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.

慢性创伤性脑病 (CTE) 是一种进行性 tau 病，见于接触性运动运动员、退伍军人和其他暴露于重复性头部撞击的人。在 CTE 中报告了白质稀疏和轴突丢失，但尚未在分子或细胞水平上进行表征。在这里，我们展示了来自 8 名经神经病理学证实的 CTE 和 8 名年龄和性别匹配的对照者的死后背外侧额叶白质细胞核的 RNA 测序图谱。使用无偏聚类方法分析这些配置文件，我们确定了十八个转录组不同的细胞组（簇），反映细胞类型和/或细胞状态，其中一个子集显示 CTE 和对照组织之间的差异。应用于与单核 RNA-seq 工作中使用的组织切片相邻的组织切片的独立原位方法产生了类似的发现。在 CTE 白质样本中发现少突胶质细胞受到最严重的影响；它们的数量减少了，并且在亚型集群中的相对比例发生了变化。此外，富含 CTE 的少突胶质细胞群显示出更多与铁代谢和细胞应激反应相关的转录物。CTE 组织在组织学上也表现出过多的铁积累。在星形胶质细胞中，CTE 和对照样本之间的总细胞数无法区分，但与对照相比，CTE 星形胶质细胞组中与神经炎症相关的转录物升高。