Temporal onset of non-motor symptoms and the body-first/brain-first dichotomy in Parkinson's disease: a cross-sectional single center experience

Abstract

Parkinson's disease (PD) is characterized by an array of motor symptoms and non-motor symptoms (NMS), with growing interest in the chronology of NMS. The α -Synuclein Origin site and Connectome (SOC) model proposes body-first and brain-first subtypes, based on the origin and spread of α -synuclein pathology, with distinct clinical phenotypes. To evaluate the temporal profile of onset of the NMS in relation to the motor symptoms in patients with PD. Additionally, motor and non-motor differences based on the SOC model subtyping were evaluated. Interim data of 400 patients with PD was analysed from a prospective study. Motor symptoms and NMS were assessed using the MDS-UPDRS and MDS-NMS. Patients were classified based on their onset of NMS as pre-motor, concurrent with motor onset, or post-motor. Patients were also subtyped as body-first (RBD: pre-motor + at-motor onset) or brain-first (RBD: post-motor onset/no RBD). All patients had at least one NMS. Pain (63%), sleep disturbances (61.75%), and anxiety (55.3%) were most prevalent. About 26.5% experienced pre-motor NMS; however, pre-motor hyposmia and constipation had a lower prevalence than expected. Body-first patients (9.5%) had significantly more cognitive decline, autonomic symptoms, while brain-first patients had higher motor severity, LEDD, pain, and PIGD phenotype. Temporal mapping of NMS revealed distinct patterns of symptom chronology and pathogenesis of these symptoms. The observed dichotomy in the brain-first and body-first subtypes partially supports the conceptual framework of the SOC dual-pathway model. Further exploration, particularly longitudinal evolution may offer further insights into the pathogenesis of NMS in PD.

Keywords: Body-first; Brain-first; Hyposmia; Non-motor symptoms; REM sleep behavior disorder (RBD).