Neurodegenerative fluid biomarkers are enriched in human cervical lymph nodes

Adam Al-Diwani; Nicholas M Provine; Andrew Murchison; Rhiannon Laban; Owen J Swann; Ivan Koychev; Fintan Sheerin; Sandro Da Mesquita; Amanda Heslegrave; Henrik Zetterberg; Paul Klenerman; Sarosh R Irani

doi:10.1093/brain/awae329

Neurodegenerative fluid biomarkers are enriched in human cervical lymph nodes

Brain. 2024 Oct 21:awae329. doi: 10.1093/brain/awae329. Online ahead of print.

Authors

Adam Al-Diwani¹, Nicholas M Provine², Andrew Murchison³, Rhiannon Laban⁴, Owen J Swann⁴, Ivan Koychev¹, Fintan Sheerin³, Sandro Da Mesquita⁵, Amanda Heslegrave^{4

6}, Henrik Zetterberg^{4

6

7

8

9

10}, Paul Klenerman^{2

11

12}, Sarosh R Irani^{5

13

14}

Affiliations

¹ Department of Psychiatry, University of Oxford, Oxford, OX3 7JX, UK.
² Pandemic Sciences Institute, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7DQ, UK.
³ Department of Radiology, Oxford University Hospitals, Oxford, OX3 9DU, UK.
⁴ UK Dementia Research Institute, Fluid Biomarker Laboratory, London, W1T 7NF, UK.
⁵ Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, USA.
⁶ Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
⁷ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, 431 39, Sweden.
⁸ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, 431 39, Sweden.
⁹ Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong.
¹⁰ Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53792, USA.
¹¹ Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 9DU, UK.
¹² Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, OX1 3SY, UK.
¹³ Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, OX3 9DU, UK.
¹⁴ Department of Neurology, Mayo Clinic, Jacksonville, Florida 32224, USA.

PMID: 39432679
DOI: 10.1093/brain/awae329

Abstract

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 (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 cohort. FNA 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 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 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.

Keywords: biomarker; cervical lymph nodes; dementia; meningeal lymphatics.