For the first time, BU researchers show a clear relationship between the amount of CTE pathology and severity of symptoms

(Boston)—Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease defined by hyperphosphorylated tau (p-tau) protein accumulating in a particular pattern in specific regions of the brain. Currently, CTE can only be diagnosed at autopsy. Like similar brain diseases, the clinical symptoms in life of people diagnosed with CTE after death can vary and there has been robust debate as to what symptoms, if any, are caused by CTE pathology.

In a new study from the BU CTE Center, researchers provide the most definitive evidence to date that CTE p-tau pathology is primarily responsible for cognitive and functional symptoms, explaining up to 49% of the variation seen in individual patients. For context, studies of Alzheimer’s disease have suggested that all pathologies, including p-tau, explain about 50% of symptoms.

“For the first time, we were able to show a clear dose-response relationship between the amount of CTE pathology and the severity of cognitive and functional symptoms, including problems with memory and executive function. These findings provide a clear step forward toward diagnosing CTE in life,” explains corresponding author Jesse Mez, MD, MS, co-director of clinical research at the CTE Center and associate professor of neurology at Boston University Chobanian & Avedisian School of Medicine.

Neuropathologists rated the amount of p-tau pathology across 11 brain regions commonly affected in CTE in 364 brain donors with autopsy-confirmed CTE. Family and friends of brain donors completed seven standardized scales assessing their loved one’s cognitive, functional, mood and behavioral symptoms. The researchers then examined the relationship between global and regional p-tau pathology and scores on the multiple scales.

They found that the amount of p-tau pathology across the brain, but most predominantly in the frontal lobe, was associated with more cognitive and functional symptoms and that the amount of p-tau pathology in the frontal lobe was associated with more neurobehavioral symptoms. However, neurobehavioral symptoms were less correlated than cognitive symptoms, with p-tau pathology only explaining about 14% of the variation in neurobehavioral symptoms.

Memory and executive function symptoms are included as core features of the 2021 NINDS Traumatic Encephalopathy Syndrome criteria, proposed by a group of multidisciplinary experts, to diagnose CTE in life. Currently, the criteria are not yet approved for use outside of research. These findings help validate the criteria, with the hope that they can eventually be used on living patients to help provide a diagnosis and treatment plan.

According to the researchers, these findings provide crucial insights into diagnosing CTE in life.

“Diagnosis is crucial before we can test therapies. With validated in-life diagnostic criteria, we will be able to design clinical trials for therapies,” says Mez.

These findings appear online in Molecular Neurodegeneration.

About the BU CTE Center

The BU CTE Center is an independent academic research center at the Boston University Avedisian & Chobanian School of Medicine. It conducts pathological, clinical and molecular research on CTE and other long-term consequences of repetitive brain trauma in athletes and military personnel. For people considering brain donation, click here. To support its research, click here.

Funding for this study was supported by the National Institute of Neurological Disorders and Stroke (U01NS086659, U01NS093334, U54NS115266, R01NS078337, R56NS078337, K23NS102399), National Institute of Aging (P30AG13846; supplement 0572063345, R01AG057902, R01AG061028, K23AG046377, R01AG1649, R01AG062348, R21HD089088, F32NS096803, F32AG056098), National Center for Advancing Translational Sciences (1UL1TR001430), Department of Veterans Affairs (I01 CX001135, CSP 501, B6796-C, I01-CX001038), Department of Defense (W81XWH-13–2-0095, W81XWH-13–2-0064, W81XWH1810580, PRARP-13267017), the Alzheimer’s Association (NIRG-15–362697, NIRG-305779), the National Operating Committee on Standards for Athletic Equipment (NOCSAE), the Nick and Lynn Buoniconti Foundation, the Concussion Legacy Foundation, the Andlinger Foundation, the WWE, and the NFL

Note to editors:

Dr. Goldstein is a paid consultant to Johnson & Johnson, Janssen Research & Development LLC, and Rebiscan Inc and has received funding from the WWE (World Wrestling Entertainment) and Ivivi Health Sciences. Dr. Nowinski is the Co-Founder and Chief Executive Officer of the Concussion Legacy Foundation, and serves as an advisor for Oxeia Biopharmaceuticals and PreCon Health, Inc. Dr. Stern is a paid consultant to Biogen, is a member of the Mackey-White Health and Safety Committee of the National Football League Players Association, receives royalties for published neuropsychological tests from Psychological Assessment Resources Inc, is a member of the Board of Directors of King-Devick Technologies, and reported grants from the National Institutes of Health during the conduct of the study. Dr. Cantu is a paid consultant to the National Football League Head Neck and Spine Committee, a vice president and chair of the scientific advisory committee of the National Operating Committee on Standards for Athletic Equipment, and a consultant to the Concussion Legacy Foundation; he also receives royalties from Houghton Mifflin Harcourt and compensation for expert legal opinion to the National Collegiate Athletic Association and National Hockey League and is a member of the Mackey-White Committee of the National Football League Players Association. Dr. McKee is a member of the Mackey-White Committee of the National Football League Players Association and reports receiving grants from the National Institutes of Health and Department of Veteran Affairs and other funding from Buoniconti Foundation during the conduct of the study. Dr. Alosco reported grants from National Institutes of Health during the conduct of the study. Dr. Katz reported grants from Boston University School of Medicine Department of Neurology during the conduct of the study, receives royalties from Springer/Demos Publishing for a text book on brain injury, serves as an expert witness in legal cases involving brain injury and concussion; receives a stipend from Encompass Health as program medical director for brain injury and chair of the annual Neurorehabilitation conference; has received honoraria for a keynote address for the HealthSouth annual Medical Directors meeting. Dr. Mez reported grants from the National Institutes of Health, Department of Defense, Alzheimer’s Association, and Concussion Legacy Foundation during the conduct of the study.