Imaging of Glial Cell Activation and White Matter Integrity in Brains of Active and Recently Retired National Football League Players

Coughlin, Jennifer M.; Wang, Yuchuan; Minn, Il; Bienko, Nicholas; Ambinder, Emily B.; Xu, Xin; Peters, Matthew E.; Dougherty, John W.; Vranesic, Melin; Koo, Soo Min; Ahn, Hye-Hyun; Lee, Merton; Cottrell, Chris; Sair, Haris I.; Sawa, Akira; Munro, Cynthia A.; Nowinski, Christopher J.; Dannals, Robert F.; Lyketsos, Constantine G.; Kassiou, Michael; Smith, Gwenn S.; Caffo, Brian; Mori, Susumu; Guilarte, Tomás R.; Pomper, Martin G.

doi:10.1001/jamaneurol.2016.3764

Cited by 141 publications

(155 citation statements)

References 48 publications

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“…This is further supported by recent in vivo brain imaging studies of football athletes, which revealed evidence of chronic microglial activation (Cherry et al, 2016; Coughlin et al, 2017). Interestingly, research in murine AD models has shown that neuroinflammatory cytokines and reactive microglia can promote tau pathology and contribute to the spread of pTau, which might explain the link between TBI-induced inflammation and CTE (Ghosh et al, 2013; Maphis et al, 2015).…”

Section: Introductionsupporting

confidence: 63%

Neuroimmunology of Traumatic Brain Injury: Time for a Paradigm Shift

Jassam

Izzy

Whalen

et al. 2017

Neuron

541

440

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SUMMARY Traumatic brain injury (TBI) is a leading cause of morbidity and disability, with a considerable socioeconomic burden. Heterogeneity of pathoanatomical subtypes and diversity in the pathogenesis and extent of injury contribute to differences in the course and outcome of TBI. Following the primary injury, extensive and lasting damage is sustained through a complex cascade of events referred to as “secondary injury”. Neuroinflammation is proposed as an important manipulable aspect of secondary injury in animal and human studies. Because neuroinflammation can be detrimental or beneficial, before developing immunomodulatory therapies, it is necessary to better understand the timing and complexity of the immune responses that follows TBI. With a rapidly increasing body of literature, there is a need for a clear summary of TBI neuroimmunology. This review presents our current understanding of the immune response to TBI in a chronological and compartment-based manner, highlighting early changes in gene expression and initial signaling pathways that lead to activation of innate and adaptive immunity. Based on recent advances in our understanding of innate immune cell activation, we propose a new paradigm to study innate immune cells following TBI that moves away from the existing M1/M2 classification of activation states towards a stimulus and disease-specific understanding of polarization state based on transcriptomic and proteomic profiling.

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Section: Introductionsupporting

confidence: 63%

Neuroimmunology of Traumatic Brain Injury: Time for a Paradigm Shift

Jassam

Izzy

Whalen

et al. 2017

Neuron

541

440

View full text Add to dashboard Cite

show abstract

“…Relative to healthy controls, chronically elevated levels of neuroinflammation, as detected via PET scan, can persists both years after a single remote TBI as well as years after exposure to repetitive neurotrauama, even in the absence of a clinically evident TBI [61][62][63][64] . Notably, one study that also investigated neuronal white matter integrity found that levels of microglial activations correlated with structural changes in the brain 63 . Recent reviews detailing this dysregulated immune response in the brain following neurotrauma highlight the phenomenon of microglial priming as a key component of this harmful pro-inflammatory state 28,29,49 .…”

Section: Immunological Perspectives Of Tbi Sequelaementioning

confidence: 99%

The bidirectional gut-brain-microbiota axis as a potential nexus between traumatic brain injury, inflammation, and disease

Sundman

Chen

Subbian

et al. 2017

Brain, Behavior, and Immunity

139

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The bidirectional gut-brain-microbiota axis as a potential nexus between traumatic brain injury, inflammation, and disease. AbstractAs head injuries and their sequelae have become an increasingly salient matter of public health, experts in the field have made great progress elucidating the biological processes occurring within the brain at the moment of injury and throughout the recovery thereafter. Given the extraordinary rate at which our collective knowledge of neurotrauma has grown, new insights may be revealed by examining the existing literature across disciplines with a new perspective. This article will aim to expand the scope of this rapidly evolving field of research beyond the confines of the central nervous system (CNS). Specifically, we will examine the extent to which the bidirectional influence of the gut-brain axis modulates the complex biological processes occurring at the time of traumatic brain injury (TBI) and over the days, months, and years that follow. In addition to local enteric signals originating in the gut, it is well accepted that gastrointestinal (GI) physiology is highly regulated by innervation from the CNS. Conversely, emerging data suggests that the function and health of the CNS is modulated by the interaction between 1) neurotransmitters, immune signaling, hormones, and neuropeptides produced in the gut, 2) the composition of the gut microbiota, and 3) integrity of the intestinal wall serving as a barrier to the external environment. Specific to TBI, existing pre-clinical data indicates that head injuries can cause structural and functional damage to the GI tract, but research directly investigating the neuronal consequences of this intestinal damage is lacking. Despite this void, the proposed mechanisms emanating from a damaged gut are closely implicated in the inflammatory processes known to promote neuropathology in the brain following TBI, which suggests the gut-brain axis may be a therapeutic target to reduce the risk of Chronic Traumatic Encephalopathy and other neurodegenerative diseases following TBI. To better appreciate how various peripheral influences are implicated in the health of the CNS following TBI, this paper will also review the secondary biological injury mechanisms and the dynamic pathophysiological response to neurotrauma. Together, this review article will attempt to connect the dots to reveal novel insights into the bidirectional influence of the gut-brain axis and propose a conceptual model relevant to the recovery from TBI and subsequent risk for future neurological conditions.

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“…Ten studies based on chronic TBI individuals examined a mixed gender experimental group and one did not provide information on the sex of study participants . All studies focusing on contact sports athletes investigated solely male experimental groups, and the two ex vivo studies did not provide any information on gender . Contact sports athletes included soccer players, boxers, American football players, baseball players, and wrestlers.…”

Section: Resultsmentioning

confidence: 99%

“…The age range of all studies was from school level to retirement age (13.5–74 years). Of all included in vivo studies, 22 used an age‐matched control group . All articles were published between 1994 and 2018.…”

Section: Resultsmentioning

confidence: 99%

“…From the 25 included studies, 14 used diverse MR techniques . Twenty‐one studies applied structural MRI, including T 1 ‐weighted (T 1 ‐w), T 2 ‐weighted (T 2 ‐w), fluid attenuated inversion recovery (FLAIR), susceptibility weighted imaging (SWI), and proton‐density weighted (PD‐w) imaging . Thirteen studies used diffusion MRI, specifically diffusion tensor imaging (DTI), generalized q‐sampling imaging (GQI), diffusion kurtosis imaging (DKI), and diffusion weighted imaging (DWI) .…”

Section: Resultsmentioning

confidence: 99%

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