CSF Proteomics in Patients With Progressive Supranuclear Palsy
Amy B. Wise, Jingyao Li, Mai Yamakawa, Joseph Loureiro, Brant K. Peterson, Kathleen A. Worringer, Rajeev Sivasankaran, Jose‐Alberto Palma, Laura L. Mitic, Hilary W. Heuer, Argentina Lario‐Lago, Adam M. Staffaroni, Annie Clark, Jack C. Taylor, Peter A. Ljubenkov, Lawren VandeVrede, Lea T. Grinberg, Salvatore Spina, William W. Seeley, Bruce L. Miller, Bradley F. Boeve, Bradford C. Dickerson, Murray Grossman, Irene Litvan, Alexander Pantelyat, Maria Carmela Tartaglia, Zihan Zhang, Anne‐Marie Wills, Jessica E. Rexach, Julio C. Rojas, Adam L. Boxer, as the 4-Repeat Tauopathy Neuroimaging Initiative
Abstract
BACKGROUND AND OBJECTIVES: Identification of fluid biomarkers for progressive supranuclear palsy (PSP) is critical to enhance therapeutic development. We implemented unbiased DNA aptamer (SOMAmer) proteomics to identify novel CSF PSP biomarkers. METHODS: This is a cross-sectional study in original (18 clinically diagnosed PSP-Richardson syndrome [PSP-RS], 28 cognitively healthy controls]), validation (23 PSP-RS, 26 healthy controls), and neuropathology-confirmed (21 PSP, 52 non-PSP frontotemporal lobar degeneration) cohorts. Participants were recruited through the University of California, San Francisco, and the 4-Repeat Neuroimaging Initiative. The original and neuropathology cohorts were analyzed with the SomaScan platform version 3.0 (5026-plex) and the validation cohort with version 4.1 (7595-plex). Clinical severity was measured with the PSP Rating Scale (PSPRS). CSF proteomic data were analyzed to identify differentially expressed targets, implicated biological pathways using enrichment and weighted consensus gene coexpression analyses, diagnostic value of top targets with receiver-operating characteristic curves, and associations with disease severity with linear regressions. RESULTS: < 0.001) cohorts. A panel of axon guidance pathway proteins discriminated between PSP and controls in original (area under the curve [AUC] = 0.924), validation (AUC = 0.815), and neuropathology-confirmed (AUC = 0.932) cohorts. Two inflammatory proteins, galectin-10 and cytotoxic T lymphocyte-associated protein-4, correlated with PSPRS scores across cohorts. DISCUSSION: Axon guidance pathway proteins and several other molecular pathways are downregulated in PSP, compared with controls. Proteins in these pathways may be useful targets for biomarker or therapeutic development.