Measuring the iron content of dopaminergic neurons in substantia nigra with MRI relaxometry

In Parkinson9s disease, the depletion of iron-rich dopaminergic neurons in substantia nigra9s nigrosome 1 precedes first motor symptoms by two decades. Monitoring this neuronal depletion at an early disease stage is needed for diagnosis and treatment monitoring. Magnetic resonance imaging (MRI) is particularly suitable for this task due to its sensitivity to tissue iron. However, the mechanisms of MRI contrast in substantia nigra are not well understood, hindering the development of specific biomarkers. We showed that the dominant contribution to the effective transverse MRI relaxation rate R2* in nigrosome 1 originates from iron accumulated in the neuromelanin of dopaminergic neurons. We linked R2* quantitatively to the product of cell density and local iron concentration in dopaminergic neurons, combining quantitative 3D iron histology, biophysical modeling, and quantitative MRI on post mortem brain tissue. This knowledge opens an avenue for monitoring neuronal iron and density in vivo and may be applied to detect early neurodegeneration in Parkinson9s disease.