Hampshire A, Macdonald A, Owen AM.
Hypoconnectivity and Hyperfrontality in Retired American Football Players.
Sci Rep. 2013;3:2972.
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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).
Cohen AD, Price JC, Weissfeld LA, James J, Rosario BL, Bi W, Nebes RD, Saxton JA, Snitz BE, Aizenstein HA, Wolk DA, Dekosky ST, Mathis CA, Klunk WE.
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.
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.
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