MCI IN RBD as a Distinct Clinical Entity: Comparative Evaluation of Diagnostic Frameworks and the cognitive domain as predictive factors of phenotypic conversion

Rapid Eye Movement Sleep Behavior Disorder (RBD) is a parasomnia characterized by loss of muscle atonia during REM sleep and the occurrence of dream-enacting behaviors, often associated with vivid and sometimes violent dreams. Increasing evidence supports that RBD represents an early clinical manifestation along the continuum of α-synuclein–related neurodegeneration and a prodromal condition preceding the development of Parkinson’s disease (PD) or dementia with Lewy bodies (DLB). Individuals with isolated RBD (iRBD) frequently exhibit subtle but measurable cognitive alterations that may reflect the initial spread of pathology. Neuropsychological changes are often concomitant in this population: numerous studies have reported executive and attentional dysfunctions (Joza et al., 2024; Leitner et al., 2024), typically configuring a non-amnestic MCI profile, often associated with an increased risk of subsequent dementia (Arnaldi et al., 2021; Joza et al., 2024). However, considerable variability persists across clinical centers, as different criteria are applied to diagnose MCI in RBD. This doctoral thesis provides novel and integrative evidence addressing this gap by systematically comparing existing diagnostic frameworks, exploring data-driven cognitive subtypes, and identifying longitudinal predictors of decline. The research was conducted within the FARPRESTO multicentre cohort of individuals with RBD and comprises two complementary studies. The first focused on the cross-sectional characterization and stratification of neuropsychological performance to identify distinct cognitive phenotypes. The second longitudinal study investigated the evolution of cognitive changes over time and the predictive value of baseline measures for the subsequent development of MCI. In the first study, the neuropsychological evaluation of 55 RBD patients was stratified to identify distinct clusters of impairment, delineating specific cognitive phenotypes within the cohort. Results revealed heterogeneous cognitive profiles—preserved, dysexecutive, and visuospatially impaired—while executive–attentional dysfunction, as captured by Trail Making Test and Modified Wisconsin Card Sorting Test performance, consistently distinguished MCI-positive subjects from unimpaired individuals, showing the highest discriminative accuracy. A pilot sample of 10 subjects was followed up longitudinally over two years; overall cognition remained stable. However, baseline executive measures predicted later MCI classification, supporting their role as early indicators of fronto-striatal dysfunction. These findings reinforce the hypothesis that executive impairment represents an early and specific cognitive marker of α-synuclein–related neurodegeneration, preceding the emergence of overt motor or behavioral symptoms. Overall, this work advances understanding of the cognitive architecture of RBD and highlights the need for RBD-specific operational criteria for MCI integrating neuropsychological and biomarker evidence. It also emphasizes the relevance of harmonized diagnostic approaches to reduce heterogeneity and improve early risk stratification, providing a framework for identifying individuals at increased risk of phenoconversion and for designing targeted longitudinal studies and neuroprotective trials.