As an August 2015 editorial in the British Journal of Medicine editorial ^[67]: "It still remains unclear if brain damage is an inevitable consequence or an avoidable risk of [contact or collison sports]."  

Dr. McKee's "study of brains with CTE appear to be all former NFL players, 1 from high school and 1 from college, but what about soccer players?" wondered Scott L. Bruce, MS, ATC, co-author of the 2004 NATA Position Statement on Sports-related Concussions and Founder of the Chattanooga Concussion Prevention Initiative, in a comment to a concussion blog entry^[17] after viewing the PBS Frontline documentary League of Denial in which she was featured. 

"Or what about athletes from other sports? What about females vs. males? What about those players who play college football, but never go on to play in the NFL? Of the number of high school players who never play college football? Are any of their brains examined for CTE? If so, what were the findings?"  

Causal link 'scientifically premature'

Similarly, the absence of cross-sectional, epidemiological, prospective or longitudinal studies on CTE has led many of the most respected experts and researchers in the concussion community to express caution in quantifying the risk of CTE posed by repetitive head impacts, although that fact, with some notable exceptions, has not been widely reported.

An exception was a recent article in which a leading concussion researcher, Dr. Michael McCrea, singled out for criticism a statement by Dr. McKee in the PBS Frontline documentary, League of Denial, in which she said she was "really wondering if every single football player doesn't have [CTE]." 

"This is one of those situations where the story has really raced out in front of the science," McCrea told a reporter for the Milwaukee Business Journal. He agreed that concussion is a serious injury and the sports industry should take it seriously. But McCrea had a problem with League of Denial using what he considered speculation that has yet to be proven in clinical research

In an article in Deadspin,^[32] Matthew McCarthy, a physician at New York-Presbyterian Hospital, writes about the "puddles of ink" that will be "spilled linking head trauma to chronic traumatic encephalopathy ... written by sportswriters who, frankly, don't understand the science and have long overstated what is actually known about the condition."  

About the Zurich statement's conclusion that no cause and effect relationship had been demonstrated, Dr. McCarthy points out that the statement "runs counter to almost everything you have read about CTE, but it received virtually no media attention in the United States when it was released. In part, that's because it speaks to the far higher burden of proof in the scientific community than the one in the public consciousness. But that's the point. The popular consensus has far outstripped the science."

As for Dr. McKee's statement to NewJersey.com, McCarthy observes that she argued that, while there was not scientific proof, there was enough to start thinking about making changes, so she "and others have chosen to bang the drum, loudly, even if they can't be sure of the exact message once we're listening."  (the fact, of course, is that changes are being made, most notably in the form of limits on full-contact practices)

In their 2013 meta-analysis of the scientific literature on CTE,^[19] Gardner, and two highly respected colleagues, Grant Iverson and Paul McCrory (the lead author of the last three international consensus statements on sport-related concussion, including the 2013 Zurich statement that prompted such expressions of outrage by McKee and Cantu), ^[13]  characterized  the "strongly presented causal assumptions in the literature relating to concussive and subconcussive brain impact exposure"  as "scientifically premature." 

In order to reach that conclusion, writes Gardner, systematic research is needed to address five specific unanswered questions:

First, it is not known whether similar, or even identical, neuropathological findings are observed in other samples that share clinical characteristics with CTE such as patients with drug or steroid abuse, alcohol abuse histories, chronic psychiatric problems, cardiovascular/cerebrovascular disease or other health conditions.  [Author's note: A 2015 meta-analysis of all reported cases of CTE^[68]  appears to suggest otherwise, however, finding no evidence to link substance abuse, genetic factors such as APOE, or pre-existing medical conditions to an increased risk of CTE]

Second, the extent to which the reported underlying neuropathology contributes to the reported clinical features (eg, cognitive deficits, psychiatric features) is uncertain.

Third, the potential existence of a genetic contribution to the observed neuropathology has not been determined. [Author's note: Again, the 2015 meta-analysis of CTE cases^[68] found no evidence to support the view that genetic factors increased risk of CTE]

Fourth, possible mediator or moderator variables for the association between the neuropathology and the clinical features have not been identified.

Finally, we do not have a methodology for identifying individuals who are at future risk or might currently have CTE.  Psychiatric problems and cognitive impairment usually have multifactorial, not unitary causation - this will require further attention in future studies. The important next step in the process of potentially answering some of the unresolved issues associated with CTE is to conduct large-scale, prospective, longitudinal, clinicopathological studies. [Note: the NCAA has recently begun such long-term studies]

To be fair, both Drs. Cantu and McKee have also called for such studies, as have many others.^[67] Indeed, Dr. Cantu, in a moment of honest and candid reflection on the impact he has as a leading authority on concussions, even went so far as to acknowledge in a postscript included in the paperback edition of his book, Concussions and Our Kids,^[44] that if there was "one thing that isn't explained as fully in the book as [he] wish[ed] ... it is the precise relationship between total head trauma (concussions and also subconcussive blows) that a child absorbs playing football and hockey and, to a lesser degree, soccer and basketball and the possibility of developing a degenerative brain disease such as CTE as an adult.  We don't know yet," he admits.  "The research continues, and it is possible that we will have an answer to that critical question soon, perhaps with a decade."

Real world consequences 

But, in the meantime, it appears that the prevailing narrative - at least in the mainstream media and among pundits and commentators - is that those that play contact and collision sports in general, and football in particular, and youth football even more specifically, are at serious risk of developing a frightening, degenerative, irreversible disease, when, as noted by Dr. McCarthy, "the study of head injuries is a lot more confusing and murky than once suspected."

The media narrative, argues Dr. McCarthy, has real world consequences in which former NFL players, and all those who ever donned a football helmet, may be, to a greater or lesser degree, "collateral damage."

As he points out in his gripping first person account of an encounter with an unidentified former NFL player in the psychiatric ward of a New York hospital, the former player was paralyzed by the fear that he was "walking around with a death sentence over [his] head."

"An aging athlete," he argued, should not have to "assume that a neurologic symptom is from CTE or that his life is about to unravel. There may be an alternate treatable explanation. And, either way, a physician should be making the diagnosis," not a journalist or even a research scientist. 

Caution urged 

 "The interpretation of causation in the modern CTE case studies should proceed cautiously," urges another 2013 literature review, ^[22] whose authors not only include McCrory and Gardner, but such pre-eminent concussion researchers as Willem H. Meeuwisse of the University of Alberta, and neurologist Jeffrey S. Kutcher of the University of Michigan, a co-author of the 2013 American Academy of Neurology's concussion guidelines. ^[23]  

In October and November 2013, four more reviews of the peer-reviewed literature ^[39-42] joined the growing body of scientists pouring cold water on the now common assumption in the media and general population that contact sports inevitably causes CTE, and that CTE causes those with the disease to commit suicide. 

In the first, published in the British Journal of Sports Medicine,^[39] a leading concussion researcher, Grant Iverson, MD, of the Department of Physical Medicine and Rehabilitation at Harvard Medical School, finds the scientific evidence insufficient to support a finding of the existence of a strong causal relationship between CTE and suicide in former athletes.  

In the second, published in the journal Behavioral Sciences and the Law, ^[40] scientists at the University of Colorado School Medicine conducted a state-of-the-science review of CTE, explored the evidence for links between traumatic brain injury (TBI), CTE and catastrophic clinical events such as suicide, and highlighted the complexity of specifically attributing suicide to CTE.  Like Iverson, they urged caution in jumping to conclusions on the basis of preliminary case study autopsies.  

In the third commentary, published in the journal Neuropsychological Review,^[41] Christopher Randolph, PhD, of Loyola University in Chicago, as noted earlier, the leading skeptic about the link between CTE and contact sports, reviews the history of so-called "classic" CTE in boxers, the literature on "modern" CTE (case studies from 2005 forward), mainly in American football players, explores the sampling and methodological issues that, he says, prevent any firm conclusions about the association between athletic head trauma and neurodegenerative diseases such as CTE being drawn, and calls, like Iverson and Wortzel, for more carefully-controlled epidemiological and prospective studies to overcome current limitations in this research and stimulate further research. 

Finally, commenting in the British Journal of Sports Medicine on a systematic review of the literature on CTE in sport^[19] published in the same issue of the journal, Charles Tator, MD, of the Division of Neurosurgery at the University of Toronto, notes the "significant advances" over the past 10 years in understanding CTE that have allowed the sports community to understand that the issue of brain degeneration as a consequence of repetitive concussion is not confined to boxers but applies at least to hockey, football, wrestling, and rugby.

• the percentage of concussed athletes that will develop CTE
• the exact relationship between concussion and brain degeneration
• how many concussions are required to cause brain degeneration
• whether subconcussive blows lead to the same neurological deficits and pathological changes as concussive blows
• whether it is possible to recognize clinical precursors to CTE, such as post-concussion syndrome
• whether the changes in the brain resulting from repetitive concussions are specific to concussions or are similar to degenerative changes that occur as a result of normal aging or diseases of aging, such as Alzheimer's, dementia, and Parkinson's disease
• how many non-concussed athletes or non-athletes will have any of the changes in the brain, such as tau protein deposits, considered specific markers for CTE.

Like Iverson, Wortzel, and Randolph, Tator says longitudinal studies of large number of at-risk athletes are "essential."  The recent editorial in the British Journal of Sports Medicine^[67] takes the same view.