New MRI research shows that repeated football head impacts can subtly reshape brain structures, offering new clues about chronic traumatic encephalopathy (CTE).
Study: Sulcal morphology in former American football players. Image credit: Alex Kravtsov/Shutterstock.com
A recent study, published in the journal Brain Communications, reported on changes in the structure of brain in former American football players.
American football is a high-contact game associated with multiple impacts to the head and body. Repetitive head impacts (RHI) may cause changes in brain structure, increasing the risk of chronic traumatic encephalopathy, a progressive neurodegenerative condition.
About CTE and brain changes
RHI occurs in many contact sports and can be associated with impaired cognitive and functional performance as well as behavioral changes. They increase the risk of neurodegenerative disease, including chronic traumatic encephalopathy (CTE).
CTE is associated with sports like American football, where RHI is common. Thus, monitoring these players for long-term consequences and identifying CTE markers in such individuals is vital.
In CTE, there is an abnormal buildup of phosphorylated tau protein in the brain, especially in the depths of the superior frontal sulci. The sulci are the furrows separating the convolutions of the brain matter of the cerebral hemispheres.
Tau accumulation is linked to cortical atrophy, resulting in wider and shallower sulci. This suggests that sulcal morphology might be a more sensitive signal for CTE risk than conventional morphological measurements like cortical thickness, volume, or surface area. Notably, wider, shallower sulci are also found in Alzheimer’s disease and other neurodegenerative disorders, but in different regions.
These sulcal changes could reflect the toxicity and neuroinflammation hypothesized to be caused by hyperphosphorylation of the tau protein, which leads to cortical atrophy and neurodegeneration. This study aimed to understand sulcal morphology in high-risk populations, helping initially to detect and stage CTE, and later to develop biomarkers and even intervention tools.
The 2021 National Institute of Neurological Disorders and Stroke (NINDS) consensus diagnostic criteria were designed to aid with symptom-based Traumatic Encephalopathy Syndrome (TES) diagnosis. Once TES is diagnosed, it is possible to estimate the probability that it was caused by CTE-related injury in terms of levels of certainty. However, a definitive diagnosis of CTE can only be made post-mortem, and in this study none of the participants were classified as having “definite CTE with TES.” For this reason, levels of certainty are reported rather than a definitive diagnosis.
Other biomarkers, including neuroimaging findings or blood-based tests, could help increase the validity of this diagnosis. Positron emission tomography (PET) promises to help detect CTE-associated changes, and flortaucipir PET is being investigated for specific tau binding in this disorder. However, its specificity for tau aggregation in CTE remains uncertain, and further validation is needed.
Scanning the brains of former football players for clues
The study examined how sulcal morphology differed in former American football players compared to the general population. These variations were examined while statistically controlling for age, history of playing football, previous diagnosis of traumatic encephalopathy, and correlations with various diagnostic tests, including neuropsychological tests, pathologic appearances, and PET results.
Other associations were assessed: age, race, body mass index, imaging site, apolipoprotein E4 status, and total intracranial volume.
The investigators based their analysis on structural magnetic resonance imaging (MRI) data from 169 former players with a mean age of 57 years, comparing them with 54 non-players of similar age without symptoms of chronic traumatic encephalopathy. The participants were part of the large multicenter DIAGNOSE CTE Research Project, which included 114 former professional and 55 former college players. Structural MRI allows the researcher to evaluate cortical structural markers possibly linked to CTE-associated neurodegeneration.
They used a scale dubbed the CalcSulc scale to assess sulcal morphology, depth and width. To do this, they measured the superior frontal and occipitotemporal sulci, two regions in each cerebral hemisphere frequently showing pathologic changes in CTE.
Brain changes don’t always mean CTE
The left superior frontal sulcus was significantly shallower in former football players compared to controls. Shallow left superior frontal sulci also correlated with greater cumulative exposure to head impact.
This may occur because the brain's structure means that the sulci experience concentrated mechanical strain during impact, making them more vulnerable to RHI. By causing axonal damage, this could trigger focal p-tau accumulation.
Conversely, the width of the left occipitotemporal sulcus was correlated with an earlier age of first involvement with the sport, and with the total duration of exposure to the sport in years.
The sulcus morphology was not correlated with a clinical TES or pathologic CTE diagnosis, neuropsychological tests, or flortaucipir PET imaging. The results suggest that cumulative head impact exposure is linked to changes in sulcus morphology. These changes are more evident in the areas most affected by CTE. However, the study failed to find TES-specific differences in sulcal morphology, underlining the need for better diagnostic criteria than symptoms and history alone.
There was no correlation between clinical severity of TES and flortaucipir PET tau binding. A similar lack of sensitivity was observed for correlations between structural MRI findings and PET imaging, suggesting that structural changes are only indirectly connected to molecular-level changes.
Pinpointing how repeated hits reshape the brain
Sulcal morphology may reflect cumulative exposure to repetitive head impacts.
It appears that sulcal shallowness results mainly from cortical atrophy, wherein the brain gyri or ridges adjacent to the sulci shrink over time. Importantly, this is the effect of repetitive head impacts rather than a marker of CTE, and not all individuals exposed to RHI develop CTE.
The brain shows regional differences in its RHI-associated changes. This could mirror variation in susceptibility, with the earlier-maturing occipitotemporal cortex being more easily damaged by RHI occurring earlier in life and sustained over a longer period. The superior frontal sulcus executes a higher level of brain function and may suffer more from sustained biomechanical strain over a prolonged period.
Further studies should validate this conclusion, using brain imaging in both living and deceased patients. Such research should clarify how RHI-related sulcal changes differ from those characteristic of CTE. This would help advance this technology as a reliable marker of CTE risk following RHI.
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