Letter to the Editor: Intense Exercise and Associated Blood–Brain Barrier Leakiness and Systemic Inflammation at the Time of Brain Injury May Be Relevant to Understanding Why Only Sports-Related Concussions Are Associated With Chronic Traumatic Encephalopathy

To the Editor:

Bazarian and colleagues report that blood concentration of S100 calcium binding protein B (S100B), a biomarker of traumatic brain injury (TBI) and blood–brain barrier (BBB) disruption, increases with exercise, and this represents a confound. ¹ But S100B elevations in the setting of intense exercise may be more than a confound; they may be a clue to the unique link between repeated sports-related concussions (SRCs) and later development of chronic traumatic encephalopathy (CTE), and explain why TBI sustained outside of sports—even when repeated—does not appear to be associated with CTE based on large autopsy studies. ^2,3

Elevated S100 after intense exercise is a robust, replicated finding, demonstrated in non-contact sports such as running, and attributed to BBB breakdown. ¹ Exercise-induced BBB breakdown is considered due to cytokines and other inflammatory mediators released by intensely active or damaged muscles, ^{4 –8} and contributes to exercise-induced mental fatigue—a phenomena distinct from physical fatigue, considered similar to sickness behavior from cytokine-induced BBB breakdown during systemic infection. ^9,10 But whereas people suffering from the flu are told to rest, exhausted athletes are often told to “push through.”

What if systemic inflammation and BBB breakdown during intense exercise represents a vulnerable state during which the consequences of even minor TBI are amplified? BBB disruption is considered critical in the pathophysiology of concussion and CTE. ^{11 –15} By definition, SRC always occurs in the setting of exercise, whereas other common causes of TBI (e.g., vehicle accidents) almost never do. Could this explain why only SRC leads to CTE?

Although there is no direct evidence supporting this idea, inflammation and co-occurring musculoskeletal injury are known to worsen TBI outcome in animals and humans. ¹⁶

An exercise regimen preceding and/or following TBI is considered universally beneficial. But intense exercise during TBI, analogous to human SRC, has not been studied. One recent study suggests that the timing of exercise may be critical: administration of VEGF-A, a growth factor upregulated by exercise, is beneficial when given after TBI, but was unexpectedly found to cause greater inflammation and worse outcome when administered immediately prior to injury, with this effect attributed to BBB disruption at the time injury. ¹⁷

Exercise intensity and voluntariness must also be considered: forced exercise can exacerbate brain damage in animal models. ^7,18,19 In humans, the distinction between forced and voluntary exercise, and determining when exercise may be excessive, is far less clear-cut.

Although new research is needed to confirm a role for intense exercise and associated BBB leakiness and inflammation in SRC pathophysiology, this idea can inform re-appraisal of prior findings. For example, a knockout sustained by a mixed martial arts (MMA) fighter at the very beginning of a fight was unexpectedly not associated with BBB disruption. ¹⁵ Maybe a similarly severe injury at the end of the match, in the setting of systemic inflammation from body damage and physical exhaustion, would have been.

In addition to causing BBB leakiness and inflammation, intense exercise has been shown to upregulate map kinases ²⁰ involved in tau phosphorylation and subsequent deposition. ²¹ Could intense exercise at the time of injury explain why perivascular tau deposition is universal in CTE, and detectable when brain tissue is available following SRC ²² (which is rare because SRCs are seldom fatal) but almost never seen in acute neuropathology studies of non-sports TBI? ²³ We recently reported possible positron emission tomography (PET)-measured tauopathy in one subject with a history of repeated SRC who sustained a complicated mild TBI while playing a sport but not in subjects who sustained similar TBIs outside of sport. ²⁴

Bodily injury and systemic factors are not solely confounds when studying TBI pathophysiology, biomarkers, and outcomes. The brain and body are intimately connected, and BBB leakiness induced by exercise and TBI amplifies this connection. Current attempts to mitigate the short- and long-term effects of repeated SRC have focused on excluding from play athletes with measurable evidence of brain injury based on neurological deficits or blood or other biomarkers. There is little evidence that this is effective. An alternate strategy might be to assess systemic factors such as inflammation, muscle damage, and BBB breakdown (which are inherently simpler to assess than brain status) to identify players predisposed to brain injury following (inevitable) concussive and subconcussive impacts, but prior to the occurrence of any measurable brain injury.