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Coughlin JM, Wang Y, Minn I, Bienko N, Ambinder EB, Xu X, Peters ME, Dougherty JW, Vranesic M, Koo SM, Ahn HH, Lee M, Cottrell C, Sair HI, Sawa A, Munro CA, Nowinski CJ, Dannals RF, Lyketsos CG, Kassiou M, Smith G, Caffo B, Mori S, Guilarte TR, Pomper MG. Imaging of Glial Cell Activation and White Matter Integrity in Brains of Active and Recently Retired National Football League Players. JAMA Neurol. 2017 Jan 1;74(1):67-74. PubMed.
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How chronic traumatic brain injury leads to dementia and increases the risk for neurodegenerative disease is not known. This study by Coughlin et al. provides evidence for the role of chronic inflammation, perhaps already early in these processes, by demonstrating profound chronic activation of microglia after mild sport-related head injuries in young football players. As stated in the accompanying commentary, increased TSPO expression might not be direct proof of a chronic proinflammatory state of microglia, but there are robust experimental data showing increased binding of TSPO ligands in activated proinflammatory microglia and a sustained microgliosis in rodent models of brain trauma.
Importantly, Coughlin et al. report that brain areas relevant for cognitive function seemed to be strongly affected. Since activated microglia can be involved in synaptic remodeling (Vasek et al., 2016) contribute to spreading of tau pathology (Maphis et al., 2015), the chronic neuroinflammatory response after sport-related injuries may be the driver of neurodegeneration. As new noninvasive PET-imaging ligands for monitoring of tau pathology become available (Barrio et al., 2015), it would be interesting to further examine tau pathology and microglia activation in the course of mild sport-related head injuries.
References:
Vasek MJ, Garber C, Dorsey D, Durrant DM, Bollman B, Soung A, Yu J, Perez-Torres C, Frouin A, Wilton DK, Funk K, DeMasters BK, Jiang X, Bowen JR, Mennerick S, Robinson JK, Garbow JR, Tyler KL, Suthar MS, Schmidt RE, Stevens B, Klein RS. A complement-microglial axis drives synapse loss during virus-induced memory impairment. Nature. 2016 Jun 22;534(7608):538-43. PubMed.
Maphis N, Xu G, Kokiko-Cochran ON, Jiang S, Cardona A, Ransohoff RM, Lamb BT, Bhaskar K. Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain. Brain. 2015 Jun;138(Pt 6):1738-55. Epub 2015 Mar 31 PubMed.
Barrio JR, Small GW, Wong KP, Huang SC, Liu J, Merrill DA, Giza CC, Fitzsimmons RP, Omalu B, Bailes J, Kepe V. In vivo characterization of chronic traumatic encephalopathy using [F-18]FDDNP PET brain imaging. Proc Natl Acad Sci U S A. 2015 Apr 21;112(16):E2039-47. Epub 2015 Apr 6 PubMed.
View all comments by Anna-Leena SirénBoston University School of Medicine
This important study extends the authors’ results to show increased TSPO signal in 14 younger and active NFL players in addition to the nine older, former NFL players on whom they previously reported (Coughlin et al., 2015). The study is also in agreement with our postmortem study of a cohort of 66 former American football athletes and 16 non-athlete controls that found increased activated microglial cell density in 18 young football players without CTE (mean age 32 years) and an even greater increase in older former football athletes with neuropathologically verified mild or severe CTE (mean age 44 and 66 years, respectively) (Cherry et al., 2016). TSPO cannot discriminate between microglia and reactive astrocytes; our study showed that activated microglia, not GFAP-positive astrocytes, were increased in football players compared to controls. We also found that the number of years of football play significantly predicted greater density of activated microglial cells in the dorsolateral frontal cortex and that the microglial activation persists for decades after retirement and increases with age. Although Coughlin et al. did not show a significant effect of years of NFL play on TSPO binding, perhaps due to limited sample size, they did not include data on total years of football exposure, which might have proved informative.
The authors also did not provide information on the dorsolateral frontal cortex, a region that often shows early pathology in CTE. However, they did show increases in TSPO binding in brain areas particularly vulnerable to tau neurofibrillary degeneration in advanced CTE, namely medial temporal lobe structures (hippocampus, entorhinal cortex, parahippocampal gyri), temporal pole, and supramarginal gyrus, suggesting that inflammation in these regions might accelerate or amplify tau neurofibrillary pathology. They also mentioned that regions such as thalamus and midbrain showed increased TSPO signal, but didn't show these comparisons. Again the thalamus and midbrain are regions of increased susceptibility to tau neurofibrillary pathology in CTE.
Overall, this study adds to the accumulating evidence that microglia activation is an early response to the repetitive head trauma that occurs during football play and can be followed years later by the development of tau pathology and CTE.
It is remains unclear at what point the inflammatory response that is initially protective converts to a self-perpetuating, destructive process that promotes neurodegeneration. Regardless, in vivo measures of glia activation will likely be a good surrogate for detection of brain injury in individuals exposed to repetitive head impacts.
References:
Coughlin JM, Wang Y, Munro CA, Ma S, Yue C, Chen S, Airan R, Kim PK, Adams AV, Garcia C, Higgs C, Sair HI, Sawa A, Smith G, Lyketsos CG, Caffo B, Kassiou M, Guilarte TR, Pomper MG. Neuroinflammation and brain atrophy in former NFL players: An in vivo multimodal imaging pilot study. Neurobiol Dis. 2015 Feb;74:58-65. Epub 2014 Nov 7 PubMed.
Cherry JD, Tripodis Y, Alvarez VE, Huber B, Kiernan PT, Daneshvar DH, Mez J, Montenigro PH, Solomon TM, Alosco ML, Stern RA, McKee AC, Stein TD. Microglial neuroinflammation contributes to tau accumulation in chronic traumatic encephalopathy. Acta Neuropathol Commun. 2016 Oct 28;4(1):112. PubMed.
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