A conceptual framework to develop a patient-reported experience questionnaire on the cystic fibrosis journey in France: the ExPaParM collaborative study.

BACKGROUND: The objective of the study was to elaborate a conceptual framework related to the domains of patient experience along the cystic fibrosis (CF) journey from the patients and parents of children with CF to inform the design of a patient-reported experience questionnaire. METHOD: A collaborative research group including patients and parents with clinicians and academic researchers was set up. They identified the situations along the CF care pathway from diagnosis to paediatric care, transition to adult care and adult follow-up, transfer to transplant centres and follow-up after transplantation. Participants were recruited by CF centres in metropolitan France and overseas departments. Semi-structured interviews were conducted, transcribed verbatim and subjected to an inductive analysis conducted in duos of researchers/co-researchers using NVivo®. The conceptual framework was discussed with the research group and presented to the CF centres during two video conferences. The protocol obtained a favourable opinion from the Ethics Evaluation Committee of INSERM (IRB00003888-no. 20-700). RESULTS: The analysis led to a conceptual framework composed of domains of the CF journey, each divided into several items. 1. CF care: Management of care by the CF centre team; in-hospital care; quality of care in the community; therapeutic education and self-management support; at-home care; new therapies and research; procreation; 2. Transplant care: management of transplant and CF care; coordination with other specialties; education and self-management support; at-home care; procreation; new therapies and research; 3. Turning points along the journey: diagnosis of CF, transition to adult care, transfer to transplantation; 4. Social life with CF: housing, employment and education, social relations, social welfare and family finances. The number of patients included and the diversity of situations made it possible to achieve a sufficient richness and saturation of codes by domain to develop patient experience questionnaires. CONCLUSION: This conceptual framework, resulting from the participants' experience, will inform the design of a patient-reported experience tool, whose construct will be tested during the next phase of the ExPaParM project to assess its fidelity, intelligibility, and ability to report patient experience of the CF journey.

Collaborative research protocol to define patient-reported experience measures of the cystic fibrosis care pathway in France: the ExPaParM study.

INTRODUCTION: In France, the cystic fibrosis (CF) care pathway is coordinated by multidisciplinary teams from specialised CF centres or transplant centres. It includes the care provided at home or out of hospital, risk prevention in daily life and adjustments to social life, which together contribute to the person's quality of life. Patient experience is used to describe and evaluate the care and life of patients living with the disease. OBJECTIVES: Our collaborative research aims to identify the most significant areas and criteria that characterise the CF pathway. It will lead to the development of a questionnaire to collect patients' experience, which can be administered to all patients or parents of children registered and followed in the centres. The article describes the protocol developed in partnership with patients and parents of children living with the disease. METHOD: A multidisciplinary research group brings together researchers, patients, parents of children with CF and health care professionals. The patient partnership is involved in the 4 phases of the protocol: (1) setting up the study, recruiting patient and parent co-researchers, training them in qualitative research methods, defining the situations and profiles of patients in the study population, elaborating the protocol; (2) selecting the study sites, recruiting participants, carrying out semi-structured interviews, analysing verbatims using the grounded theory approach; (3) co-elaborating Patient-Reported Experience Measures (PREM) questionnaires adapted to the 4 types of participants: parents, adolescents, non-transplanted adults and transplanted adults; (4) validating the construct with participants and professionals from the study centres. RESULTS: The protocol obtained a favourable opinion from the Ethics Evaluation Committee of INSERM (IRB00003888-no. 20-700). Training was provided to the 5 patients and 2 parent co-researchers to enable them to participate effectively in the research. Eleven centres participated in the recruitment of participants in mainland France and Reunion Island. Eighty hours of interviews were conducted. DISCUSSION: The PREM questionnaires to be elaborated will have to undergo psychometric validation before being used by the actors of the CF network to assess the impact on the care pathways of quality approaches or new therapies available in cystic fibrosis. Trial Registration Registry: IRB00003888 - no. 20-700. Issue date: 06/09/2020.

Intra-amniotic digoxin for feticide between 21 and 30 weeks of gestation: a prospective study.

OBJECTIVE: Intra-amniotic injection of digoxin is a well-known method for feticide before inducing a termination of pregnancy (TOP) at 17-24 weeks of gestation. Information on its effectiveness when administered after 24 weeks of gestation is limited. This study evaluated the efficacy of intra-amniotic digoxin injection for inducing fetal demise within 18-24 hours, at 21-30 weeks of gestation, and its safety. DESIGN: Prospective cohort study. SETTING: Tertiary university medical centre. POPULATION: Women at 21-30 weeks of gestation with a singleton pregnancy, admitted for TOP. METHODS: Intra-amniotic injection of 2 mg of digoxin was performed 1 day before medical TOP. Fetal heart activity was evaluated by ultrasound for 18-24 hours after the injection. Serum digoxin level and maternal electrocardiogram (ECG) were evaluated 6, 10, and 20 hours after injection. MAIN OUTCOME MEASURE: Frequency of successful fetal demise. RESULTS: Fifty-nine women participated in the study. The mean gestational age was 24+2  weeks (range 21+0 -30+0 ), with 29 (49.2%) beyond 24+0  weeks of gestation. Fetal cardiac activity arrest was achieved in 55/59 cases (93.2%). Normal maternal ECG recordings were noted in all cases. Mean serum digoxin levels 6 and 10 hours after injection were in the therapeutic range (1.3 ± 0.7 ng/l and 1.24 ± 0.49 ng/l, respectively) and below the toxic level (2 ng/l). Extramural delivery following digoxin did not occur. There were no cases of chorioamnionitis. CONCLUSION: Intra-amniotic digoxin for feticide at 21-30 weeks of gestation in a singleton pregnancy appears effective and safe before TOP at advanced gestational ages. TWEETABLE ABSTRACT: This study shows that feticide by intra-amniotic digoxin injection at 21-30 weeks of gestation appears effective and safe.

Feedback control of unstable periodic orbits in equivariant Hopf bifurcation problems.

Symmetry-breaking Hopf bifurcation problems arise naturally in studies of pattern formation. These equivariant Hopf bifurcations may generically result in multiple solution branches bifurcating simultaneously from a fully symmetric equilibrium state. The equivariant Hopf bifurcation theorem classifies these solution branches in terms of their symmetries, which may involve a combination of spatial transformations and temporal shifts. In this paper, we exploit these spatio-temporal symmetries to design non-invasive feedback controls to select and stabilize a targeted solution branch, in the event that it bifurcates unstably. The approach is an extension of the Pyragas delayed feedback method, as it was developed for the generic subcritical Hopf bifurcation problem. Restrictions on the types of groups where the proposed method works are given. After addition of the appropriately optimized feedback term, we are able to compute the stability of the targeted solution using standard bifurcation theory, and give an account of the parameter regimes in which stabilization is possible. We conclude by demonstrating our results with a numerical example involving symmetrically coupled identical nonlinear oscillators.

Clinicopathologic correlations in 172 cases of rapid eye movement sleep behavior disorder with or without a coexisting neurologic disorder.

OBJECTIVE: To determine the pathologic substrates in patients with rapid eye movement (REM) sleep behavior disorder (RBD) with or without a coexisting neurologic disorder. METHODS: The clinical and neuropathologic findings were analyzed on all autopsied cases from one of the collaborating sites in North America and Europe, were evaluated from January 1990 to March 2012, and were diagnosed with polysomnogram (PSG)-proven or probable RBD with or without a coexisting neurologic disorder. The clinical and neuropathologic diagnoses were based on published criteria. RESULTS: 172 cases were identified, of whom 143 (83%) were men. The mean±SD age of onset in years for the core features were as follows - RBD, 62±14 (range, 20-93), cognitive impairment (n=147); 69±10 (range, 22-90), parkinsonism (n=151); 68±9 (range, 20-92), and autonomic dysfunction (n=42); 62±12 (range, 23-81). Death age was 75±9 years (range, 24-96). Eighty-two (48%) had RBD confirmed by PSG, 64 (37%) had a classic history of recurrent dream enactment behavior, and 26 (15%) screened positive for RBD by questionnaire. RBD preceded the onset of cognitive impairment, parkinsonism, or autonomic dysfunction in 87 (51%) patients by 10±12 (range, 1-61) years. The primary clinical diagnoses among those with a coexisting neurologic disorder were dementia with Lewy bodies (n=97), Parkinson's disease with or without mild cognitive impairment or dementia (n=32), multiple system atrophy (MSA) (n=19), Alzheimer's disease (AD)(n=9) and other various disorders including secondary narcolepsy (n=2) and neurodegeneration with brain iron accumulation-type 1 (NBAI-1) (n=1). The neuropathologic diagnoses were Lewy body disease (LBD)(n=77, including 1 case with a duplication in the gene encoding α-synuclein), combined LBD and AD (n=59), MSA (n=19), AD (n=6), progressive supranulear palsy (PSP) (n=2), other mixed neurodegenerative pathologies (n=6), NBIA-1/LBD/tauopathy (n=1), and hypothalamic structural lesions (n=2). Among the neurodegenerative disorders associated with RBD (n=170), 160 (94%) were synucleinopathies. The RBD-synucleinopathy association was particularly high when RBD preceded the onset of other neurodegenerative syndrome features. CONCLUSIONS: In this large series of PSG-confirmed and probable RBD cases that underwent autopsy, the strong association of RBD with the synucleinopathies was further substantiated and a wider spectrum of disorders which can underlie RBD now are more apparent.

Three-wave interactions and spatiotemporal chaos.

Three-wave interactions form the basis of our understanding of many pattern-forming systems because they encapsulate the most basic nonlinear interactions. In problems with two comparable length scales, it is possible for two waves of the shorter wavelength to interact with one wave of the longer, as well as for two waves of the longer wavelength to interact with one wave of the shorter. Consideration of both types of three-wave interactions can generically explain the presence of complex patterns and spatiotemporal chaos. Two length scales arise naturally in the Faraday wave experiment, and our results enable some previously unexplained experimental observations of spatiotemporal chaos to be interpreted in a new light. Our predictions are illustrated with numerical simulations of a model partial differential equation.

Inclusion of RBD improves the diagnostic classification of dementia with Lewy bodies.

OBJECTIVE: To determine whether adding REM sleep behavior disorder (RBD) to the dementia with Lewy bodies (DLB) diagnostic criteria improves classification accuracy of autopsy-confirmed DLB. METHODS: We followed 234 consecutive patients with dementia until autopsy with a mean of 4 annual visits. Clinical diagnoses included DLB, Alzheimer disease (AD), corticobasal syndrome, and frontotemporal dementia. Pathologic diagnoses used the 2005 DLB consensus criteria and included no/low likelihood DLB (non-DLB; n = 136) and intermediate/high likelihood DLB (DLB; n = 98). Regression modeling and sensitivity/specificity analyses were used to evaluate the diagnostic role of RBD. RESULTS: Each of the 3 core features increased the odds of autopsy-confirmed DLB up to 2-fold, and RBD increased the odds by 6-fold. When clinically probable DLB reflected dementia and 2 or more of the 3 core features, sensitivity was 85%, and specificity was 73%. When RBD was added and clinically probable DLB reflected 2 or more of 4 features, sensitivity improved to 88%. When dementia and RBD were also designated as probable DLB, sensitivity increased to 90% while specificity remained at 73%. The VH, parkinsonism, RBD model lowered sensitivity to 83%, but improved specificity to 85%. CONCLUSIONS: Inclusion of RBD as a core clinical feature improves the diagnostic accuracy of autopsy-confirmed DLB.

REM sleep behavior disorder preceding other aspects of synucleinopathies by up to half a century.

BACKGROUND: Idiopathic REM sleep behavior disorder (RBD) may be the initial manifestation of synucleinopathies (Parkinson disease [PD], multiple system atrophy [MSA], or dementia with Lewy bodies [DLB]). METHODS: We used the Mayo medical records linkage system to identify cases presenting from 2002 to 2006 meeting the criteria of idiopathic RBD at onset, plus at least 15 years between RBD and development of other neurodegenerative symptoms. All patients underwent evaluations by specialists in sleep medicine to confirm RBD, and behavioral neurology or movement disorders to confirm the subsequent neurodegenerative syndrome. RESULTS: Clinical criteria were met by 27 patients who experienced isolated RBD for at least 15 years before evolving into PD, PD dementia (PDD), DLB, or MSA. The interval between RBD and subsequent neurologic syndrome ranged up to 50 years, with the median interval 25 years. At initial presentation, primary motor symptoms occurred in 13 patients: 9 with PD, 3 with PD and mild cognitive impairment (MCI), and 1 with PDD. Primary cognitive symptoms occurred in 13 patients: 10 with probable DLB and 3 with MCI. One patient presented with primary autonomic symptoms, diagnosed as MSA. At most recent follow-up, 63% of patients progressed to develop dementia (PDD or DLB). Concomitant autonomic dysfunction was confirmed in 74% of all patients. CONCLUSIONS: These cases illustrate that the alpha-synuclein pathogenic process may start decades before the first symptoms of PD, DLB, or MSA. A long-duration preclinical phase has important implications for epidemiologic studies and future interventions designed to slow or halt the neurodegenerative process.

The role of aromatic phenylalanine residues in binding carotenoid to light-harvesting model and wild-type complexes.

The mode of carotenoid (Crt) binding to polypeptide and specifying its function is as yet largely unknown. Statistical analysis of major photosystems I and II suggests that aromatic residues make up a significant part of the Crt binding pockets. Phenylalanine residues ensure approximately 25%--at some carbon atoms even up to 40%--of the total contacts with Crts. By use of an alanine-leucine model transmembrane helix that replaces the native helix of the bacterial light-harvesting complex 2 (LH2) alpha-subunit, we study the effects of polypeptide residues on cofactor binding in a model sequence context. Here, it is shown that phenylalanine residues located in the close vicinity of the Crts' polyene backbone significantly contribute to the binding of the Crt to the model protein. The replacement of a phenylalanine with leucine in the model helix results in significant reduction in the complexes' Crt content. This effect is strongly enhanced by the removal of a second phenylalanine in close vicinity to the Crt, i.e., of the wild-type (WT) beta-subunit. Remarkably, the mutation of only two phenylalanine residues in the LH2 WT sequence, alpha-Phe at position -12 and beta-Phe at -8, results in the loss of nearly 50% of functional Crt. Resonance Raman spectra indicate that the Crt conformation is fundamentally altered by the absence of the phenylalanines' aromatic side chains, suggesting that they lock the Crt into a precise, well-defined configuration. Thus, binding and specific functionalisation of Crt in the model and WT light-harvesting complex is reliant on the aromatic residue phenylalanine. The use of the light-harvesting complex as a model system thus substantiates the notion that the aromatic residue phenylalanine is a key factor for the binding of Crt to transmembrane proteins.

Amplification in the auditory periphery: the effect of coupling tuning mechanisms.

A mathematical model describing the coupling between two independent amplification mechanisms in auditory hair cells is proposed and analyzed. Hair cells are cells in the inner ear responsible for translating sound-induced mechanical stimuli into an electrical signal that can then be recorded by the auditory nerve. In nonmammals, two separate mechanisms have been postulated to contribute to the amplification and tuning properties of the hair cells. Models of each of these mechanisms have been shown to be poised near a Hopf bifurcation. Through a weakly nonlinear analysis that assumes weak periodic forcing, weak damping, and weak coupling, the physiologically based models of the two mechanisms are reduced to a system of two coupled amplitude equations describing the resonant response. The predictions that follow from an analysis of the reduced equations, as well as performance benefits due to the coupling of the two mechanisms, are discussed and compared with published experimental auditory nerve data.

Quasipatterns in parametrically forced systems.

We examine two mechanisms that have been put forward to explain the selection of quasipatterns in single- and multifrequency forced Faraday wave experiments. Both mechanisms can be used to generate stable quasipatterns in a parametrically forced partial differential equation that shares some characteristics of the Faraday wave experiment. One mechanism, which is robust and works with single-frequency forcing, does not select a specific quasipattern: we find, for two different forcing strengths, 12-fold and 14-fold quasipatterns. The second mechanism, which requires more delicate tuning, can be used to select particular angles between wavevectors in the quasipattern.

Pathophysiology of REM sleep behaviour disorder and relevance to neurodegenerative disease.

REM sleep behaviour disorder (RBD) is a parasomnia characterized by the loss of normal skeletal muscle atonia during REM sleep with prominent motor activity accompanying dreaming. The terminology relating to RBD, and mechanisms underlying REM sleep without atonia and RBD based on data in cat and rat are presented. Neuroimaging data from the few published human cases with RBD associated with structural lesions in the brainstem are presented, in which the dorsal midbrain and pons are implicated. Pharmacological manipulations which alter RBD frequency and severity are reviewed, and the data from human neuropathological studies are presented. An anatomic framework and new schema for the pathophysiology of RBD are proposed based on recent data in rat regarding the putative flip-flop switch for REM sleep control. The structure in man analogous to the subcoeruleus region in cat and sublaterodorsal nucleus in rat is proposed as the nucleus (and its associated efferent and afferent pathways) crucial to RBD pathophysiology. The association of RBD with neurological disease ('secondary RBD') is presented, with emphasis on RBD associated with neurodegenerative disease, particularly the synucleinopathies. The hypothesized pathophysiology of RBD is presented in relation to the Braak staging system for Parkinson's disease, in which the topography and temporal sequence of synuclein pathology in the brain could explain the evolution of parkinsonism and/or dementia well after the onset of RBD. These data suggest that many patients with 'idiopathic' RBD are actually exhibiting an early clinical manifestation of an evolving neurodegenerative disorder. Such patients may be appropriate for future drug therapies that affect synuclein pathophysiology, in which the development of parkinsonism and/or dementia could be delayed or prevented. We suggest that additional clinicopathological studies be performed in patients with dementia or parkinsonism, with and without RBD, as well as in patients with idiopathic RBD, to further elucidate the pathophysiology and also characterize the clinical and pathophysiological relevance of RBD in neurodegenerative disease. Furthermore, longitudinal studies in patients with idiopathic RBD are warranted to characterize the natural history of such patients and prepare for future therapeutic trials.

Pathologic gambling in patients with restless legs syndrome treated with dopaminergic agonists.

Pathologic gambling is an impulse control disorder previously reported to complicate dopamine agonist therapy in patients with Parkinson disease. It has not been described in association with dopamine agonist therapy of other conditions. We report three patients treated in our sleep disorders center who developed pathologic gambling while receiving treatment with dopamine agonists for restless legs syndrome.

Insights into REM sleep behavior disorder pathophysiology in brainstem-predominant Lewy body disease.

BACKGROUND AND PURPOSE: Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia reflecting changes in the brain, but which specific neuronal networks are involved in human RBD pathogenesis has not yet been determined. To date, only one case of idiopathic RBD has undergone autopsy, in which "incidental Lewy body disease" was found. Due to the severe neuronal loss and gliosis in the substantia nigra (SN) and locus ceruleus (LC) in this case, degeneration of brainstem monoaminergic neurons was postulated as the underlying substrate for RBD. Additional cases of idiopathic RBD with neuropathologic examination may help clarify which key brainstem structures are involved. PATIENT AND METHODS: Case report with neuropathologic analysis. RESULTS: A man with polysomnographically proven RBD (onset age 57 years), but no other neurologic signs or symptoms, underwent neuropathologic examination upon his death at age 72. Histopathologic analysis showed Lewy body disease, but no significant neuronal loss or gliosis was present in the SN or LC. CONCLUSIONS: This case represents another example of Lewy body disease associated with RBD. The minimal degenerative changes in the SN and LC call into question the role of these nuclei in RBD, at least in our case. We suggest additional cases of idiopathic RBD undergo neuropathologic analyses to better delineate the neurologic substrate of this intriguing parasomnia.

The Tomato mosaic virus 30 kDa movement protein interacts differentially with the resistance genes Tm-2 and Tm-2(2).

In tomato plants ( Lycopersicon esculentum Mill.), the genes Tm-2 and Tm-2(2) confer resistance to Tomato mosaic virus (ToMV). Sequence analysis of ToMV strains able to break the Tm-2 or Tm-2(2) resistance revealed distinct amino acid exchanges in the viral 30 kDa protein, suggesting that the movement protein is recognized by both resistance genes to induce the plant defense reaction. To analyze the interactions between the ToMV movement protein and the Tm-2 and Tm-2(2) genes in detail, we generated transgenic tomato lines expressing various movement protein gene constructs. Crosses of the transgenic tomato lines with cultivars containing either the Tm-2 or the Tm-2(2) gene demonstrated that both genes are able to elicit a hypersensitive reaction in response to movement proteins from resistance inducing ToMV strains. However, the domains and the structural requirements for induction of the necrotic response by the ToMV movement protein are completely different for either resistance gene. In the context of the Tm-2 gene, the resistance determinant lies within the N-terminal 188 amino acids of the ToMV movement protein. Interaction of the 30 kDa protein with the Tm-2(2) gene requires two distinct domains localized at the C-terminus and in a different region of the protein, respectively.

Synucleinopathy pathology and REM sleep behavior disorder plus dementia or parkinsonism.

OBJECTIVE: To determine if synucleinopathy pathology is related to REM sleep behavior disorder (RBD) plus dementia or parkinsonism. METHODS: The clinical and neuropathologic findings were analyzed on all autopsied cases evaluated at Mayo Clinic Rochester from January 1990 to April 2002 who were diagnosed with RBD and a neurodegenerative disorder. Ubiquitin and/or alpha-synuclein immunocytochemistry was used in all cases. The clinical and neuropathologic diagnoses were based on published criteria. RESULTS: Fifteen cases were identified (14 men). All had clear histories of dream enactment behavior, and 10 had RBD confirmed by polysomnography. RBD preceded dementia or parkinsonism in 10 (66.7%) patients by a median of 10 (range 2 to 29) years. The clinical diagnoses included dementia with Lewy bodies (DLB) (n = 6); multiple-system atrophy (MSA) (n = 2); combined DLB, AD, and vascular dementia (n = 1); dementia (n = 1); dementia with parkinsonism (n = 1); PD (n = 1); PD with dementia (n = 1); dementia/parkinsonism/motor neuron disease (n = 1); and AD/Binswanger's disease (n = 1). The neuropathologic diagnoses were Lewy body disease (LBD) in 12 (neocortical in 11 and limbic in 1) and MSA in 3. Three also had argyrophilic grain pathology. In the LBD cases, concomitant AD pathology was present in six (one also with Binswanger's pathology, and one also with multiple subcortical infarcts). CONCLUSION: In the setting of degenerative dementia or parkinsonism, RBD often reflects an underlying synucleinopathy.

Narcolepsy associated with other central nervous system disorders.

The authors identified patients with the coexistence of narcolepsy and another CNS disorder seen between 1975 and 1998 at their institution. Eighteen patients were identified, nine with narcolepsy commencing within 1 year before or after the other disorder. Seven patients (39%) had hypothalamic-pituitary syndromes. When they occur together, narcolepsy and other CNS disorders frequently emerge at about the same time, suggesting a causative relationship. Hypothalamic-pituitary pathology was the most common association.

Association of REM sleep behavior disorder and neurodegenerative disease may reflect an underlying synucleinopathy.

Our objective was to examine whether rapid eye movement (REM) sleep behavior disorder occurs in disproportionally greater frequency in multiple system atrophy (MSA), Parkinson's disease (PD), and dementia with Lewy bodies (DLB), collectively known as the synucleinopathies, compared to other nonsynucleinopathy neurodegenerative disorders. In study 1, we reviewed the clinical records of 398 consecutive patients evaluated at Mayo Clinic Rochester for parkinsonism and/or cognitive impairment. The frequency of suspected and polysomnogram (PSG)-confirmed REM sleep behavior disorder (RBD) among subjects with the synucleinopathies MSA, PD, or DLB was compared to the frequency among subjects with the nonsynucleinopathies Alzheimer's disease (AD), frontotemporal dementia (FTD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), mild cognitive impairment (MCI), primary progressive aphasia (PPA), and posterior cortical atrophy (PCA). In study 2, we reviewed the clinical records of 360 consecutive patients evaluated at Mayo Clinic Jacksonville for parkinsonism and/or cognitive impairment. The frequency of probable RBD among patients with PD and DLB was compared to the frequency among patients with AD and MCI. In study 3, we reviewed the brain biopsy or postmortem autopsy diagnoses of 23 Mayo Clinic Rochester patients who had been clinically examined for possible RBD and a neurodegenerative disorder. In study 1, patients with MSA, PD, or DLB were more likely to have probable and PSG-confirmed RBD compared to subjects with the nonsynucleinopathies (probable RBD 77/120=64% vs. 7/278=3%, p < 0.01; PSG-confirmed RBD 47/120=39% vs. 1/278=0%, p < 0.01). In study 2, patients with PD and DLB were more likely to have probable RBD compared to those with AD and MCI (56% vs. 2%, p < 0.01). In study 3, of the 23 autopsied patients who had been questioned about possible RBD, 10 were clinically diagnosed with RBD. The neuropathologic diagnoses in these 10 included Lewy body disease in nine, and MSA in one. Of the other 13 cases, 12 did not have a history suggesting RBD, and the one case who did had normal electromyographic atonia during REM sleep on PSG and autopsy findings of PSP. Only one of these 13 had a synucleinopathy. The positive predictive values for RBD indicating a synucleinopathy for studies 1-3 were 91.7%, 94.3%, and 100.0%, respectively. Clinically suspected and PSG-proven RBD occurs with disproportionally greater frequency in MSA, PD, and DLB compared to other neurodegenerative disorders. In the setting of degenerative dementia and/or parkinsonism, we hypothesize that RBD is a manifestation of an evolving synucleinopathy.