Neuromelanin‐Sensitive MRI as a Marker of Clinical Severity and Disease Burden in Parkinson's Disease: A Systematic Review and Meta‐analysis

Abstract

The neuropathology of Parkinson's disease (PD) is characterized in part by the degeneration of catecholaminergic neurons, particularly dopaminergic neurons in the substantia nigra pars compacta (SNpc) and noradrenergic neurons in the locus coeruleus (LC), yet no validated in vivo biomarker quantifies this process. Neuromelanin‐sensitive magnetic resonance imaging (NM‐MRI) enables noninvasive assessment of these neuronal populations, although relationships with clinical severity, disease burden, and progression remain incompletely defined. We conducted the first Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA)‐guided systematic review and random‐effects meta‐analysis examining associations between NM‐MRI measures and clinical outcomes in PD, including subgroup, meta‐regression, and sensitivity analyses. Reduced NM‐MRI measures were associated with greater motor impairment (18 studies; pooled r  = −0.406), longer disease duration (14; r  = −0.426), higher Hoehn and Yahr stage (10; r  = −0.336), and higher levodopa equivalent daily dose (6; r  = −0.337) (all P  < 0.001). Thirty‐nine studies (1983 patients with PD) were included in the systematic review. Narrative synthesis demonstrated distinct SNpc/LC associations: SNpc measures were primarily associated with motor dysfunction and disease stage, displaying hemispheric asymmetry, intranigral topography, and phenotype‐specific patterns, whereas LC measures were preferentially linked to cognitive, affective, autonomic, and sleep‐related symptoms. Four longitudinal studies (~1.5–3 years) reported declines in selected NM‐MRI measures (~5%–19% annually). Multimodal studies suggested NM‐MRI captures a complementary dimension of nigrostriatal pathology alongside dopaminergic, iron‐sensitive, and diffusion‐based markers. NM‐MRI provides a biologically interpretable in vivo measure of catecholaminergic neuron integrity and survival in PD, with consistent cross‐sectional associations with clinical disease burden. Emerging longitudinal and multimodal evidence supports its potential as a progression‐sensitive imaging biomarker for disease‐modifying clinical trials. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.