CSF biomarkers associated with disease heterogeneity in early Parkinson’s disease: the Parkinson’s Progression Markers Initiative study

Ju-Hee Kang, Brit Mollenhauer, Christopher S. Coffey, Jon B. Toledo, Daniel Weintraub, Douglas R. Galasko, David J. Irwin, Vivianna Van Deerlin, Alice S. Chen-Plotkin, Chelsea Caspell-Garcia, Teresa Waligórska, Peggy Taylor, Nirali Shah, Sarah Pan, Pawel Zero, Mark Frasier, Kenneth Marek, Karl Kieburtz, Danna Jennings, Caroline M. Tanner, Tanya Simuni, Andrew Singleton, Arthur W. Toga, Sohini Chowdhury, John Q. Trojanowski, Leslie M. Shaw, The Parkinson’s Progression Marker Initiative

The development of biomarkers to predict the progression of Parkinson's disease (PD) from its earliest stage through its heterogeneous course is critical for research and therapeutic development. The Parkinson's Progression Markers Initiative (PPMI) study is an ongoing international multicenter, prospective study to validate biomarkers in drug-naïve PD patients and matched healthy controls (HC). We quantified cerebrospinal fluid (CSF) alpha-synuclein (α-syn), amyloid-beta1-42 (Aβ1-42), total tau (t-tau), and tau phosphorylated at Thr181 (p-tau) in 660 PPMI subjects at baseline, and correlated these data with measures of the clinical features of these subjects. We found that CSF α-syn, t-tau and p-tau levels, but not Aβ1-42, were significantly lower in PD compared with HC, while the diagnostic value of the individual CSF biomarkers for PD diagnosis was limited due to large overlap. The level of α-syn, but not other biomarkers, was significantly lower in PD patients with non-tremor-dominant phenotype compared with tremor-dominant phenotype. In addition, in PD patients the lowest Aβ1-42, or highest t-tau/Aβ1-42 and t-tau/α-syn quintile in PD patients were associated with more severe non-motor dysfunction compared with the highest or lowest quintiles, respectively. In a multivariate regression model, lower α-syn was significantly associated with worse cognitive test performance. APOE ε4 genotype was associated with lower levels of Aβ1-42, but neither with PD diagnosis nor cognition. Our data suggest that the measurement of CSF biomarkers in early-stage PD patients may relate to disease heterogeneity seen in PD. Longitudinal observations in PPMI subjects are needed to define their prognostic performance.