The locus coeruleus is the major source of noradrenaline to the brain and contributes to a wide range of physiological and cognitive functions including arousal, attention, autonomic control, and adaptive behaviour. Neurodegeneration and pathological aggregation of tau protein in the locus coeruleus are early features of progressive supranuclear palsy (PSP). This pathology is proposed to contribute to the clinical expression of disease, including the PSP Richardson's syndrome. We test the hypothesis that tau pathology and neuronal loss are associated with clinical heterogeneity and severity in PSP.We used immunohistochemistry in post mortem tissues from 31 patients with a clinical diagnosis of PSP (22 with Richardson's syndrome) and 6 control cases. We quantified the presence of hyperphosphorylated tau, the number of pigmented cells indicative of noradrenergic neurons, and the percentage of pigmented neurons with tau-positive inclusions. Ante mortem assessment of clinical severity using the PSP rating scale was available within 1.8 (±0.9) years for 23 patients.We found an average 49% reduction of pigmented neurons in PSP patients relative to controls. The loss of pigmented neurons correlated with disease severity, even after adjusting for disease duration and the interval between clinical assessment and death. The degree of neuronal loss was negatively associated with tau-positive inclusions, with an average of 44% of pigmented neurons displaying tau-inclusions.Degeneration and tau pathology in the locus coeruleus are related to clinical heterogeneity of PSP. The noradrenergic deficit in the locus coeruleus is a candidate target for pharmacological treatment. Recent developments in ultra-high field magnetic resonance imaging to quantify in vivo structural integrity of the locus coeruleus may provide biomarkers for noradrenergic experimental medicines studies in PSP.

中文翻译：

---

进行性核上性麻痹的蓝斑病灶病理及其与疾病严重程度的关系。

蓝斑是大脑中去甲肾上腺素的主要来源，并有助于广泛的生理和认知功能，包括唤醒，注意，自主控制和适应性行为。tau蛋白在蓝斑中的神经变性和病理性聚集是进行性核上性麻痹（PSP）的早期特征。提出该病理学有助于疾病的临床表达，包括PSP理查森氏综合征。我们检验了tau病理和神经元丢失与PSP的临床异质性和严重程度有关的假设。我们对31例临床诊断为PSP的患者（22例Richardson综合征）和6例对照病例的死后组织进行了免疫组织化学分析。我们量化了高磷酸化tau的存在，指示去甲肾上腺素能神经元的色素沉着细胞的数量，以及带有tau阳性包涵体的色素沉着神经元的百分比。在23（1.8）±（±0.9）年内，可以使用PSP评分量表对临床严重程度进行死前评估，与对照组相比，我们发现PSP患者的色素神经元平均减少了49％。甚至在调整疾病持续时间和临床评估与死亡之间的时间间隔后，色素沉着神经元的丢失也与疾病的严重程度相关。神经元丢失的程度与tau阳性包涵体呈负相关，平均44％的有色神经元显示tau包涵体。蓝斑轨迹的变性和tau病理与PSP的临床异质性有关。蓝斑中的去甲肾上腺素缺乏症是药物治疗的候选靶点。超高强度磁共振成像以量化蓝斑的体内结构完整性的最新进展可能为PSP中的去甲肾上腺素实验医学研究提供生物标记。