Chronic traumatic encephalopathy (CTE) is a progressive tauopathy found in contact sport athletes, military veterans, and others exposed to repetitive head impacts. White matter rarefaction and axonal loss have been reported in CTE but have not been characterized on a molecular or cellular level. Here, we present RNA sequencing profiles of cell nuclei from postmortem dorsolateral frontal white matter from eight individuals with neuropathologically confirmed CTE and eight age- and sex-matched controls. Analyzing these profiles using unbiased clustering approaches, we identified eighteen transcriptomically distinct cell groups (clusters), reflecting cell types and/or cell states, of which a subset showed differences between CTE and control tissue. Independent in situ methods applied on tissue sections adjacent to that used in the single-nucleus RNA-seq work yielded similar findings. Oligodendrocytes were found to be most severely affected in the CTE white matter samples; they were diminished in number and altered in relative proportions across subtype clusters. Further, the CTE-enriched oligodendrocyte population showed greater abundance of transcripts relevant to iron metabolism and cellular stress response. CTE tissue also demonstrated excessive iron accumulation histologically. In astrocytes, total cell numbers were indistinguishable between CTE and control samples, but transcripts associated with neuroinflammation were elevated in the CTE astrocyte groups compared to controls. These results demonstrate specific molecular and cellular differences in CTE oligodendrocytes and astrocytes and suggest that white matter alterations are a critical aspect of CTE neurodegeneration.

Chronic traumatic encephalopathy (CTE) is a progressive tauopathy found in contact sport athletes, military veterans, and others exposed to repetitive head impacts (RHI)1–6. White matter atrophy and axonal loss have been reported in CTE but have not been characterized on a molecular or cellular level2,7,8. Here, we present RNA sequencing profiles of cell nuclei from postmortem dorsolateral frontal white matter from eight individuals with neuropathologically confirmed CTE and eight age- and sex-matched controls. Analyzing these profiles using unbiased clustering approaches, we identified eighteen transcriptomically distinct cell groups (clusters), reflecting cell types and/or cell states, of which a subset showed differences between CTE and control tissue. Independent in situ methods applied on tissue sections adjacent to that used in the single-nucleus RNA-seq work yielded similar findings. Oligodendrocytes were found to be most severely affected in the CTE white matter samples; they were diminished in number and altered in relative proportions across subtype clusters. Further, the CTE-enriched oligodendrocyte population showed greater abundance of transcripts relevant to iron metabolism and cellular stress response. CTE tissue also demonstrated excessive iron accumulation histologically. Astrocyte alterations were more nuanced; total astrocyte number was indistinguishable between CTE and control samples, but transcripts associated with neuroinflammation were elevated in the CTE astrocyte groups as compared to controls. These results demonstrate specific molecular and cellular differences in CTE oligodendrocytes and astrocytes and may provide a starting point for the development of diagnostics and therapeutic interventions.

Chronic traumatic encephalopathy (CTE) is a progressive tauopathy found in contact sport athletes, military veterans, and others exposed to repetitive head injury (McKee et al. 2009(McKee et al. , 2013(McKee et al. , 2016Omalu et al. 2005Omalu et al. , 2006Martland 1928;Critchley 1949). White matter atrophy and axonal loss have been reported in CTE but have not been characterized on a molecular or cellular level (McKee et al. 2013;Holleran et al. 2017;Hsu et al. 2018). Here, we report 24,735 single nucleus RNA-seq profiles from dorsolateral frontal white matter cell nuclei from eight individuals with neuropathologically confirmed CTE and eight age-and sex-matched controls. We identified eighteen transcriptionally distinct nuclei clusters, as well as cell-type-specific differences between conditions. The findings support a global loss of oligodendrocytes (OLs) in CTE, alterations in OL subpopulations, and suggest pathological iron accumulation in OL subpopulations. Total astrocyte number was not different between CTE and controls but showed upregulation of transcripts associated with neuroinflammation. These findings provide novel insight into the molecular and cellular underpinnings of white matter atrophy in CTE, which may lead to an improved understanding of the disease pathogenesis.