Large-scale cerebrospinal fluid proteomics identifies diagnostic biomarker candidates across the clinico-pathological continuum of frontotemporal lobar degeneration
- 1Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA
Abstract
Frontotemporal lobar degeneration (FTLD), predominantly comprised of tau and TDP-43 proteinopathies, is a common cause of early-onset dementia. Biomarkers that reliably classify FTLD subtypes are limited, thereby hindering in-vivo diagnosis and clinical trial stratification. We conducted large-scale, multi-platform cerebrospinal fluid proteomics in 566 individuals, including 274 FTLD-spectrum (48 autopsy-confirmed FTLD-TDP, 90 autopsy-confirmed FTLD-tau), 171 Alzheimers disease, and 95 controls. In neuropathological subtype contrasts, elevated matrix metalloproteinase MMP10 classified Picks disease (PiD) versus other subtypes with near-perfect accuracy across proteomic platforms. We further validated CSF MMP10 as a potential PiD diagnostic biomarker via a targeted immunoassay in an independent, autopsy-confirmed FTLD cohort. Post-synaptic proteins HOMER1 and DLG4 exhibited elevations across FTLD-TDP subtypes (A, B, and C) versus FTLD-tau. Network analysis identified RNA metabolism and pro-inflammatory signatures in FTLD-TDP, and cytoskeletal and heat shock signatures in progressive supranuclear palsy. These findings reveal candidate diagnostic biomarkers and proteomic pathways underlying FTLD clinico-pathological heterogeneity.
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BibTeX
@misc{saloner2026largescale,
title = {{Large-scale cerebrospinal fluid proteomics identifies diagnostic biomarker candidates across the clinico-pathological continuum of frontotemporal lobar degeneration}},
author = {R. Saloner and L. Cornelis and J. Downer and C. Dietz and B. Chan and M. Hughes and M. Olzinski and Y. Cobigo and A. Lario-Lago and H. Heuer and K. Cody and M. Wood and K. A. Q. Cousins and D. Wolk and E. B. Lee and D. Irwin and A. Abdelhak and B. F. Boeve and G. D. Rabinovici and R. La Joie and L. T. Grinberg and S. Spina and E. W. Paolillo and A. Staffaroni and L. VandeVrede and P. A. Ljubenkov and M. L. Gorno-Tempini and H. J. Rosen and J. S. Yokoyama and J. H. Kramer and K. B. Casaletto and B. Miller and W. W. Seeley and J. C. Rojas and A. L. Boxer},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.29.755483},
url = {https://www.biorxiv.org/content/10.64898/2026.09.29.755483v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Large-scale cerebrospinal fluid proteomics identifies diagnostic biomarker candidates across the clinico-pathological continuum of frontotemporal lobar degeneration
AU - R. Saloner
AU - L. Cornelis
AU - J. Downer
AU - C. Dietz
AU - B. Chan
AU - M. Hughes
AU - M. Olzinski
AU - Y. Cobigo
AU - A. Lario-Lago
AU - H. Heuer
AU - K. Cody
AU - M. Wood
AU - K. A. Q. Cousins
AU - D. Wolk
AU - E. B. Lee
AU - D. Irwin
AU - A. Abdelhak
AU - B. F. Boeve
AU - G. D. Rabinovici
AU - R. La Joie
AU - L. T. Grinberg
AU - S. Spina
AU - E. W. Paolillo
AU - A. Staffaroni
AU - L. VandeVrede
AU - P. A. Ljubenkov
AU - M. L. Gorno-Tempini
AU - H. J. Rosen
AU - J. S. Yokoyama
AU - J. H. Kramer
AU - K. B. Casaletto
AU - B. Miller
AU - W. W. Seeley
AU - J. C. Rojas
AU - A. L. Boxer
PY - 2026
DA - 2026/09/29
PB - bioRxiv
DO - 10.64898/2026.09.29.755483
UR - https://www.biorxiv.org/content/10.64898/2026.09.29.755483v1
AB - Frontotemporal lobar degeneration (FTLD), predominantly comprised of tau and TDP-43 proteinopathies, is a common cause of early-onset dementia. Biomarkers that reliably classify FTLD subtypes are limited, thereby hindering in-vivo diagnosis and clinical trial stratification. We conducted large-scale, multi-platform cerebrospinal fluid proteomics in 566 individuals, including 274 FTLD-spectrum (48 autopsy-confirmed FTLD-TDP, 90 autopsy-confirmed FTLD-tau), 171 Alzheimers disease, and 95 controls. In neuropathological subtype contrasts, elevated matrix metalloproteinase MMP10 classified Picks disease (PiD) versus other subtypes with near-perfect accuracy across proteomic platforms. We further validated CSF MMP10 as a potential PiD diagnostic biomarker via a targeted immunoassay in an independent, autopsy-confirmed FTLD cohort. Post-synaptic proteins HOMER1 and DLG4 exhibited elevations across FTLD-TDP subtypes (A, B, and C) versus FTLD-tau. Network analysis identified RNA metabolism and pro-inflammatory signatures in FTLD-TDP, and cytoskeletal and heat shock signatures in progressive supranuclear palsy. These findings reveal candidate diagnostic biomarkers and proteomic pathways underlying FTLD clinico-pathological heterogeneity.
ER -