Peripheral Treg-monocyte immune signatures relate to neurodegeneration and prognosis in patients with primary tauopathies

Peripheral Treg-monocyte immune signatures relate to neurodegeneration and prognosis in patients with primary tauopathies | medRxiv Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search Peripheral Treg-monocyte immune signatures relate to neurodegeneration and prognosis in patients with primary tauopathies View ORCID Profile Kei Onn Lai , Julia Goddard , Harry Crook , Roosmarijn Frohn , Stacey L Kigar , Natalia Savinykh Yarkoni , Peter Swann , Robert Durcan , Julie Wiggins , Win Li , Hugo Paula , View ORCID Profile Timothy Rittman , Amanda Heslegrave , View ORCID Profile James B Rowe , Matthias Brendel , Henrik Zetterberg , Josef Priller , John T O’Brien , View ORCID Profile Maura Malpetti doi: https://doi.org/10.64898/2026.03.17.26348492 Kei Onn Lai 1 Department of Clinical Neurosciences, University of Cambridge , Cambridge, UK 2 UK Dementia Research Institute at Cambridge , Cambridge, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Kei Onn Lai Julia Goddard 1 Department of Clinical Neurosciences, University of Cambridge , Cambridge, UK 2 UK Dementia Research Institute at Cambridge , Cambridge, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site Harry Crook 1 Department of Clinical Neurosciences, University of Cambridge , Cambridge, UK 2 UK Dementia Research Institute at Cambridge , Cambridge, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site Roosmarijn Frohn 1 Department of Clinical Neurosciences, University of Cambridge , Cambridge, UK 2 UK Dementia Research Institute at Cambridge , Cambridge, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site Stacey L Kigar 3 Department of Psychiatry, University of Cambridge , Cambridge, United Kingdom 4 Department of Medicine, University Cambridge , Cambridge, United Kingdom Find this author on Google Scholar Find this author on PubMed Search for this author on this site Natalia Savinykh Yarkoni 3 Department of Psychiatry, University of Cambridge , Cambridge, United Kingdom 4 Department of Medicine, University Cambridge , Cambridge, United Kingdom Find this author on Google Scholar Find this author on PubMed Search for this author on this site Peter Swann 3 Department of Psychiatry, University of Cambridge , Cambridge, United Kingdom Find this author on Google Scholar Find this author on PubMed Search for this author on this site Robert Durcan 1 Department of Clinical Neurosciences, University of Cambridge , Cambridge, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site Julie Wiggins 1 Department of Clinical Neurosciences, University of Cambridge , Cambridge, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site Win Li 1 Department of Clinical Neurosciences, University of Cambridge , Cambridge, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site Hugo Paula 1 Department of Clinical Neurosciences, University of Cambridge , Cambridge, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site Timothy Rittman 1 Department of Clinical Neurosciences, University of Cambridge , Cambridge, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Timothy Rittman Amanda Heslegrave 5 UK Dementia Research Institute at UCL , London, UK 6 Department of Neurodegenerative Disease, UCL Institute of Neurology , Queen Square, London Find this author on Google Scholar Find this author on PubMed Search for this author on this site James B Rowe 1 Department of Clinical Neurosciences, University of Cambridge , Cambridge, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for James B Rowe Matthias Brendel 7 Munich Cluster for Systems Neurology (SyNergy) , Munich, Germany 8 Department of Nuclear Medicine, LMU Hospital , LMU Munich, Munich, Germany 9 German Center for Neurodegenerative Diseases (DZNE) , Munich, Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site Henrik Zetterberg 5 UK Dementia Research Institute at UCL , London, UK 6 Department of Neurodegenerative Disease, UCL Institute of Neurology , Queen Square, London 10 Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg , Mölndal, Sweden 11 Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital , Mölndal, Sweden 12 Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health , Madison, WI, USA 13 Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison , Madison, WI, USA 14 Centre for Brain Research, Indian Institute of Science , Bangalore, India Find this author on Google Scholar Find this author on PubMed Search for this author on this site Josef Priller 15 University of Edinburgh and UK Dementia Research Institute at Edinburgh , UK 16 Department of Psychiatry and Psychotherapy, Technical University of Munich , and DZPG, Munich, Germany 17 Charité - Universitätsmedizin Berlin , and DZNE, Berlin, Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site John T O’Brien 3 Department of Psychiatry, University of Cambridge , Cambridge, United Kingdom Find this author on Google Scholar Find this author on PubMed Search for this author on this site Maura Malpetti 1 Department of Clinical Neurosciences, University of Cambridge , Cambridge, UK 2 UK Dementia Research Institute at Cambridge , Cambridge, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Maura Malpetti For correspondence: mm2243{at}medschl.cam.ac.uk Abstract Full Text Info/History Metrics Supplementary material Data/Code Preview PDF Abstract Background Neuroinflammation is a common hallmark of primary tauopathies, and is associated with worse clinical outcomes over time. However, accurate prognosis in these disorders remains challenging, and current fluid biomarkers provide limited insight into the contribution of peripheral immune cells to PSP/CBS pathogenesis. Our study aims to characterise blood-based immune cell profiles in patients with progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), and test their associations with neurodegeneration and clinical outcomes. Methods Peripheral blood immune cells from fresh whole blood were characterized with high-dimensional mass cytometry (29 markers) in n=60 people with PSP/CBS and n=21 age- and sex-matched controls. Cell type abundance was defined as the ratio of counts for each gated population divided by total live cells. Hierarchical clustering of cell types and principal component analysis were used to derive data-driven immune clusters. Correlation network analysis and diffusion-based network propagation integrated cell counts with plasma inflammation markers to prioritise mediators of intercellular signalling. Associations between immunological markers, plasma concentrations of neurofilament light chain (NfL), cognition, and survival were assessed using regression and Cox proportional hazards models. Results Patients with PSP/CBS showed a global increase in covariance among immune cell populations, indicating heightened coordination within the peripheral immune network. A monocyte-driven cluster (Cluster 1) showed higher scores in PSP/CBS, reflecting impaired phenotypic transition from classical to nonclassical monocytes, and was associated with higher NfL levels, poorer cognitive performance, and worse prognosis. In contrast, a Treg-driven cluster (Cluster 2) showed lower scores in PSP/CBS, and was associated with better cognition and longer survival. Integrated multimodal networks identified a small set of immune-regulatory molecules and cytokines mediating crosstalk between Treg/Th17-like cells and monocytic populations, supporting a dysregulated Treg–monocyte axis in PSP/CBS. Conclusions We identified peripheral blood-based immunophenotypic profiles of individuals with PSP/CBS that are associated with neurodegeneration, cognitive decline, and survival. Dysregulated monocyte maturation and reduced Treg-related immune configurations are enriched in patients with worse outcomes, suggesting that specific peripheral immune cell subsets may serve as fluid biomarkers and potential immunotherapy targets in primary tauopathies. Competing Interest Statement The authors have declared no competing interest. Funding Statement This study was co‐funded by Race Against Dementia Alzheimers Research UK (ARUK‐RADF2021A‐010); CurePSP Research Grant (689‐2024‐01‐Pipeline); Kissick Family Foundation Frontotemporal Dementia Grant Program (KFF-FTD-3449204717); the Progressive Supranuclear Palsy Association (G124028); Alzheimers Research UK PhD Scholarship (ARUK-PhD2023-018); the Dementias Platform UK and Medical Research Council (MC_UU_00030/14; MR/T033371/1); the Wellcome trust (103838; 220258); the Cambridge University Centre for Parkinson‐Plus (RG95450); the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (BRC‐1215‐20014; NIHR203312: the views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care). This work is also supported by the UK Dementia Research Institute through UK DRI Ltd, principally funded by the Medical Research Council. H.Z. is a Wallenberg Scholar and a Distinguished Professor at the Swedish Research Council supported by grants from the Swedish Research Council (#2023‐00356; #2022‐01018 and #2019‐02397), the European Union Horizon Europe research and innovation programme under grant agreement No 101053962, Swedish State Support for Clinical Research (#ALFGBG‐71320), The NULISA measurements were specifically supported by grants from the Galen and Hilary Weston Foundation, the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, and the UK Dementia Research Institute at UCL (UKDRI‐1003) to H.Z. and A.H. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Participants with mental capacity gave their written informed consent to take part in the study according to the Declaration of Helsinki. For those who lacked capacity, their participation followed the consultee process in accordance with UK law. The research protocols were approved by the National Research Ethics Services East of England Cambridge Central Committee. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability All data produced in the present work are contained in the manuscript, and are available upon reasonable request to authors Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . 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