Spatially resolved transcriptomics reveals a unique disease signature and potential biomarkers for chronic traumatic encephalopathy.

Chronic traumatic encephalopathy (CTE) is a poorly understood environmental tauopathy uniquely associated with repetitive head injury. It is clinically ambiguous and at present can only be diagnosed post-mortem. There is a pressing need to understand CTE pathophysiology in order to identify targets for possible intervention and biomarkers for in-life diagnosis. However, molecular characterization of the disease is hampered by the stochastic distribution of CTE lesions. Here, we have taken advantage of Visium spatial transcriptomics to map gene expression in discrete CTE lesions and matched normal tissue from the same individuals. In doing so, we derived a common 21-gene "signature" of CTE lesions that highlights astrocytic activation, neuroinflammation, blood-brain barrier function, and extracellular matrix remodeling as key features of CTE lesions. Almost all CTE signature genes were strongly expressed in astrocytes and ontological and protein association analyses implicated extracellular matrix functions as drivers of the disease. These findings provide the first glimpse into the intricate molecular dynamics underlying CTE lesions in situ and present 21 candidate molecules for the development of in-life CTE diagnostics.