Predicting Parkinson's Disease Before It Strikes: A Brain Imaging Study in At-Risk Individual

Idiopathic REM Sleep Behavior Disorder, Neurodegeneration, Parkinson Disease, Prodromal Parkinson Disease

REM sleep behavior disorder, iRBD, Parkinson's disease, Neurodegeneration, MRI, Polysomnography, Prodromal Parkinson, Diffusion tensor imaging, Resting-state fMRI, Prognostic model, Cognitive assessment

This study aims to characterize neurodegeneration progression in patients with polysomnography (PSG)-confirmed longstanding idiopathic REM sleep behavior disorder (iRBD) and to develop a prognostic model for clinical evolution and earlier identification of cases at risk of short-term conversion to clinically defined Parkinson's disease (PD). The study uses a multiparametric approach combining longitudinal clinical, neuropsychological, quantitative PSG, and multiparametric brain MRI markers (structural MRI, diffusion tensor imaging, resting-state functional MRI) to track neurodegeneration from the prodromal stage of PD and predict individual disease evolution. 50 patients with PSG-confirmed iRBD (duration since diagnosis greater than or equal to 5 years) and 50 age- and sex-matched healthy controls will be assessed at baseline and every year for 3 years at IRCCS Ospedale San Raffaele, Milan, Italy.

Parkinson's disease (PD) is a chronic, debilitating neurodegenerative disorder characterized by progressive motor dysfunction and various non-motor features. Better understanding and prediction of PD progression from the earliest stage will improve disease management and clinical trial design. Idiopathic REM sleep behavior disorder (iRBD) is the most specific marker of prodromal PD, since the majority of individuals with iRBD eventually develop PD or a related synucleinopathy. Longitudinal studies have shown that the estimated risk for the clinical diagnosis of a synucleinopathy from the time of iRBD diagnosis is about 35% at 5 years, 75% at 10 years, and 90% at 14 years. Therefore, studying iRBD provides a unique window to observe neurodegenerative synucleinopathies in their prodromal stages, before parkinsonism or dementia becomes fully manifest. This is a national, monocentric, longitudinal observational study with additional procedures. Patients with iRBD will be screened to evaluate eligibility: patients will be included if they have PSG-confirmed longstanding iRBD duration since diagnosis equal or greater than 5 years, without a clinically defined PD. All patients undergo clinical and cognitive assessments, quantitative PSG, and MRI visits at baseline (T0) and every year for 3 years. PSG is performed to diagnose iRBD and investigate PSG changes over time. MRI evaluations investigate structural alterations and resting-state (RS) functional connectivity. Longitudinal measures of cortical/subcortical atrophy, white matter damage, and RS connectivity will be assessed. A group of 50 healthy subjects similar for age (50-75 years old) and sex to patients with iRBD will be recruited. They will undergo clinical evaluation and PSG at study entry (to exclude sleep disorders), and motor, neuropsychological and MRI assessments at baseline and every year for 3 years. Clinical assessments include: Unified Parkinson's Disease Rating Scale (UPDRS), Single-Question Screen for REM sleep behavior disorder, REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ), Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), Beck Depression Inventory-II (BDI-II). Motor assessments include: Five Times Sit-To-Stand, Ten-Meter Walking Test (10MWT), Timed Up and Go Test (TUG), TUG with cognitive task, Nine Hole Peg Test. Neuropsychological assessments include: MMSE, Digit span forward and backward, Corsi block-tapping test, Rey's List, Raven's Progressive Matrices, Trail Making Test A and B (TMT-A and TMT-B), Attentive Matrices, Verbal Fluency (phonemic and semantic cues), Token Test, Copy of Rey-Osterrieth complex figure. PSG recording includes: electroencephalogram (six channels), electrooculogram, electromyography (submentalis muscle and bilateral tibialis anterior muscles), electrocardiogram, and sleep respiratory pattern. Brain MRI sequences include: 3D sagittal T1-weighted fast field echo (structural MRI), diffusion tensor (DT) MRI, and T2\*-weighted EPI sequence for resting-state fMRI. Statistical analyses include: t-test, Mann-Whitney U-test or Pearson chi-square for between-group comparisons; longitudinal linear generalized models for repeated measures or Wilcoxon test for within-group changes over time; multivariable linear mixed-effects models for predictors of motor/nonmotor progression; multivariable Cox model for predictors of conversion to full clinical disease in iRBD.

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