Primum non nocere: a call for balance when reporting on CTE

Stewart, William; Allinson, Kieren; Al‐Sarraj, Safa; Bachmeier, Corbin; Barlow, Karen M.; Belli, Antonio; Burns, Mark P.; Carson, Alan; Crawford, Fiona; Dams-O’Connor, Kristen; Diaz‐Arrastia, Ramon; Dixon, C. Edward; Edlow, Brian L.; Ferguson, Scott; Fischl, Bruce; Folkerth, Rebecca D.; Gentleman, Steve; Giza, Christopher C.; Grady, M. Sean; Helmy, Adel; Herceg, Mark; Holton, Janice L.; Howell, David D.; Hutchinson, Peter J.; Iacono, Diego; Iglesias, Juan Eugenio; Ikonomović, Miloš D.; Johnson, Victoria E.; Keene, C. Dirk; Kofler, Julia; Koliatsos, Vassilis E.; Lee, Edward B.; Levin, Harvey S.; Lifshitz, Jonathan; Ling, Helen; Loane, David J.; Love, Seth; Maas, Andrew I. R.; Marklund, Niklas; Master, Christina L.; McElvenny, Damien; Meaney, David F.; Menon, David; Montine, Thomas J.; Mouzon, Benoit; Mufson, Elliott J.; Ojo, Joseph; Prins, Mayumi L.; Révész, Tamás; Ritchie, Craig; Smith, Colin; Sylvester, Richard; Tang, Cheuk Y.; Trojanowski, John Q.; Urankar, Kathryn; Vink, Robert; Wellington, Cheryl L.; Wilde, Elisabeth A.; Wilson, Lindsay; Yeates, Keith Owen; Smith, Douglas H.

doi:10.1016/s1474-4422(19)30020-1

Cited by 52 publications

(26 citation statements)

References 6 publications

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“…Highprofile cases of athletes with CTE have garnered a great deal of media attention. CTE prevalence is still being elucidated along with additional details for diagnostic criteria [145]. CTE is a term used to describe brain degeneration that is likely caused by repetitive TBIs.…”

Section: Protein Aggregationmentioning

confidence: 99%

Biological links between traumatic brain injury and Parkinson’s disease

Delic

Beck

Pang

et al. 2020

acta neuropathol commun

111

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Parkinson's Disease (PD) is a progressive neurodegenerative disorder with no cure. Clinical presentation is characterized by postural instability, resting tremors, and gait problems that result from progressive loss of A9 dopaminergic neurons in the substantia nigra pars compacta. Traumatic brain injury (TBI) has been implicated as a risk factor for several neurodegenerative diseases, but the strongest evidence is linked to development of PD. Mild TBI (mTBI), is the most common and is defined by minimal, if any, loss of consciousness and the absence of significant observable damage to the brain tissue. mTBI is responsible for a 56% higher risk of developing PD in U.S. Veterans and the risk increases with severity of injury. While the mounting evidence from human studies suggests a link between TBI and PD, fundamental questions as to whether TBI nucleates PD pathology or accelerates PD pathology in vulnerable populations remains unanswered. Several promising lines of research point to inflammation, metabolic dysregulation, and protein accumulation as potential mechanisms through which TBI can initiate or accelerate PD. Amyloid precursor protein (APP), alpha synuclein (α-syn), hyper-phosphorylated Tau, and TAR DNA-binding protein 43 (TDP-43), are some of the most frequently reported proteins upregulated following a TBI and are also closely linked to PD. Recently, upregulation of Leucine Rich Repeat Kinase 2 (LRRK2), has been found in the brain of mice following a TBI. Subset of Rab proteins were identified as biological substrates of LRRK2, a protein also extensively linked to late onset PD. Inhibition of LRRK2 was found to be neuroprotective in PD and TBI models. The goal of this review is to survey current literature concerning the mechanistic overlap between TBI and PD with a particular focus on inflammation, metabolic dysregulation, and aforementioned proteins. This review will also cover the application of rodent TBI models to further our understanding of the relationship between TBI and PD.

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Section: Protein Aggregationmentioning

confidence: 99%

Biological links between traumatic brain injury and Parkinson’s disease

Delic

Beck

Pang

et al. 2020

acta neuropathol commun

111

View full text Add to dashboard Cite

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“…The authors also claim that the lack of clinical and pathological criteria to diagnose modern CTE is a critical limitation that obstructs any understanding of CTE, while simultaneously ignoring any publications that provide clinical and diagnostic criteria for CTE, thereby creating a hollow argument. 31,47 Recent studies using "modern" techniques of p-tau and Aβ immunocytochemistry show identical neuropathological features in contemporary boxers as in American football players, 4,11,14 evidence demonstrating that modern and classic CTE are the same neurodegenerative disorder affecting different contact sport athletes from different eras. The implication that there are three diseases, one a "new condition" and a "variant of a single disease" or "another unrelated pathology (e.g.…”

Section: Beta-amyloid Pathology Is Not a Primary Feature Of Ctementioning

confidence: 99%

“…Since 2016, multiple international groups have used the NINDS criteria to evaluate and publish the neuropathological findings of CTE in various cohorts, including soccer players, 6,7,27 American football players, [28][29][30] a bull rider, 9 and rugby players. 8 Although some authors denounce the NINDS pathological criteria for CTE as "preliminary," [31][32][33] implying imprecision and insignificance, there is abundant evidence in the literature of their usefulness and value.…”

mentioning

confidence: 99%

The Neuropathology of Chronic Traumatic Encephalopathy: The Status of the Literature

McKee

2020

Semin Neurol

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Chronic traumatic encephalopathy (CTE) is a tauopathy associated with repetitive mild head trauma, including concussion and asymptomatic subconcussive impacts. CTE was first recognized in boxers almost a century ago and has been identified more recently in contact sports athletes, military veterans exposed to blast, and victims of domestic violence. Like most neurodegenerative diseases, CTE is diagnosed conclusively by a neuropathological examination of brain tissue. CTE is characterized by the buildup of hyperphosphorylated tau (p-tau) in neurofibrillary tangles (NFTs), neurites, and, sometimes, astrocytes, surrounding small blood vessels in a patchy distribution at the sulcal depths of the cerebral cortex. In 2015, using the McKee proposed criteria for the neuropathological diagnosis of CTE, a consensus panel of expert neuropathologists confirmed CTE as a unique neurodegenerative disease with a pathognomonic lesion and published the preliminary NINDS (National Institute of Neurological Disorders and Stroke) criteria for CTE. Since that time, the NINDS criteria for CTE have been implemented and validated in multiple international publications. Using the NINDS criteria, the largest clinicopathological series of CTE to date was reported that included 177 former American football players, including 110 (99%) of 111 former National Football League players, 48 (91%) of 53 former college football players, and 3 (21%) of 14 former high school players. Studies have also shown a significant association between cumulative exposure to repetitive head trauma, as judged by the length of American football playing career, and risk for and severity of CTE. There is also a significant relationship of the length of football playing career with p-tau pathology, inflammation, white matter rarefaction, and age at death in CTE. While p-tau pathology, inflammation, white matter rarefaction, and arteriolosclerosis contribute to dementia in CTE, whether they also influence the behavioral and mood symptoms in CTE has yet to be determined. There have been several instances of aging-related tau astrogliopathy (ARTAG), a common astrocytic pathology in the elderly, misdiagnosed as CTE in the recent literature, provoking claims that CTE pathology is present in people not known to have experienced repetitive head trauma. Although ARTAG is often found in CTE, the pathognomonic lesion of CTE is a neuronal lesion consisting of NFTs and neurites, with or without p-tau immunoreactive astrocytes. Some authors consider β-amyloid (Aβ) to be a primary feature of CTE, yet the data indicate that CTE is a primary tauopathy, with Aβ deposition a function of age and inheritance of the ApoEe4 allele. Some authors also question the progressive nature of CTE pathology, although there is clear evidence in most individuals that p-tau pathology increases in density and affects more brain regions with survival. This review is intended to outline the status of the evidence-based literature regarding CTE neuropathology and to address the misrepresentations and confusions that have arisen in recent reviews and a letter of correspondence.

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“…Yet, such observations continue to be made. For a recent example of the third of these fallacies (row 3), refer to Stewart et al, 27 who invoke a claim that CTE has been reported in asymptomatic individuals as if it can lessen the probability of a causal link between CTE and symptoms. Notwithstanding questions over whether their citations a It is even quite possible, when inaction in the face of a legitimate risk would have devastating consequences compared to the harm done by responding to an FP, that decision-makers could rationally act to control or prevent a risk deemed overwhelmingly likely to be artifactual or otherwise untrue.…”

Section: Key Features Of the Evidence Base For The Rhi Issuementioning

confidence: 99%

“…The healthy worker effect is particularly potent when the occupation depends crucially on extreme physical fitness, as is the case here. a plea for balance from the medical and scientific communities, Stewart et al 27 invoke "first do no harm," as if the only way to cause harm is by providing information that might contribute to specific or general FPs. Balance is indeed laudable, but it cannot be attained when restricting attention to FPs and communicating what is unknown, to the exclusion of FNs and communicating what is known.…”

Section: From Analysis To Actionmentioning

confidence: 99%

A Decision-Analytic Approach to Addressing the Evidence About Football and Chronic Traumatic Encephalopathy

Brand

Finkel

2019

Semin Neurol

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Doubts can be raised about almost any assertion that a particular exposure can lead to an increase in a given adverse health effect. Even some of the most well-accepted causal associations in public health, such as that linking cigarette smoking to increased lung cancer risk, have intriguing research questions remaining to be answered. The inquiry whether an exposure causes a disease is never wholly a yes/no question but ought to follow from an appraisal of the weight of evidence supporting the positive conclusion in light of any coherent theories casting doubt on this evidence and the data supporting these. More importantly, such an appraisal cannot be made sensibly without considering the relative consequences to public health and economic welfare of specific actions based on unwarranted credulity (false positives) versus unwarranted skepticism (false negatives). Here we appraise the weight of evidence for the premise that repeated head impacts (RHIs) in professional football can increase the incidence of chronic traumatic encephalopathy (CTE) and, in turn, cause a variety of cognitive and behavioral symptoms. We first dismiss four logical fallacies that should not affect the appraisal of the weight of evidence. We then examine four alternative hypotheses in which RHI is not associated with CTE or symptoms (or both), and we conclude that the chances are small that the RHI→ CTE→ symptoms link is coincidental or artifactual. In particular, we observe that there are many specific interventions for which, even under a skeptical appraisal of the weight of evidence, the costs of a false positive are smaller than the false negative costs of refusing to intervene.

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Primum non nocere: a call for balance when reporting on CTE

Cited by 52 publications

References 6 publications

Biological links between traumatic brain injury and Parkinson’s disease

Biological links between traumatic brain injury and Parkinson’s disease

The Neuropathology of Chronic Traumatic Encephalopathy: The Status of the Literature

A Decision-Analytic Approach to Addressing the Evidence About Football and Chronic Traumatic Encephalopathy

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