Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease characterized by hyperphosphorylated tau (p-tau) accumulation. The clinical features associated with CTE pathology are unclear. In brain donors with autopsy-confirmed CTE, we investigated the association of CTE p-tau pathology density and location with cognitive, functional, and neuropsychiatric symptoms. In 364 brain donors with autopsy confirmed CTE, semi-quantitative p-tau severity (range: 0–3) was assessed in 10 cortical and subcortical regions. We summed ratings across regions to form a p-tau severity global composite (range: 0–30). Informants completed standardized scales of cognition (Cognitive Difficulties Scale, CDS; BRIEF-A Metacognition Index, MI), activities of daily living (Functional Activities Questionnaire), neurobehavioral dysregulation (BRIEF-A Behavioral Regulation Index, BRI; Barratt Impulsiveness Scale, BIS-11), aggression (Brown-Goodwin Aggression Scale), depression (Geriatric Depression Scale-15, GDS-15), and apathy (Apathy Evaluation Scale, AES). Ordinary least squares regression models examined associations between global and regional p-tau severity (separate models for each region) with each clinical scale, adjusting for age at death, racial identity, education level, and history of hypertension, obstructive sleep apnea, and substance use treatment. Ridge regression models that incorporated p-tau severity across all regions in the same model assessed which regions showed independent effects. The sample was predominantly American football players (333; 91.2%); 140 (38.5%) had low CTE and 224 (61.5%) had high CTE. Global p-tau severity was associated with higher (i.e., worse) scores on the cognitive and functional scales: MI ( $$\beta$$ standardized = 0.02, 95%CI = 0.01–0.04), CDS ( $$\beta$$ standardized = 0.02, 95%CI = 0.01–0.04), and FAQ ( $$\beta$$ standardized = 0.03, 95%CI = 0.01–0.04). After false-discovery rate correction, p-tau severity in the frontal, inferior parietal, and superior temporal cortex, and the amygdala was associated with higher CDS ( $$\beta$$ sstandardized = 0.17–0.29, ps < 0.01) and FAQ ( $$\beta$$ sstandardized = 0.21–0.26, ps < 0.01); frontal and inferior parietal cortex was associated with higher MI ( $$\beta$$ sstandardized = 0.21–0.29, ps < 0.05); frontal cortex was associated with higher BRI ( $$\beta$$ standardized = 0.21, p < 0.01). Regions with effects independent of other regions included frontal cortex (CDS, MI, FAQ, BRI), inferior parietal cortex (CDS) and amygdala (FAQ). P-tau explained 13–49% of variance in cognitive and functional scales and 6–14% of variance in neuropsychiatric scales. Accumulation of p-tau aggregates, especially in the frontal cortex, are associated with cognitive, functional, and certain neurobehavioral symptoms in CTE.

中文翻译：

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尸检证实的慢性创伤性脑病中局部 tau 病理学的认知、功能和神经精神相关性

慢性创伤性脑病 (CTE) 是一种以过度磷酸化 tau (p-tau) 积累为特征的神经退行性疾病。与 CTE 病理学相关的临床特征尚不清楚。在尸检证实患有 CTE 的脑供体中，我们研究了 CTE p-tau 病理密度和位置与认知、功能和神经精神症状的关联。在 364 名尸检证实患有 CTE 的脑供体中，对 10 个皮质和皮质下区域的半定量 p-tau 严重程度（范围：0-3）进行了评估。我们将各个地区的评级相加，形成 p-tau 严重性全球综合评分（范围：0-30）。受访者完成标准化认知量表（认知困难量表，CDS；BRIEF-A元认知指数，MI）、日常生活活动（功能活动问卷）、神经行为失调量表（BRIEF-A行为调节指数，BRI；Barratt冲动量表，BIS- 11）、攻击性（布朗-古德温攻击量表）、抑郁（老年抑郁量表-15，GDS-15）和冷漠（冷漠评估量表，AES）。普通最小二乘回归模型检查了全球和区域 p-tau 严重程度（每个区域单独的模型）与每个临床量表之间的关联，并根据死亡年龄、种族身份、教育水平以及高血压病史、阻塞性睡眠呼吸暂停和物质进行调整使用治疗。将所有区域的 p-tau 严重程度纳入同一模型的岭回归模型评估了哪些区域显示出独立的影响。样本主要是美国橄榄球运动员（333 人；91.2%）； 140 名 (38.5%) 的 CTE 较低，224 名 (61.5%) 的 CTE 高。总体 p-tau 严重程度与认知和功能量表的较高（即较差）分数相关：MI（$$\beta$$ 标准化 = 0.02，95%CI = 0.01–0.04）、CDS（$$\beta$ $ 标准化 = 0.02，95%CI = 0.01–0.04），以及常见问题解答（$$\beta$$ 标准化 = 0.03，95%CI = 0.01–0.04）。错误发现率校正后，额叶、下顶叶、上颞叶皮层和杏仁核的 p-tau 严重程度与较高的 CDS 相关（$$\beta$$ sstandardized = 0.17–0.29，ps < 0.01）和常见问题解答($$\beta$$ 标准化 = 0.21–0.26, ps < 0.01);额叶和下顶叶皮质与较高的 MI 相关（$$\beta$$ sstandardized = 0.21–0.29，ps < 0.05）；额叶皮层与较高的 BRI 相关（$$\beta$$ 标准化 = 0.21，p < 0.01）。具有独立于其他区域的影响的区域包括额叶皮层（CDS、MI、FAQ、BRI）、下顶叶皮层（CDS）和杏仁核（FAQ）。 P-tau 解释了认知和功能量表中 13-49% 的变异以及神经精神量表中 6-14% 的变异。 p-tau 聚集体的积累，尤其是在额叶皮层中的积累，与 CTE 中的认知、功能和某些神经行为症状相关。