Repetitive brain injury has the focus of many studies due to the long-lasting effects and the high risk for injury in participants of high impact sports. While there are many neurodegenerative consequences of these injuries, cellular and genetic consequences are not well understood.
“Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease linked to exposure to repetitive head impacts (RHI), yet little is known about its pathogenesis,” wrote the authors of a new study published in Science.
Both CTE and RHI can cause brain injury, but they are physiologically distinct, with CTE often presenting with tau buildup and other similarities to Alzheimer’s disease (AD).
To explore the similarities and differences between these three related but distinct conditions, researchers from Boston Children’s Hospital, Mass General Brigham, and Boston University collaborated to classify the genetic phenotypes of patients with CTE, RHI, and AD. Their study is titled, “Diverse somatic genomic alterations in single neurons in chronic traumatic encephalopathy.”
Using single-cell genomic sequencing the team aimed to identify somatic genetic mutations in the brain—specifically, the analysis focused on hundreds of neurons in the prefrontal cortex obtained from dozens of individuals. Postmortem frozen human brain tissue samples included 15 individuals with CTE, 4 with RHI without CTE, 7 with AD, and 19 neurotypical control samples.
The analysis showed that the patterning identified in CTE derived neurons were similar to the abnormalities observed in neurons from individuals with AD. Meanwhile, the cells from individuals with RHI without CTE did not show the same patterns in somatic genomic damage.
“Our results suggest that CTE develops through some process in addition to head trauma,” said co-author Chris Walsh, MD, PhD, investigator at the Howard Hughes Medical Institute at Boston Children’s Hospital. “We suspect it involves immune activation in a way similar to Alzheimer’s disease, happening years after trauma.”
This study highlights the need more in-depth analysis of head trauma and chronic neurodegenerative diseases. While RHI is known to be a likely precursor to CTE, the progression between conditions is unknown and not all individuals suffering from RHI develop CTE. In the present study tissues from individuals with RHI showed similar mutation loads to the control tissues.
“One of the most significant aspects of our work is the introduction of a new, single-cell genome approach to CTE,” said co-author Michael Miller, MD, PhD, a neuropathologist at Mass General Brigham. “Our study provides further evidence that CTE is a bona fide neurodegenerative disease defined by its unique neuropathological features.”
More work is needed to understand the genomic intricacies of CTE development and the similarities it shares with AD. “Our results suggest that neurons in CTE experience stereotyped mutational processes shared with AD; the absence of similar changes in RHI neurons without CTE suggests that CTE involves mechanisms beyond RHI alone,” the authors concluded.
