Revisiting PD: Unraveling the brain-first and body-first perspectives

Abstract

Parkinson’s disease (PD) has undergone significant advancements in diagnosis and treatment over the past century, with apparent dopaminergic cell degeneration on dopamine transporter scans and a strong response to medication being key features. However, the etiology remains complex, involving various pathogenic mechanisms beyond alpha-synuclein accumulation. The recent brain-first versus body-first hypothesis, emerging from advances in functional imaging and clinical symptom clustering, suggests distinct starting points of alpha-synuclein pathology-either in the brain or the body, with subsequent spread via neural connections. This theory, exemplified by the alpha-synuclein origin site and connectome (SOC) model, proposes that body-first PD may originate in the enteric nervous system and spread to the brain, while brain-first PD starts within the central nervous system, such as the olfactory bulb or amygdala. While the SOC model offers valuable insights into the progression of PD, it raises several controversies. Critics argue that the model may oversimplify the disease’s complexity, failing to account for overlapping symptoms and the varying progression rates observed in different subtypes. Furthermore, there are concerns about the lack of longitudinal data and the potential for reclassification of PD subtypes over time. Despite these challenges, the ongoing development of imaging techniques that reflect in-vivo pathology holds promise for resolving these controversies and advancing the selection of patients for disease-modifying therapies.