The role of neuroinflammation in chronic traumatic encephalopathy

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disorder caused by repeated concussive or subconcussive blows to the head. Clinically, this disease is characterized by cognitive dysfunction, short-term memory loss, and motor deficits. Pathologically, deposition of the abnormal protein tau, cerebral atrophy, and white matter degeneration is common. CTE has been categorized into Stages I-IV based on increased severity of protein deposition and cerebral atrophy. Acutely, mild traumatic brain injury (TBI) damages the long white matter tracks in the corpus callosum. In addition, it initiates a neuroinflammatory cascade aimed at protecting healthy tissue by clearing any toxic or damaging debris. This cascade results predominantly from the activation of the resident immune cells of the brain, microglia. Inflammation begins immediately and then subsides weeks or months after injury. However, pathological chronic activation of microglia can occur that can cause cell death and degeneration. Several studies have linked traumatic brain injury as well as chronic neuroinflammation to a variety of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and chronic traumatic encephalopathy (CTE). The present study quantifies the level of inflammation found in the brains of those diagnosed with varying stages of CTE compared to normal, healthy controls. The thickness of the corpus callosum was measured to investigate the correlation between microglial density and white matter degeneration. Cases were selected from the donated brains of former athletes and military veterans who had a history of repetitive mild TBI. Eleven healthy control cases, ten early stage (Stage I/II), and nine late stage (Stage III/IV) CTE cases were selected for analysis. Tissue sections of the anterior and posterior cingulate of each case were stained for microglia, reactive astrocytes, and macrophages using IBA-1, GFAP, and CD68 markers. The percent area stained of each section was calculated to compare inflammatory cell density across progressive stages of the disease. Analysis showed a significant thinning of the corpus callosum of Stage III/IV CTE cases compared to normal controls. There was a significant decrease in microglia and reactive astrocytes of both the anterior and posterior portions of the corpus callosum in both early and advanced stage CTE cases compared to healthy controls. Corpus callosum thickness was significantly decreased in advanced stage (III-IV), but not early stage (I-II) disease. Overall, this suggests that neuroinflammation is decreased in the corpus callosum in CTE despite marked degeneration. Repetitive mild TBI might impair mechanisms of brain inflammation and repair