Functional neuroimaging scans could be more sensitive than behavioral tests at revealing brain damage in athletes who suffer repeated head hits, according to new research published in the October 16 Scientific Reports. Researchers led by Adam Hampshire of Imperial College London found that some frontal lobe areas in retired American football players were overactive, while other regions connected poorly with the rest of the brain. The brain abnormalities correlated with the players’ recollections of how many times they had left games due to head injuries. Furthermore, the dysfunction mirrored brain metabolic changes seen in people with early mild cognitive impairment (MCI) and mapped to areas of structural damage in the football players’ brains. “This is an exciting study that moves us closer to being able to diagnose and monitor functional impairments and chronic traumatic encephalopathy (CTE) in living subjects,” Ann McKee of Boston University, Massachusetts, noted in an email to Alzforum. A degenerative condition, CTE results from multiple concussions and other head injuries.

The report adds to a growing number of studies exploring links between brain injury in early life and dementia and neuropsychiatric problems down the road. The recent high-profile deaths of some retired National Football League (NFL) players has driven interest in the subject (see ARF news story; ARF six-part series; ARF conference story). Last year, scientists reported that NFL athletes are three to four times more likely than the general population to die with dementia (ARF news story). Another study offered clues for how the brain damage could occur, showing that cognitive deficiency in NFL players tracked with axonal breakdown in the white matter of the brain detected by diffusion tensor imaging (ARF news story). Still, researchers have a hard time documenting mental deficits in professional football players using neuropsychological tests (see Belanger et al., 2010). Often the athletes “will not show much impairment on simple tasks in a laboratory environment, but they have all sorts of problems in the real world,” Hampshire said in an Alzforum interview. “We wanted to see if it was possible to develop an in-vivo method for detecting and quantifying the type of damage that could be acquired through multiple concussions.”

Collaborating with Imperial College colleague Adrian Owen, Hampshire used functional MRI (fMRI) to measure brain activity changes in 13 retired NFL players (average age 53 years) and 20 age-matched controls while they engaged in a spatial problem-solving task. None of the subjects had a history of neurological or psychiatric disease, and they all had normal MRI scans. Relative to controls, the NFL group performed only slightly worse on the spatial task. Yet some frontal lobes structures important for executive function—namely, the dorsolateral and frontopolar cortices—were hyperactive.

The analysis also showed that functional connectivity in the dorsal frontoparietal network was low in the retired players. “It’s as though those other regions were not communicating with each other as they should, and consequently the frontal lobe areas were having to work harder,” Hampshire said. He took this as evidence for compensatory mechanisms, which allowed the brains of the 13 NFL alumni to perform simple lab tasks despite underlying connectivity problems. That the reduced connectivity correlated with the number of times the players had been taken out of games with a head injury, suggests there could be a relationship between abnormal brain connectivity and head impacts during the athletes’ careers, the authors said.

Aside from usual caveats, including the small sample size and the requirement for independent replication, “this is an extremely promising study,” Samuel Gandy, Mount Sinai School of Medicine, New York, wrote in an email to Alzforum. It is impressive that the fMRI changes were obvious enough to be recognized at the level of the individual, Gandy said, noting that many biomarkers that associate with brain disease at the group level are not sufficiently robust to shine through in individuals (see full comment below). Moreover, the affected areas were hyperactive and hypoconnected, resembling the dual changes found in the basal forebrain in early mild cognitive impairment, Gandy noted (see ARF news story).

Given the anatomical overlap between the hyperactive and hypoconnected areas in this study and the structural damage previously seen in NFL players with early CTE, McKee suggests future studies should determine if the fMRI changes are specific to CTE, perhaps using recently developed tau PET ligands (see ARF conference story ). CTE has a distinctive pattern of tau pathology. Others have reported fMRI abnormalities in high school (Talavage et al., 2013) and college ((Johnson et al., 2012) football players, and further studies could also help determine if the fMRI changes in the current study “are a continuum of a process that started much earlier in life,” McKee said. Thomas Talavage of Purdue University, West Lafayette, Indiana, told Alzforum his group has preliminary data suggesting that frontal cortex connectivity in high school football players decreases over the course of a season, consistent with the current report.

Hampshire said the new findings could be applied toward developing an fMRI measure of frontal-lobe dysfunction to confirm that an athlete’s cognitive impairments result from earlier head impacts. This could be useful in legal negotiations of financial compensation for long-term side effects of acquired injuries, Hampshire said. In a recent settlement in which the NFL agreed to pay $765 million to former players who had sued over head injury-related issues, legal experts said the plaintiffs likely would have lost in court because of their inability to prove what caused their medical problems after retiring from the league (see Wall Street Journal story).

It is hard to recruit controls to match the size, previous athleticism, and life experiences of a retired NFL cohort, and fMRI differences can stem from potentially confounding factors such as weight, head size, and brain dimensions. To address this, the authors examined individual differences in these parameters and found no correlation with dorsolateral and frontopolar activation in NFL or control groups. A recent study showed that subject motion in the scanner can cause spurious correlations in fMRI analyses ( Power et al., 2012). It is not clear how well the present study compensated for motion, David Brody of Washington University, St. Louis, Missouri, told Alzforum.—Esther Landhuis

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  1. For five decades, chronic traumatic encephalopathy (CTE), formerly known as dementia pugilistica, was exclusively associated with delayed neurodegeneration with prominent tauopathy. The clinical syndromes varied from pure dementia to parkinsonism without or with dementia. In 2005, all that changed when Bennet Omalu and Steve DeKosky described the first case of CTE in an NFL player. Since then, somewhere between 50 and 100 cases have been described in the literature, and these have been associated not only with boxing and football but also with ice hockey, soccer, and battlefield exposure to blast injury due to improvised explosive devices.

    Obviously, not all boxers and not all football players develop CTE. Genetic risks play at least some roles, with APOE epsilon 4 and neprilysin among the implicated genes, but these genetic risks have been identified in only a minority of patients. In addition to genetic markers that reveal CTE disease traits, there is great interest in identifying biomarkers that reveal disease states. Neuroimaging markers represent one area of great interest, and both fluorodeoxyglucose (FDG) PET and amyloid PET evidence of traumatic brain injury-induced dysfunction and neuropathology, respectively, have been reported.

    Functional MRI modalities are also under study, and, in this new paper, Hampshire and colleagues in Canada and the U.K. report that retired NFL players show consistent fMRI changes that are so obvious as to be recognizable at the level of the individual. This is very important since many biomarkers in brain disease have been significantly associated at the group level but have not been sufficiently robust to be detectable at the individual level. The fMRI changes are in the dorsolateral and frontopolar cortices, and they functionally associate with executive defects. This reflects the brain regions most affected by coup injuries, as the skull is pushed rapidly backward at the moment of head impact, compressing the frontal pole and dorsolateral frontal cortices. These regions contrast with those reported to be abnormal in blast-exposed military personnel in whom the orbitofrontal cortices are the focus of the dysfunction.

    This is an extremely promising study with the usual caveats about the requirement for independent replication and the relatively small sample size (13 retired NFL players). A functional study such as this would be predicted to be more sensitive and more closely associated with clinical dysfunction than molecular imaging (amyloidopathy, tauopathy) might be. Of note, the dysfunctional areas are hyperactive and hypoconnected, reminiscent of the FDG changes in the basal forebrain reported by DeKosky and Bill Klunk in the earliest phases of MCI (see Cohen et al., 2009).

    References:

    . Basal cerebral metabolism may modulate the cognitive effects of Abeta in mild cognitive impairment: an example of brain reserve. J Neurosci. 2009 Nov 25;29(47):14770-8. PubMed.

  2. This is a noteworthy report that is the first to demonstrate functional MRI abnormalities in retired NFL players. The anatomical areas where frontal lobe hyperactivation and hypoconnectivity were found line up extremely well with the areas of structural damage that we find in NFL players with early chronic traumatic encephalopathy (CTE). It will be critical to determine in future studies if these changes are specific to CTE, perhaps by using the newly described paired helical filament-tau PET ligands in this same cohort. It also will be important to determine how the fMRI changes found in football players in high school (Talavage et al., 2013) and college ( Johnson et al., 2012) are similar to the abnormalities described here, and whether changes in the NFL players’ brains represent a process that started much earlier in life. It also would be helpful to know more about the subjects’ demographics and neuropsychological profiles. A possible concern is that the larger size of most NFL athletes compared with non-athlete controls may have resulted in greater physical discomfort during fMRI that might have accentuated the abnormalities. But overall, this is an exciting study that moves us closer to being able to diagnose and monitor functional impairments and CTE in living subjects, as is so urgently needed.

References

News Citations

  1. Meet the New Progressive Tauopathy: CTE in Athletes, Soldiers
  2. Keystone: Sports-Related Injury and Chronic Traumatic Encephalopathy
  3. Dementia Four Times More Likely in Pro Football Players
  4. In Former Footballers, MRI Links Cognitive Problems to Axon Damage
  5. Research Brief: Compensation or Constitution—Metabolism in MCI

Paper Citations

  1. . Neuropsychological performance following a history of multiple self-reported concussions: a meta-analysis. J Int Neuropsychol Soc. 2010 Mar;16(2):262-7. PubMed.
  2. . Functionally-Detected Cognitive Impairment in High School Football Players Without Clinically-Diagnosed Concussion. J Neurotrauma. 2013 Apr 11; PubMed.
  3. . Alteration of brain default network in subacute phase of injury in concussed individuals: resting-state fMRI study. Neuroimage. 2012 Jan 2;59(1):511-8. PubMed.
  4. . Spurious but systematic correlations in functional connectivity MRI networks arise from subject motion. Neuroimage. 2012 Feb 1;59(3):2142-54. PubMed.

Other Citations

  1. ARF news story

External Citations

  1. Wall Street Journal story

Further Reading

Papers

  1. . Functionally-Detected Cognitive Impairment in High School Football Players Without Clinically-Diagnosed Concussion. J Neurotrauma. 2013 Apr 11; PubMed.
  2. . Alteration of brain default network in subacute phase of injury in concussed individuals: resting-state fMRI study. Neuroimage. 2012 Jan 2;59(1):511-8. PubMed.

Primary Papers

  1. . Hypoconnectivity and Hyperfrontality in Retired American Football Players. Sci Rep. 2013;3:2972. PubMed.