Neurodegenerative fluid biomarkers are enriched in human cervical lymph nodes

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.

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Publication Details

Journal
Brain
Published
2024-10-18
DOI
https://doi.org/10.1093/brain/awae329
Citations
15
Primary Topic
Cerebrospinal fluid and hydrocephalus
Type
article
Field-Weighted Citation Impact
4.02

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article

Neurodegenerative fluid biomarkers are enriched in human cervical lymph nodes

Ivan Koychev, Andrew G. Murchison, Nicholas M. Provine, Paul Klenerman et al.
15 citations
Brain
Cerebrospinal fluid and hydrocephalus
4.02
article

Neurodegenerative fluid biomarkers are enriched in human cervical lymph nodes

Ivan Koychev, Andrew G. Murchison, Nicholas M. Provine, Paul Klenerman, Sarosh R. Irani, Adam Al‐Diwani, Owen Swann, Rhiannon Laban, Sandro Dá Mesquita, Fintan Sheerin, Amanda Heslegrave, Henrik Zetterberg
article en
15 citations

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. 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.

BrainVol. 148(2)
University of Wisconsin–Madison (US), Sahlgrenska University Hospital (SE), John Radcliffe Hospital (GB), University of Oxford (GB), Medawar Building for Pathogen Research (GB), UK Dementia Research Institute (GB), Mayo Clinic in Florida (US), National Hospital for Neurology and Neurosurgery (GB), University College London (GB), University of Gothenburg (SE)
Mayo Clinic, Alzheimer's Association, Glaucoma Research Foundation, Alzheimer's Drug Discovery Foundation, Wellcome, BrightFocus Foundation, National Institute on Handicapped Research, Familjen Erling-Perssons Stiftelse, Cure Alzheimer's Fund, Stiftelsen för Gamla Tjänarinnor, EU Joint Programme – Neurodegenerative Disease Research, National Institute for Health and Care Research, Department of Health and Social Care, Academy of Medical Sciences, University College London, University of Oxford, European Commission, Fondation pour la Recherche Médicale, Hjärnfonden, Vetenskapsrådet, Medical Research Council Canada, BMA Foundation for Medical Research, Norges Idrettshøgskole, UK Dementia Research Institute, Dementias Platform UK, Olav Thon Stiftelsen, National Institutes of Health, Horizon 2020 Framework Programme, HORIZON EUROPE Framework Programme, Medical Research Council, UCLH Biomedical Research Centre, NIHR Oxford Biomedical Research Centre, National Institute on Aging, H2020 Marie Skłodowska-Curie Actions, Institute on Aging, College of Medicine, University of Florida
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Openalex Percentile: Top 5%
Cerebrospinal fluid and hydrocephalus
4.02
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