. 2024 Aug 13;103(3):e209585.

doi: 10.1212/WNL.0000000000209585. Epub 2024 Jul 3.

CSF Proteomics in Patients With Progressive Supranuclear Palsy

Amy Wise¹, Jingyao Li¹, Mai Yamakawa¹, Joseph Loureiro¹, Brant Peterson¹, Kathleen Worringer¹, Rajeev Sivasankaran¹, Jose-Alberto Palma¹, Laura Mitic¹, Hilary W Heuer¹, Argentina Lario-Lago¹, Adam M Staffaroni¹, Annie Clark¹, Jack Taylor¹, Peter A Ljubenkov¹, Lawren Vandevrede¹, Lea T Grinberg¹, Salvatore Spina¹, William W Seeley¹, Bruce L Miller¹, Bradley F Boeve¹, Bradford C Dickerson¹, Murray Grossman¹, Irene Litvan¹, Alexander Pantelyat¹, Maria Carmela Tartaglia¹, Zihan Zhang¹, Anne-Marie A Wills¹, Jessica Rexach¹, Julio C Rojas¹, Adam L Boxer¹; as the 4-Repeat Tauopathy Neuroimaging Initiative¹

Affiliations

Affiliation

¹ From the Weill Institute for Neurosciences (A.W., L.M., H.W.H., A.L.-L., A.M.S., A.C., J.T., P.A.L., L.V., L.T.G., S.S., W.W.S., B.L.M., J.C.R., A.L.B.), Department of Neurology, Memory and Aging Center, University of California, San Francisco; Novartis Institutes for Biomedical Research, Inc. (J. Li, J. Loureiro, B.P., K.W., R.S., J.-A.P.), Cambridge, MA; Department of Neurology (M.Y., J.R.), University of California, Los Angeles; The Bluefield Project to Cure FTD (L.M.); Department of Neurology (B.F.B.), Mayo Clinic, Rochester, MN; Department of Neurology (B.C.D., A.-M.A.W.), Massachusetts General Hospital and Harvard Medical School, Boston; Department of Neurology (M.G.), University of Pennsylvania, Philadelphia; Department of Neurology (I.L.), University of California, San Diego; Department of Neurology (A.P.), Johns Hopkins University, Baltimore, MD; Department of Neurology (M.C.T.), University of Toronto, Ontario, Canada; and Departments of Mathematics and Statistics (Z.Z.), University of California, Los Angeles.

PMID: 38959435
PMCID: PMC11226322
DOI: 10.1212/WNL.0000000000209585

CSF Proteomics in Patients With Progressive Supranuclear Palsy

Amy Wise et al. Neurology. 2024.

. 2024 Aug 13;103(3):e209585.

doi: 10.1212/WNL.0000000000209585. Epub 2024 Jul 3.

Authors

Affiliation

¹ From the Weill Institute for Neurosciences (A.W., L.M., H.W.H., A.L.-L., A.M.S., A.C., J.T., P.A.L., L.V., L.T.G., S.S., W.W.S., B.L.M., J.C.R., A.L.B.), Department of Neurology, Memory and Aging Center, University of California, San Francisco; Novartis Institutes for Biomedical Research, Inc. (J. Li, J. Loureiro, B.P., K.W., R.S., J.-A.P.), Cambridge, MA; Department of Neurology (M.Y., J.R.), University of California, Los Angeles; The Bluefield Project to Cure FTD (L.M.); Department of Neurology (B.F.B.), Mayo Clinic, Rochester, MN; Department of Neurology (B.C.D., A.-M.A.W.), Massachusetts General Hospital and Harvard Medical School, Boston; Department of Neurology (M.G.), University of Pennsylvania, Philadelphia; Department of Neurology (I.L.), University of California, San Diego; Department of Neurology (A.P.), Johns Hopkins University, Baltimore, MD; Department of Neurology (M.C.T.), University of Toronto, Ontario, Canada; and Departments of Mathematics and Statistics (Z.Z.), University of California, Los Angeles.

PMID: 38959435
PMCID: PMC11226322
DOI: 10.1212/WNL.0000000000209585

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: A total of 136 participants were included (median age 70.6 ± 8 years, 68 [50%] women). One hundred fifty-five of 5,026 (3.1%), 959 of 7,595 (12.6%), and 321 of 5,026 (6.3%) SOMAmers were differentially expressed in PSP compared with controls in original, validation, and neuropathology-confirmed cohorts, with most of the SOMAmers showing reduced signal (83.1%, 95.1%, and 73.2%, respectively). Three coexpression modules were associated with PSP across cohorts: (1) synaptic function/JAK-STAT (β = -0.044, corrected p = 0.002), (2) vesicle cytoskeletal trafficking (β = 0.039, p = 0.007), and (3) cytokine-cytokine receptor interaction (β = -0.032, p = 0.035) pathways. Axon guidance was the top dysregulated pathway in PSP in original (strength = 1.71, p < 0.001), validation (strength = 0.84, p < 0.001), and neuropathology-confirmed (strength = 0.78, p < 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.

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Conflict of interest statement

L. Mitic is supported by the Bluefield Project to Cure FTD. L. Vandevrede is supported by K23AG073514 and grants from the Alzheimer's Association and American Academy of Neurology, site PI for clinical trials sponsored by Biogen, consulted for Retrotope. M. Grossman is deceased, to the best of our knowledge, he had no relevant disclosures. A. Pantelyat is supported by NIH/NIA K23AG059891, NIH/National Institute of Neurological Disorders and Stroke U01NS102035; NIH/NIA R01AG038791; Scientific Advisory Board, MedRhythms, Inc. J.C. Rojas NIA/NIH K23AG59888 is site principal investigator for Clinical trials sponsored by Eisai and Eli-Lilly. Go to Neurology.org/N for full disclosures.

Figures

**Figure 1. CSF SOMAmer Proteomic Signatures in PSP**
Volcano plots with CSF expression profiles of PSP compared with age-matched controls for the (A) original cohort, (B) validation cohort, (C) neuropathology-confirmed FTLD-tau PSP, and (D) neuropathology-confirmed FTLD-tau PSP vs FTLD TDP. Protein expression values are adjusted for age and sex. Markers significantly decreased are in blue, and markers significantly increased are in red. Vertical dotted lines represent 0.20 or −0.20 log fold change, for biological significance. Horizontal line is p value = 0.05. EPHA5 = ephrin receptor A5; FTLD = frontotemporal lobar degeneration; GFAP = glial fibrillary acidic protein; Log FC = log fold change; MAPT = microtubule-associated protein tau; NfL = neurofilament light chain; NPTX2 = neuronal pentraxin 2.

**Figure 2. Top 6 Targets Differentiating PSP vs Controls in Original, Validation, and Pathology-Confirmed FTLD Cohorts**
Box plots show individual data points with median, interquartile range, and range values for the top CSF protein targets with altered expression in PSP. FTLD = frontotemporal lobar degeneration; PSP = progressive supranuclear palsy; PSP-RS = PSP-Richardson syndrome.

**Figure 3. Diagnostic Value of CSF Axon Guidance Pathway Proteins in PSP**
The receiver-operating characteristic curve graph shows the diagnostic accuracy of axon guidance pathway targets identified in the original cohort (EPHA4, PLXNA1, EPHB2, ROBO3, UNC5D, EPHA5, and EPHB6), entered as a panel for original, validation, and pathology-confirmed FTLD cohorts. FTLD = frontotemporal lobar degeneration; PSP = progressive supranuclear palsy; PSP-RS = PSP-Richardson syndrome.

**Figure 4. Correlations of CSF Protein Targets With Measures of Disease Severity**
Plots display correlations corrected for multiple comparisons of representative CSF targets with PSPRS in original and validation cohorts with galectin-10 (CLC) and cytotoxic T-lymphocyte–associated protein 4 (CTLA-4). AUC = area under the curve; PSPRS = Progressive Supranuclear Palsy Rating Scale.

See this image and copyright information in PMC

References

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CSF Proteomics in Patients With Progressive Supranuclear Palsy

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CSF Proteomics in Patients With Progressive Supranuclear Palsy

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