The Body-First Trajectory: Mapping the Hidden Prologue of Lewy Body Diseases

In Parkinson's disease (PD) and dementia with Lewy bodies (DLB), clinical diagnosis is often made only after the underlying biology has largely run its course.By the time motor symptoms such as tremor or cognitive decline become clinically evident, dopaminergic neurons in the central nervous system have frequently already undergone substantial and irreversible degeneration.1 Moreover, this temporal gap is compounded by diagnostic-pathologic discordance: syndrome-based labels remain imperfect proxies for pathology, often confounded by external factors such as potentially inappropriate medication use which can mimic or exacerbate symptoms.2 Indeed, in a national brain-biobank series, only about twothirds of clinically diagnosed idiopathic PD cases corresponded to Lewy body disease pathology, making a strong case for a biologically anchored classification.3 Bridging this temporal gap between biological pathology and clinical diagnosis represents one of the most urgent challenges in modern neurology.Importantly, this challenge extends beyond early diagnosis itself and constitutes a fundamental prerequisite for the development of truly disease-modifying therapies.In this context, Dr. David S. Goldstein's recent review article, "Preclinical Catecholaminergic Biomarkers of Central Lewy Body Diseases, " published in the previous issue, offers a clear and scientifically grounded roadmap for addressing this critical gap. 4 By integrating decades of mechanistic research with long-term follow-up data from the landmark PDRisk study, the author provides compelling support for the body-first model, proposing that Lewy body diseases may originate in peripheral autonomic structures rather than in the brain.The central strength of this review lies in its integrated framework, which aligns previously disparate biomarkers along a unified biological timeline.Cardiac sympathetic denervation, alterations in cerebrospinal fluid catecholamine metabolites, and the recently highlighted α-synuclein seeding activity are interpreted not as isolated findings, but as interconnected components of a continuous triphasic course progressing from homeostasis to dyshomeostasis and, ultimately, to overt clinical disease (Fig. 1).Particularly noteworthy is the observation that cardiac 18 F-dopamine uptake may decline even while central dopaminergic reward pathways remain preserved on 18 F-dopa positron emission tomography (PET) imaging.This finding challenges the prevailing brain-centric diagnostic paradigm and provides a critical clue to the clinical heterogeneity observed between PD and DLB, thereby laying conceptual groundwork for personalized precision medicine.The validity of such an integrated approach is further supported by parallel advancements in Alzheimer's disease research.A recent study by Lee et al. 5 demonstrated that discrepancies between biological staging based on tau PET and clinical staging can serve as powerful predictors of disease heterogeneity.This reinforces the notion that mapping the non-linear relationship between biological progression and clinical manifestation-as Goldstein proposes for Lewy body disease-is an essential step toward realizable precision medicine across the spectrum of neurodegenerative diseases.