Cardiac Sympathetic Dysfunction Reveals Asymmetric Dopaminergic Neurodegeneration in Drug-naive Parkinson Disease

PURPOSE: Asymmetric nigrostriatal dopaminergic degeneration in Parkinson disease (PD) is linked to motor and nonmotor manifestations and may reflect Lewy body propagation patterns, particularly in brain-first pathology. The clinical determinants of nigrostriatal dopaminergic asymmetry, however, remain unclear. METHODS: We studied 121 drug-naive patients with PD to examine associations between the striatal asymmetry index (AI) and clinical features, including olfactory function, constipation, and cardiac sympathetic dysfunction measured by 123I-metaiodobenzylguanidine (MIBG) scintigraphy. RESULTS: Patients with pronounced striatal asymmetry (AI >20%) exhibited lower prevalences of hypertension and smoking, a higher frequency of tremor-dominant phenotype, and predominantly right-sided motor symptoms compared with those with symmetric dopaminergic degeneration (AI ≤20%). They also had higher cardiac 123I-MIBG uptake and less severe orthostatic blood pressure decline. Unexpectedly, olfactory dysfunction severity was not associated with striatal AI. Multivariable regression analysis revealed that cardiac sympathetic dysfunction independently and robustly correlates with symmetric degeneration of nigrostriatal dopaminergic neurons (β=0.287, t=3.032, P=0.003). Hierarchical clustering grouped cardiac sympathetic dysfunction and striatal AI in the same lowest-level cluster (linkage dissimilarity = 0.66), indicating a close association. Patients exhibiting markedly reduced cardiac 123I-MIBG uptake demonstrated more symmetric dopaminergic degeneration compared with those with normal uptake (striatal AI: 10.8±10.2% vs. 23.5±15.8%; P=0.003). CONCLUSIONS: Cardiac sympathetic Lewy body burden appears to play a central role in shaping nigrostriatal dopaminergic asymmetry in early PD. Cardiac sympathetic denervation may act as a phenotypic modifier, influencing the spatial pattern of neurodegeneration and contributing to clinical heterogeneity.