Fig 4. Top biomarkers are robust and predict cognitive trajectory.
(A) Volcano plot showing the effect of dopaminergic therapy on plasma protein levels, tested in 10 PD individuals, comparing ON versus OFF medication state in the same individuals. Nominally significant differences in ON versus OFF state were found for only two proteins (paired t test nominal p < 0.01), and none of our four top biomarker proteins was affected substantially. (B-C) Effect of plasma handling (samples compared with versus without a 30-minute RT incubation followed by an extra freeze–thaw cycle) in two reference pools. Plasma handling caused substantial changes in levels of some proteins, but none of our four top biomarkers was affected. (D) Cross-sectional relationship between PD biomarker measures (log10 of RFU) and baseline cognitive function as measured by DRS score (Spearman’s correlation, *FDR-adjusted p < 0.05). (E-H) Cox proportional hazards analyses investigating differences in subsequent rates of clinical conversion to MCI or dementia, stratified by GHR measures at baseline in the Discovery Cohort (tertiles shown, panels E,F) and the Replication Cohort (tertiles shown, panels G,H). For the Replication Cohort, cognitive assignments were based on published norms for the MoCA, longitudinally assessed at the UTSW site. (E,G) Cox regression curves showing adjusted trajectories for each tertile of baseline GHR measures in each cohort. (F,H) Forest plots depicting hazard ratios for groups as defined by tertile of biomarker measures at baseline, sex, age, and disease duration. **p < 0.01. ACY1, aminoacylase-1; BSP, bone sialoprotein; DRS, Mattis Dementia Rating Scale-2; FDR, false discovery rate; GHR, growth hormone receptor; IGFBP-1, insulin-like growth factor binding protein 1; MCI, mild cognitive impairment; MoCA, Montreal Cognitive Assessment; OMD, osteomodulin; PCSK9, proprotein convertase subtilisin/kexin type 9; PD, Parkinson’s disease; PDBP, Parkinson’s Disease Biomarker Program; RFU, relative fluorescence unit; RT, room temperature; UPenn, University of Pennsylvania; UTSW, University of Texas Southwestern Medical Center.