Brain, blood, and cerebrospinal fluid vascular biomarkers reflect distinct biology in Parkinson's disease

Blood-brain barrier (BBB) biomarker pipelines in Parkinson's disease (PD) use brain transcriptomics, plasma proteomics, and cerebrospinal fluid (CSF) measures interchangeably, but whether they report on the same biology is untested. We pre-registered a PPMI study combining single-nucleus midbrain RNA-seq (18,120 vascular cells, three cohorts), whole-blood RNA-seq, a 20-protein BBB panel in plasma and CSF (Olink Explore 384 and HT), and the CSF/serum albumin ratio (Qalb). In 130 patients with all four measurements, every pairwise correlation was below the |ρ| < 0.20 decoupling threshold (maximum |ρ| = 0.19), including plasma versus CSF for the identical 20 proteins (ρ = -0.14). The brain signature was dominated by an HSP90/HSP70 chaperone module (90× and 57× enrichment, p_BH < 10 ⁻ ⁹) but did not transfer to blood (AUC = 0.54), and the pre-registered motor-progression interaction was null. Brain, plasma, and CSF vascular axes capture distinct biology in PD; biomarker validation should not assume convergence.