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.

Background/Objectives: Gender differences influence the clinical manifestations, progression, and treatment response in obstructive sleep apnea (OSA) syndrome, suggesting the existence of distinct gender-related phenotypes potentially driven by anatomical, physiological, and hormonal factors. However, the impact of gender on OSA-related cognitive profiles remains unknown. This study aimed to investigate the neuropsychological and polysomnographic (PSG) differences between OSA females and males in order to detect the impact of gender on clinical manifestation and PSG features. Methods: Data were collected from 28 OSA patients (14 females and 14 males matched for age, education, and disease severity). All patients performed a complete neuropsychological evaluation, Epworth sleepiness scale, and whole-night PSG. To evaluate the relationship between specific sleep profiles and cognitive performance, PSG parameters were correlated to scores obtained on neuropsychological tests. Results: Both male and female groups performed within the normal range across all administered neuropsychological tests, according to Italian normative values. Compared with OSA males, female patients showed significantly lower values on the Rey–Osterrieth Complex Figure (ROCF) Recall Test. By contrast, no significant statistical clinical difference emerged between the two OSA groups in terms of clinical manifestation and sleep parameters. Conclusions: This study improves the knowledge on gender-related cognitive impairment in OSA patients. Our preliminary findings demonstrate that the ROCF Recall Test may be altered in OSA females, but not in males. Further longitudinal studies are needed to investigate whether OSA female patients will develop a frank dementia over time.