Assessing clinicopathological correlation in chronic traumatic encephalopathy: rationale and methods for the UNITE study

Abstract

Introduction: Chronic traumatic encephalopathy (CTE) is a progressive neurodegeneration associated with repetitive head impacts. Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) is a U01 project recently funded by the National Institute of Neurological Disorders and Stroke and the National Institute of Biomedical Imaging and Bioengineering. The goal of the UNITE project is to examine the neuropathology and clinical presentation of brain donors designated as "at risk" for the development of CTE based on prior athletic or military exposure. Here, we present the rationale and methodology for UNITE.

Methods: Over the course of 4 years, we will analyze the brains and spinal cords of 300 deceased subjects who had a history of repetitive head impacts sustained during participation in contact sports at the professional or collegiate level or during military service. Clinical data are collected through medical record review and retrospective structured and unstructured family interviews conducted by a behavioral neurologist or neuropsychologist. Blinded to the clinical data, a neuropathologist conducts a comprehensive assessment for neurodegenerative disease, including CTE, using published criteria. At a clinicopathological conference, a panel of physicians and neuropsychologists, blinded to the neuropathological data, reaches a clinical consensus diagnosis using published criteria, including proposed clinical research criteria for CTE.

Results: We will investigate the validity of these clinical criteria and sources of error by using recently validated neuropathological criteria as a gold standard for CTE diagnosis. We also will use statistical modeling to identify diagnostic features that best predict CTE pathology.

Conclusions: The UNITE study is a novel and methodologically rigorous means of assessing clinicopathological correlation in CTE. Our findings will be critical for developing future iterations of CTE clinical diagnostic criteria.

Fig. 1

Overall flowchart of the study methodology

Fig. 2

Recruitment mechanisms in place at the U.S. Department of Veterans Affairs–Boston University–Concussion Legacy Foundation Brain Donation Registry and Brain Bank since Understanding Neurologic Injury and Traumatic Encephalopathy project recruitment began. Next-of-kin recruitment: A potential donor’s legal next of kin contacts the brain bank near the time of death to ask about participation. Active recruitment: A member of the brain bank staff contacts a potential donor’s next of kin near the time of death to ask about participation. Brain Donation Registry: A potential donor contacts the brain bank and pledges to donate upon death. Medical examiner: A medical examiner contacts the brain bank upon suspicion of a diagnosis of chronic traumatic encephalopathy or if an individual’s family member expresses to the medical examiner interest in brain donation. Consultations: A neuropathologist contacts the brain bank to release tissue for further evaluation

Fig. 3

Adapted clinical diagnostic criteria for traumatic encephalopathy syndrome^a. Abbreviations: CSF cerebrospinal fluid, CTE chronic traumatic encephalopathy, PET positron emission tomography, p-tau phosphorylated tau, RHI repetitive head injuries, TBI traumatic brain injury, TES traumatic encephalopathy syndrome. ^aCriteria adapted from Montenigro et al. [5]

Fig. 4

Clinical consensus diagnostic form completed by each clinician. ALS amyotrophic lateral sclerosis, CNS central nervous system, CTE chronic traumatic encephalopathy, FTD frontotemporal degeneration, TBI traumatic brain injury, TES traumatic encephalopathy syndrome