Clinical markers of disease progression in the prodromal to overt alpha-synucleinopathy continuum.

Clinical progression from prodromal to overt stages of alpha-synucleinopathies is highly heterogeneous, and there is an urgent need for reliable clinical progression markers. Exploiting the Disease Course Mapping (DCM) model, we investigated how clinical signs evolve in patients with idiopathic/isolated REM sleep behaviour disorder (iRBD), extracting clinical progression measures for use at the single-subject level. Furthermore, we correlated them with both established and innovative neurodegeneration biomarkers. We trained a DCM model using cognitive and motor scores of a longitudinal cohort of 766 patients with iRBD (166 female, 67.9 ± 7.4 years). We personalized the model by extracting three parameters to describe the single subject in comparison to the averaged population data. We tested the model on a blind set of 49 patients with iRBD (seven female, 68.5 ± 7.1 years) who underwent both longitudinal clinical evaluations and instrumental evaluation at the first observation. In the blind set, we correlated the individual model parameters with presynaptic dopaminergic impairment, an established biomarker of substantia nigra neurodegeneration, and cortical electrophysiological dysfunction-measured by high-density electroencephalography (HD-EEG)-an innovative neurodegeneration biomarker. We identified three individual clinical markers reflecting early/late (time-shift, τ) and fast/slow (acceleration factor, α) disease progression, as well as the individual clinical trajectory (i.e. earlier motor or cognitive impairment, intermarker spacing, ω). The individual model parameters are significantly associated with phenoconversion, with a 73% chance of distinguishing between clinically stable patients (non-converters) and those converting during the longitudinal observation to an overt alpha-synucleinopathy (converters). Motor scores progress 35% faster than cognitive scores in our iRBD cohort. Converter iRBD patients exhibited a faster and earlier disease progression than non-converters, and on average, they showed an earlier worsening of motor scores than cognitive scores, regardless of the clinical diagnosis of overt parkinsonism. Patients with iRBD who developed parkinsonism worsened earlier than those who developed dementia. At baseline, an earlier progression was related to presynaptic dopaminergic impairment and higher phase synchronization in the theta band (4-8 Hz). Higher synchronization in the theta band was also associated with an earlier worsening of motor scores than cognitive scores. In this study, we investigated a large longitudinal iRBD cohort, applying an advanced disease progression model. We found three individual clinical markers that were able to monitor disease progression and showed significant association with both established and innovative neurodegeneration biomarkers. We suggest that these clinical markers could be used as efficacy end points in disease-modifying clinical trials.