Serum MicroRNAs Predict Isolated Rapid Eye Movement Sleep Behavior Disorder and Lewy Body Diseases

Abstract

Background: Isolated rapid eye movement sleep behavior disorder (IRBD) is a well-established clinical risk factor for Lewy body diseases (LBDs), such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB).

Objective: To elucidate whether serum microRNA (miRNA) deregulation in IRBD can antedate the diagnosis of LBD by performing a longitudinal study in different progression stages of IRBD before and after LBD diagnosis and assessing the predictive performance of differentially expressed miRNAs by machine learning-based modeling.

Methods: Using genome-wide miRNA analysis and real-time quantitative polymerase chain reaction validation, we assessed serum miRNA profiles from patients with IRBD stratified by dopamine transporter (DaT) single-photon emission computed tomography into DaT-negative IRBD (n = 17) and DaT-positive IRBD (n = 21), IRBD phenoconverted into LBD (n = 13), and controls (n = 20). Longitudinally, we followed up the IRBD cohort by studying three time point serum samples over 26 months.

Results: We found sustained cross-sectional and longitudinal deregulation of 12 miRNAs across the RBD continuum, including DaT-negative IRBD, DaT-positive IRBD, and LBD phenoconverted IRBD (let-7c-5p, miR-19b-3p, miR-140, miR-22-3p, miR-221-3p, miR-24-3p, miR-25-3p, miR-29c-3p, miR-361-5p, miR-425-5p, miR-4505, and miR-451a) (false discovery rate P < 0.05). Age- and sex-adjusted predictive modeling based on the 12 differentially expressed miRNA biosignatures discriminated IRBD and PD or DLB from controls with an area under the curve of 98% (95% confidence interval: 89-99%).

Conclusions: Besides clinical diagnosis of IRBD or imaging markers such as DaT single-photon emission computed tomography, specific miRNA biosignatures alone hold promise as progression biomarkers for patients with IRBD for predicting PD and DLB clinical outcomes. Further miRNA studies in other PD at-risk populations, such as LRRK2 mutation asymptomatic carriers or hyposmic subjects, are warranted. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: Parkinson's disease (PD); biomarkers; disease prediction; dopamine transporter single-photon emission computed tomography (DaT-SPECT); isolated REM-sleep behavior disorder (IRBD).

FIG 1

Longitudinal microRNA (miRNA) expression levels in serum from patients with dopamine transporter (DaT)‐negative idiopathic rapid eye movement sleep behavior disorder (IRBD), DaT‐positive IRBD, and LBD compared with healthy controls. Dashed line, DaT‐positive IRBD; dotted line, DaT‐negative IRBD. LBD, Lewy body disease (Parkinson's disease and dementia with Lewy bodies).

FIG 2

Differential expression and diagnostic accuracy of the 12 miRNA biosignatures. (A) Receiver operating characteristic (ROC) curve showing the discriminative ability from the 12 miRNA biosignatures to predict the subject probability of disease, IRBD, or PD/DLB versus being a healthy control subject (n = 71). Table showing performance metrics obtained through machine learning analysis for binary classification of individuals within the disease or control groups. (B) Unsupervised hierarchical clustering displaying real‐time quantitative polymerase chain reaction expression levels of the 12 miRNA signatures. Red pixels indicate miRNA overexpression, and green decreased expression levels. AUC, area under the curve; CI, confidence interval; DEmiR, differentially expressed microRNA; DLB, dementia with Lewy bodies; IRBD, idiopathic rapid eye movement sleep behavior disorder; LBD, Lewy body disease (PD and DLB); NPV, negative predictive value; PD, Parkinson's disease; PPV, positive predictive value. [Color figure can be viewed at wileyonlinelibrary.com]