Tracking prodromal α-synucleinopathies: novel fluid- and tissue-based biomarker approaches for iRBD phenoconversion.

Isolated rapid eye movement sleep (REM) behavior disorder (iRBD) represents the strongest predictor of α-synucleinopathies, with over 90% of patients developing Parkinson's disease, dementia with Lewy bodies, or multiple system atrophy after a decade. As such, iRBD provides a critical window for early diagnosis and intervention. While molecular imaging techniques have been widely explored as powerful biomarkers for early disease detection, validated, more accessible tests based on biospecimens capable of reliably predicting phenoconversion remain lacking, creating a crucial gap in the clinical management of at-risk individuals. This review provides a critical overview of the latest findings in biofluid and tissue-based biomarkers in iRBD, emphasizing the most promising candidates and outlining key directions for future research and clinical applications. While cerebrospinal fluid (CSF)-based α-synuclein has widely proven high diagnostic and prognostic accuracy, blood, urine, stool, skin, olfactory, and oral mucosa samples offer a feasible approach for scalable, population-level screenings in prodromal α-synucleinopathies. The development of multimodal biomarker panels combining accessible biofluids and tissue samples may pave the way for early intervention and more effective risk stratification in future neuroprotective trials for α-synucleinopathies. Statement of Significance This review provides an up-to-date synthesis of the most recent and high-impact studies on biomarkers in isolated rapid eye movement sleep (REM) sleep behavior disorder (iRBD). The growing emphasis on the applicability of less invasive and more clinically accessible biofluids and peripheral tissues reflects a broader clinical shift toward noninvasive approaches capable of supporting population-level screening and targeted interventions. Currently, no validated laboratory tests exist in clinical practice to reliably predict iRBD phenoconversion to overt α-synucleinopathies, creating a critical gap in early stage disease management. The insights presented here will be essential for developing early diagnostic tools and refining patient stratification strategies, both of which are essential for upcoming disease-modifying trials targeting early stage α-synucleinopathies.