Inflammation and neuronal gene expression changes differ in early versus late chronic traumatic encephalopathy brain

Area of Science:

• Neuroscience
• Genomics
• Pathology

Background:

• Understanding the molecular basis of chronic traumatic encephalopathy (CTE) remains incomplete.
• Factors like years of play and genetic variants influence CTE tau pathology, but their effect on gene expression across disease stages is unknown.

Purpose of the Study:

• To analyze the largest post-mortem CTE whole-transcriptome dataset.
• To investigate how years of play, tau pathology, and genetic risk variants (APOE, TMEM106B) affect gene expression in CTE.
• To compare early (low pathology) and late (high pathology) disease stages.

Main Methods:

• Whole-transcriptome mRNASeq analysis of post-mortem brain samples.
• Comparison of CTE cases with controls with repetitive head impacts but no CTE pathology.
• Stratification of samples into low and high tau pathology groups based on McKee CTE staging.

Main Results:

• Severe CTE showed substantial gene expression changes, mainly involving neuroinflammation and neuroimmunity.
• Early disease (low pathology) implicated fewer genes and processes, with an inverse relationship between gene expression and tau pathology compared to severe disease.
• Distinct gene expression patterns were observed between early and late CTE stages.

Conclusions:

• The molecular mechanisms of early CTE may differ significantly from late stages.
• Years of play and tau pathology impact CTE expression through distinct mechanisms.
• Pathology-modifying risk variants may influence CTE via separate biological pathways.