Cardiac 123I-Meta-Iodobenzylguanidine Imaging as a Biomarker for Body-First Parkinson’s Disease: Linking Peripheral α-Synuclein to Clinical Subtyping

Recent neuropathological and imaging studies support the concept of "brain-first vs. body-first" Parkinson's disease (PD), which is based on the α-synuclein origin site and connectome model. The body-first phenotype is characterized by early involvement of the peripheral autonomic nervous system, particularly the cardiac sympathetic nerves and enteric nerves. 123I-meta-iodobenzylguanidine (123I-MIBG) myocardial scintigraphy is a well-established method for evaluating cardiac sympathetic innervation. This review explores the potential of 123I-MIBG scintigraphy as a biomarker to differentiate the body-first phenotype from the brain-first phenotype. Reduced 123I-MIBG uptake has been observed in idiopathic rapid eye movement (REM) sleep behavior disorder, pure autonomic failure, and incidental Lewy body disease-conditions strongly associated with prodromal or early-stage PD. Postmortem and biopsy evidence indicates α-synuclein accumulation in cardiac nerves and other peripheral sites, which is consistent with bottom-up progression. α-Synuclein seed amplification assays further corroborate the association between the peripheral α-synuclein burden and reduced 123I-MIBG uptake. While 123I-MIBG myocardial scintigraphy is a promising tool, its limitations include cost, limited availability, and potential confounding from underlying cardiac conditions. Nonetheless, early detection of cardiac sympathetic denervation via 123I-MIBG imaging may enhance diagnosis, support subtype classification, and improve the understanding of PD pathogenesis.