Digging for Details on Traumatic Brain Injury
By using the NACC dataset, researchers have conducted the largest matched case-series study to date of the clinical and neuropsychological effects of chronic traumatic encephalopathy neuropathologic change (CTE-NC). The analysis, published in Neurology, identifies neuropathological comorbidities that are more common in those with CTE-NC, but did not find major differences in clinical presentation when matched for major co-pathologies. Their research suggests that much more research is needed to delineate clinical characteristics of CTE-NC to shed more light on this enigmatic condition.
CTE-NC has puzzled researchers for decades. A large body of data shows that repetitive head injuries can increase the risk for neurological problems later in life, but the exact nature of that relationship has been hard to assess. “If you have a history of moderate to severe traumatic brain injury, it does appear that your risk of dementia increases,” says Jeff Schaffert, Dedman Family Scholar in Clinical Care at The University of Texas Southwestern Medical Center and first author on the new study. Work by his group and others, however, has suggested that once dementia begins, the course of cognitive decline is no different in people with or without traumatic brain injury.
To date, studies on CTE-NC have suffered from a lack of subjects. Christian LoBue at UT Southwestern Medical Center, along with Dr. Schaffert, released an analysis in 2020 also based on NACC data and found only six patients with CTE-NC out of the available 339 who had been assessed. “At the time, that was the largest in-person dataset that we had for people who were later confirmed to have CTE neuropathologic change, and that was true up until we redid the study,” says Schaffert.
Many Alzheimer’s Disease Research Centers have since added CTE-related tests to their data collection protocols, so Schaffert and his colleagues, along with collaborators at Beth Israel Deaconess Medical Center in Boston and The University of Texas at Dallas, were able to find 29 qualifying subjects for the current study. Once they’d identified their patients, they identified matched controls without CTE-NC to compare on a range of clinical and neuropsychological outcomes. The team hoped to “clarify how much the pathology is impacting clinical symptoms, because we have a lot of clinical data and it’s collected in a very systematic way,” says Schaffert.
“If you have a history of moderate to severe traumatic brain injury, it does appear that your risk of dementia increases”
Because of the larger sample size, the current study was also able to assess neuropsychiatric symptoms such as depression, agitation, hallucinations, and anxiety. One major change in the field has been eliminating depression as a core diagnostic feature for the clinical presentation of CTE-NC, called Traumatic Encephalopathy Syndrome or TES. “If you were a former collegiate football player, for example, all you had to do was have a history of depression to meet criteria for TES and so anybody with a history of depression is then labeled as having a possible neurodegenerative disease; it was way too over-inclusive,” says Schaffert. Instead, the new study looked at other neuropsychiatric features as well as other neuropathologic changes.
The depth of the NACC protocols and the diligence of Schaffert and his colleagues made the study rigorous. “We looked at really comprehensive neurocognitive functioning, not just a screening, and we also had a gold standard measure of neuropsychiatric features [and] in-person neurological exams,” says Schaffert.
Overall, the analysis found no difference in clinical symptoms between cases and controls, but those with CTE-NC had higher rates of hippocampal sclerosis and other tauopathies, and inclusions of TAR DNA-binding protein 43, which has been linked to many neurodegenerative diseases. Though many of the results ended up being negative, Schaffert remains enthusiastic about the NACC dataset as a tool for probing difficult scientific questions. “It’s an incredible resource, especially for early career investigators,” he says, adding that he has been publishing research based on the dataset for almost a decade.
The new work also helps define the current limitations of CTE-NC data, pointing to the kinds of studies that will be needed to advance the field. Schaffert hopes that someday reliable biomarkers for the condition will be developed, but to do that much larger numbers of people with and without the condition need to be studied. Several groups are now trying to establish such CTE-NC-focused datasets.
Schaffert J, Iyengar N, Magill R, LoBue C, Chiang HS, White CL, Hart J, Didehbani N, Cullum CM. Clinical and Neuropsychological Profiles in People With Chronic Traumatic Encephalopathy Neuropathologic Change: Matched Case-Series Study. Neurology. 2025 Sep 23;105(6):e214012. doi: 10.1212/WNL.0000000000214012. Epub 2025 Aug 29. Erratum in: Neurology. 2025 Dec 9;105(11):e214368. doi: 10.1212/WNL.0000000000214368. PMID: 40882174.