Presynaptic dopaminergic imaging as a neurodegeneration staging biomarker in the alpha-synucleinopathy continuum

To define how dopamine transporter (DaT) SPECT can be used to stage neurodegeneration in neuronal alpha-synucleinopathy patients at the individual level. This is an international multicenter study involving 1067 subjects (mean age 69.8 ± 8.7 years; 63.2% males) who underwent DaT-SPECT as a neurodegeneration biomarker. 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’s 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 = 232) or converters (cRBD, n = 168). 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). The combination of the most affected putamen and the least affected caudate best staged patients across the continuum (p < 0.001). Our data suggest that the most affected putamen z-scores can be used to define three levels of neurodegeneration, such as undetected (above − 1), moderate (between − 1 and − 2), and severe (below − 2). Cox regression analysis in iRBD patients showed that these cutoffs predicted phenoconversion (hazard ratios 3.10–5.03), outperforming clinical risk metrics (MDS-UPDRS-III, MMSE, and hyposmia) for overall and motor-predominant phenoconversion. 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.