Validity of the 2014 traumatic encephalopathy syndrome criteria for CTE pathology

Abstract

Introduction: Validity of the 2014 traumatic encephalopathy syndrome (TES) criteria, proposed to diagnose chronic traumatic encephalopathy (CTE) in life, has not been assessed.

Methods: A total of 336 consecutive brain donors exposed to repetitive head impacts from contact sports, military service, and/or physical violence were included. Blinded to clinical information, neuropathologists applied National Institute on Neurological Disorders and Stroke/National Institute of Biomedical Imaging and Bioengineering CTE criteria. Blinded to neuropathological information, clinicians interviewed informants and reviewed medical records. An expert panel adjudicated TES diagnoses.

Results: A total of 309 donors were diagnosed with TES; 244 donors had CTE pathology. TES criteria demonstrated sensitivity and specificity of 0.97 and 0.21, respectively. Cognitive (odds ratio [OR] = 3.6; 95% confidence interval [CI]: 1.2-5.1), but not mood/behavior or motor symptoms, were significantly associated with CTE pathology. Having Alzheimer's disease (AD) pathology was significantly associated with reduced TES accuracy (OR = 0.27; 95% CI: 0.12-0.59).

Discussion: TES criteria provided good evidence to rule out, but limited evidence to rule in, CTE pathology. Requiring cognitive symptoms in revised criteria and using AD biomarkers may improve CTE pathology prediction.

Keywords: 2014 traumatic encephalopathy syndrome research diagnostic criteria; Alzheimer's disease; attention; behavioral dysregulation; chronic traumatic encephalopathy; dementia; depression; diagnostic validity; executive function; explosivity; inter-rater reliability; memory; neuropathology; repetitive head impact exposure; traumatic brain injury.

FIGURE 1

Representative images of common pathologies found in brain donors with discrepant clinical and neuropathological diagnoses. All images are 10‐μm paraffin‐embedded tissue sections. Calibration bars indicate 100 μm. A, Perivascular chronic traumatic encephalopathy (CTE) lesions in the dorsolateral frontal (DLF) cortex: Immunostaining is with mouse monoclonal antibody for phosphorylated tau (p‐tau; AT8; Pierce Endogen) and counterstaining is with Luxol fast blue‐hematoxylin and eosin (LHE). Positive p‐tau immunostaining appears dark red. Neurofibrillary tangles (NFTs) and dot‐like and threadlike neurites encircle blood vessels (arrows). B, Lewy body inclusion in the dorsolateral frontal lobe: Immunostaining is with rabbit polyclonal antibody for alpha‐synuclein (Chemicon) and counterstaining is with LHE. Positive intraneuronal alpha‐synuclein immunostaining appears dark red. C, Pathological hallmarks of Alzheimer's disease (AD) in the DLF cortex: Staining is with Bielschowsky silver. NFTs (blue arrow), neuropil threads (green arrow), and neuritic plaques (black arrow) are densely distributed in the neuropil. D, AD in the CA1 region of the hippocampus: AT8‐immunostaining. P‐tau‐positive NFTs (blue arrow), neurites, and neuritic plaques (black arrow) are densely distributed throughout CA1. E, Microinfarct in septal cortex: Staining is with LHE. There is pallor, cystic tissue loss, and gliosis. F, Arteriolosclerosis in the deep white matter: LHE staining. A small arteriole shows hyalinized thickening of the vessel wall (black asterisk)

FIGURE 2

Association of traumatic encephalopathy syndrome (TES) criteria components on odds of chronic traumatic encephalopathy (CTE) pathology. The presence of cognitive symptoms was significantly associated with 3.6× increased odds of CTE pathology and the presence of features for ≥12 months was significantly associated with 3.5× increased odds of CTE pathology. There were not significant associations for behavior/mood symptoms or motor symptoms with CTE pathology. Models were adjusted for age ≥ 60 and race. Red bars indicate significant associations at the P = .05 level

FIGURE 3

Association of other pathologies on accuracy of traumatic encephalopathy syndrome‐chronic traumatic encephalopathy (TES‐CTE) diagnosis in donors age ≥ 60. Among donors age > 60, the presence of Alzheimer's disease (AD) pathology was significantly associated with reduced accuracy of the TES‐CTE consensus diagnoses by 3.7× compared to diagnoses made in the absence of AD pathology. There were not significant associations for Lewy body disease, frontotemporal lobar degeneration, or cerebrovascular pathology with accuracy of the TES‐CTE consensus diagnoses. Models were adjusted for race. The red bar indicates significant associations at the P = .05 level