic tool for concussion. Downstream injury from mTBI stems from oxidative damage leading to the production of neurotoxic aldehydes. A collagen-based 3D corticomimetic scaffold was developed affording an in vitro model of concussion, which confirmed increased aldehyde production in live neurons following impact. To evaluate total aldehyde levels in vivo following mTBI, a novel CEST-MRI contrast agent, ProxyNA3, has been implemented in a new model of closed-head, awake, single-impact concussion developed in aged and young mice with aldehyde dehydrogenase 2 (ALDH2) deficiency. Behavioural tests confirm deficits immediately after injury. ProxyNA3-MRI was performed before impact, and on days two- and seven- post-impact. MRI signal enhancement significantly increased at two days post-injury and decreased to baseline seven days post-injury in all mice. An increase in astrocyte activation at seven days post-injury confirms the onset of a neuroinflammatory response following aldehyde production in the brain. The data suggest that advanced age and ALDH2 deficiency contribute to increased aldehydic load following mTBI. Overall, ProxyNA3 was capable of mapping concussion-associated aldehydes, supporting its application as an objective diagnostic tool for concussion.