Jacobs Heidi I L, Riphagen Joost M, Ramakers Inez H G B, Verhey Frans R J
Department of Radiology, Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA.
Faculty of Health, Medicine and Life Sciences, School for Mental Health and Neuroscience, Alzheimer Centre Limburg, Maastricht University, Maastricht, The Netherlands.
Mol Psychiatry. 2021 Mar;26(3):897-906. doi: 10.1038/s41380-019-0437-x. Epub 2019 May 28.
The locus coeruleus (LC) supplies norepinephrine to the brain, is one of the first sites of tau deposition in Alzheimer's disease (AD) and modulates a variety of behaviors and cognitive functions. Transgenic mouse models showed that norepinephrine dysregulation after LC lesions exacerbates inflammatory responses, blood-brain barrier leakage (BBB), and cognitive deficits. Here, we investigated relationships between central norepinephrine metabolism, tau and beta-amyloid (Aβ), inflammation, BBB-dysfunction, neuropsychiatric problems, and memory in-vivo in a memory clinic population (total n = 111, 60 subjective cognitive decline, 36 mild cognitively impaired, and 19 AD dementia). Cerebrospinal fluid (CSF) and blood samples were collected and analyzed for 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), CSF/plasma albumin ratio (Q-alb), Aβ, phosphorylated tau, and interleukins. The verbal word learning task and the neuropsychiatric inventory assessed memory functioning and neuropsychiatric symptoms. Structural equation models tested the relationships between all fluid markers, cognition and behavior, corrected for age, education, sex, and clinical dementia rating score. Our results showed that neuropsychiatric symptoms show strong links to both MHPG and p-tau, whereas memory deficits are linked to MHPG via a combination of p-tau and inflammation-driven amyloidosis (30-35% indirect effect contribution). These results suggest that the LC-norepinephrine may be pivotal to understand links between AD pathology and behavioral and cognitive deficits in AD.
蓝斑（LC）向大脑供应去甲肾上腺素，是阿尔茨海默病（AD）中tau蛋白沉积的首批部位之一，并调节多种行为和认知功能。转基因小鼠模型显示，LC损伤后去甲肾上腺素失调会加剧炎症反应、血脑屏障渗漏（BBB）和认知缺陷。在此，我们在一个记忆门诊人群（共111例，60例主观认知下降，36例轻度认知障碍，19例AD痴呆）中研究了中枢去甲肾上腺素代谢、tau蛋白和β-淀粉样蛋白（Aβ）、炎症、BBB功能障碍、神经精神问题与体内记忆之间的关系。收集脑脊液（CSF）和血液样本，分析其中的3-甲氧基-4-羟基苯乙二醇（MHPG）、CSF/血浆白蛋白比率（Q-alb）、Aβ、磷酸化tau蛋白和白细胞介素。言语单词学习任务和神经精神量表评估记忆功能和神经精神症状。结构方程模型测试了所有体液标志物、认知和行为之间的关系，并对年龄、教育程度、性别和临床痴呆评定量表得分进行了校正。我们的结果表明，神经精神症状与MHPG和p-tau均有密切联系，而记忆缺陷则通过p-tau和炎症驱动的淀粉样变性的组合与MHPG相关（间接效应贡献为30-35%）。这些结果表明，LC-去甲肾上腺素可能是理解AD病理学与AD行为和认知缺陷之间联系的关键。
