Incipient chronic traumatic encephalopathy in active American football players: neuropsychological assessment and brain perfusion measures

Chronic traumatic encephalopathy (CTE) is a degenerative disease caused by exposure to repetitive head impacts. It can be seen in contact or collision sport athletes or in military veterans [1, 2]. Neuropathologically, it is characterized by the deposition of paired helical filament tau aggregates in neurons, astrocytes, and cell processes around small blood vessels at the depths of cortical sulci, initially in the frontal, temporal, and parietal cortices and, in later stages, more extensively in the brain and brain stem. This pattern differentiates CTE from other neurodegenerative diseases; for example, unlike Alzheimer’s disease, CTE typically involves neuritic amyloid-beta plaque deposition only in advanced stages of disease. It is unclear if cognitive impairment, mood disorders, and behavioral dyscontrol, frequently observed in patients with CTE, are associated with focal tau deposition, tau-related degeneration, or other consequences of traumatic brain injury (TBI) [1]. It has been observed that dementia development is mainly associated with lesions, such as white matter (WM) rarefaction and dorsolateral frontal cortex neurofibrillary tangles deposition that are related to the length of the career [3].

Previous research has shown conflicting results on the causal role that sports play in the development of CTE. The lack of a causal interpretation hinders a valid surveillance of such activities and prevents clinical, neuropsychological, and neuroimaging comparisons [4‐8]. A possible cause of the discrepancy between the results of the studies on CTE is the selection of control groups. Some studies, in fact, do not separate sportsmen from not athletes; others distinguish only “athletes” versus “not athletes,” without considering other characteristics that may create large differences across athletes, such as the type of sport. In some sports, there might also be differences in trauma load according to specific sport characteristics such as the field position. This is typically the case of American football. To reduce these biases, it is necessary to consider the interindividual variability of the sports history and the annual and total trauma load of each athlete. Concerning American football, significant pieces of information are the number of years of activity, the number of games and training sessions per year, the field position, age, and other practiced sports.

Because CTE can be definitely diagnosed only through post-mortem examination, it would be important to have possible clinical and radiological correlates of it. In vivo detection of the disease can help in assessing its epidemiology, risk factors, and course, and finding treatments and prevention strategies. In particular, it is hard to in vivo identify mild traumatic brain injury (mTBI) because its clinical features are usually absent or mild in the acute phase, and the latency between TBIs and CTE development may be of many years [9‐12].

Neuropsychological and neuroimaging assessments can be ways for evaluating in vivo CTE. A few neuropsychological and neuroimaging studies on CTE may be found in the literature. TBI has been found related to alterations of cerebral perfusion, evaluated with arterial spin labeling (ASL) techniques, in particular, in American football players. A reduction of thalamic perfusion was observed, and it was associated with cognitive dysfunctions in information processing and speed of response, memory, learning, verbal fluency, and executive functions [13]. Mild but repetitive TBIs have been found able to induce CTE development [14] and to provoke a reduction of cerebral perfusion in thalamus, optical radiation, and other white matter areas [7]. The most frequently observed neuropsychological alterations in subjects with a history of TBI concern information processing speed, executive functions, and associative memory [15, 16]. At later stages, in full-blown CTE, there is also more severe cognitive impairment with attention and language difficulties and memory loss.

The aims of this study were (1) to investigate the possible relationship between the neuropsychological profile of active American football players and their traumatic load; (2) to study if TBI associated with American football activity is associated with a specific cerebral perfusion pattern; (3) and if this perfusion pattern correlates with neuropsychological performances.

In this study, we found different cognitive performances between American football players stratified according to their field position and career length, statistically significant hypoperfusion in sensory-motor areas, and poorer neuropsychological performances correlated with lower perfusion in specific brain areas in these athletes.

Previous studies frequently failed in the identification of a real traumatic risk of certain sports because they considered all team players as a homogeneous group [9, 14, 32‐35]. The introduction of the concept of traumatic load obtained with the TraQ questionnaire allowed us to identify, in the same team, subjects with a specific cognitive traumatic risk, categorizing field positions. We showed differences in cognitive performances in American football players according to their field position and career length. Although the performances of all the players were within normal limits, different field positions were associated to different cognitive performances. In particular, the type-3 and type-1 are associated with worse executive functioning, verbal competence, and visual abilities. Indeed, the type-3 position, the one who receives frequent and potentially intense hits had worse performance of the Symbol Digit Modalities Test compared to the Type-1 position, and even worse compared to the type-2 position that suffers few traumatic injuries. Type-1 field position, the one of offensive and defensive linemen, known to be related to more frequent low intensity TBIs, was found to be associated with poorer performance of the TMT-A. Longer career was associated to poor executive functioning, in particular to a worse Stroop result and a trend for worse phonemic fluency. These observations may induce to hypothesize that frequent minor head trauma, repeated for a long time, is more dangerous for developing at least an impairment of cognitive abilities, which can be the beginning of CTE, characterized by cognitive impairment, mood disorders, behavioral dyscontrol, and focal neurological deficits. Interestingly, these cognitive functions depend on those cerebral areas which have been found to have reduced perfusion at the ASL evaluation. It can be hypothesized that low intensity recurrent TBIs may induce microvascular damage that in turn produces a progressive neuronal loss. From this point of view, the traumatic effect on neurons should be mediated by a vascular functional and/or anatomical dysregulation. Longitudinal studies will be required to identify if the vascular impairment precedes or follows the neuronal loss and the subclinical cognitive decline.

The hypoperfusion found in pre- and postcentral gyri may be interpreted in different ways; more expert players (the ones with a longer career) may have motor neural circuits more trained and more efficacious and consequently with a reduced energy consumption that requires a lower grade of perfusion. Alternatively, we may hypothesize that the summation of recurrent mild trauma is able to induce a slow but progressive neuronal density decrease [2] and consequently, a reduction in energy consumption that in turn may be supported by a lower cerebral perfusion.

The regular use of TraQ might permit to identify specific sportsmen categories at risk of cognitive decline. It seems interesting that American football players in Italy showed, in a previous comparative study, a lower amount of cognitive performances reduction compared to US players [36]. The authors concluded that the possible cause of this difference was the lower amount of contact activity (games and training) in Italy and an older age of starting the American football activity (respectively 9 years in USA and 16.7 in Italy). This is in line with our observation that cognitive impairment is due to a temporal summation of low intensity recurrent traumatic events.

Furthermore, the observation that starting this sport practice at younger age in American football is related to an increased risk of developing cognitive disturbances induces to another consideration: the same traumatic load in terms of frequency and intensity may induce greater damages in a not fully developed brain. This must increase the attention on the juvenile categories of athletes.

Previous studies found that global cerebral perfusion is reduced in sport-associated TBI and especially in the following areas: cingulate cortex, left inferior frontal cortex, thalamus, middle and upper frontal cortex, left pre-central and post-central cortex, left transverse temporal cortex, precuneus, anterior cingulate and cerebellum [4, 6]. Moreover, brain hypoperfusion is implicated in the evolution of damage consequent to TBI, especially associated with edema, contusions and bleeding. This evidence would allow to attribute to MRI ASL technique a predictive and prognostic role of the posttraumatic functional outcome as well as to better define the severity of the TBI itself [37].

A limitation of this study is the small sample size and the current absence of follow-up data.

Future studies should also assess early brain alterations due to mild TBI, like microbleeds, using specific imaging techniques. For example, susceptibility weighted imaging (SWI) MRI is able to identify cerebral microbleeds, iron, and tau protein deposits, of which the role in pathogenesis and development of CTE is demonstrated [17, 38‐40]. A second task for future studies would be to perform long follow-up of athletes including neuropsychological and brain perfusion evaluations, and eventual rehabilitative strategies for preventing or avoiding the cognitive worsening.

In conclusion, our study pointed out diminished cognitive functions and the coexisting dysregulation of the cerebral local perfusion in the same cortical areas that resulted impaired. From this perspective, it could be hypothesized that MRI functional impairment and structural damages induced by repetitive, low energy trauma are the two faces of the same medal. The observation of the hypoperfusion of the impaired areas highlights the importance of microcirculation in TBI even if we cannot support, on the basis of these results, that the vascular dysregulation is the mediator between trauma and cerebral hypofunction or assess whether it is one of a series of consequences of the same traumatic situation.

Another relevant information we obtained is the importance to subdivide athletes of the same sport according to specific traumatic load when the effect of TBI of a specific sport is under investigation. Field position, the length of a career, the amount of practices and games, are all relevant elements that influence the traumatic effect of a sport in different ways on each player.