Plasma immune signatures associate with neurodegeneration in frontotemporal lobar degeneration
- 11Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK, 2 UK Dementia Research Institute at the University of Cambridge, 3 Cambridge Un
Abstract
Frontotemporal lobar degeneration (FTLD) encompasses clinically and biologically heterogeneous syndromes that are unlikely to be captured by a single blood biomarker. Although plasma neurofilament light (NfL) chain reflects neuroaxonal injury, multiplex profiling may identify complementary inflammatory, vascular and proteostatic processes relevant to clinical phenotype and progression. We characterised plasma CNS-related and inflammatory proteomic signatures across FTLD-related clinical syndromes and tested their associations with neuroaxonal injury, clinical severity, regional brain atrophy and survival. Plasma samples from 177 participants with behavioural variant frontotemporal dementia (bvFTD), primary progressive aphasia (PPA), progressive supranuclear palsy (PSP) or corticobasal syndrome (CBS) and 67 healthy controls were analysed using the high-sensitivity nucleic acid-linked immuno-sandwich assay (NULISA) platform. We quantified 130 CNS-related and 250 inflammation-related proteins. Differential expression and multivariate classification analyses were complemented by hierarchical clustering, penalised regression and survival analyses. Canonical correlation analysis tested multivariate associations between disease-associated proteins and regional MRI brain volumes. Sixty-one CNS-related and 61 inflammation-related proteins differed between participants with FTLD-related syndromes and controls after false-discovery-rate correction. NfL was the strongest individual discriminator between all patients and controls, with an area under the receiver operating characteristic curve of 0.91. In exploratory full-cohort models, the multivariate CNS signature achieved an area under the curve of 0.93, compared with 0.82 for the multivariate inflammation signature. However, inflammatory proteins provided stronger discrimination for selected syndrome comparisons, including PPA versus PSP. Among inflammation-related proteins, SPP1 and CD276 showed the strongest positive associations with NfL. Higher CD276 and SPP1 were associated with increased mortality, whereas higher amyloid-{beta}42 was associated with lower mortality. A multivariate protein signature weighted towards tumour necrosis factor and immune signalling was associated with lower regional brain volumes across predominantly frontotemporal and limbic regions (canonical correlation 0.43; permutation p=0.018).
Plasma multiplex proteomics identified complementary dimensions of neuroaxonal injury and immune dysregulation across frontotemporal lobar degeneration-related syndromes. CNS-related proteins, particularly NfL, predominantly captured case-control neurodegeneration, whereas inflammatory signatures provided additional information about syndrome heterogeneity, structural brain changes and survival. SPP1, CD276 and broader immune-related signatures are candidates for independent biomarker validation and mechanistic investigation.
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BibTeX
@misc{schaik2026plasma,
title = {{Plasma immune signatures associate with neurodegeneration in frontotemporal lobar degeneration}},
author = {M. van Schaik and K. O. Lai and N. L. Shapiro and A. Jäck and J. Goddard and H. Crook and R. Frohn and P. S. Jones and S. Y. Tan and O. Swann and R. Mulvaney and A. Heslegrave and H. Zetterberg and M. Brendel and K. A. Tsvetanov and J. B. Rowe and M. Malpetti},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.28.26364155},
url = {https://www.medrxiv.org/content/10.64898/2026.09.28.26364155v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Plasma immune signatures associate with neurodegeneration in frontotemporal lobar degeneration
AU - M. van Schaik
AU - K. O. Lai
AU - N. L. Shapiro
AU - A. Jäck
AU - J. Goddard
AU - H. Crook
AU - R. Frohn
AU - P. S. Jones
AU - S. Y. Tan
AU - O. Swann
AU - R. Mulvaney
AU - A. Heslegrave
AU - H. Zetterberg
AU - M. Brendel
AU - K. A. Tsvetanov
AU - J. B. Rowe
AU - M. Malpetti
PY - 2026
DA - 2026/09/28
PB - medRxiv
DO - 10.64898/2026.09.28.26364155
UR - https://www.medrxiv.org/content/10.64898/2026.09.28.26364155v1
AB - Frontotemporal lobar degeneration (FTLD) encompasses clinically and biologically heterogeneous syndromes that are unlikely to be captured by a single blood biomarker. Although plasma neurofilament light (NfL) chain reflects neuroaxonal injury, multiplex profiling may identify complementary inflammatory, vascular and proteostatic processes relevant to clinical phenotype and progression. We characterised plasma CNS-related and inflammatory proteomic signatures across FTLD-related clinical syndromes and tested their associations with neuroaxonal injury, clinical severity, regional brain atrophy and survival. Plasma samples from 177 participants with behavioural variant frontotemporal dementia (bvFTD), primary progressive aphasia (PPA), progressive supranuclear palsy (PSP) or corticobasal syndrome (CBS) and 67 healthy controls were analysed using the high-sensitivity nucleic acid-linked immuno-sandwich assay (NULISA) platform. We quantified 130 CNS-related and 250 inflammation-related proteins. Differential expression and multivariate classification analyses were complemented by hierarchical clustering, penalised regression and survival analyses. Canonical correlation analysis tested multivariate associations between disease-associated proteins and regional MRI brain volumes. Sixty-one CNS-related and 61 inflammation-related proteins differed between participants with FTLD-related syndromes and controls after false-discovery-rate correction. NfL was the strongest individual discriminator between all patients and controls, with an area under the receiver operating characteristic curve of 0.91. In exploratory full-cohort models, the multivariate CNS signature achieved an area under the curve of 0.93, compared with 0.82 for the multivariate inflammation signature. However, inflammatory proteins provided stronger discrimination for selected syndrome comparisons, including PPA versus PSP. Among inflammation-related proteins, SPP1 and CD276 showed the strongest positive associations with NfL. Higher CD276 and SPP1 were associated with increased mortality, whereas higher amyloid-{beta}42 was associated with lower mortality. A multivariate protein signature weighted towards tumour necrosis factor and immune signalling was associated with lower regional brain volumes across predominantly frontotemporal and limbic regions (canonical correlation 0.43; permutation p=0.018). Plasma multiplex proteomics identified complementary dimensions of neuroaxonal injury and immune dysregulation across frontotemporal lobar degeneration-related syndromes. CNS-related proteins, particularly NfL, predominantly captured case-control neurodegeneration, whereas inflammatory signatures provided additional information about syndrome heterogeneity, structural brain changes and survival. SPP1, CD276 and broader immune-related signatures are candidates for independent biomarker validation and mechanistic investigation.
ER -