Large-scale cerebrospinal fluid proteomics identifies diagnostic biomarker candidates across the clinico-pathological continuum of frontotemporal lobar degeneration

  1. Rowan Saloner
  2. Louisa Cornelis
  3. Joshua Downer
  4. Connor Dietz
  5. Brandon Chan
  6. Michelle Hughes
  7. Molly Olzinski
  8. Yann Cobigo
  9. Argentina Lario-Lago
  10. Hilary Heuer
  11. Karly Cody
  12. Madeline Wood
  13. Katheryn A.Q. Cousins
  14. David Wolk
  15. Edward B. Lee
  16. David Irwin
  17. Ahmed Abdelhak
  18. Bradley F. Boeve
  19. Gil D. Rabinovici
  20. Renaud La Joie
  21. Lea T. Grinberg
  22. Salvatore Spina
  23. Emily W. Paolillo
  24. Adam Staffaroni
  25. Lawren VandeVrede
  26. Peter A. Ljubenkov
  27. Maria Luisa Gorno-Tempini
  28. Howard J. Rosen
  29. Jennifer S. Yokoyama
  30. Joel H. Kramer
  31. Kaitlin B. Casaletto
  32. Bruce Miller
  33. William W. Seeley
  34. Julio C. Rojas
  35. Adam L. Boxer
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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 Alzheimer’s disease, and 95 controls. In neuropathological subtype contrasts, elevated matrix metalloproteinase MMP10 classified Pick’s 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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  1. Mentioned by @rridrobot.bsky.social on Bluesky

    Authors published a paper in Biorxiv, they used Biogen Idec in the study. Including #RRIDs will make this less ambiguous. SciScore made a table with this resource, see “Automated Services” module (download as csv, xml or #jats) #STMpublishing #RRID

  2. Mentioned by @prepub-neurodegen.bsky.social on Bluesky

    Large-scale cerebrospinal fluid proteomics identifies diagnostic biomarker candidates across the clinico-pathological continuum of frontotemporal lobar degeneration #NeuroDegeneration 🧪🧠 https://www.biorxiv.org/content/10.64898/2026.09.29.755483v1

  3. Mentioned by @biorxivpreprint.bsky.social on Bluesky

    Large-scale cerebrospinal fluid proteomics identifies diagnostic biomarker candidates across the clinico-pathological continuum of frontotemporal lobar degeneration https://www.biorxiv.org/content/10.64898/2026.09.29.755483v1

  4. Mentioned by @biorxiv-neursci.bsky.social on Bluesky

    Large-scale cerebrospinal fluid proteomics identifies diagnostic biomarker candidates across the clinico-pathological continuum of frontotemporal lobar degeneration https://www.biorxiv.org/content/10.64898/2026.09.29.755483v1

  5. Version published to 10.64898/2026.09.29.755483v1 on bioRxiv