Faster disease progression in Parkinson's disease with glucocerebrosidase genotype: But not apparent immediate from diagnosis.

Parkinson's disease (PD) has a prodromal stage characterized by non-motor symptoms, such as autonomic dysfunction, hyposmia, REM sleep behavior disorder (RBD), depressive symptoms, and daytime sleepiness. Additionally, mild motor symptoms that are not severe enough to be diagnosed as parkinsonism may also appear during this period. Among the non-motor symptoms at the prodromal stage, RBD is considered the most indicative because of its high likelihood of future development of neurodegenerative disorders. Consequently, many studies on the prodromal stage of PD have focused on patients with idiopathic RBD (iRBD). However, the clinical progression of PD from the prodromal stage exhibits substantial heterogeneity from case to case, and recent studies indicate certain subtypes of the prodromal progression of PD. For example, in the “body-first” subtype, alpha-synuclein pathology and degeneration start in the peripheral autonomic nervous system, most likely the enteric nervous system, and spread upward to the sympathetic trunk and brainstem, whereas the “brain-first” subtype is associated with pathology starting in the olfactory bulb or amygdala, reaching the substantia nigra, and then spreading downward to the middle and lower brainstem, and eventually to the peripheral nervous system. Therefore, to identify subjects at risk of developing PD, it is necessary to evaluate not only RBD but also various non-motor and motor symptoms. Our research group has been conducting a cohort study on at-risk subjects with PD who were identified through a questionnaire survey in a general population (the NaT-PROBE study). We reported that approximately 5.7% of healthy participants had ≥2 prodromal symptoms, and they were defined as high-risk subjects for PD. At the baseline evaluation, approximately one-third of the high-risk subjects presented with abnormalities on either MIBG myocardial scintigraphy or DaT-SPECT. Those with abnormal MIBG myocardial scintigraphy results presented non-motor symptoms such as lower OSIT-J scores and higher RBDSQ scores, and those with abnormal DaT-SPECT results presented higher MDS-UPDRS III scores, indicating that this cohort included various subtypes of prodromal PD. This cohort also focused primarily on non-motor symptoms because self-report questionnaires to evaluate subtle motor symptoms had not been established.