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Longitudinal T1-weighted anatomical and neuromelanin-sensitive MRI was performed in two cohorts, including patients with iRBD, patients with early or progressing Parkinson\u2019s disease, and control subjects. Based on the aligned substantia nigra segmentations using a study-specific brain anatomical template, parametric maps of the probability of a voxel belonging to the substantia nigra were calculated for patients with various degrees of disease severity and controls. For each voxel in the substantia nigra, probability map of controls, correlations between signal-to-noise ratios on neuromelanin-sensitive MRI in patients with iRBD and Parkinson\u2019s disease and clinical scores of motor disability, cognition and mood\/behaviour were calculated. Our results showed that in patients, compared to the healthy control subjects, the volume of the substantia nigra was progressively reduced for increasing disease severity. The neuromelanin signal changes appeared to start in the posterolateral motor areas of the substantia nigra and then progressed to more medial areas of this region. The ratio between the volume of the substantia nigra in patients with Parkinson\u2019s disease relative to the controls was best fitted by a mono-exponential decay. Based on this model, the pre-symptomatic phase of the disease started at 5.3 years before disease diagnosis, and 23.1% of the substantia nigra volume was lost at the time of diagnosis, which was in line with previous findings using post-mortem histology of the human substantia nigra and radiotracer studies of the human striatum. Voxel-wise patterns of correlation between neuromelanin-sensitive MRI signal-to-noise ratio and motor, cognitive and mood\/behavioural clinical scores were localized in distinct regions of the substantia nigra. This localization reflected the functional organization of the nigrostriatal system observed in histological and electrophysiological studies in non-human primates (motor, cognitive and mood\/behavioural domains). In conclusion, neuromelanin-sensitive MRI enabled us to assess voxel-wise modifications of substantia nigra\u2019s morphology in vivo in humans, including healthy controls, patients with iRBD and patients with Parkinson\u2019s disease, and identify their correlation with nigral function across all motor, cognitive and behavioural domains. This insight could help assess disease progression in drug trials of disease modification.<\/jats:p>","DOI":"10.1093\/brain\/awaa216","type":"journal-article","created":{"date-parts":[[2020,6,15]],"date-time":"2020-06-15T15:11:13Z","timestamp":1592233873000},"page":"2757-2770","source":"Crossref","is-referenced-by-count":137,"title":["Spatiotemporal changes in substantia nigra neuromelanin content in Parkinson\u2019s disease"],"prefix":"10.1093","volume":"143","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6727-0935","authenticated-orcid":false,"given":"Emma","family":"Biondetti","sequence":"first","affiliation":[{"name":"Institut du Cerveau \u2013 ICM, \u00a0INSERM U 1127, CNRS UMR 7225, Sorbonne Universit\u00e9, Paris, France"},{"name":"ICM, Centre de NeuroImagerie de Recherche \u2013 CENIR, Paris, France"},{"name":"ICM, Team \u201cMovement Investigations and Therapeutics\u201d (MOV\u2019IT), Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9983-5873","authenticated-orcid":false,"given":"Rahul","family":"Gaurav","sequence":"additional","affiliation":[{"name":"Institut du Cerveau \u2013 ICM, \u00a0INSERM U 1127, CNRS UMR 7225, Sorbonne Universit\u00e9, Paris, France"},{"name":"ICM, Centre de NeuroImagerie de Recherche \u2013 CENIR, Paris, France"},{"name":"ICM, Team \u201cMovement Investigations and Therapeutics\u201d (MOV\u2019IT), Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lydia","family":"Yahia-Cherif","sequence":"additional","affiliation":[{"name":"Institut du Cerveau \u2013 ICM, \u00a0INSERM U 1127, CNRS UMR 7225, Sorbonne Universit\u00e9, Paris, France"},{"name":"ICM, Centre de NeuroImagerie de Recherche \u2013 CENIR, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graziella","family":"Mangone","sequence":"additional","affiliation":[{"name":"Institut du Cerveau \u2013 ICM, \u00a0INSERM U 1127, CNRS UMR 7225, Sorbonne Universit\u00e9, Paris, France"},{"name":"National Institute of Health and Medical Research - INSERM, Clinical Investigation Centre, Piti\u00e9-Salp\u00eatri\u00e8re Hospital, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2070-1299","authenticated-orcid":false,"given":"Nadya","family":"Pyatigorskaya","sequence":"additional","affiliation":[{"name":"Institut du Cerveau \u2013 ICM, \u00a0INSERM U 1127, CNRS UMR 7225, Sorbonne Universit\u00e9, Paris, France"},{"name":"ICM, Team \u201cMovement Investigations and Therapeutics\u201d (MOV\u2019IT), Paris, France"},{"name":"Department of Neuroradiology, Piti\u00e9-Salp\u00eatri\u00e8re Hospital, Public Assistance - Paris Hospitals (AP-HP), Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romain","family":"Valabr\u00e8gue","sequence":"additional","affiliation":[{"name":"Institut du Cerveau \u2013 ICM, \u00a0INSERM U 1127, CNRS UMR 7225, Sorbonne Universit\u00e9, Paris, France"},{"name":"ICM, Centre de NeuroImagerie de Recherche \u2013 CENIR, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Ewenczyk","sequence":"additional","affiliation":[{"name":"Institut du Cerveau \u2013 ICM, \u00a0INSERM U 1127, CNRS UMR 7225, Sorbonne Universit\u00e9, Paris, France"},{"name":"ICM, Team \u201cMovement Investigations and Therapeutics\u201d (MOV\u2019IT), Paris, France"},{"name":"Department of Neurology, Piti\u00e9-Salp\u00eatri\u00e8re Hospital, Public Assistance - 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