Greater understanding of the early stages of what chronic traumatic encephalopathy (CTE) looks like in the brain, and how different that is to later stages, has been established through new research.
CTE is experienced by many athletes, veterans and people who are subject to domestic violence, with repetitive head impacts established as the primary risk factor.
Symptoms of CTE can manifest years after exposure to head impacts, and little is known about what happens to the brain before the later stages, where tau protein is found through pathology.
To help address the gap in knowledge of early-stage CTE development, Boston University Chobanian & Avedisian School of Medicine conducted genetic analysis of the largest collection of post-mortem CTE brains, primarily from professional athletes, donated to the BU CTE Brain Bank.
They found evidence that early and late CTE brains are similar in some ways but dramatically different in others. In particular, neuro-inflammation and neuronal stress are strongly implicated in disease, albeit to different extents and in different directions depending on the severity of 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.
“A better understanding of the early CTE disease process may lead to more informative diagnostics, biomarkers and ultimately therapies,” said co-corresponding author Dr Adam Thomas Labadorf, assistant professor of neurology.
“In addition, since the type of pathology found in the brains of people with CTE is similar to that found in Alzheimer’s disease (AD), a better understanding of how the brain responds to this kind of pathology in CTE is likely to better inform our understanding AD as well.”
The research studied the prefrontal cortex tissue from 76 individuals (66 CTE, ten 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 differ from those with late stage.
The researchers 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.
They then identified genes and biological processes associated with total years of play as a measure of exposure, amount of tau pathology present at time of death, and the presence of APOE and TMEM106B risk variants.
The researchers found substantial gene expression changes were associated with severe disease for most of these factors, primarily implicating diverse, strongly involved neuro-inflammatory and neuro-immune processes.
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,” explained co-corresponding author Dr Thor Stein, a neuropathologist at VA Boston Healthcare System and associate professor of pathology and laboratory medicine.
“In addition, if there are distinct markers of early disease progression that are absent in late disease, this would provide an opportunity to explore different diagnostics and biomarkers that we otherwise wouldn’t know to look for.”
