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), 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 body-first phenotype from brain-first phenotype. Reduced ¹²³I-MIBG uptake has been observed in idiopathic 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 indicate α-synuclein accumulation in cardiac nerves and other peripheral sites, consistent with a bottom-up progression. α-Synuclein seed amplification assays further corroborate the association between 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 understanding of PD pathogenesis.