Concussion: Beyond the Cascade

Abstract

Sport concussion affects millions of athletes each year at all levels of sport. Increasing evidence demonstrates clinical and physiological recovery are becoming more divergent definitions, as evidenced by several studies examining blood-based biomarkers of inflammation and imaging studies of the central nervous system (CNS). Recent studies have shown elevated microglial activation in the CNS in active and retired American football players, as well as in active collegiate athletes who were diagnosed with a concussion and returned to sport. These data are supportive of discordance in clinical symptomology and the inflammatory response in the CNS upon symptom resolution. In this review, we will summarize recent advances in the understanding of the inflammatory response associated with sport concussion and broader mild traumatic brain injury, as well as provide an outlook for important research questions to better align clinical and physiological recovery.

Keywords: PET; TSPO; concussion; microglial activation; neuroinflammation; positron emission tomography.

Figure 1

A depiction of the neurometabolic cascade [1,14] is supported by animal and human models as it aligns with clinical recovery based on clinical measures of SRC and a clinical examination. However, advanced neuroimaging techniques inclusive of fMRI [12], DTI [16,17,18], fractional anisotropy [13], and positron emission tomography [19,20,21] indicate a gap between clinical recovery as defined as a return to pre-injury values on clinical measures of SRC in conjunction with a clinical examination and physiological recovery which is defined as persisting physiological deficits despite achieving clinical recovery.

Scheme 1

PET image analysis pipeline. A subject experiences SRC and receives a 90 min dynamic PET/CT using [¹⁸F]DPA-714 to target CNS-derived microglial activation. Upon scan completion, MRI and dynamic PET data are motion-corrected and mapped using a compatible atlas. The MRI and PET are co-registered to compute the IDIF at the PET voxel level. The IDIF calculation facilitates the derivation of Vt maps in the whole brain, computed at the voxel level. The previously aligned MR atlas allows regional computation of Vt within the brain.

Figure 2

Microglial activation persists in collegiate athletes following concussion. [¹⁸F]DPA-714 PET signal is markedly increased in SRC athletes compared to healthy controls, despite being clinically cleared to RTS. Dynamic PET acquisitions were summed from 45–60 min post-injection to generate SUV PET images, which were normalized to each subject’s body weight.

Figure 3

PET acquisition sequences generate PET data with distinct data outcomes. (A) Static PET sequences sample only a subset of the entire data set and result in semi-quantitative data outputs. (B) Dynamic PET sequences utilize the entire acquisition and can generate quantitative, tissue- and receptor-binding-specific data [103].