Al-Diwani Adam, Provine Nicholas M, Murchison Andrew, Laban Rhiannon, Swann Owen J, Koychev Ivan, Sheerin Fintan, Da Mesquita Sandro, Heslegrave Amanda, Zetterberg Henrik, Klenerman Paul, Irani Sarosh R
Department of Psychiatry, University of Oxford, Oxford OX3 7JX, UK.
Pandemic Sciences Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, UK.
Brain. 2025 Feb 3;148(2):394-400. doi: 10.1093/brain/awae329.
In animal models, brain neurodegeneration biomarkers drain into cervical lymph nodes (CLNs), and this drainage function is reduced with ageing. If this occurred in humans, CLNs may provide a readily accessible measure of this aspect of protein clearance. We tested this hypothesis in people using ultrasound-guided fine needle aspiration. We measured amyloid-beta 40 and 42, phosphorylated tau 181 (pTau181), glial fibrillary acidic protein and neurofilament light using single molecule array in CLN aspirates and plasma from: (i) a discovery cohort of 25 autoimmune patients; and (ii) plasma, CLNs and capillary blood in four healthy volunteers, an optimization cohort. Ultrasound-guided fine needle aspiration was well-tolerated by all participants. In both cohorts, all biomarkers were detected in all plasma and CLN samples, other than neurofilament light (8/17 of discovery cohort). CLN biomarker concentrations were significantly greater than plasma concentrations for all except neurofilament light, most markedly for pTau181 (266-fold; P < 0.02), whose CLN concentrations decreased with age (Spearman r = -0.66, P = 0.001). This study presents the first evidence that neurodegenerative biomarkers are detectable in human CLNs. Raised CLN:plasma biomarker ratios suggest their concentration in CLNs may offer a distinct compartment for minimally-invasive measurement of brain clearance and lymphatic drainage, with potential applicability to study of ageing and future clinical trials.
在动物模型中，脑内神经退行性变生物标志物会引流至颈部淋巴结（CLN），且这种引流功能会随着年龄增长而降低。如果在人类中也是如此，那么颈部淋巴结可能为蛋白质清除这一方面提供一种易于获取的测量指标。我们使用超声引导下细针穿刺对人类进行了这一假设的验证。我们使用单分子阵列技术，对以下样本中的淀粉样β蛋白40和42、磷酸化tau蛋白181（pTau181）、胶质纤维酸性蛋白和神经丝轻链进行了测量：（i）一个由25名自身免疫性疾病患者组成的发现队列；以及（ii）四名健康志愿者（一个优化队列）的血浆、颈部淋巴结和毛细血管血。所有参与者对超声引导下细针穿刺的耐受性良好。在两个队列中，除神经丝轻链外（发现队列中的17个样本中有8个），所有血浆和颈部淋巴结样本中均检测到了所有生物标志物。除神经丝轻链外，所有生物标志物在颈部淋巴结中的浓度均显著高于血浆浓度，pTau181最为明显（266倍；P < 0.02），其在颈部淋巴结中的浓度随年龄增长而降低（斯皮尔曼相关系数r = -0.66，P = 0.001）。本研究首次证明在人类颈部淋巴结中可检测到神经退行性生物标志物。升高的颈部淋巴结与血浆生物标志物比值表明，其在颈部淋巴结中的浓度可能为脑清除和淋巴引流的微创测量提供一个独特的区域，具有应用于衰老研究和未来临床试验的潜力。
