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We enrolled 277 controls, 400 patients with idiopathic\/isolated REM sleep behavior disorder (iRBD), representing the prodromal alpha-synucleinopathy stage, and 390 patients with an overt stage, including 175 with overt Parkinson\u2019s disease (oPD) and 215 with overt dementia with Lewy bodies (oDLB). iRBD patients were followed over time and were stratified as non-converters (ncRBD,\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u2009232) or converters (cRBD,\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u2009168). The ability of DaT-SPECT to stage the neuronal alpha-synucleinopathy continuum was evaluated using forward stepwise logistic regression models, assuming that this stratification reflects progressive neurodegeneration stages (controls, ncRBD, cRBD, and overt PD\/DLB).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The combination of the most affected putamen and the least affected caudate best staged patients across the continuum (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001). Our data suggest that the most affected putamen z-scores can be used to define three levels of neurodegeneration, such as undetected (above \u2212\u20091), moderate (between \u2212\u20091 and \u2212\u20092), and severe (below \u2212\u20092). Cox regression analysis in iRBD patients showed that these cutoffs predicted phenoconversion (hazard ratios 3.10\u20135.03), outperforming clinical risk metrics (MDS-UPDRS-III, MMSE, and hyposmia) for overall and motor-predominant phenoconversion.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>DaT-SPECT z-score thresholds provide a ready-to-use three-tier staging system for alpha-synucleinopathies, enabling objective assessment of neurodegeneration severity and phenoconversion risk at the individual level.<\/jats:p>\n                  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Giuseppe Plazzi has received honoraria for Scientific Advisory Board activities from Alkermes, Bioprojet, Centessa, Idorsia, and Takeda. Val J. Lowe serves as a consultant for Bayer Schering Pharma, Piramal Life Sciences, Life Molecular Imaging, Eisai Inc., AVID Radiopharmaceuticals, Eli Lilly and Company, PeerView Institute for Medical Education, and Merck Research and receives research support from GE Healthcare, Siemens Molecular Imaging, AVID Radiopharmaceuticals, and the NIH (NIA, NCI). Michele T. Hu serves as a consultant for Helicon, NeuHealth Digital, Roche and Manus Neurodynamica. Previous consultancies are: Lundbeck, ESCAPE Bio, Evidera, Biogen MA, CuraSen Therapeutics, Roche Products Ltd, Jazz Pharma, Aventis Pharma. She is an advisory founder and shareholder of NeuHealth Digital Ltd (company number: 14492037), a digital biomarker platform to remotely manage condition progression for Parkinson\u2019s. Beatrice Orso received a research grant from GE Healthcare. Fabio Pizza participated to Advisory Board (Takeda), received support for congress attendance (Bioprojet), received fees for symposia (Bioprojet). Laura Bonanni received research grants by the Italian Ministry of Health and by the Italian Ministry of Education. She serves as consultant for Eli Lilly Andr\u00e9s Perissinotti has received honoraria from GE Healthcare as speaker in symposiums.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}