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Abstract：
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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 ([Formula: see text] standardized = 0.02, 95%CI = 0.01-0.04), CDS ([Formula: see text] standardized = 0.02, 95%CI = 0.01-0.04), and FAQ ([Formula: see text] 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 ([Formula: see text] sstandardized = 0.17-0.29, ps < 0.01) and FAQ ([Formula: see text] sstandardized = 0.21-0.26, ps < 0.01); frontal and inferior parietal cortex was associated with higher MI ([Formula: see text] sstandardized = 0.21-0.29, ps < 0.05); frontal cortex was associated with higher BRI ([Formula: see text] 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.
CONCLUSIONS: Accumulation of p-tau aggregates, especially in the frontal cortex, are associated with cognitive, functional, and certain neurobehavioral symptoms in CTE.
METHODS: 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.
RESULTS: 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 ([Formula: see text] standardized = 0.02, 95%CI = 0.01-0.04), CDS ([Formula: see text] standardized = 0.02, 95%CI = 0.01-0.04), and FAQ ([Formula: see text] 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 ([Formula: see text] sstandardized = 0.17-0.29, ps < 0.01) and FAQ ([Formula: see text] sstandardized = 0.21-0.26, ps < 0.01); frontal and inferior parietal cortex was associated with higher MI ([Formula: see text] sstandardized = 0.21-0.29, ps < 0.05); frontal cortex was associated with higher BRI ([Formula: see text] 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.
CONCLUSIONS: Accumulation of p-tau aggregates, especially in the frontal cortex, are associated with cognitive, functional, and certain neurobehavioral symptoms in CTE.
摘要：
背景：慢性创伤性脑病（CTE）是一种神经退行性疾病，其特征是过度磷酸化tau（p-tau）积累。与CTE病理相关的临床特征尚不清楚。在尸检证实CTE的大脑捐赠者中，我们调查了CTEp-tau病理密度和位置与认知，功能，神经精神症状.
方法：在364名尸检证实CTE的脑捐献者中，在10个皮质和皮质下区域评估了半定量p-tau严重程度(范围:0-3).我们对各地区的评级进行了汇总，形成了一个p-tau严重性全球综合指数(范围：0-30)。信息员完成了标准化的认知量表(认知困难量表，CDS；简要元认知指数，MI),日常生活活动(功能活动问卷)，神经行为失调(BRIEF-A行为调节指数，BRI；Barratt冲动量表，BIS-11),侵略（布朗-古德温侵略量表），抑郁症（老年抑郁量表-15，GDS-15），和冷漠(冷漠评价量表，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（每个区域的单独模型）与每个临床量表之间的关联，调整死亡年龄，种族身份，教育水平,高血压病史,阻塞性睡眠呼吸暂停,和物质使用治疗。在同一模型中纳入所有区域的p-tau严重性的岭回归模型评估了哪些区域显示出独立的影响。
结果：样本主要是美式足球运动员（333；91.2％）；140（38.5％）的CTE较低，224（61.5％）的CTE较高。全局p-tau严重程度与更高(即，更差)认知和功能量表得分：MI([公式：见正文]标准化=0.02，95CI=0.01-0.04)，CDS([公式：见正文]标准化=0.02，95CI=0.01-0.04)，和常见问题解答([公式：见正文]标准化=0.03，95CI=0.01-0.04)。错误发现率校正后，正面的p-tau严重程度，下顶叶，和颞叶上皮质,杏仁核与较高的CDS（[公式：见文本]sstandardized=0.17-0.29，ps<0.01）和FAQ（[公式：见文本]sstandarzed=0.21-0.26，ps<0.01）相关；额叶和顶叶下皮质与较高的MI相关（[公式：见文本]sstandarzed=0.21-0.29，ps<0.05）；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),下顶叶皮质（CDS）和杏仁核（FAQ）。P-tau解释了认知和功能量表变化的13-49％，神经精神量表变化的6-14％。
结论：p-tau聚集体的积累，尤其是额叶皮层,与认知有关，功能，和CTE中的某些神经行为症状。
方法：在364名尸检证实CTE的脑捐献者中，在10个皮质和皮质下区域评估了半定量p-tau严重程度(范围:0-3).我们对各地区的评级进行了汇总，形成了一个p-tau严重性全球综合指数(范围：0-30)。信息员完成了标准化的认知量表(认知困难量表，CDS；简要元认知指数，MI),日常生活活动(功能活动问卷)，神经行为失调(BRIEF-A行为调节指数，BRI；Barratt冲动量表，BIS-11),侵略（布朗-古德温侵略量表），抑郁症（老年抑郁量表-15，GDS-15），和冷漠(冷漠评价量表，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（每个区域的单独模型）与每个临床量表之间的关联，调整死亡年龄，种族身份，教育水平,高血压病史,阻塞性睡眠呼吸暂停,和物质使用治疗。在同一模型中纳入所有区域的p-tau严重性的岭回归模型评估了哪些区域显示出独立的影响。
结果：样本主要是美式足球运动员（333；91.2％）；140（38.5％）的CTE较低，224（61.5％）的CTE较高。全局p-tau严重程度与更高(即，更差)认知和功能量表得分：MI([公式：见正文]标准化=0.02，95CI=0.01-0.04)，CDS([公式：见正文]标准化=0.02，95CI=0.01-0.04)，和常见问题解答([公式：见正文]标准化=0.03，95CI=0.01-0.04)。错误发现率校正后，正面的p-tau严重程度，下顶叶，和颞叶上皮质,杏仁核与较高的CDS（[公式：见文本]sstandardized=0.17-0.29，ps<0.01）和FAQ（[公式：见文本]sstandarzed=0.21-0.26，ps<0.01）相关；额叶和顶叶下皮质与较高的MI相关（[公式：见文本]sstandarzed=0.21-0.29，ps<0.05）；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),下顶叶皮质（CDS）和杏仁核（FAQ）。P-tau解释了认知和功能量表变化的13-49％，神经精神量表变化的6-14％。
结论：p-tau聚集体的积累，尤其是额叶皮层,与认知有关，功能，和CTE中的某些神经行为症状。
