CSF markers of neuroinflammation, synaptic dysfunction and [F]DOPA-PET in Parkinson's disease.

Introduction: Neuromelanin containing cell loss, neuroinflammation and synaptic dysfunction are believed to contribute to Parkinson's disease (PD) pathogenesis. [F]DOPA PET reflects dopamine storage capacity in the putamen, while midbrain off-target retention of [F]RO948 is hypothesized to reflect neuromelanin.

Objectives: To investigate associations between disease duration, cerebrospinal fluid (CSF) markers of neurodegeneration, synaptic dysfunction, neuroinflammation, and dopamine synaptic loss as measured by [F]DOPA PET in PD patients. We further aimed to explore whether reduced midbrain retention of [F]RO948 relates to [F]DOPA PET and CSF markers.

Methods: Participants were part of the BioFINDER studies. CSF biomarkers were analyzed for controls (n = 623), PD participants (n = 226) and Dementia with Lewy bodies (DLB; n = 33). [F]RO948 PET was performed in controls (n = 514), PD (n = 77) and DLB (n = 47) and [F]DOPA PET in PD (n = 58) and DLB (n = 22).

Results: PD patients showed higher CSF neurofilament light (NfL) levels (pg/ml [mean ± SD] 159 ± 139) vs. controls (137 ± 90, p < 0.001), and lower neurogranin (pg/ml [mean ± SD] 620 ± 255) vs (772 ± 283, p < 0.001). Lower [F]DOPA uptake correlated with longer disease duration (ρ = -0.46, p < 0.001), higher NfL (ρ = -0.39, p = 0.03), lower neurogranin (ρ = 0.50, p = 0.003) and NPTX2 levels (ρ = 0.36, p = 0.049). We found no associations between neuroinflammatory markers and [F]DOPA PET. Substantia nigra [F]RO948 signal was lower in PD ([mean ± SD] 1.67 ± 0.22) vs controls (1.76 ± 0.3, p < 0.001) but did not correlate with disease duration, CSF markers or [F]DOPA-PET.

Conclusions: In PD patients, a decrease in [F]DOPA PET retention correlated with disease duration as well as CSF neurodegenerative and synaptic biomarkers but not with inflammatory biomarkers or [F]RO948 PET midbrain off-target retention.