Lifespan pigmentation changes of the substantia nigra detected by neuromelanin-sensitive MRI

Background: Neuromelanin is a pigment with strong iron-chelating properties preferentially found in dopaminergic neurons of the substantia nigra, pars compacta (SNpc). Parkinson's disease is characterized by pronounced, MRI detectable neuromelanin loss, but the neuroprotective or neurotoxic role of neuromelanin remains debated. Histological studies demonstrated neuromelanin increases with age, but this has not been confirmed in vivo and there is uncertainty whether neuromelanin declines, stabilizes or increases from middle age.Methods: This study aimed to establish physiological changes of pigmentation of the SNpc using a pooled dataset of neuromelanin-sensitive 3T MRI from 134 healthy individuals, aged 5~83 years. Neuromelanin-related brightness (regional contrast-to-ratio) and calibrated hyperintense volumes were analyzed using linear and non-linear regression models to characterize age effects. Laterality, sex, and subregional effects were also assessed.Results: For brightness, age effects were best described as a quadratic trajectory explaining 81.5% of the observed variance in SNpc showing a strong increase from childhood to adolescence, with plateauing in middle age and a decline in older age. Similar but less pronounced effects were seen in hyperintense volumes. We also show an anteriorposterior gradient in SNpc contrast, larger normalized NM-rich volume in women >47 of age, but no laterality effect.Conclusions: Using optimized neuromelanin-MRI in a lifespan sample, we demonstrate a strong age effect with an inverted U-shape of SNpc pigmentation-related contrast from childhood to old age. This age trajectory of physiological SNpc pigmentation needs to be taken into account for diagnostic applications of depigmentation. The study also paves the way for systematic investigations of the mechanisms of neuromelanin in healthy and pathological brain development and aging.