Circadian alterations in isolated Rapid-Eye-Movement sleep behavior disorder: associations with clinical, glymphatic, and dopaminergic imaging markers

Abstract

Alterations in sleep-wake patterns are well-recognized features of overt alpha-synucleinopathies. However, their presence in prodromal stages, characterized by isolated Rapid-Eye-Movement (REM) sleep behavior disorder, remains controversial, and their association with clinical symptoms and imaging risk factors has been underexplored. In this study, we used seven-day ambulatory circadian monitoring to characterize circadian and sleep-wake disturbances in a well-characterized sample of forty-two patients with video-polysomnography-confirmed isolated REM sleep behavior disorder and 23 healthy controls. We investigated the associations between circadian disturbances and non-motor clinical symptoms, assessed in a comprehensive neuropsychological protocol, alongside imaging proxies of glymphatic system functioning, namely the Diffusion Tensor Imaging Along the Perivascular Spaces index, and the volume of perivascular spaces and choroid plexuses. Moreover, we assessed the associations between circadian alterations and striatal dopaminergic uptake in the most affected putamen, a well-established risk factor for conversion to alpha-synucleinopathies, as assessed with presynaptic dopaminergic imaging. Patients with isolated REM sleep behavior disorder exhibited reduced diurnal physical activity, along with reduced amplitude and increased fragmentation of the sleep probability and motor activity rhythms. Circadian alterations correlated with greater neuropsychiatric symptoms and reduced psychomotor and mental speed. Patients with isolated REM sleep behavior disorder exhibited a decreased Diffusion Tensor Imaging Along the Perivascular Spaces and larger volume of perivascular spaces, but only the former was associated with sleep impairment. Decreased putaminal dopaminergic uptake was associated with rest-activity rhythm fragmentation. These results show that circadian alterations are observed in early stages of neurodegeneration and are associated with clinical and imaging risk markers of conversion to alpha-synucleinopathies, posing them as possible targets for intervention in prodromal disease stages.Statement of Significance This study identifies circadian rhythm disturbances as a core feature of isolated REM sleep behavior disorder, a prodromal phase of alpha-synucleinopathies, and shows that these are linked to clinical symptoms and neuroimaging markers of neurodegeneration. Our findings underscore the relevance of circadian dysfunction in early disease stages, offering new perspectives for identifying individuals at risk before motor symptoms emerge. This work also suggests that circadian alterations may be relevant to glymphatic system impairment and dopaminergic degeneration. A critical next step is to determine whether these circadian changes predict clinical progression or respond to targeted interventions, supporting their potential as translational biomarkers and therapeutic targets in early neurodegenerative disease.