Neurodegenerative fluid biomarkers are enriched in human cervical lymph nodes

Al-Diwani, A.; Provine, N.; Murchison, A.; Laban, R.; Swann, O.; Koychev, I.; Sheerin, F.; Da Mesquita, S.; Heslegrave, A.; Zetterberg, H.; Klenerman, P.; Irani, S.

doi:10.1101/2024.04.26.591238

bioRxiv · 10.1101/2024.04.26.591238

Neurodegenerative fluid biomarkers are enriched in human cervical lymph nodes

Al-Diwani, A.·Provine, N.·Murchison, A.·Laban, R.·Swann, O.·Koychev, I.·Sheerin, F.·Da Mesquita, S.·Heslegrave, A.·Zetterberg, H.·Klenerman, P.·Irani, S.

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Abstract

In animal models, brain neurodegeneration biomarkers drain into cervical lymph nodes (CLNs). If this occurred in humans, CLNs may provide a readily accessible source of these biomarkers, draining the site of primary pathology. We tested this hypothesis in discovery and validation cohorts using ultrasound-guided fine needle aspiration (FNA). We measured amyloid-beta 40 and 42, phospho-Tau-181, 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 from ii) plasma, CLNs and capillary blood in four healthy volunteers, an optimisation-validation cohort. FNA was well-tolerated by all participants. In both cohorts, all biomarkers were detected in all plasmas and CLNs, 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 phospho-Tau-181 (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, which may offer a sensitive compartment for minimally-invasive sampling in clinical trials. Further, age-associated phospho-Tau-181 reduction with age suggests FNA of CLNs may measure the integrity of brain lymphatic drainage in vivo.

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Al-Diwani, A., Provine, N., Murchison, A., Laban, R., Swann, O., Koychev, I., Sheerin, F., Da Mesquita, S., Heslegrave, A., Zetterberg, H., Klenerman, P., Irani, S.. 2024-04-28. Neurodegenerative fluid biomarkers are enriched in human cervical lymph nodes. https://doi.org/10.1101/2024.04.26.591238

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