Lysosomal and synaptic dysfunction markers in longitudinal cerebrospinal fluid spanning from healthy subjects to prodromal and manifest Parkinson’s disease

Lysosomal and synaptic dysfunctions are hallmarks in multiple neurodegenerative diseases including Alzheimer’s disease and Parkinson’s disease (PD) and could be relevant from a biomarker perspective. Biomarker data on prodromal and early PD are not yet available. We performed targeted mass spectrometry measurements cross-sectionally and longitudinally over 10 years with an established biomarker panel, assessing autophagy and synaptic function in cerebrospinal fluid (CSF) in prodromal subjects with isolated REM sleep behavior disorder (iRBD), drug-naïve de novo PD subjects at baseline, and sex- and age-matched healthy controls. Multiple markers of autophagy, synaptic plasticity, and secretory pathways showed reduced expression in PD and iRBD compared to controls. Machine learning identified neuronal pentraxin receptor and neurosecretory protein VGF as the most relevant for discriminating between groups. CSF levels of LAMP2, neuronal pentraxins, and syntaxins correlated with clinical progression and showed predictive potential for motor- and non-motor symptoms as a valid basis for future drug trials.