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

Differential serum microRNAs in premotor LRRK2 G2019S carriers from Parkinson’s disease

“…Similarly, two earlier studies showed distinct miRNA fingerprints in iPD and monogenic PD patients with LRRK2, SNCA, or GBA mutations 31,42 . In addition, miR-19b-3p and miR-29c-3p were previously associated with iPD 25,26,29,30,43,44 or idiopathic RBD 27,28 , and were also deregulated in our study only in iPD but not in G2019S carriers. Altogether, these results align with previous findings 31,42 indicating group-specific miRNA deregulation between iPD and L2PD and an overall greater miRNA deregulation effect in iPD than in L2PD, which is compliant with the complex multifactorial etiology of iPD 45,46 .…”

“…After discarding commercially available assays which did not amplify at a minimum quality level in serum samples, by real-time quantitative PCR (RT-qPCR) we tested a total of 12 candidate miRNAs. These included 10 candidate DEmiR detected by the array (miR-122-5p, miR-16-5p, miR-185-5p, miR-19b-3p, miR-22-3p, miR-221-3p, miR-29c-3p, miR-3196, miR-4505, miR-451a, miR-6125 and miR-8069), and 2 additional candidate miRNA earlier reported in iPD (miR-29c-3p) 25,27 or well-established PD prodromal stages (idiopathic RBD) (miR-451a) 28 . Among the candidate miRNAs selected from the array, miR-185-5p, miR-6125, miR-3196, miR-4505, and miR-22-3p were detected in more than one comparison (Supplementary Table 1), and miR-19b-3p and miR-221-3p were previously reported as deregulated miRNAs in PD 25 and idiopathic RBD 28 .…”

“…By RT-qPCR, we assessed the expression levels of ten candidate miRNAs found in the genome-wide analysis across different comparisons (Supplementary Table 2) and two additional candidate miRNA earlier reported in iPD (miR-29c-3p) 25,27 or PD prodromal stages (miR-451a) 28 . Using the same serum samples, we validated 8 DEmiR, which were deregulated in one or more G2019S carrier groups (miR-122-5p, miR-16-5p, miR-185-5p, miR-221-3p, miR-3196, miR-4505, miR-451a, and miR-8069) (Fig.…”

Glutathione Depletion and MicroRNA Dysregulation in Multiple System Atrophy: A Review

“…Four independent miRNA microarrays revealed several dysregulated miRNAs in MSA patients: miR-19b-3p, miR-25-3p and miR-92a-3p [ 18 , 112 , 113 , 114 , 115 , 119 ]. miR-19b-3p has been reported as a biomarker of PD in several studies [ 140 , 141 ]. Interestingly, both miR-25-3p and miR-19b-3p have been detected in the serum of patients with an isolated form of REM sleep behavior disorder, representing the prodromal state of the α-synucleinopathies, suggesting that these miRNAs could be potential prognostic biomarkers for α-synucleinopathies [ 142 ].…”

Detection of a Parkinson's Disease–Specific MicroRNA Signature in Nasal and Oral Swabs

“…For instance, a recent study found sustained deregulation of 12 miRNAs across the RBD continuum. 18 We ourselves investigated the expression of miRNAs in routine colonic biopsies from PD cases by miRNA sequencing (miRNA-seq) and found several differentially expressed submucosa-enriched miRNAs, with hsa-miRNA-486-5p having the highest effect size for PD. 19 Because colonic biopsies are less well suited for routine diagnostics, we here tested the diagnostic value of the eight most promising candidate miRNAs from our previous report in buccal (oral) and nasal swabs in PD and iRBD cases and in healthy controls.…”