Unlike in Alzheimer's Disease, neurofibrillary tangles in athletes with CTE tend to accumulate perivascularly within the superficial neocortical layers. It is interesting to note that TAU pathology in CTE is partially and extensively distributed, possible related to multi-directional mechanical force from physical trauma (McKee et al, 2009; Neuropath Exp Neurol 68, 709-35.) It is theorized that accumulation of hyperphosphor is related to a protein that is thought to result in development of CTE and associated neurobehavioral disturbances.

There is a direct relationship between level of Substance P (excitatory neurotransmitter- a peptide) and concussion with level of substance P elevating after concussion.

Often omitted in discussion of CTE, or for that matter, traumatic brain injury is PTSD. In particular, the literature addresses the intersection of TBI and PTSD. Athletes, especially in football, are subjected to violent collisions and/ or witness a violent collision of a team member. Both of these events are included in "target events" for PTSD. PTSD is a neurobiological event.

It is important to recognize CTE as a progressive neurodegenerative disease associated with repetitive head impacts (RBI). The inherent prevalence of CTE in players in the NFL is in offensive and defensive linemen who have a high prevalence of repetitive impact sub-concussive hits. Clinical research criteria may be sensitive, but is not specific to a pathological diagnosis of CTE. There is some promising research (Stern, et al 2016) on ID of CTE via biomarkers. In a research study with NFL players, the NFL group had higher exosaumal tau than the control group (p<0.0001). Exosaumal tau discriminated between experimental and control groups with 82% sensitivity , 100% specificity, 100% positive predictive value and 53% negative predictive value. Within the NFL group higher exosaumal tau was associated with worse performance on tests of memory (p=0.0126) and psychomotor speed (p=0.0093).

There is a clinical presentation of CTE, viz, a constellation of cognitive, eg, episodic memory and executive dysfunction), mood (eg, depression, apathy) and behavioral (eg, aggression, impulsivity) changes with dementia often reported as the disease progresses.

(Stern, et al. 2016) found that the NFL group had significantly higher plasma exosaumal tau than the control group (p<0.0001). Exosaumal tau are nanovesicles released by most cells throughout the body, including the brain, into the extracellular environment through exocytosis of plasma membrane anchored vesicles. In recent research, exosomes have been investigated for neurodegenerative disease and focuses on cell-to-cell transmission of pathogenic proteins.

(Ban et al, 2016) note a common misconception of the presence of tau protein associated with a diagnosis of CTE. The authors note that in the published autopsy cases of athletes suspected to have CTE over the past 11 years (n=85) only 17 (20%) of individuals were found to have the neuropathological findings consistent with the author's criteria for CTE with no coexisting neuropathology.

What about recent media reports indicating that CTE has been found in "96% of NFL players" and "79% of all football players?" (Ban, et al 2016) notes that there is a lack of published peer-reviewed scientific studies supporting there claims.

Although (Ban et al, 2016) appears to understate the effects of cumulative brain trauma on athlete's lives, many research studies address the experimental effects of cumulative concussive events. (Lezak, 2004) addresses first injury (blunt force concussive event) and second injury (Cascade of neurobiological events resulting in disruption of neural firing and cellular transport). Successive concussive events are increasingly deleterious to cognitive and behavioral systems. (Ban 2016) does present provocative data disputing studies linking repetitive brain impact and development of cognitive impairment and depression in later life. He notes that a retrospective cohort study with a median follow-up of 50 years found no increased risk of dementia, Parkinson's disease or amyotrophic lateral sclerosis among 438 men who played high school football between 1946 and 1956 compared with 140 male classmates who did not play football. The authors note that only a prospective study that records clinical findings and impact of exposure in the antemortem period with histopathological correlation will be able to more effectively answer questions pertaining to subconcussive injury and CTE.

Similarly, the research is controversial in terms of subconcussive events. (Ban et al, 2016) notes that the majority of evidence for the rate of cumulative subconcussive hits comes from studies of rodents over the past 15 years.

(McKee et al 2013) note interestingly that although data suggests progressive effects from CTE pathology, it is an issue as to whether same individuals are resilient with static or reversible pathology.

Future Directions

(Ban et al, 2016) notes that longitudinal studies with multiple time point sampling are necessary. Findings would need to be correlated with normal tau accumulation in non-traumatized brains for older subjects to asses' impact of normal aging on tau accumulation. Clinical trials are in process to validate tracers as tau markers.

Media-Driven vs. Science

(Ban et al, 2016) concludes that it is not premature to conclude that playing contact sports will result in CTE. He notes the need for large scale, longitudinal studies.

(Gardner et al, 2015) similarly concludes that the contribution of CTE to neurobehavioral syndromes is unclear. The investigators presented research from UCSF, the site for the NFL's Neurological Care Program. They found evidence in some patients with TBI of probable underlying neurodegenerative processes. Interestingly, depression was identified across all groups.

The authors conclude that TBI may be linked to abnormal neuronal aggregation of multiple proteins implicated in neurodegenerative disease.

Summary and Findings

Although there are questions raised about methodology and design issues, there is a large body of research indicating neurobehavioral change, damage to neurocellular networks, cognitive impairment, and impact on executive function with TBI. Even though CTE can only be diagnosed by autopsy, repetitive impacts to brain tissue can certainly not be categorized as benign events. PTSD is in and of itself a neurobiological disorder resulting in overactivation of the noradrenergic operation system. Individuals with TBI and PTSD both suffer from greatly magnified states of hypervigilance, arousal, and misperception of the environment. CTE has increasingly come under focus in research.

(Ban et al, 2016) research is cause for pause for us to resist a causal connection between repetitive head trauma in sports and CTE. Until we have more data on cell derivation and biological markers for CTE and data from longitudinal studies, we have no definitive answer. The jury is still out!