Chronic Traumatic Encephalopathy (CTE) Differs in Early and Late Stage

The genetic analysis of the brain affected with chronic traumatic encephalopathy (CTE) mainly from professional athletes, donated to the BU CTE Brain Bank provided evidence that early and late CTE brains are similar in some ways but dramatically different in others. Neuroinflammation and neuronal stress are strongly implicated in disease, depending on the severity of the disease. This is the first study to show that the molecular pathways involved in early CTE are different from those involved in late-stage disease.

Current Understanding of Chronic Traumatic Encephalopathy

People who play contact sports, members of the military, and victims of domestic violence, are exposed to repetitive Head impacts (RHI), which is the primary risk factor for developing chronic traumatic encephalopathy (CTE). Symptoms often manifest years to decades after exposure to RHI and very little is known about what happens in the brain in the interim.

The brains of people who die from CTE are marked by the accumulation of a protein called tau, the same protein found to aggregate in Alzheimer's Disease (AD) brain. The amount of tau pathology in CTE correlates with the severity of the disease, where early-stage brains have very little pathology and late stage show severe, widespread involvement.

The amount of RHI exposure, which for athletes can be measured in terms of the number of years they played a violent sport, as well as genetic risk variants influence the extent of tau pathology and associated disease severity.

However, the molecular and genetic mechanisms that underly the development of disease, and to what extent those effects are consistent throughout disease progression, are poorly understood. A better understanding of the early CTE disease process may lead to more informative diagnostics, biomarkers, and ultimately therapies.

In addition, since the type of pathology found in the brains of people with CTE is like that found in AD, a better understanding of how the brain responds to this kind of pathology in CTE is likely to better inform our understanding of AD as well.

Early Versus Late Chronic Traumatic Encephalopathy Brain

Researchers studied the prefrontal cortex tissue from 76 individuals (66 CTE, 10 control) who donated their brains to the BU UNITE Brain Bank. The sample set contained brains that spanned the full range of disease severity, affording the researchers the unique opportunity to see whether the gene expression in people with early-stage CTE differs from those with late-stage.

They generated gene expression data for each individual and then performed bioinformatic and statistical analyses of the different subsets of these samples to look for gene expression patterns that are associated with different clinical, histological, and genetic markers that are relevant to CTE. The findings appear in the journal BMC Medical Genomics.

They found substantial gene expression changes were associated with severe disease for most of these factors. In contrast, low pathology groups had many fewer gene expression changes and neuroimmune or inflammatory processes implicated and showed striking differences for some factors when compared with severe disease.

According to the researchers, if the active disease process in early disease differs substantially from late-stage disease, this could have important implications for both diagnostic and therapeutic targets.

This might explain why therapeutic targets identified from late-stage human tissue have largely failed to influence disease progression in clinical trials for many neurodegenerative diseases. In addition, if there are distinct markers of early disease progression that are absent in late disease.



Source-Eurekalert