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Background: Rapid eye movement sleep behavior disorder (RBD) is linked to the diffuse-malignant subtype and higher cognitive burden in Lewy body disease (LBD)., Objective: This study explores brain β-amyloid deposition and its association with cognitive decline across the RBD-LBD continuum., Methods: Patients with isolated RBD (iRBD), Parkinson's disease with probable RBD (PDRBD), and dementia with Lewy bodies with probable RBD (DLBRBD) underwent 18 F-florbetaben positron emission tomography, 3T magnetic resonance imaging scans, and comprehensive neuropsychological assessments. Subjects were categorized as cognitively normal (NC), mild cognitive impairment (MCI), or dementia. Global and regional standardized uptake value ratios (SUVR) were estimated in predefined cognitive volumes of interest (VOI) derived from voxel-wise comparison analysis among the cognitive groups, namely the prefrontal, parietal, precentral cortices, lingual gyrus, and supplementary motor area. Generalized linear models assessed the relationship between 18 F-florbetaben SUVRs and neuropsychological testing, adjusting for age and sex. Subgroup analysis focused on the polysomnography-confirmed iRBD-continuum subset (n = 41) encompassing phenoconverters and nonconverters in our prospective iRBD cohort., Results: Eighty-six subjects were classified as follows: 14 NC, 54 MCI, and 18 dementia. The proportion of positive β-amyloid scans increased with advanced cognitive stages (P = 0.038). β-Amyloid signals in cognitive VOIs were elevated in subgroups showing impairment in Trail-Making Test B (TMT-B). A linear association between TMT-B z score and global cortical β-amyloid levels was observed in the iRBD-continuum subset (P = 0.013)., Conclusion: Cortical β-amyloid accumulates with declines in executive function within the RBD-LBD continuum. TMT-B performance may be a useful marker associating with β-amyloid load, particularly in the iRBD population. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Visuoperceptual dysfunction is common in Parkinson's disease (PD) and is also reported in its prodromal phase, isolated REM sleep behavior disorder (iRBD). We aimed to investigate color discrimination ability and complex visual illusions known as pareidolias in patients with iRBD and PD compared to healthy controls, and their associating clinical factors. 46 iRBD, 43 PD, and 64 healthy controls performed the Farnsworth-Munsell 100 hue test and noise pareidolia tests. Any relationship between those two visual functions and associations with prodromal motor and non-motor manifestations were evaluated, including MDS-UPDRS part I to III, Cross-Cultural Smell Identification Test, sleep questionnaires, and comprehensive neuropsychological assessment. iRBD and PD patients both performed worse on the Farnsworth-Munsell 100 hue test and had greater number of pareidolias compared to healthy controls. No correlations were found between the extent of impaired color discrimination and pareidolia scores in either group. In iRBD patients, pareidolias were associated with frontal executive dysfunction, while impaired color discrimination was associated with visuospatial dysfunction, hyposmia, and higher MDS-UPDRS-III scores. Pareidolias in PD patients correlated with worse global cognition, whereas color discrimination deficits were associated with frontal executive dysfunction. Color discrimination deficits and pareidolias are frequent but does not correlate with each other from prodromal to clinically established stage of PD. The different pattern of clinical associates with the two visual symptoms suggests that evaluation of both color and pareidolias may aid in revealing the course of neurodegeneration in iRBD and PD patients., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Introduction: Constipation is associated with higher clinical severity and predicts cognitive decline in Parkinson's disease (PD). Whether the non-motor marker is associated with unfavorable motor and cognitive trajectories from the prodromal stage remains unclear., Methods: In a longitudinal prospective cohort of subjects with isolated REM sleep behavior disorders (iRBD), subjects underwent repeated MDS-UPDRS and Mini-Mental Status Examination (MMSE) assessments. Generalized-estimating-equations (GEE) regression model was used to compare the time-dependent trajectories of MDS-UPDRS-III and MMSE scores between subjects with and without constipation at baseline., Results: Twenty-nine subjects with constipation at baseline (iRBD+constipation) and 24 without (iRBD-constipation) were followed over 4.085 ± 2.645 years. The iRBD+constipation group presented faster decline of both MDS-UPDRS-III and MMSE scores, with additional estimated annual progression of +1.242 and -0.713 points, respectively, compared to the iRBD-constipation group (time*group p < 0.05)., Conclusion: Constipation in isolated RBD is associated with accelerated progression of cognitive impairment and motor symptoms., Competing Interests: Declaration of competing interest The authors report no competing interests related to this study., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: Isolated/idiopathic rapid eye movement sleep behavior disorder (iRBD) is a powerful early predictor of dementia with Lewy bodies (DLB) and Parkinson's disease (PD). This provides an opportunity to directly observe the evolution of prodromal DLB and to identify which cognitive variables are the strongest predictors of evolving dementia., Methods: IRBD participants (n = 754) from 10 centers of the International RBD Study Group underwent annual neuropsychological assessment. Competing risk regression analysis determined optimal predictors of dementia. Linear mixed-effect models determined the annual progression of neuropsychological testing., Results: Reduced attention and executive function, particularly performance on the Trail Making Test Part B, were the strongest identifiers of early DLB. In phenoconverters, the onset of cognitive decline began up to 10 years prior to phenoconversion. Changes in verbal memory best differentiated between DLB and PD subtypes., Discussion: In iRBD, attention and executive dysfunction strongly predict dementia and begin declining several years prior to phenoconversion., Highlights: Cognitive decline in iRBD begins up to 10 years prior to phenoconversion. Attention and executive dysfunction are the strongest predictors of dementia in iRBD. Decline in episodic memory best distinguished dementia-first from parkinsonism-first phenoconversion., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Objective: To investigate structural and functional connectivity changes in brain olfactory-related structures in a longitudinal prospective cohort of isolated REM sleep behavior disorder (iRBD) and their clinical correlations, longitudinal evolution, and predictive values for phenoconversion to overt synucleinopathies, especially Lewy body diseases., Methods: The cohort included polysomnography-confirmed iRBD patients and controls. Participants underwent baseline assessments including olfactory tests, neuropsychological evaluations, the Movement Disorders Society-Unified Parkinson's Disease Rating Scale, 3T brain MRI, and 18 F-FP-CIT PET scans. Voxel-based morphometry (VBM) was performed to identify regions of atrophy in iRBD, and volumes of relevant olfactory-related regions of interest (ROI) were estimated. Subgroups of patients underwent repeated volumetric MRI and resting-state functional MRI (fMRI) scans after four years., Results: A total of 51 iRBD patients were included, with 20 of them converting to synucleinopathy (mean time to conversion 3.08 years). Baseline VBM analysis revealed atrophy in the right olfactory cortex and gyrus rectus in iRBD. Subsequent ROI comparisons with controls showed atrophy in the amygdala. These olfactory-related atrophies tended to be associated with worse depression, anxiety, and urinary problems in iRBD. Amygdala 18 F-FP-CIT uptake tended to be reduced in iRBD patients with hyposmia (nonsignificant after multiple comparison correction) and correlated with urinary problems. Resting-state fMRI of 23 patients and 32 controls revealed multiple clusters with aberrant olfactory-related functional connectivity. Hypoconnectivity between the putamen and olfactory cortex was associated with mild parkinsonian signs in iRBD. Longitudinal analysis of volumetric volumetric MRI in 22 iRBD patients demonstrated four-year progression of olfactory-related atrophy. Cox regression analysis revealed that this atrophy significantly predicted phenoconversion., Interpretation: Progressive atrophy of central olfactory structures may be a potential indicator of Lewy body disease progression in iRBD., (© 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: A brain glucose metabolism pattern related to phenoconversion in patients with idiopathic/isolated REM sleep behaviour disorder (iRBDconvRP) was recently identified. However, the validation of the iRBDconvRP in an external, independent group of iRBD patients is needed to verify the reproducibility of such pattern, so to increase its importance in clinical and research settings. The aim of this work was to validate the iRBDconvRP in an independent group of iRBD patients., Methods: Forty iRBD patients (70 ± 5.59 years, 19 females) underwent brain [ 18 F]FDG-PET in Seoul National University. Thirteen patients phenoconverted at follow-up (7 Parkinson disease, 5 Dementia with Lewy bodies, 1 Multiple system atrophy; follow-up time 35 ± 20.56 months) and 27 patients were still free from parkinsonism/dementia after 62 ± 29.49 months from baseline. We applied the previously identified iRBDconvRP to validate its phenoconversion prediction power., Results: The iRBDconvRP significantly discriminated converters from non-converters iRBD patients (p = 0.016; Area under the Curve 0.74, Sensitivity 0.69, Specificity 0.78), and it significantly predicted phenoconversion (Hazard ratio 4.26, C.I.95%: 1.18-15.39)., Conclusions: The iRBDconvRP confirmed its robustness in predicting phenoconversion in an independent group of iRBD patients, suggesting its potential role as a stratification biomarker for disease-modifying trials., (© 2023. The Author(s).)

The neurodegenerative synucleinopathies, including Parkinson's disease and dementia with Lewy bodies, are characterized by a typically lengthy prodromal period of progressive subclinical motor and non-motor manifestations. Among these, idiopathic REM sleep behaviour disorder is a powerful early predictor of eventual phenoconversion, and therefore represents a critical opportunity to intervene with neuroprotective therapy. To inform the design of randomized trials, it is essential to study the natural progression of clinical markers during the prodromal stages of disease in order to establish optimal clinical end points. In this study, we combined prospective follow-up data from 28 centres of the International REM Sleep Behavior Disorder Study Group representing 12 countries. Polysomnogram-confirmed REM sleep behaviour disorder subjects were assessed for prodromal Parkinson's disease using the Movement Disorder Society criteria and underwent periodic structured sleep, motor, cognitive, autonomic and olfactory testing. We used linear mixed-effect modelling to estimate annual rates of clinical marker progression stratified by disease subtype, including prodromal Parkinson's disease and prodromal dementia with Lewy bodies. In addition, we calculated sample size requirements to demonstrate slowing of progression under different anticipated treatment effects. Overall, 1160 subjects were followed over an average of 3.3 ± 2.2 years. Among clinical variables assessed continuously, motor variables tended to progress faster and required the lowest sample sizes, ranging from 151 to 560 per group (at 50% drug efficacy and 2-year follow-up). By contrast, cognitive, olfactory and autonomic variables showed modest progression with higher variability, resulting in high sample sizes. The most efficient design was a time-to-event analysis using combined milestones of motor and cognitive decline, estimating 117 per group at 50% drug efficacy and 2-year trial duration. Finally, while phenoconverters showed overall greater progression than non-converters in motor, olfactory, cognitive and certain autonomic markers, the only robust difference in progression between Parkinson's disease and dementia with Lewy bodies phenoconverters was in cognitive testing. This large multicentre study demonstrates the evolution of motor and non-motor manifestations in prodromal synucleinopathy. These findings provide optimized clinical end points and sample size estimates to inform future neuroprotective trials., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The isolated rapid-eye-movement sleep behavior disorder (iRBD) is a prodromal condition of Lewy body disease including Parkinson's disease and dementia with Lewy bodies (DLB). We aim to investigate the longitudinal evolution of DLB-related cortical thickness signature in a prospective iRBD cohort and evaluate the possible predictive value of the cortical signature index in predicting dementia-first phenoconversion in individuals with iRBD., Methods: We enrolled 22 DLB patients, 44 healthy controls, and 50 video polysomnography-proven iRBD patients. Participants underwent 3-T magnetic resonance imaging (MRI) and clinical/neuropsychological evaluations. We characterized DLB-related whole-brain cortical thickness spatial covariance pattern (DLB-pattern) using scaled subprofile model of principal components analysis that best differentiated DLB patients from age-matched controls. We analyzed clinical and neuropsychological correlates of the DLB-pattern expression scores and the mean values of the whole-brain cortical thickness in DLB and iRBD patients. With repeated MRI data during the follow-up in our prospective iRBD cohort, we investigated the longitudinal evolution of the cortical thickness signature toward Lewy body dementia. Finally, we analyzed the potential predictive value of cortical thickness signature as a biomarker of phenoconversion in iRBD cohort., Results: The DLB-pattern was characterized by thinning of the temporal, orbitofrontal, and insular cortices and relative preservation of the precentral and inferior parietal cortices. The DLB-pattern expression scores correlated with attentional and frontal executive dysfunction (Trail Making Test-A and B: R = - 0.55, P = 0.024 and R = - 0.56, P = 0.036, respectively) as well as visuospatial impairment (Rey-figure copy test: R = - 0.54, P = 0.0047). The longitudinal trajectory of DLB-pattern revealed an increasing pattern above the cut-off in the dementia-first phenoconverters (Pearson's correlation, R = 0.74, P = 6.8 × 10 -4 ) but no significant change in parkinsonism-first phenoconverters (R = 0.0063, P = 0.98). The mean value of the whole-brain cortical thickness predicted phenoconversion in iRBD patients with hazard ratio of 9.33 [1.16-74.12]. The increase in DLB-pattern expression score discriminated dementia-first from parkinsonism-first phenoconversions with 88.2% accuracy., Conclusion: Cortical thickness signature can effectively reflect the longitudinal evolution of Lewy body dementia in the iRBD population. Replication studies would further validate the utility of this imaging marker in iRBD., (© 2023. The Author(s).)

Background: It remains unclear how brain metabolic activities transform in response to dopamine deficiency in the prodromal and early phases of Parkinson's disease (PD)., Objective: To investigate the relationship between nigrostriatal dopaminergic denervation and brain glucose metabolism in patients with isolated rapid eye movement sleep behavior disorder (iRBD) and early PD., Methods: This cohort study included 28 patients with polysomnography-confirmed iRBD, 24 patients with de novo PD with probable rapid eye movement sleep behavior disorder ( denovo PD), and 28 healthy controls (HCs) who underwent two positron emission tomography scans with 18 F-fluorodeoxyglucose (all participants) and 18 F-N-3-fluoropropyl-2β-carboxymethoxy-3β-(4-iodophenyl)-nortropane (except for one denovo PD patient and 15 HCs). We analyzed striatal and voxel-wise whole-brain glucose metabolism in relation to nigrostriatal dopaminergic integrity and comparatively investigated the whole-brain metabolic connectivity among the groups. We also assessed longitudinal metabolic changes against progressive dopaminergic denervation over 4 years in the iRBD group., Results: From HCs to iRBD and finally to the denovo PD, dopaminergic integrity positively correlated with metabolic activity in the caudate, whereas a negative correlation was observed in the posterior putamen. In the iRBD group, there was a metabolic increase in the inferior orbitofrontal cortex against putaminal dopaminergic denervation at baseline, but negative correlations were newly observed in the superior orbitofrontal cortex and superior frontal gyrus at the 4-year follow-up. The denovo PD group showed negative correlations in the cerebellum and fusiform gyrus. Intra- and inter-regional metabolic connectivities in the parieto-occipital cortices were enhanced in the iRBD group compared with the denovo PD and HC groups. In the iRBD group, overall metabolic connectivity was strengthened along with enhanced basal ganglia-frontal connection by advancing dopaminergic denervation., Conclusions: Our findings suggest diverse trajectories of metabolic responses associated with dopaminergic denervation between individual brain areas in the prodromal and early PD stages. © 2022 International Parkinson and Movement Disorder Society., (© 2022 International Parkinson and Movement Disorder Society.)

Background and Objectives: Mild cognitive impairment (MCI) in isolated REM sleep behavior disorder (iRBD) is a risk factor for subsequent neurodegeneration. We aimed to identify brain metabolism and functional connectivity changes related to MCI in patients with iRBD and the neuroimaging markers' predictive value for phenoconversion., Methods: This is a prospective cohort study of patients with iRBD with a mean follow-up of 4.2 ± 2.6 years. At baseline, patients with iRBD and age- and sex-matched healthy controls (HCs) underwent 18 F-fluorodeoxyglucose (FDG)-PET and resting-state fMRI scans and a comprehensive neuropsychological test battery. Voxel-wise group comparisons for FDG-PET data were performed using a general linear model. Seed-based connectivity maps were computed using brain regions showing significant hypometabolism associated with MCI in patients with iRBD and compared between groups. A Cox regression analysis was applied to investigate the association between brain metabolism and risk of phenoconversion., Results: Forty patients with iRBD, including 21 with MCI (iRBD-MCI) and 19 with normal cognition (iRBD-NC), and 24 HCs were included in the study. The iRBD-MCI group revealed relative hypometabolism in the inferior parietal lobule, lateral and medial occipital, and middle and inferior temporal cortex bilaterally compared with HC and the iRBD-NC group. In seed-based connectivity analyses, the iRBD-MCI group exhibited decreased functional connectivity of the left angular gyrus with the occipital cortex. Of 40 patients with iRBD, 12 patients converted to Parkinson disease (PD) or dementia with Lewy bodies (DLB). Hypometabolism of the occipital pole (hazard ratio [95% CI] 6.652 [1.387-31.987]), medial occipital (4.450 [1.143-17.327]), and precuneus (3.635 [1.009-13.093]) was associated with higher phenoconversion rate to PD/DLB., Discussion: MCI in iRBD is related to functional and metabolic changes in broad brain areas, particularly the occipital and parietal areas. Moreover, hypometabolism in these brain regions was a predictor of phenoconversion to PD or DLB. Evaluation of cognitive function and neuroimaging characteristics could be useful for risk stratification in patients with iRBD., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Mild cognitive impairment (MCI) is a common feature of isolated rapid-eye-movement sleep behavior disorder (iRBD). Here, we assessed cognitive functions and MCI in a prospective iRBD cohort and investigated their association with disease-specific brain metabolic patterns., Methods: Forty-four patients with polysomnography-confirmed iRBD performed a standardized battery of neuropsychological examinations every two years. We used previously established spatial covariance patterns from de novo drug-naïve Parkinson's disease with concomitant RBD ( denovo PDRBD-RP) and iRBD (iRBD-RP) using 18 F-fluorodeoxyglucose PET scan. We compared those expressions between iRBD with normal cognition (iRBD-NC) and with mild cognitive impairment (iRBD-MCI), and evaluated whether they predict progressive cognitive deterioration., Results: Twenty iRBD patients (45 %) had MCI at baseline and 12 patients (27 %, about 7 % per year) had clinically significant cognitive deterioration after 4 years. The iRBD-MCI and iRBD-NC groups showed similar rates of cognitive change, but iRBD-MCI consistently performed worse in the domains of verbal memory and executive function. Elevated denovo PDRBD-RP expression predicted cognitive deterioration (hazard ratio = 5.98 [1.70-21.06]), whereas iRBD-RP did not., Conclusions: Increased disease-specific brain metabolic patterns are associated with iRBD-MCI and impending cognitive deterioration with the risk of progression to Lewy body dementia., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: It remains unclear whether and how the isolated rapid eye movement (REM) sleep behavior disorder (iRBD)-related metabolic pattern (RBDRP) changes with disease progression in iRBD., Objective: To examine longitudinal changes in RBDRP expression in iRBD patients and to explore trajectories of relative metabolic activities of individual brain regions constituting RBDRP., Methods: In this cohort study, 25 iRBD patients (mean age [±standard deviation], 69.2 ± 5.3 years; 12 [48%] patients were men) and 24 age-matched healthy controls were included. The patients underwent at least two 18 F-fluorodeoxyglucose positron emission tomography scans at baseline and at the 2-year and/or 4-year follow-ups. We measured the RBDRP expression of the patients and controls which was validated by reproduction in a separate iRBD cohort (n = 13)., Results: At baseline, the RBDRP expression discriminated iRBD patients from healthy controls. However, the RBDRP expression z scores tended to decrease over time in the patients, especially with longer follow-ups, and this tendency was observed even in patients with high-risk of phenoconversion. Furthermore, the degree of RBDRP expression at baseline did not predict the disease conversion. The RBDRP breakdown was mainly provoked by the attenuation of relative hypermetabolism in the frontal cortex including premotor areas and relative hypometabolism in the occipital cortex. The putaminal metabolic activity increased steadily with the disease progression., Conclusions: The RBDRP expression in iRBD patients was altered significantly over time. Some of the brain metabolic changes seem to represent attempted functional compensation against ongoing neurodegeneration. The RBDRP expression measurement at one time point may not be a reliable biomarker for predicting disease conversion. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Patients with isolated rapid-eye-movement sleep behaviour disorder (RBD) are commonly regarded as being in the early stages of a progressive neurodegenerative disease involving α-synuclein pathology, such as Parkinson's disease, dementia with Lewy bodies, or multiple system atrophy. Abnormal α-synuclein deposition occurs early in the neurodegenerative process across the central and peripheral nervous systems and might precede the appearance of motor symptoms and cognitive decline by several decades. These findings provide the rationale to develop reliable biomarkers that can better predict conversion to clinically manifest α-synucleinopathies. In addition, biomarkers of disease progression will be essential to monitor treatment response once disease-modifying therapies become available, and biomarkers of disease subtype will be essential to enable prediction of which subtype of α-synucleinopathy patients with isolated RBD might develop., Competing Interests: Declaration of interests CHA reports personal fees from Acadia, Acorda, Amneal, Axovant, Jazz, Lundbeck, Neurocrine, Scion, and Sunovion, outside the submitted work. DA reports consulting fees from Fidia and Bioprojet. BFB reports personal fees from the Scientific Advisory Board-Tau Consortium and grants from Biogen, NIH, the Mangurian Foundation, Alector, the Little Family Foundation, the Turner Family, and EIP Pharma, outside the submitted work. PD reports grants from the Czech Ministry of Health, the Czech Science Foundation, the EU's Horizon 2020 research and innovation programme, and personal fees from BenevolentAI Bio, Retrophin, and Alexion Pharmaceuticals, outside the submitted work. RF reports grants from the Italian Ministry of Health, during the conduct of the study. J-FG reports grants from the Canadian Institutes of Health Research and the Canada Research Chair, during the conduct of the study. ZG-O reports grants from the Michael J Fox Foundation, Parkinson Canada, the Canadian Consortium on Neurodegeneration in Aging, the Canada First Research Excellence Fund, and personal fees from Lysosomal Therapeutics, Idorsia, Prevail Therapeutics, Deerfield, Inception Sciences (Ventus), Denali, Ono Therapeutics, and Neuron23, outside the submitted work. BH reports personal fees from Axovant, Roche, Takeda, Jazz, BenevolentAI Bio, ONO, AOP Orphan, Inspire, and Novartis, and travel support from Habel Medizintechnik Vienna, during the conduct of the study, and has a patent (“Detection of Leg Movements II” Österreichische Patentanmeldung A50649/2019) pending. MTH reports grants from Parkinson's UK, Oxford Biomedical Research Centre, MJFF, H2020 EU, GE Healthcare, and the PSP association, and personal fees from Biogen, Roche, Curasen Pharmaceuticals Consultancy Honoraria, outside the submitted work. AJ reports a grant from ParkinsonFonds Deutschland, outside the submitted work. CL reports grants from the Oxford NIHR Biomedical Research Centre, outside the submitted work. GP reports personal fees from UCB, Bioprojet, Jazz Pharma, and Idorsia, outside the submitted work. FP reports personal fees from Vanda Pharmaceuticals, Sanofi, Zambon, Fidia, Bial, Eisai Japan, and Italfarmaco, outside the submitted work. MR reports grants from NIHR, during the conduct of the study, and grants from Britannia Pharmaceuticals and Eli Lilly, and non-financial support from IXICO, outside the submitted work. WHO reports grants from ParkinsonFonds Deutschland, the Michael J Fox Foundation, and Deutsche Forschungsgemeinschaft (DFG), during the conduct of the study, and personal fees from Adamas, MODAG, Roche, and UCB, outside the submitted work, and is Hertie-Senior-Research Professor supported by the Charitable Hertie-Foundation. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: To elucidate the role of Parkinson disease (PD)-related brain metabolic patterns as a biomarker in isolated REM sleep behavior disorder (iRBD) for future disease conversion., Methods: This is a prospective cohort study consisting of 30 patients with iRBD, 25 patients with de novo PD with a premorbid history of RBD, 21 patients with longstanding PD on stable treatment, and 24 healthy controls. The iRBD group was longitudinally followed up. All participants underwent 18 F-fluorodeoxyglucose (FDG) PET and were evaluated with olfaction, cognition, and the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) at baseline. From FDG-PET scans, we derived metabolic patterns from the longstanding PD group (PD-RP) and de novo PD group with RBD (dnPDRBD-RP). Subsequently, we calculated the PD-RP and dnPDRBD-RP scores in patients with iRBD. We validated the metabolic patterns in each PD group and separate iRBD cohort (n = 14)., Results: The 2 patterns significantly correlated with each other and were spatially overlapping yet distinct. The MDS-UPDRS motor scores significantly correlated with PD-RP ( p = 0.013) but not with dnPDRBD-RP ( p = 0.076). In contrast, dnPDRBD-RP correlated with olfaction in butanol threshold test ( p = 0.018) in patients with iRBD, but PD-RP did not ( p = 0.21). High dnPDRBD-RP in patients with iRBD predicted future phenoconversion with all cutoff ranges from 1.5 to 3 SD of the control value, whereas predictability of PD-RP was only significant in a partial range of cutoff., Conclusion: The dnPDRBD-RP is an efficient neuroimaging biomarker that reflects prodromal features of PD and predicts phenoconversion in iRBD that can be applied individually., Classification of Evidence: This study provides Class IV evidence that a de novo PD pattern on FDG-PET predicts future conversion to neurodegenerative disease in patients with iRBD., (© 2021 American Academy of Neurology.)

Objective: To elucidate longitudinal changes in the dopamine transporter (DAT) availability in association with the prodromal markers in idiopathic REM sleep behavior disorder (iRBD), we analyzed a longitudinal prospective iRBD cohort data., Method: The study cohort consisted of patients with iRBD, individuals with Parkinson disease (PD), and healthy controls. All participants were evaluated for olfaction, neuropsychological tests, and the Movement Disorders Society-Unified Parkinson's Disease Rating Scale and underwent 18 F-FP-CIT PET scans every 2 years. We calculated the DAT pattern by performing the principal component analysis of tracer uptakes in 6 striatal regions., Result: DAT patterns in patients with iRBD with baseline hyposmia, constipation, and mild parkinsonian signs distributed toward the PD pattern and clearly distinguished from the healthy control pattern. The DAT pattern moved toward the PD pattern over time in some patients with iRBD during the follow-up, and baseline hyposmia was the only biomarker significantly associated with this change. Baseline PD pattern of DAT predicted 58% of disease converters (hazard ratio 4.95 [95% confidence interval 1.16-21.08]). The combination of hyposmia and baseline PD pattern of DAT predicted 67% of the conversion (hazard ratio 7.89 [confidence interval 1.85-33.69]). The estimated sample size required for a simulated neuroprotective clinical trial was 63 per group when the annual change of DAT pattern was used as an outcome in the subgroup with baseline DAT PD pattern and hyposmia, which is the smallest number reported so far., Conclusion: Baseline and longitudinal monitoring of the DAT pattern can be a useful biomarker in identifying individuals with a high risk of disease conversion and in selecting the potential population for clinical trials in iRBD., (© 2020 American Academy of Neurology.)

Objective: To investigate serum inflammatory cytokine profiles in patients with isolated REM sleep behavior disorder (iRBD) and to explore whether these markers are associated with phenoconversion risk to α-synucleinopathies., Methods: In this prospective cohort study, we analyzed serum samples from patients with polysomnography-confirmed iRBD (n = 30) and healthy controls (n = 12). We measured the following cytokines: interleukin (IL)-1β, IL-2, IL-6, IL-10, and tumor necrosis factor-α (TNF-α). All patients underwent motor and non-motor evaluations and dopamine transporter imaging at baseline for predicting the phenoconversion risk. We followed the patients quarterly over up to 6 years to identify disease conversion. We also assessed longitudinal changes in cytokine levels from baseline at the 2- and 4-year follow-up visits., Results: The baseline cytokine levels did not differ between the patients and controls. However, the TNF-α levels were significantly increased in a subgroup of the patients with multiple markers (≥3) for phenoconversion risk compared to those without (p = 0.008) and controls (p = 0.003). At longitudinal analyses, patients with TNF-α levels above the median showed a higher incidence of phenoconversion than those with lower TNF-α levels (47% vs. 7%; p = 0.008), and this significant association persisted after adjusting for covariates (p = 0.026). The cytokine levels over 4 years of follow-up period did not change significantly., Conclusions: Our data suggest a possible link between serum TNF-α and phenoconversion risk in iRBD. Further studies are warranted to confirm the role of peripheral TNF-α in the pathogenesis of neurodegeneration in this disorder., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objectives: We investigated retinal change and its relationship with neurodegeneration markers in a prodromal Parkinson cohort., Methods: A total of 30 patients with idiopathic rapid eye movement sleep behavior disorder were recruited. Participants underwent olfactory testing, macular optical coherence tomography, microperimetry, contrast sensitivity test, and brain N-(3-[ 18 F]fluoropropyl)-2-carbomethoxy-3-(4-iodophenyl) nortropane positron emission tomography. We measured the ganglion cell complex thicknesses and investigated its correlation with olfactory function and striatal dopamine transporter availability. A linear mixed-effect model was applied with adjustment for multiple comparisons., Results: The parafoveal ganglion-cell-complex thickness in this cohort lay between our healthy control and drug-naïve Parkinson's disease group data. Idiopathic rapid eye movement sleep behavior disorder patients also had contrast sensitivity impairment as in Parkinson's disease with a nonsignificant change in macular sensitivities. Macular ganglion cell complex thickness correlated with olfactory scores and with striatal dopamine transporter availabilities., Conclusions: Macular ganglion cell complex thinning may be a marker of neurodegeneration in prodromal Parkinson's disease. © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)

Objective: Rapid eye movement sleep behavior disorder (RBD) is a common sleep disturbance in patients with neurodegenerative disorders. We aimed to compare sleep parameters among the different types of RBD patients., Methods: A total of 122 patients with dream enactment behavior were screened. Of these, 92 patients who were diagnosed with RBD by polysomnography were included in this study. Enrolled patients with RBD were classified into four groups based on the following diagnoses: idiopathic RBD (iRBD); RBD with Parkinson disease (PD-RBD); multiple system atrophy (MSA) with RBD (MSA-RBD); and dementia with Lewy bodies (DLB) with RBD (DLB-RBD). Various clinical and polysomnographic parameters were compared., Results: Among the 92 patients with RBD, 35 had iRBD, 25 had PD-RBD, 17 had MSA-RBD, and 15 had DLB-RBD. The mean apnea-hypopnea index of atypical parkinsonism with RBD (AP-RBD) group was 16.2 ± 17.7 events/h (MSA-RBD, 14.0 ± 16.6; DLB-RBD, 18.8 ± 19.1), which was significantly higher than the other groups (p < 0.05). The proportion of patients with 100% supine sleep in the AP-RBD group (44%) was higher than that in the iRBD group (14%; p = 0.030). The proportion of OSA with 100% supine sleep position was significantly higher in the MSA-RBD and DLB-RBD groups than in the iRBD group (p = 0.042 and p = 0.029, respectively)., Conclusion: Our study demonstrated that patients in the MSA-RBD and DLB-RBD groups had a tendency to sleeping in the supine position and a higher vulnerability to OSA compared to other RBD groups. Further cohort studies are needed to evaluate the influence of these factors on the development of parkinsonism., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose To examine whether the loss of nigral hyperintensity (NH) on 3.0-T susceptibility-weighted (SW) magnetic resonance (MR) images can help identify high synucleinopathy risk in patients with idiopathic rapid eye movement sleep behavior disorder (iRBD). Materials and Methods Between March 2014 and April 2015, 18 consecutively recruited patients with iRBD were evaluated with 3.0-T SW imaging and iodine 123-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane ( 123 I-FP-CIT) single photon emission computed tomography and compared with 18 healthy subjects and 18 patients with Parkinson disease (PD). Two readers blinded to clinical diagnosis independently assessed the images. 123 I-FP-CIT uptake ratios were compared by using the Kruskal-Wallis test, and intra- and interobserver agreements were assessed with the Cohen κ. The synucleinopathy conversion according to NH status was evaluated in patients with iRBD after follow-up. Results NH was intact in seven patients with iRBD and lost in 11. The 123 I-FP-CIT uptake ratios were comparable between those with intact NH (mean, 3.22 ± 0.47) and healthy subjects (mean, 3.37 ± 0.47) (P = .495). The 123 I-FP-CIT uptake ratios in the 11 patients with iRBD and NH loss (mean, 2.48 ± 0.44) were significantly lower than those in healthy subjects (mean, 3.37 ± 0.47; P < .001) but higher than those in patients with PD (mean, 1.80 ± 0.33; P < .001). The intra- and interobserver agreements were excellent (κ > 0.9). Five patients with iRBD and NH loss developed symptoms of parkinsonism or dementia 18 months after neuroimaging. Conclusion NH loss at 3.0-T SW imaging may be a promising marker for short-term synucleinopathy risk in iRBD. © RSNA, 2017 Online supplemental material is available for this article.

Objectives: To investigate neural substrates of symptomatic rapid eye movement sleep behavior disorder (RBD) in Parkinson's disease (PD) by analyzing brain changes based on both hypothesis-free and hypothesis-driven neuroimaging analyses., Methods: A total of 63 subjects (14 PDRBD-, 24 PDRBD+, and 25 age-matched healthy controls = HC) were enrolled in this study. RBD was defined by RBD screening questionnaire with video-polysomnographic confirmation. All subjects underwent volumetric and diffusion tensor imaging. The whole brain gray- and white-matter changes were analyzed and the central ascending cholinergic pathway involving the pedunculopontine nucleus and thalamus was compared with a region-of-interest analysis and probabilistic tractography., Results: The PDRBD+ group showed decreased gray matter volume of the left posterior cingulate and hippocampus compared to the PDRBD- and additional gray matter decrease in the left precuneus, cuneus, medial frontal gyrus, postcentral gyrus and both inferior parietal lobule compared to the HC group (uncorrected p < 0.001, k = 50). There were no significant differences in white matter changes between the PDRBD- and PDRBD+ groups both by fractional anisotropy and mean diffusivities. However, both PD groups showed widespread changes by fractional anisotropy reductions and mean diffusivity increments compared to HC (p < 0.05 corrected). There were no significant differences in tract-based spatial statistics and the normalized tract volumes as well as the diffusion indices of both the thalamus and pedunculopontine nuclei among the study groups., Conclusions: The appearance of RBD in PD may be related to regional gray matter changes in the left posterior cingulate and hippocampus but not localized to the brainstem., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The effect of subthalamic nucleus (STN) deep brain stimulation (DBS) on rapid eye movement sleep behavior disorder (RBD) in Parkinson's disease (PD) is not well known. We evaluated the change in the incidence of probable RBD after bilateral STN DBS in PD patients. Ninety patients with PD treated with bilateral STN DBS underwent retrospective assessment of RBD by interview before and after DBS. Forty-seven (52.2%) of the 90 patients had RBD preoperatively. RBD was resolved only in one patient and persisted in 46 patients at 1 year after DBS. RBD developed de novo in 16 patients (de novo RBD group) within 1 year after DBS, resulting in 62 (68.9%) of the 90 patients having RBD 1 year after DBS. Patients with RBD at any time within 1 year after DBS (RBD group, n = 63) were older than the patients without RBD (non-RBD group, n = 27). The sum of the Unified Parkinson Disease Rating Scale (UPDRS) axial score for the "on" state was lower in the RBD group than in the non-RBD group after DBS (p = 0.029). Comparing the de novo RBD group and non-RBD group, the UPDRS Part III and total score and the levodopa equivalent daily doses for the "on" states decreased more in the de novo RBD group than in the non-RBD group (p < 0.05). The incidence of clinical RBD increased after bilateral STN DBS because de novo RBD developed and pre-existing RBD persisted after DBS., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: The anatomical substrates associated with generalized muscle atonia during REM sleep are located on the pontine tegmentum and medial medulla oblongata. We examined whether patients with REM sleep behavior disorder (RBD) have abnormal ocular movements suggesting brainstem or cerebellar dysfunction in Parkinson's disease (PD)., Methods: Cross-sectional survey for the existence of RBD and abnormal ocular movements. Ocular movements were examined by video-oculography (VOG)., Results: A total of 202 patients were included in this study. One hundred and sixteen (57.4%) of the 202 patients have clinically probable RBD, and 28 (24.1%) of the 116 with clinically probable RBD patients had abnormal VOG findings suggesting brainstem or cerebellar dysfunction; whereas 86 of the 202 patients did not have clinically probable RBD, and only 7 (8.1%) of the 86 patients had abnormal VOG findings suggesting brainstem or cerebellar dysfunction (P=0.001)., Conclusion: This study suggests that the presence of RBD is associated with more severe or extensive brainstem pathology or different distribution of pathology in PD., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

INTRODUCTION: Isolated/idiopathic rapid eye movement sleep behavior disorder (iRBD) is a powerful early predictor of dementia with Lewy bodies (DLB) and Parkinson's disease (PD). This provides an opportunity to directly observe the evolution of prodromal DLB and to identify which cognitive variables are the strongest predictors of evolving dementia. METHODS: IRBD participants (n = 754) from 10 centers of the International RBD Study Group underwent annual neuropsychological assessment. Competing risk regression analysis determined optimal predictors of dementia. Linear mixed‐effect models determined the annual progression of neuropsychological testing. RESULTS: Reduced attention and executive function, particularly performance on the Trail Making Test Part B, were the strongest identifiers of early DLB. In phenoconverters, the onset of cognitive decline began up to 10 years prior to phenoconversion. Changes in verbal memory best differentiated between DLB and PD subtypes. DISCUSSION: In iRBD, attention and executive dysfunction strongly predict dementia and begin declining several years prior to phenoconversion. Highlights: Cognitive decline in iRBD begins up to 10 years prior to phenoconversion.Attention and executive dysfunction are the strongest predictors of dementia in iRBD.Decline in episodic memory best distinguished dementia‐first from parkinsonism‐first phenoconversion. [ABSTRACT FROM AUTHOR]