Validity of the 2014 traumatic encephalopathy syndrome criteria for CTE pathology

Mez, Jesse; Alosco, Michael L.; Daneshvar, Daniel H.; Saltiel, Nicole; Baucom, Zachary; Abdolmohammadi, Bobak; Uretsky, Madeline; Nicks, Raymond; Martin, Brett; Palmisano, Joseph; Nowinski, Christopher J.; Montenigro, Philip H.; Solomon, Todd M.; Mahar, Ian; Cherry, Jonathan D.; Alvarez, Victor E.; Dwyer, Brigid; Goldstein, Lee E.; Katz, Douglas I.; Cantu, Robert C.; Kowall, Neil W.; Tripodis, Yorghos; Huber, Bertrand R.; Stein, Thor D.; Stern, Robert; McKee, Ann C.

doi:10.1002/alz.12338

Cited by 50 publications

(53 citation statements)

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“…4,7 Not all symptoms are related to p-tau pathology. 8 Repetitive head impacts are associated with an array of pathologies that contribute to cognitive and neuropsychiatric function. 1,[9][10][11][12] Autopsy studies show white matter degeneration and microvascular injury are late pathologies of repetitive head impacts that contribute to neurocognitive impairment.…”

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confidence: 99%

Association Between Antemortem FLAIR White Matter Hyperintensities and Neuropathology in Brain Donors Exposed to Repetitive Head Impacts

et al. 2022

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Background and Objectives:Late neuropathologies of repetitive head impacts from contact sports can include chronic traumatic encephalopathy (CTE) and white matter degeneration. White matter hyperintensities (WMH) on fluid attenuated inversion recovery (FLAIR) MRI scans are often viewed as microvascular disease from vascular risk, but might have unique underlying pathologies and risk factors in the setting of repetitive head impacts. We investigated the neuropathological correlates of antemortem WMH in brain donors exposed to repetitive head impacts. The association between WMH, and repetitive head impact exposure and informant-reported cognitive and daily function were tested.Methods:This imaging-pathological correlation study included symptomatic deceased men exposed to repetitive head impacts. Donors had antemortem FLAIR scans from medical records and were without evidence of CNS neoplasm, large vessel infarcts, hemorrhage, and/or encephalomalacia. WMH were quantified using log-transformed values for total lesion volume (TLV), calculated using the lesion prediction algorithm from the Lesion Segmentation Toolbox. Neuropathological assessments included semi-quantitative ratings of white matter rarefaction, cerebrovascular disease, p-tau severity (CTE stage, dorsolateral frontal cortex), and Aβ. Among football players, years of play was a proxy for repetitive head impact exposure. Retrospective informant-reported cognitive and daily function were assessed using the Cognitive Difficulties Scale (CDS) and Functional Activities Questionnaire (FAQ). Regression models controlled for demographics, diabetes, hypertension, and MRI resolution. Statistical significance was defined as p<0.05.Results:The sample included 75 donors: 67 football players and 8 non-football contact sport athletes and/or military veterans. Dementia was the most common MRI indication (64%). Fifty-three (70.7%) had CTE at autopsy. Log-TLV was associated with white matter rarefaction (OR=2.32, 95% CI=1.03,5.24, p=0.04), arteriolosclerosis (OR=2.38, 95% CI=1.02,5.52, p=0.04), CTE stage (OR=2.58, 95% CI=1.17,5.71, p=0.02), and dorsolateral frontal p-tau severity (OR=3.03, 95% CI=1.32,6.97, p=0.01). There was no association with Aβ. More years of football play was associated with log-TLV (b=0.04, 95% CI=0.01,0.06, p=0.01). Greater log-TLV correlated with higher FAQ (unstandardized beta=4.94, 95% CI=0.42,8.57, p=0.03) and CDS scores (unstandardized beta=15.35, 95% CI=-0.27,30.97, p=0.05).Discussion:WMH might capture long-term white matter pathologies from repetitive head impacts, including those from white matter rarefaction and p-tau, in addition to microvascular disease. Prospective imaging-pathological correlation studies are needed.Classification of Evidence:This study provides Class IV evidence of associations between FLAIR white matter hyperintensities, and neuropathological changes (white matter rarefaction, arteriolosclerosis, p-tau accumulation), years of American football play, and reported cognitive symptoms in symptomatic brain donors exposed to repetitive head impacts.

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Association Between Antemortem FLAIR White Matter Hyperintensities and Neuropathology in Brain Donors Exposed to Repetitive Head Impacts

et al. 2022

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“…These TES criteria were not intended as diagnostic of CTE, but rather to facilitate CTE research. Later refinement of TES criteria has proven useful in clinical research ( 46 ), but appears more accurate in excluding a diagnosis of CTE, than positively identifying CTE ( 47 ).…”

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confidence: 99%

Chronic Traumatic Encephalopathy as a Preventable Environmental Disease

et al. 2022

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In this Perspective we explore the evolution of our understanding of chronic traumatic encephalopathy (CTE) and its relationship with repetitive head injury. As with many neurodegenerative conditions, there is an imperfect correspondence between neuropathology and clinical phenotype, but unlike other neurodegenerative diseases, CTE has a discrete and easily modifiable risk factor: exposure to repetitive head injury. Consequently, evaluation of the evidence regarding exposure to repetitive head injury and CTE risk should be undertaken using public or occupational health frameworks of medical knowledge. The current debate over the existence of CTE as a disease of concern is fuelled in part by immediate medico-legal considerations, and the involvement of high-profile athletes, with inevitable media interest. Moving beyond this debate has significant potential to address and reduce disease impact in the near future, and provide novel insights into mechanisms underlying abnormal protein accumulation in CTE and other neurodegenerative diseases.

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“… 4 Revisions of the TES criteria to include cognitive symptoms and application of biomarkers for Alzheimer’s disease have been proposed, as CTE and Alzheimer’s disease share tau aggregation as characteristic pathology. 2 , 3 , 5 , 6 Without the means to diagnose CTE in life, there are no treatment options for the diverse symptomology and co-morbidities experienced by the impacted individuals. 7–9 To move towards ante-mortem diagnosis of CTE, PET imaging studies in traumatic brain injury (TBI) populations with tau-targeting radiopharmaceuticals are underway using PET tracers optimized for Alzheimer’s disease-tau including [ 18 F]FDDNP, [ 18 F]flortaucipir (a.k.a.…”

Section: Introductionmentioning

confidence: 99%

Characterization of neuroinflammatory positron emission tomography biomarkers in chronic traumatic encephalopathy

Varlow

Knight

McQuade

et al. 2022

Brain Communications

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Chronic traumatic encephalopathy is a neurological disorder associated with head trauma and is confirmed upon autopsy. PET imaging of chronic traumatic encephalopathy may provide a means to move toward ante-mortem diagnosis and therapeutic intervention following brain injuries. Characterization of the neuroinflammatory PET biomarkers, 18 kDa translocator protein and monoamine oxidase-B was conducted using [3H]PBR-28 and [3H]L-deprenyl, respectively, in post-mortem chronic traumatic encephalopathy brain tissue. [3H]PBR-28 displayed high specific binding in both chronic traumatic encephalopathy (95.40 ± 1.87%; n = 11 cases) and healthy controls (89.89 ± 8.52%, n = 3 cases). Cell-type expression of the 18 kDa translocator protein was confirmed by immunofluorescence to microglia, astrocyte and macrophage markers. [3H]L-deprenyl also displayed high specific binding in chronic traumatic encephalopathy (96.95 ± 1.43%; n = 12 cases) and healthy controls (93.24 ± 0.43%; n = 2 cases), with the distribution co-localized to astrocytes by immunofluorescence. Saturation analysis was performed to quantify the target density of the 18 kDa translocator protein and monoamine oxidase-B in both chronic traumatic encephalopathy and healthy control tissue. Using [3H]PBR-28 the target density of the 18 kDa translocator protein in healthy controls was 177.91 ± 56.96 nM (n = 7 cases; mean ± SD) however, a highly variable target density (345.84 ± 372.42 nM; n = 11 cases; mean ± SD) was measured in chronic traumatic encephalopathy. [3H]L-deprenyl quantified an monoamine oxidase-B target density of 304.23 ± 115.93 nM (n = 8 cases; mean ± SD) in healthy control tissue and is similar to the target density in chronic traumatic encephalopathy tissues (365.80 ± 128.55 nM; n = 12 cases; mean ± SD). A two-sample t-test determined no significant difference in the target density values of the 18 kDa translocator protein and monoamine oxidase-B between healthy controls and chronic traumatic encephalopathy (P > 0.05), albeit a trend towards increased expression of both targets was observed in chronic traumatic encephalopathy. To our knowledge, this work represents the first in vitro characterization of 18 kDa translocator protein and monoamine oxidase-B in chronic traumatic encephalopathy and reveals the variability in neuroinflammatory pathology following brain injuries. These preliminary findings will be considered when designing PET imaging studies after brain injury, and for the ultimate goal of imaging chronic traumatic encephalopathy in vivo.

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Validity of the 2014 traumatic encephalopathy syndrome criteria for CTE pathology

Cited by 50 publications

References 46 publications

Association Between Antemortem FLAIR White Matter Hyperintensities and Neuropathology in Brain Donors Exposed to Repetitive Head Impacts

Association Between Antemortem FLAIR White Matter Hyperintensities and Neuropathology in Brain Donors Exposed to Repetitive Head Impacts

Chronic Traumatic Encephalopathy as a Preventable Environmental Disease

Characterization of neuroinflammatory positron emission tomography biomarkers in chronic traumatic encephalopathy

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