Validity of Traumatic Encephalopathy Syndrome Clinical Research Criteria for Chronic Traumatic Encephalopathy Pathology: The Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) Study
Jesse Mez1, Michael Alosco1, Daniel Daneshvar2, Nicole Saltiel1, Zachary Baucom1, Yorghos Tripodis1, Bobak Abdolmohammadi1, Madeline Uretsky1, Raymond Nicks1, Brett Martin1, Joseph Palmisano1, Philip Montenigro1, Todd Solomon3, Victor Alvarez1, Brigid Dwyer1,4, Lee Goldstein1, Douglas Katz1,4, Neil Kowall1,5, Robert Cantu1,6, Yorghos Tripodis1, Bertrand Huber1,5, Thor Stein1,5, Robert Stern1, Ann McKee1,5
1Boston University, 2Stanford University, 3Avanir Pharmaceuticals, 4Braintree Rehabilitation Hospital, 5VA Boston Healthcare System, 6Emerson Hospital

In 2014, we proposed traumatic encephalopathy syndrome (TES) criteria to diagnose chronic traumatic encephalopathy (CTE) in life. This study’s goal was to assess the validity of TES criteria using CTE pathology as the gold standard.

CTE is a neurodegenerative disease associated with repetitive head impact (RHI) exposure. Currently, CTE can only be diagnosed post-mortem.
Brain donors with contact sport play or military service were eligible. Blinded to clinical information, neuropathologists conducted comprehensive gross and microscopic brain examinations, including diagnosing CTE using published criteria. Blinded to neuropathological information, neurologists and neuropsychologists collected clinical information through family interviews and medical record review. In bi-monthly clinicopathological conferences, an expert clinical panel reviewed the clinical history and reached consensus diagnoses based on TES criteria.

The sample included 302 brain donors [age range: 14 to 89 years, mean: 61.5 years (19.9 SD)].  286 donors (92.6%) were contact sport athletes, 85 donors (29.2%) served in the military and 249 donors (87.4%) sustained 4 or more concussions. 284 donors (91.9%) were diagnosed with probable or possible CTE by the consensus panel using TES criteria. 228 donors (74.3%) had CTE pathology. TES criteria demonstrated a sensitivity of 0.97, specificity of 0.23 and accuracy of 0.78. Of 61 false positives, 37 had other neurodegenerative or vascular pathology. All 6 false negatives had mild CTE pathology (5 stage I, 1 stage II). TES criteria do not require cognitive symptoms. By augmenting the criteria to require cognitive symptoms, specificity improved (0.37) with limited reduction in sensitivity (0.90).

Among RHI-exposed brain donors, TES criteria demonstrated high sensitivity, but low specificity for CTE pathology. Inclusion of required cognitive symptoms in TES criteria markedly improved specificity without compromising sensitivity. These results will inform revised TES criteria. Diagnosis of CTE in life is necessary for counseling patients and developing therapeutics.