In Former Footballers, MRI Links Cognitive Problems to Axon Damage
It's clear that the brain-hammering impacts of professional football and other concussion-prone sports render some players susceptible to neurodegenerative disease, but even so, many questions remain as to exactly what is happening in their brains. To get a closer look, researchers led by John Hart at the University of Texas at Dallas put a small group of retired, aging National Football League (NFL) players through some clinical paces. In the January 7 JAMA Neurology (formerly Archives of Neurology), the scientists report that symptoms of cognitive impairment and depression correlated with white matter damage and changes in cerebral blood flow. The data provide some clues to underlying mechanisms of brain damage, and raise questions only longitudinal studies can answer. Hart told Alzforum he wonders when the structural damage occurs, if it progresses, and whether it directly causes impairment. Overall, the imaging data fit with the growing body of evidence that repeated mild head injuries, such as those sustained in many sports, can lead to a degenerative condition called chronic traumatic encephalopathy (CTE). Former NFL linebacker Junior Seau, who committed suicide last May at the age of 43, yesterday became the latest pro football star to be posthumously diagnosed with CTE (see The New York Times story).
"The main value of the study is that it potentially identifies a novel target for measuring disease progression and developing therapies," wrote Ramon Diaz-Arrastia and Daniel Perl at Uniformed Services University of the Health Sciences, Bethesda, Maryland, in an accompanying editorial. "White matter disruption is not widely recognized as a prominent feature of CTE." Martha Shenton at Brigham and Women's Hospital, Boston, Massachusetts, agreed, noting, "This is the first study to show white matter pathology in NFL players."
At present, CTE can be diagnosed only at autopsy. Pathologists report that the condition differs from Alzheimer's disease, being distinguished mainly by tau and TDP-43 deposits (see ARF CTE series and ARF Webinar). Recent studies indicate that distorted axonal tracts also characterize the disorder (see McKee et al., 2012; ARF related news story). Axonal damage occurs in boxers (see ARF related news story and ARF news story), and Shenton has found white matter disruption in soccer players (see Koerte et al., 2012).
Hart and colleagues recruited 26 retired football players living in the North Texas area to undergo several types of magnetic resonance imaging (MRI). With a mean age of 60, the men were more than three decades past their playing years, and had sustained a lifetime average of four known concussions each. Twelve volunteers were cognitively normal, four were depressed but otherwise cognitively normal, and 10 had mild cognitive deficits, primarily in naming, word finding, and visual and verbal episodic memory (two of these men were also depressed). To investigate white matter integrity, the authors used diffusion tensor imaging (DTI), which measures the flow of water through axons. Cognitively impaired and/or depressed former players had significantly worse scores in frontal and parietal regions compared to their unimpaired colleagues or to age-matched controls with no history of concussion. Intriguingly, the six depressed participants showed more widespread axonal damage than did the cognitively impaired group. Likewise, using fluid attenuated inversion recovery (FLAIR), an MRI technique in which tissue lesions show up as bright spots, the authors found more lesions in the white matter of cognitively impaired participants compared to controls.
In addition, the authors performed arterial spin labeling (ASL) to estimate cerebral blood flow (see ARF related news story). Compared to controls, cognitively impaired volunteers had less blood flow in the left temporal pole and occipital region. They had greater flow in the left inferior parietal lobe, posterior superior temporal gyrus, bilateral mid-cingulate gyri, and right middle frontal gyrus. Over time, cerebral blood flow can go up in regions where white matter lesions are forming, and then drop after the lesion appears, Hart told Alzforum (see Kraut et al., 2008). The blood flow alterations hint that lesions may be actively forming in the cognitively impaired former players, but longitudinal studies will be needed to confirm this, Hart said. Thomas Talavage at Purdue University, West Lafayette, Indiana, noted that the blood flow changes match up well with locations where he has found changes in functional MRI as a consequence of repeated head injury.
Among the 26 former players, do some have CTE? This question cannot be answered definitively, because clinical criteria for CTE are still under development (see ARF related news story). However, Bob Stern at Boston University, Massachusetts, noted that mild memory impairments like those seen in this group are common in the disorder. People with CTE can also exhibit aggression, lack of impulse control, suicidal impulses, and poor executive function. In future work, it would be interesting to assess these features in former NFL players, as well as look for changes in tau biomarkers, Stern suggested. Stern and Shenton are currently conducting such studies in football players. The NFL recently donated $30 million to the National Institutes of Health to study CTE in athletes, military personnel, and the general population (see ARF related news story). Meanwhile, researchers at the Lou Ruvo Center for Brain Health in Las Vegas, Nevada, and at Sahlgrenska University Hospital in Gothenburg, Sweden, are collecting imaging and fluid biomarkers from boxers in longitudinal studies (see ARF related news story).
Hart mosly wants to know whether the white matter changes date from the time of injury or develop progressively. To study this, he plans to examine young NFL players soon after they have sustained a concussion and track brain changes longitudinally. He also continues to follow the current cohort, most of whom agreed to donate their brains after death.
Another pressing question is what distinguishes athletes who become cognitively impaired from those who do not. Hart saw no difference between the groups in how many concussions they had or how many years they played in the NFL, although playing time approached significance as a risk factor. The two groups also had similar lifestyles and cardiovascular risk factors. Hart is analyzing genetic data from the former players to see if genes might play a role. Previous work suggests that the ApoE4 allele ramps up the risk of developing dementia after brain injury (see, e.g., ARF related news story; Mayeux et al., 1995), but more risk alleles for Alzheimer's have since been identified and could be analyzed as well.
Sub-concussive impacts could be the determining factor, suggested Talavage, noting, "Concussions are an obvious marker, but they do not seem to be the factor that is most correlated with long-term problems." For example, soccer players receive mostly sub-concussive hits from "heading" balls, and still show subtle white matter damage (see Koerte et al., 2012). National Public Radio reported that Junior Seau had had no formally diagnosed concussions. Hart agrees that sub-concussive impacts might be important, and plans to look at this. He added that many participants in his study went right back into the game after getting hit. Newly adopted NFL rules sideline players after head injury until all symptoms have cleared up (see ARF related news story). "With the present guidelines, I don't know if this [type of injury] will be as much of a problem down the road," Hart speculated. "We might already be making some positive steps."
Hart and colleagues will present related work that focuses specifically on their brain imaging findings in depressed participants at the American Academy of Neurology meeting in San Diego in March.—Madolyn Bowman Rogers
Posted: 16 Jan 2013
Paper: Neuroimaging of Cognitive Dysfunction and Depression in Aging Retired National Football League Players: A Cross-sectional Study.
This is a very interesting study, again pointing to subcortical brain structures as the main sites of damage in mild traumatic brain injury.
Now, we should specifically target living patients with progressive CTE using all the biomarkers we have to determine how much AD and how many other pathologies they have.
View all comments by Henrik Zetterberg
News Citations
Meet the New Progressive Tauopathy: CTE in Athletes, Soldiers 20 Nov 2012
Boxing: Study of Human Model for CTE Enters Second Round 21 Nov 2012
Stress and Trauma: Shaken Brains, Shaken Lives 22 Apr 2011
F18 PET Tracers, New MRI Method to Expand Reach of Brain Imaging 22 Nov 2011
CTE Needs Consensus on Lifetime Diagnosis 27 Nov 2012
CTE Advocates Pivot Toward Preventing Concussions in Kids 28 Nov 2012
ApoE4 Affects Recovery from Head Injury 22 Nov 2002
NFL Does About Face on Head Injury, Funds Researchers 12 Jan 2010
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Sports Concussions, Dementia, and APOE Genotyping: What Can Scientists Tell the Public? What's Up for Research? 9 Jun 2008
McKee AC, Stein TD, Nowinski CJ, Stern RA, Daneshvar DH, Alvarez VE, Lee HS, Hall G, Wojtowicz SM, Baugh CM, Riley DO, Kubilus CA, Cormier KA, Jacobs MA, Martin BR, Abraham CR, Ikezu T, Reichard RR, Wolozin BL, Budson AE, Goldstein LE, Kowall NW, Cantu RC. The spectrum of disease in chronic traumatic encephalopathy. Brain. 2013 Jan;136(Pt 1):43-64. PubMed.
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External Citations
The New York Times story
Butting Heads—Autopsies Fuel Debate on Football and Neurodegeneration 24 Jan 2007
Research Brief: Sixth Case of Brain Damage in NFL Player 29 Jan 2009
Keystone: Sports-Related Injury and Chronic Traumatic Encephalopathy 7 May 2012
Dementia Four Times More Likely in Pro Football Players 7 Sep 2012
New AlzRisk Analysis: Brain Injury Promotes Dementia, But Is It AD? 24 Aug 2012
Diaz-Arrastia R, Perl D. Cognitive Dysfunction and Contact Sports. JAMA Neurol. 2013 Jan 7;:1-2. PubMed.
Hart J, Kraut MA, Womack KB, Strain J, Didehbani N, Bartz E, Conover H, Mansinghani S, Lu H, Cullum CM. Neuroimaging of Cognitive Dysfunction and Depression in Aging Retired National Football League Players: A Cross-sectional Study. JAMA Neurol. 2013 Jan 7;:1-10. PubMed.