Association of Cerebrospinal Fluid β-Amyloid 1-42, T-tau, P-tau<sub>181</sub>, and α-Synuclein Levels With Clinical Features of Drug-Naive Patients With Early Parkinson Disease
Authors: Ju-Hee Kang, David J. Irwin, Alice S. Chen-Plotkin, Andrew Siderowf, Chelsea Caspell, Christopher S. Coffey, Teresa Waligórska, Peggy Taylor, Sarah Pan, Mark Frasier, Kenneth Marek, Karl Kieburtz, Danna Jennings, Tanya Simuni, Caroline M. Tanner, Andrew Singleton, Arthur W. Toga, Sohini Chowdhury, Brit Mollenhauer, John Q. Trojanowski, Leslie M. Shaw, Shirley Lasch, Emily Flagg, Werner Poewe, Todd Sherer, Claire Meunier, Alice Rudolph, Cindy Casaceli, John Seibyl, Susan Mendick, Norbert Schuff, Liz Uribe, Jon Yankey, Karen Crawford, Alison Scutti, Paola Casalin, Giulia Malferrari, Keith Hawkins, David Russell, Laura Leary, Stewart Factor, Barbara Sommerfeld, Penelope Hogarth, Emily Pighetti, Karen Williams, David Standaert, Stephanie Guthrie, Robert Hauser, Joseph Jankovic, Christine Hunter, Matthew Stern, Abigail Darin, Jim Leverenz, Marne Baca, Sam Frank, Cathi-Ann Thomas, Irene Richard, Cheryl Deeley, Linda Rees, Fabienne Sprenger, Wolfgang Oertel, Diana Willeke, Holly Shill, Hubert Fernandez, Jennifer Mule, Daniela Berg, Katharina Gauss, Douglas Galasko, Deborah Fontaine, Zoltan Mari, Arita McCoy, David Brooks, Bina Shah, Paolo Barone, Stuart Isaacson, Angela James, Alberto Espay, Kristy Espay, Dominic Rowe, Madelaine Ranola
Journal: JAMA Neurology (2013)

<h3>Importance</h3> We observed a significant correlation between cerebrospinal fluid (CSF) levels of tau proteins and α-synuclein, but not β-amyloid 1-42 (Aβ1-42), and lower concentration of CSF biomarkers, as compared with healthy controls, in a cohort of entirely untreated patients with Parkinson disease (PD) at the earliest stage of the disease studied so far. <h3>Objective</h3> To evaluate the baseline characteristics and relationship to clinical features of CSF biomarkers (Aβ1-42, total tau [T-tau], tau phosphorylated at threonine 181 [P-tau<sub>181</sub>], and α-synuclein) in drug-naive patients with early PD and demographically matched healthy controls enrolled in the Parkinson’s Progression Markers Initiative (PPMI) study. <h3>Design, Setting, and Participants</h3> Cross-sectional study of the initial 102 research volunteers (63 patients with PD and 39 healthy controls) of the PPMI cohort. <h3>Main Outcomes and Measures</h3> The CSF biomarkers were measured by INNO-BIA AlzBio3 immunoassay (Aβ1-42, T-tau, and P-tau<sub>181</sub>; Innogenetics Inc) or by enzyme-linked immunosorbent assay (α-synuclein). Clinical features including diagnosis, demographic characteristics, motor, neuropsychiatric, and cognitive assessments, and DaTscan were systematically assessed according to the PPMI study protocol. <h3>Results</h3> Slightly, but significantly, lower levels of Aβ1-42, T-tau, P-tau<sub>181</sub>, α-synuclein, and T-tau/Aβ1-42 were seen in subjects with PD compared with healthy controls but with a marked overlap between groups. Using multivariate regression analysis, we found that lower Aβ1-42 and P-tau<sub>181</sub>levels were associated with PD diagnosis and that decreased CSF T-tau and α-synuclein were associated with increased motor severity. Notably, when we classified patients with PD by their motor phenotypes, lower CSF Aβ1-42 and P-tau<sub>181</sub>concentrations were associated with the postural instability–gait disturbance–dominant phenotype but not with the tremor-dominant or intermediate phenotype. Finally, we found a significant correlation of the levels of α-synuclein with the levels of T-tau and P-tau<sub>181</sub>. <h3>Conclusions and Relevance</h3> In this first report of CSF biomarkers in PPMI study subjects, we found that measures of CSF Aβ1-42, T-tau, P-tau<sub>181</sub>, and α-synuclein have prognostic and diagnostic potential in early-stage PD. Further investigations using the entire PPMI cohort will test the predictive performance of CSF biomarkers for PD progression.