Prodromal Recognition of Non-Motor Symptoms and Biomarkers in Parkinson's Disease

Abstract

The diagnosis of Parkinson's disease (PD) is often delayed due to over-reliance on motor manifestations, despite the fact that pathological changes including abnormal aggregation of alpha-synuclein (α-syn) and progressive dopaminergic neuronal loss in the substantia nigra pars compacta begin years before overt symptoms emerge. This interval, termed the prodromal phase, represents a critical window for potential intervention. This review summarizes the application value of non-motor symptoms (NMS) and their biomarkers in prodromal identification. Evidence on four NMS categories, namely isolated rapid eye movement sleep behavior disorder (iRBD), autonomic dysfunction, sensory impairment, and neuropsychiatric symptoms, is synthesized. Fluid biomarkers including cerebrospinal fluid (CSF) α-syn seed amplification assay, plasma proteins, and urine proteins, as well as neuroimaging tools including magnetic resonance imaging striatal metrics and meta-iodobenzylguanidine scintigraphy, are evaluated. The findings indicate that while iRBD and CSF α-syn seed amplification assay offer strong predictive value, no single modality suffices for reliable prodromal screening. A multi-modal strategy combining clinical symptoms, fluid markers, and imaging data appears more promising. By consolidating dispersed evidence across subspecialties, this review aims to offer clinicians and researchers an integrated reference for selecting and refining early detection strategies.