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 two-thirds 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 ¹⁸F-dopamine uptake may decline even while central dopaminergic reward pathways remain preserved on ¹⁸F-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.

Fig. 1. Integrated timeline of preclinical biomarkers in “body-first” Lewy body diseases. Schematic overview illustrating how early peripheral autonomic involvement—exemplified by cardiac sympathetic denervation—can precede overt central clinical manifestations. Key preclinical biomarkers are aligned along a unified biological trajectory, including CSF catecholamine metabolites, α-synuclein SAA, autonomic function tests, and neuroimaging (PET/SPECT). These modalities are conceptualized within a triphasic course from homeostasis/compensation to dyshomeostasis and finally clinical symptoms, highlighting a window for early detection and intervention before homeostatic failure and symptomatic disease. CSF, cerebrospinal fluid; LBD, Lewy body disease; PET, positron emission tomography; SAA, seed amplification assay; SPECT, single-photon emission computed tomography.

To be sure, important challenges remain before these biomarkers can be fully integrated into routine clinical practice, including the need for multicenter validation and limitations in accessibility to specialized imaging modalities. In this regard, scalable screening strategies utilizing deep learning on longitudinal medical records could serve as a practical “prescreening” filter, effectively identifying high-risk individuals who would benefit most from the advanced physiological and imaging investigations outlined by Goldstein.⁴,⁶ The trajectory of Alzheimer’s disease research offers a compelling precedent for this approach. As highlighted in recent expert recommendations, the integration of biomarkers like amyloid PET into preclinical and prodromal staging systems has been a key driver in the success of disease-modifying therapies, subsequently elevating such imaging from research tools to essential components of clinical practice.⁷ Similarly, the systematic model articulated by Dr. Goldstein offers a robust rationale for future investigations by clarifying what should be measured, when such measurements are most informative, and why they are biologically meaningful (Fig. 1).

We anticipate that this review will serve as an essential reference point for clinicians and researchers engaged in the design of preclinical studies on Lewy body diseases and will play a pivotal role in shaping the next generation of biomarker-driven research in this field.

Availability of Data and Material

Data sharing not applicable to this article as no datasets were generated or analyzed during the study.