- March 19, 2026
- Maura Malpetti, et al., University of Cambridge
Topic/Product:
CNS Disease Panel 120, Inflammation Panel 250
Disease Area:
Neurodevelopmental Disabilities (NDD)
Sample Type:
Plasma
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.
Authors & Affiliations
Kei Onn Lai¹², Julia Goddard¹², Harry Crook¹², Roosmarijn Frohn¹², Stacey L. Kigar³⁴, Natalia Savinykh Yarkoni³⁴, Peter Swann³, Robert Durcan¹, Julie Wiggins¹, Win Li¹, Hugo Paula¹, Timothy Rittman¹, Amanda Heslegrave⁵⁶, James B. Rowe¹, Matthias Brendel⁷⁸⁹, Henrik Zetterberg⁵⁶¹⁰¹¹¹²¹³¹⁴, Josef Priller¹⁵¹⁶¹⁷, John T. O’Brien³, and Maura Malpetti* ¹²
¹ Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
² UK Dementia Research Institute at Cambridge, Cambridge, UK
³ Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
⁴ Department of Medicine, University of Cambridge, Cambridge, United Kingdom
⁵ UK Dementia Research Institute at UCL, London, UK
⁶ Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK
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
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
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