• 1H MRS
• brain
• diffusion-weighted imaging
• football players
• magnetic resonance imaging
• soccer

• Humans
• Male
• Magnetic Resonance Imaging/methods
• Soccer
• Adult
• Young Adult
• Case-Control Studies
• Brain/diagnostic imaging
• Adolescent

• CNS/PNS
• Hippo cell signaling
• TAZ
• YAP
• heparan sulfate proteoglycans

• Female
• Pregnancy
• Humans
• Heparan Sulfate Proteoglycans
• Hippo Signaling Pathway
• Acetylcholinesterase
• Extracellular Matrix
• Extracellular Matrix Proteins
• Wnt Signaling Pathway
• Receptor Protein-Tyrosine Kinases

• nil Melrose Personal Research Fund, Sydney

• Cortex
• Minor traumatic brain injury
• Mitochondria
• Neonatal opioid withdrawal syndrome
• Neuroinflammation
• Opioid
• Synaptosome

• P41 EB013598 NIBIB NIH HHS
• R01 NS102156 NINDS NIH HHS
• R01 AG056770 NIA NIH HHS
• R21 NS096718 NINDS NIH HHS
• F32 AG054126 NIA NIH HHS
• K08 NS114170 NINDS NIH HHS

Interest and uptake of science and medicine peer-reviewed literature by readers outside of a paper’s topical subject, field or even discipline is ever-expanding. While the application of knowledge from one field or discipline to others can stimulate innovative solutions to problems facing modern society, it is also fraught with danger for misuse. In the practice of law in the United States, academic papers are submitted to the courts as evidence in personal injury litigation from both the plaintiff (complainant) and defendant. Such transcendence of an academic publication over disciplinary boundaries is immediately met with the challenge of application by a group that inherently lacks in-depth knowledge on the scientific method, the practice of evidence-based medicine, or the publication process as a structured and internationally synthesized process involving peer review and guided by ethical standards and norms. A modern-day example of this is the ongoing conflict between the sensitivity of diffusion tensor imaging (DTI) and the legal standards for admissibility of evidence in litigation cases of mild traumatic brain injury (mTBI). In this review, we amalgamate the peer-reviewed research on DTI in mTBI with the court’s rationale underlying decisions to admit or exclude evidence of DTI abnormalities to support claims of brain injury. We found that the papers which are critical of the use of DTI in the courtroom reflect a primary misunderstanding about how diagnostic biomarkers differ legally from relevant and admissible evidence. The clinical use of DTI to identify white matter abnormalities in the brain at the chronic stage is a valid methodology both clinically as well as forensically, contributes data that may or may not corroborate the existence of white matter damage, and should be admitted into evidence in personal injury trials if supported by a clinician. We also delve into an aspect of science publication and peer review that can be manipulated by scientists and clinicians to publish an opinion piece and misrepresent it as an unbiased, evidence-based, systematic research article in court cases, the decisions of which establish precedence for future cases and have implications on future legislation that will impact the lives of every citizen and erode the integrity of science and medicine practitioners.

• Diffuse axonal injury
• Mild brain injury
• Magnetic resonance imaging
• Neuroimaging
• Medicolegal
• Litigation
• Medical jurisprudence
• Ethics
• Peer review
• Publishing

• Chronic traumatic encephalopathy
• dementia
• depression
• neurodegenerative
• pain
• photobiomodulation
• post-traumatic stress disorder
• sleep
• traumatic brain injury
• traumatic encephalopathy syndrome

• Humans
• Male
• Brain/diagnostic imaging
• Cognition
• Magnetic Resonance Imaging
• Neuropsychological Tests
• Head

• RF1 AG071566 NIA NIH HHS

• Delirium & cognitive disorders
• Magnetic resonance imaging
• SPORTS MEDICINE

• Humans
• Soccer/injuries
• Athletic Injuries/diagnostic imaging
• Athletic Injuries/etiology
• Prospective Studies
• Brain Concussion/diagnostic imaging
• Brain Concussion/etiology
• Cognition

• GE Healthcare
• University Hospital Strasbourg
• Philipps

• biomarker
• cavum septum pellucidum
• diffusion weighted imaging
• mild traumatic brain injury
• neuroimaging

• Chronic traumatic encephalopathy
• Concussion
• Magnetic resonance imaging
• Neurodegenerative disease
• Neuroimaging
• Positron emission tomography
• Repetitive head trauma
• Traumatic brain injury
• Traumatic encephalopathy syndrome

• Alzheimer Disease/diagnostic imaging
• Alzheimer Disease/epidemiology
• Alzheimer Disease/metabolism
• Blast Injuries/diagnostic imaging
• Blast Injuries/epidemiology
• Blast Injuries/metabolism
• Chronic Traumatic Encephalopathy/diagnostic imaging
• Chronic Traumatic Encephalopathy/epidemiology
• Chronic Traumatic Encephalopathy/metabolism
• Craniocerebral Trauma/diagnostic imaging
• Craniocerebral Trauma/epidemiology
• Craniocerebral Trauma/metabolism
• Diagnosis, Differential
• Football/injuries
• Humans
• Magnetic Resonance Imaging/methods
• Neurodegenerative Diseases/diagnostic imaging
• Neurodegenerative Diseases/epidemiology
• Neurodegenerative Diseases/metabolism
• Neuroimaging/methods
• Positron-Emission Tomography/methods

• P30 AG062422 NIA NIH HHS
• P30AG062422 NIA NIH HHS
• P50AG023501 NIA NIH HHS
• National Institute on Aging
• Rainwater Charitable Foundation

• fighters
• processing speed
• psychomotor speed
• repetitive head trauma
• static & dynamic functional connectivity

• P20 AG068053 NIA NIH HHS
• P20 GM109025 NIGMS NIH HHS
• R01 EB014284 NIBIB NIH HHS
• R01 NS117547 NINDS NIH HHS

• Brain/diagnostic imaging
• Brain/pathology
• Brain Injuries, Traumatic/diagnostic imaging
• Brain Injuries, Traumatic/pathology
• Chronic Traumatic Encephalopathy/diagnostic imaging
• Chronic Traumatic Encephalopathy/pathology
• Diagnostic Imaging/methods
• Humans
• Neuroimaging/methods

• KL2 TR002346 NCATS NIH HHS

• DTI
• RHI
• cognitive impairment
• graph-theoretical analysis
• repeated head impacts
• rich-club analysis

Cognitive dysfunction has long been recognized as a frequently observed symptom in individuals with repetitive mild traumatic brain injury (rmTBI) such as professional boxers. The exact neurobiological mechanisms underlying this cognitive deficit have not yet been identified, but it is agreed upon that the prefrontal cortex (PFC) is one of the most commonly affected brain regions in professional boxers. Noting the pivotal role of the two major brain metabolites in human cognitive functions, γ-aminobutyric acid (GABA) and glutamate/glutamine (Glx), we hypothesized that alterations in levels of GABA and Glx in the PFC would be prominent and may correlate with cognitive deficits in professional boxers. Twenty male professional boxers (Boxers) and 14 age-matched healthy males who had never experienced any TBI (CON) were recruited. Using a 3T magnetic resonance imaging (MRI) scanner, single-voxel proton magnetic resonance spectroscopy with Mescher-Garwood point-resolved spectroscopy (MEGA-PRESS) sequence was performed to evaluate the levels of GABA and Glx in the PFC. Cognitive function was assessed using the memory and attention domains from the Cambridge Neuropsychological Test Automated Battery. The Boxers showed lower GABA level in the PFC compared to the CON, while also showing lower performance in the attention and memory domains. There were no significant between-group differences in Glx levels. Furthermore, the GABA level correlated with memory performance in the Boxers, but not in attention performance. The current findings may suggest that alterations in GABA levels in the PFC may be a potential neurochemical correlate underlying memory dysfunction related to rmTBI.

• GABA
• cognitive impairment
• prefrontal cortex
• professional boxers
• traumatic brain injury

• Chronic traumatic encephalopathy
• Neurodegeneration
• Repetitive head impacts
• Subconcussive trauma
• Traumatic encephalopathy syndrome

• Adolescent
• Adult
• Anisotropy
• Athletes
• Cross-Sectional Studies
• Diffusion Tensor Imaging
• Female
• Humans
• Longitudinal Studies
• Magnetic Resonance Imaging/methods
• Male
• Middle Aged
• Neuroimaging/methods
• Prospective Studies
• Sex Factors
• Soccer
• White Matter/diagnostic imaging
• White Matter/pathology
• Young Adult

• R01 NS082432 NINDS NIH HHS
• T32 GM007288 NIGMS NIH HHS

• chronic traumatic encephalopathy
• magnetic resonance
• neuroimaging
• tau-pathology
• traumatic brain injury

• Chronic traumatic encephalopathy
• Head trauma
• Magnetic resonance imaging
• Neuroimaging
• Traumatic brain injury

Repeated head trauma experienced by active professional fighters results in various structural, functional and perfusion damage. However, whether there are common regions of structural and perfusion damage due to fighting and whether these structural and perfusion differences are associated with neuropsychological measurements in active professional fighters is still unknown. To that end, T1-weighted and pseudocontinuous arterial spin labeling MRI on a group of healthy controls and active professional fighters were acquired. Voxelwise group comparisons, in a univariate and multivariate sense, were performed to investigate differences in gray and white matter density (GMD, WMD) and cerebral blood flow (CBF) between the two groups. A significantly positive association between global GMD and WMD was obtained with psychomotor speed and reaction time, respectively, in our cohort of active professional fighters. In addition, regional WMD deficit was observed in a cluster encompassing bilateral pons, hippocampus, and thalamus in fighters (0.49 ± 0.04 arbitrary units (a.u.)) as compared to controls (0.51 ± 0.05a.u.). WMD in the cluster of active fighters was also significantly associated with reaction time. Significantly lower CBF was observed in right inferior temporal lobe with both partial volume corrected (46.9 ± 14.93 ml/100 g/min) and non-partial volume corrected CBF maps (25.91 ± 7.99 ml/100 g/min) in professional fighters, as compared to controls (65.45 ± 22.24 ml/100 g/min and 35.22 ± 12.18 ml/100 g/min respectively). A paradoxical increase in CBF accompanying right cerebellum and fusiform gyrus in the active professional fighters (29.52 ± 13.03 ml/100 g/min) as compared to controls (19.43 ± 12.56 ml/100 g/min) was observed with non-partial volume corrected CBF maps. Multivariate analysis with both structural and perfusion measurements found the same clusters as univariate analysis in addition to a cluster in right precuneus. Both partial volume corrected and non-partial volume corrected CBF of the cluster in the thalamus had a significantly positive association with the number of fights. In addition, GMD of the cluster in right precuneus was significantly associated with psychomotor speed in our cohort of active professional fighters. Our results suggest a heterogeneous pattern of structural and CBF deficits due to repeated head trauma in active professional fighters. This finding indicates that investigating both structural and CBF changes in the same set of participants may help to understand the pathophysiology and progression of cognitive decline due to repeated head trauma.

•

Repetitive head trauma revealed no global structural or global perfusion deficits.

• Brain morphology
• Cerebral blood flow
• Cognitive impairment
• Neurovascular coupling
• Repeated head trauma

• Alzheimer’s disease chronic traumatic encephalopathy
• dementia
• traumatic brain injury

Chronic traumatic encephalopathy (CTE) is a tauopathy associated with prior exposure to repetitive head impacts, such as those incurred through American football and other collision sports. Diagnosis is made through neuropathological examination. Many of the clinical features of CTE are common in the general population, with and without a history of head impact exposure, making clinical diagnosis difficult. As is now common in the diagnosis of other neurodegenerative disorders, such as Alzheimer’s disease, there is a need for methods to diagnose CTE during life through objective biomarkers.

The aim of this study was to examine tau-positive exosomes in plasma as a potential CTE biomarker.

Subjects were 78 former National Football League (NFL) players and 16 controls. Extracellular vesicles were isolated from plasma. Fluorescent nanoparticle tracking analysis was used to determine the number of vesicles staining positive for tau.

The NFL group had higher exosomal tau than the control group (p <  0.0001). Exosomal tau discriminated between the groups, with 82% sensitivity, 100% specificity, 100% positive predictive value, and 53% negative predictive value. Within the NFL group, higher exosomal tau was associated with worse performance on tests of memory (p = 0.0126) and psychomotor speed (p = 0.0093).

These preliminary findings suggest that exosomal tau in plasma may be an accurate, noninvasive CTE biomarker.

• Biomarker
• chronic traumatic encephalopathy
• diagnosis
• exosome
• football
• neurodegeneration
• plasma
• tau

The effect of repeated subconcussive head impacts in youth and high school sports on the developing brain is poorly understood. Emerging neuroimaging data correlated with biomechanical exposure metrics are beginning to demonstrate relationships across a variety of modalities. The long-term consequences of these changes are unknown. A review of the currently available literature on the effect of subconcussive head impacts on youth and high school-age male football players provides compelling evidence for more focused studies of these effects in these vulnerable populations.

Concussions are known to cause clinical symptoms, which are especially concerning for youth and high school athletes. However, the effects of repeated head impacts that do not cause a diagnosed concussion, known as subconcussive head impacts, are currently unknown. Recent research has identified similar changes in the brain following repeated nonconcussive impacts to the head, once thought to be caused only by the occurrence of concussion with the presence of clinical symptoms. Similarly, many reports suggest that a higher exposure to head impacts is associated with a greater amount of structural and/or functional changes in the brain. Given the similar effects on the brain, with or without symptoms, more work is needed to determine the long-term effects of subconcussive head impacts on individual athletes, particularly in the youth and high school age population.

• MEG
• MRI
• contact sports
• diffusion imaging
• functional imaging
• head impacts
• neurocognitive testing
• repetitive head impacts
• sport-related head impacts

• GCaMP
• long-term calcium imaging
• network firing rate
• single neuron ablation
• single neuron firing rate

• Ablation Techniques/instrumentation
• Ablation Techniques/methods
• Animals
• Calcium/metabolism
• Cells, Cultured
• Laser Therapy/instrumentation
• Laser Therapy/methods
• Minimally Invasive Surgical Procedures
• Models, Biological
• Nerve Net/pathology
• Nerve Net/surgery
• Neurons/cytology
• Neurons/metabolism
• Neurosurgical Procedures
• Rats
• Single-Cell Analysis/methods

• Diffusion tensor imaging
• Magnetic resonance imaging
• Magnetic resonance spectroscopy
• Positron emission tomography
• Traumatic brain injury
• Veteran
• fMRI

• DTI
• Diffusion MRI
• Free-water
• MRI
• Magnetization transfer
• Neuroimaging
• Neuroinflammation
• PET
• Schizophrenia

• Animals
• Brain/diagnostic imaging
• Brain/immunology
• Humans
• Inflammation/diagnostic imaging
• Inflammation/metabolism
• Neuroimaging
• Schizophrenia/diagnostic imaging
• Schizophrenia/immunology

• P41 EB015902 NIBIB NIH HHS
• P41 RR013218 NCRR NIH HHS
• R01 MH074794 NIMH NIH HHS
• R01 MH102377 NIMH NIH HHS

• MRI
• biomarkers
• head trauma
• neurodegenerative disorders
• traumatic brain injury

• Concussion
• boxing
• dementia
• return to play
• traumatic brain injury

• American football
• Chronic traumatic injury
• Sports-related injury
• Traumatic brain injury

• DCE-MRI
• Ktrans estimation
• blood-brain barrier
• parameter optimization
• permeability

• neuroimaging
• repetitive head injury

• Brain/pathology
• Brain Injuries/diagnosis
• Chronic Disease
• Humans
• Image Processing, Computer-Assisted
• Neuroimaging/methods
• Time Factors

• U01 NS086659 NINDS NIH HHS
• L30 NS063444 NINDS NIH HHS
• R01-NS078337 NINDS NIH HHS
• R56 NS078337 NINDS NIH HHS
• R01 NS078337 NINDS NIH HHS
• U01-NS086659 NINDS NIH HHS

• boxing
• chronic traumatic encephalopathy
• concussion
• football
• mild traumatic brain injury
• neuropathology

• Athletic Injuries/complications
• Biomechanical Phenomena
• Brain Injuries/complications
• Brain Injuries/etiology
• Chronic Disease
• Disease Progression
• Humans
• Male
• Middle Aged
• Neurodegenerative Diseases/etiology
• Risk Factors

• chronic traumatic encephalopathy
• concussion
• football
• history
• neurodegenerative disorders
• traumatic brain injury

The long-term consequences of repetitive head impacts have been described since the early 20th century. Terms such as punch drunk and dementia pugilistica were first used to describe the clinical syndromes experienced by boxers. A more generic designation, chronic traumatic encephalopathy (CTE), has been employed since the mid-1900s and has been used in recent years to describe a neurodegenerative disease found not just in boxers but in American football players, other contact sport athletes, military veterans, and others with histories of repetitive brain trauma, including concussions and subconcussive trauma. This article reviews the literature of the clinical manifestations of CTE from 202 published cases. The clinical features include impairments in mood (for example, depression and hopelessness), behavior (for example, explosivity and violence), cognition (for example, impaired memory, executive functioning, attention, and dementia), and, less commonly, motor functioning (for example, parkinsonism, ataxia, and dysarthria). We present proposed research criteria for traumatic encephalopathy syndrome (TES) which consist of four variants or subtypes (TES behavioral/mood variant, TES cognitive variant, TES mixed variant, and TES dementia) as well as classifications of ‘probable CTE’ and ‘possible CTE’. These proposed criteria are expected to be modified and updated as new research findings become available. They are not meant to be used for a clinical diagnosis. Rather, they should be viewed as research criteria that can be employed in studies of the underlying causes, risk factors, differential diagnosis, prevention, and treatment of CTE and related disorders.