Seeing Parkinson’s Before It Strikes: Ultra-High Field Micro-Connectomics in REM Sleep Behavior Disorder as a Preclinical Biomarker of Nigrostriatal Degeneration

ZHIXUAN WANG^*

• Aquinas International Academy, Garden Grove, United States

The prodromal phase of Parkinson's disease (PD), during which neurodegeneration precedes clinical motor symptoms by years, offers a critical window for intervention. In this Hypothesis and Theory article, we propose that quantitative susceptibility mapping (QSM) and advanced diffusion MRI at ultra-high field (UHF) strengths (≥7 T, with future 14 T) can noninvasively detect early nigrostriatal pathology in prodromal PD -specifically in patients with idiopathic REM sleep behavior disorder (iRBD). QSM provides a surrogate measure of iron deposition, while diffusion MRI (including free-water and multi-shell models) sensitively quantifies axonal microstructural integrity. We synthesize evidence from cutting-edge human and animal studies showing iron accumulation and microstructural connectivity changes in the substantia nigra (SN) and basal ganglia long before motor onset. In particular, we highlight convergent findings that iRBD -a strong clinical predictor of PD onset -exhibits nigrostriatal changes such as increased SN iron and altered white-matter pathways. We outline a theoretical "micro-connectomics" pipeline that integrates UHF QSM and diffusion metrics to map the nigrostriatal network and identify early biomarkers of PD. Finally, we discuss how this bold multimodal imaging approach could serve as a preclinical biomarker platform to stratify high-risk individuals for neuroprotective trials. Our central hypothesis is that UHF QSM and diffusion MRI together will reveal iron-laden, axonally degraded nigrostriatal regions in RBD years before symptom onset, providing a critical entry point for disease-modifying interventions.