PDF(Pubmed)
Abstract：
Abnormally phosphorylated tau, an indicator of Alzheimer\'s disease, accumulates in the first decades of life in the locus coeruleus (LC), the brain\'s main noradrenaline supply. However, technical challenges in in-vivo assessments have impeded research into the role of the LC in Alzheimer\'s disease. We studied participants with or known to be at-risk for mutations in genes causing autosomal-dominant Alzheimer\'s disease (ADAD) with early onset, providing a unique window into the pathogenesis of Alzheimer\'s largely disentangled from age-related factors. Using high-resolution MRI and tau PET, we found lower rostral LC integrity in symptomatic participants. LC integrity was associated with individual differences in tau burden and memory decline. Post-mortem analyses in a separate set of carriers of the same mutation confirmed substantial neuronal loss in the LC. Our findings link LC degeneration to tau burden and memory in Alzheimer\'s, and highlight a role of the noradrenergic system in this neurodegenerative disease.
摘要：
异常磷酸化tau，阿尔茨海默病的指标,在蓝斑(LC)的最初几十年中积累，大脑的主要去甲肾上腺素供应。然而,体内评估中的技术挑战阻碍了对LC在阿尔茨海默病中的作用的研究。我们研究了具有或已知具有导致常染色体显性遗传阿尔茨海默病（ADAD）的基因突变风险的参与者，为阿尔茨海默病的发病机制提供了一个独特的窗口，在很大程度上与年龄相关因素相分离。使用高分辨率MRI和tauPET，我们发现有症状的参与者的头端LC完整性较低.LC完整性与tau负担和记忆力下降的个体差异有关。在一组单独的相同突变的携带者中进行的事后分析证实了LC中的大量神经元损失。我们的发现将LC变性与阿尔茨海默氏症的tau负担和记忆联系起来，并强调了去甲肾上腺素能系统在这种神经退行性疾病中的作用。
