Life span pigmentation changes of the substantia nigra detected by neuromelanin‐sensitive MRI

Abstract

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 have 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 data set 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 nonlinear 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 the 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 anterior‐posterior gradient in SNpc contrast, larger normalized neuromelanin‐rich volume in women > 47 years old, but no laterality effect. Conclusions : Using optimized neuromelanin MRI in a life span sample, we demonstrate a strong age effect with inverted U‐shaped 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. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Regional Distributions of Iron, Copper and Zinc and Their Relationships With Glia in a Normal Aging Mouse Model

“…Due to its exceptionally high iron content, the substantia nigra adopts two different iron storage systems, one based on ferritin and the other, on neuromelanin (Tribl et al, 2009), enabling synergistic regulation of iron homeostasis. However, our age-related observation of decreased ferritin along with reports signifying declining neuromelanin content (Tribl et al, 2009;Xing et al, 2018) in the aged substantia nigra, suggest an increased ferrous iron pool that can precipitate oxidative stress during brain aging, contributing to the increased risk of neurodegenerative diseases, particularly PD, with aging (Dexter et al, 1987;Xu et al, 2018).…”

Parkinson’s Disease in Women and Men: What’s the Difference?

“…Sex variance in prooxidantantioxidant balance and malondialdehyde levels, a product of lipid peroxidation, has been observed in PD patients [125]. Interestingly, a recent neuromelanin (NM) imaging study highlighted a bigger normalized NM-rich volume in the women SN compared with men older than 47 years, suggesting that this difference may underpin the high male-to-female ratio of the PD prevalence [126]. Neuromelanin, a pigment with paramagnetic properties, acts as a scavenger removing potentially toxic substances through the autooxidation of catecholamines and/or binding redox-active metal ions such as iron.…”

Neuromelanin, aging, and neuronal vulnerability in Parkinson's disease

“…Also, in a recent retrospective study on healthy individuals of different ages (from 5-83 years), the neuromelanin-sensitive MRI SNpc signal peaked in middle age before declining in older ages, which was attributed to an age-related decrease of melanized nigral neurons. 87 Overall, neuromelanin-filled neurons from apparently healthy aged individuals exhibit early signs of neuronal dysfunction/degeneration. Whether these changes precede clinical PD or are part of normal brain aging remains to be determined.…”