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Hypoxia at high altitude facilitates changes in ventilatory control that can lead to nocturnal periodic breathing (nPB). Here, we introduce a placebo‐controlled approach to prevent nPB by increasing inspiratory CO2 and used it to assess whether nPB contributes to the adverse effects of hypoxia on sleep architecture. In a randomized, single‐blinded, crossover design, 12 men underwent two sojourns (three days/nights each, separated by 4 weeks) in hypobaric hypoxia corresponding to 4000 m altitude, with polysomnography during the first and third night of each sojourn. During all nights, subjects' heads were encompassed by a canopy retaining exhaled CO2, and CO2 concentration in the canopy (i.e. inspiratory CO2 concentration) was controlled by adjustment of fresh air inflow. Throughout the placebo sojourn inspiratory CO2 was ≤0.2%, whereas throughout the other sojourn it was increased to 1.76% (IQR, 1.07%–2.44%). During the placebo sojourn, total sleep time (TST) with nPB was 54.3% (37.4%–80.8%) and 45.0% (24.5%–56.5%) during the first and the third night, respectively (P = 0.042). Increased inspiratory CO2 reduced TST with nPB by an absolute 38.1% (28.1%–48.1%), the apnoea–hypopnoea index by 58.1/h (40.1–76.1/h), and oxygen desaturation index ≥3% by 56.0/h (38.9.1–73.2/h) (all P < 0.001), whereas it increased the mean arterial oxygen saturation in TST by 2.0% (0.4%–3.5%, P = 0.035). Increased inspiratory CO2 slightly increased the percentage of N3 sleep during the third night (P = 0.045), without other effects on sleep architecture. Increasing inspiratory CO2 effectively prevented hypoxia‐induced nPB without affecting sleep macro‐architecture, indicating that nPB does not explain the sleep deterioration commonly observed at high altitudes. Key points: Periodic breathing is common during sleep at high altitude, and it is unclear how this affects sleep architecture.We developed a placebo‐controlled approach to prevent nocturnal periodic breathing (nPB) with inspiratory CO2 administration and used it to assess the effects of nPB on sleep in hypobaric hypoxia.Nocturnal periodic breathing was effectively mitigated by an increased inspiratory CO2 fraction in a blinded manner.Prevention of nPB did not lead to relevant changes in sleep architecture in hypobaric hypoxia.We conclude that nPB does not explain the deterioration in sleep architecture commonly observed at high altitude. [ABSTRACT FROM AUTHOR]

Background: Correct diagnosis of rapid eye movement sleep behavior disorder (RBD) is critical due to its link to α‐synucleinopathies and risk of injuries and requires video‐polysomnography (V‐PSG). Usefulness of screening questionnaires outside the context of validation studies is limited. Objective: The aim was to assess the performance of three validated RBD screening questionnaires compared with gold‐standard V‐PSG. Methods: In this bicentric prospective study, 400 consecutive subjects referred to a sleep center for the first time filled three RBD questionnaires (RBD Screening Questionnaire, RBD Single Question, and Innsbruck RBD Inventory) in random order before sleep experts' interview. Subjects positive for at least one questionnaire were invited to undergo V‐PSG. Data from patients negative for all questionnaires undergoing V‐PSG for other reasons were also evaluated. Questionnaire performances were compared to gold‐standard V‐PSG RBD diagnosis. Results: Three hundred ninety‐nine patients (median age: 51 [interquartile range: 37–64] years, 54.9% men) participated. Two hundred thirty‐eight (59.6%) were positive for at least one questionnaire, and RBD was diagnosed using V‐PSG in 30 patients (7.5%). Questionnaire specificity was 48.1% to 67.4%, sensitivity 80% to 92%, accuracy 51% to 68.3%, negative predictive value 94.2% to 98%, and positive predictive value 14.1% to 20.7%, with no relevant differences in performances among the evaluated questionnaires. Conclusions: RBD questionnaires have low specificity and low positive predictive value and should not be used as a standalone tool for the diagnosis of RBD. Further development of RBD screening methods is needed, particularly for upcoming neuroprotective trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Summary: Patients with restless legs syndrome (RLS) use various terms when describing their symptoms. Whether gender might influence this has not been investigated so far. The aim of this study was to evaluate possible gender differences in spontaneous descriptions of RLS symptoms. This prospective study, conducted in 100 consecutive German‐speaking RLS patients, used a single standardized question. Answers were digitally recorded and transcribed. A content‐related linguistic analysis of the transcripts was performed by two independent blinded raters. The lengths of the answers and content‐related linguistic features were compared between women and men. Ninety‐eight patients were included in the final analysis, 59 women (60.2%) and 39 men (39.8%), with a median age of 62 (23–94) and 63 (31–82) years, respectively (p = 0.602). Demographic and clinical features, including educational level and RLS treatment class, did not differ between genders (p > 0.05). Total word or sentence count showed no gender differences (p = 0.159 and 0.259, respectively), although men used more words per sentence than women (p = 0.018). More men than women described quiescegenic (i.e., triggered by rest or inactivity) symptoms (p = 0.006) and successful attempts at relief (p = 0.039). There was a non‐significant trend toward a more frequent use of the first‐person perspective in men (median times used = 5 [0–10.5] vs. 3.8 [0–17.5], p = 0.068). The more frequent mention of quiescegenic symptoms and successful attempts at relief in men could indicate differences in phenotypic presentation of RLS between genders, a more precise description of RLS symptoms or a higher experience of self‐efficacy in men compared to women. [ABSTRACT FROM AUTHOR]

Isolated REM sleep behaviour disorder (RBD) is an early-stage α-synucleinopathy in most, if not all, affected subjects. Detection of pathological α-synuclein in peripheral tissues of patients with isolated RBD may identify those progressing to Parkinson's disease, dementia with Lewy bodies or multiple system atrophy, with the ultimate goal of testing preventive therapies. Real-time quaking-induced conversion (RT-QuIC) provided evidence of α-synuclein seeding activity in CSF and olfactory mucosa of patients with α-synucleinopathies. The aim of this study was to explore RT-QuIC detection of α-synuclein aggregates in olfactory mucosa of a large cohort of subjects with isolated RBD compared to patients with Parkinson's disease and control subjects. This cross-sectional case-control study was performed at the Medical University of Innsbruck, Austria, the Hospital Clinic de Barcelona, Spain, and the University of Verona, Italy. Olfactory mucosa samples obtained by nasal swab in 63 patients with isolated RBD, 41 matched Parkinson's disease patients and 59 matched control subjects were analysed by α-synuclein RT-QuIC in a blinded fashion at the University of Verona, Italy. Median age of patients with isolated RBD was 70 years, 85.7% were male. All participants were tested for smell, autonomic, cognitive and motor functions. Olfactory mucosa was α-synuclein RT-QuIC positive in 44.4% isolated RBD patients, 46.3% Parkinson's disease patients and 10.2% control subjects. While the sensitivity for isolated RBD plus Parkinson's disease versus controls was 45.2%, specificity was high (89.8%). Among isolated RBD patients with positive α-synuclein RT-QuIC, 78.6% had olfactory dysfunction compared to 21.4% with negative α-synuclein RT-QuIC (P < 0.001). The extent of olfactory dysfunction was more severe in isolated RBD patients positive than negative for olfactory mucosa a-synuclein RT-QuIC (P < 0.001). We provide evidence that the α-synuclein RT-QuIC assay enables the molecular detection of neuronal α-synuclein aggregates in olfactory mucosa of patients with isolated RBD and Parkinson's disease. Although the overall sensitivity was moderate in this study, nasal swabbing is attractive as a simple, non-invasive test and might be useful as part of a screening battery to identify subjects in the prodromal stages of α-synucleinopathies. Further studies are needed to enhance sensitivity, and better understand the temporal dynamics of α-synuclein seeding in the olfactory mucosa and spreading to other brain areas during the progression from isolated RBD to overt α-synucleinopathy, as well the impact of timing, disease subgroups and sampling technique on the overall sensitivity. [ABSTRACT FROM AUTHOR]

Background: There is only partial overlap in the genetic background of isolated rapid-eye-movement sleep behavior disorder (iRBD) and Parkinson's disease (PD).Objective: To examine the role of autosomal dominant and recessive PD or atypical parkinsonism genes in the risk of iRBD.Methods: Ten genes, comprising the recessive genes PRKN, DJ-1 (PARK7), PINK1, VPS13C, ATP13A2, FBXO7, and PLA2G6 and the dominant genes LRRK2, GCH1, and VPS35, were fully sequenced in 1039 iRBD patients and 1852 controls of European ancestry, followed by association tests.Results: We found no association between rare heterozygous variants in the tested genes and risk of iRBD. Several homozygous and compound heterozygous carriers were identified, yet there was no overrepresentation in iRBD patients versus controls.Conclusion: Our results do not support a major role for variants in these genes in the risk of iRBD. © 2020 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Summary : Restless legs syndrome is a common neurological disorder with a clear female predominance. This study aims to evaluate gender differences in clinical, laboratory and polysomnographic features in patients with restless legs syndrome. For this retrospective analysis, 42 women and 42 men from the Innsbruck RLS database matched by age and therapy were included. Demographic data as well as different severity scales (IRLS, RLS‐6 and CGI) were evaluated. Laboratory parameters included several indicators of serum iron status. In all patients, polysomnography was performed according to the AASM guidelines, and periodic leg movements during sleep were scored according to the AASM criteria. IRLS, RLS‐6 and CGI revealed more severe symptoms in women (IRLS median [range]: 17.5 [0–35] versus 13.5 [0–32], p = 0.028; RLS‐6 median [range]: 18 [0–39] versus 12 [1–42], p = 0.014). Women had lower serum ferritin levels than men (median [range] in μg L−1: 74 [9–346] versus 167 [15–389], p < 0.001). Twenty‐two women and eight men (53.7% versus 22.2%, p = 0.003) had ferritin values below 75 μg L−1. Periodic leg movements during sleep indices were significantly lower in women than in men (median [range] in number per hr: 11.4 [0–62.5] versus 40 [0–154], p = 0.004, and 12.6 [0–58.5] versus 40 [0.5–208], p = 0.002, for night I and night II, respectively). Restless legs syndrome severity as measured by validated scales was worse in women, while periodic leg movements during sleep indices were higher in men. These results suggest a possible gender difference in phenotypical presentation of restless legs syndrome, manifesting with predominantly sensory symptoms in women and predominantly motor symptoms in men. [ABSTRACT FROM AUTHOR]

Objective: Rapid eye movement sleep behavior disorder (RBD) is a prodromal synucleinopathy, as >80% will eventually convert to overt synucleinopathy. We performed an in-depth analysis of the SNCA locus to identify RBD-specific risk variants.Methods: Full sequencing and genotyping of SNCA was performed in isolated/idiopathic RBD (iRBD, n = 1,076), Parkinson disease (PD, n = 1,013), dementia with Lewy bodies (DLB, n = 415), and control subjects (n = 6,155). The iRBD cases were diagnosed with RBD prior to neurodegeneration, although some have since converted. A replication cohort from 23andMe of PD patients with probable RBD (pRBD) was also analyzed (n = 1,782 cases; n = 131,250 controls). Adjusted logistic regression models and meta-analyses were performed. Effects on conversion rate were analyzed in 432 RBD patients with available data using Kaplan-Meier survival analysis.Results: A 5'-region SNCA variant (rs10005233) was associated with iRBD (odds ratio [OR] = 1.43, p = 1.1E-08), which was replicated in pRBD. This variant is in linkage disequilibrium (LD) with other 5' risk variants across the different synucleinopathies. An independent iRBD-specific suggestive association (rs11732740) was detected at the 3' of SNCA (OR = 1.32, p = 4.7E-04, not statistically significant after Bonferroni correction). Homozygous carriers of both iRBD-specific SNPs were at highly increased risk for iRBD (OR = 5.74, p = 2E-06). The known top PD-associated variant (3' variant rs356182) had an opposite direction of effect in iRBD compared to PD.Interpretation: There is a distinct pattern of association at the SNCA locus in RBD as compared to PD, with an opposite direction of effect at the 3' of SNCA. Several 5' SNCA variants are associated with iRBD and with pRBD in overt synucleinopathies. ANN NEUROL 2020;87:584-598. [ABSTRACT FROM AUTHOR]

Objective: Restless legs syndrome is a frequent neurological disorder with substantial burden on individual well‐being and public health. Genetic risk loci have been identified, but the causatives genes at these loci are largely unknown, so that functional investigation and clinical translation of molecular research data are still inhibited. To identify putatively causative genes, we searched for highly significant mutational burden in candidate genes. Methods: We analyzed 84 candidate genes in 4,649 patients and 4,982 controls by next generation sequencing using molecular inversion probes that targeted mainly coding regions. The burden of low‐frequency and rare variants was assessed, and in addition, an algorithm (binomial performance deviation analysis) was established to estimate independently the sequence variation in the probe binding regions from the variation in sequencing depth. Results: Highly significant results (considering the number of genes in the genome) of the conventional burden test and the binomial performance deviation analysis overlapped significantly. Fourteen genes were highly significant by one method and confirmed with Bonferroni‐corrected significance by the other to show a differential burden of low‐frequency and rare variants in restless legs syndrome. Nine of them (AAGAB, ATP2C1, CNTN4, COL6A6, CRBN, GLO1, NTNG1, STEAP4, VAV3) resided in the vicinity of known restless legs syndrome loci, whereas 5 (BBS7, CADM1, CREB5, NRG3, SUN1) have not previously been associated with restless legs syndrome. Burden test and binomial performance deviation analysis also converged significantly in fine‐mapping potentially causative domains within these genes. Interpretation: Differential burden with intragenic low‐frequency variants reveals putatively causative genes in restless legs syndrome. ANN NEUROL 2020;87:184–193 [ABSTRACT FROM AUTHOR]

Background: Restless legs syndrome is a sensorimotor neurological disorder of the limbs that impairs quality of life and disturbs sleep. However, there has been progress in understanding the disease involving the dopaminergic system as well as iron metabolism. The exact pathophysiological mechanisms of restless legs syndrome remain elusive. We tried to elucidate the underlying mechanisms in iron metabolism in restless legs syndrome subjects on a systemic, cellular, and mitochondrial level.Methods: We conducted a study prospectively recruiting 168 restless legs syndrome patients and 119 age-matched healthy controls focusing on iron metabolism using human monocytes as surrogates.Results: Evaluation of systemic iron metabolism parameters in the circulation showed no significant difference between patients and controls. We observed a significant reduction in mRNA levels of heme oxygenase 1 and mitochondrial iron genes like mitoferrin 1 and 2 in monocytes isolated from restless legs syndrome patients, indicating mitochondrial iron deficiency. Interestingly, we also observed reduced expression of iron regulatory protein 2 along with impaired activity of mitochondrial aconitase and reduced mitochondrial superoxide formation in restless legs syndrome subjects. Along this line, patients had reduced mitochondrial respiratory capacity that improved in restless legs syndrome subjects under treatment with dopaminergic drugs compared with untreated patients.Conclusions: Our data suggest that restless legs syndrome is linked to mitochondrial iron deficiency and associated impairment of mitochondrial function. This is partly corrected by treatment with dopaminergic drugs compared with untreated patients, which may be linked to an effect of dopamine on cellular iron homeostasis. © 2018 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Hypoxia at high altitude facilitates changes in ventilatory control that can lead to nocturnal periodic breathing (nPB). Here, we introduce a placebo‐controlled approach to prevent nPB by increasing inspiratory CO2 and used it to assess whether nPB contributes to the adverse effects of hypoxia on sleep architecture. In a randomized, single‐blinded, crossover design, 12 men underwent two sojourns (three days/nights each, separated by 4 weeks) in hypobaric hypoxia corresponding to 4000 m altitude, with polysomnography during the first and third night of each sojourn. During all nights, subjects' heads were encompassed by a canopy retaining exhaled CO2, and CO2 concentration in the canopy (i.e. inspiratory CO2 concentration) was controlled by adjustment of fresh air inflow. Throughout the placebo sojourn inspiratory CO2 was ≤0.2%, whereas throughout the other sojourn it was increased to 1.76% (IQR, 1.07%–2.44%). During the placebo sojourn, total sleep time (TST) with nPB was 54.3% (37.4%–80.8%) and 45.0% (24.5%–56.5%) during the first and the third night, respectively (P = 0.042). Increased inspiratory CO2 reduced TST with nPB by an absolute 38.1% (28.1%–48.1%), the apnoea–hypopnoea index by 58.1/h (40.1–76.1/h), and oxygen desaturation index ≥3% by 56.0/h (38.9.1–73.2/h) (all P < 0.001), whereas it increased the mean arterial oxygen saturation in TST by 2.0% (0.4%–3.5%, P = 0.035). Increased inspiratory CO2 slightly increased the percentage of N3 sleep during the third night (P = 0.045), without other effects on sleep architecture. Increasing inspiratory CO2 effectively prevented hypoxia‐induced nPB without affecting sleep macro‐architecture, indicating that nPB does not explain the sleep deterioration commonly observed at high altitudes. Key points: Periodic breathing is common during sleep at high altitude, and it is unclear how this affects sleep architecture.We developed a placebo‐controlled approach to prevent nocturnal periodic breathing (nPB) with inspiratory CO2 administration and used it to assess the effects of nPB on sleep in hypobaric hypoxia.Nocturnal periodic breathing was effectively mitigated by an increased inspiratory CO2 fraction in a blinded manner.Prevention of nPB did not lead to relevant changes in sleep architecture in hypobaric hypoxia.We conclude that nPB does not explain the deterioration in sleep architecture commonly observed at high altitude. [ABSTRACT FROM AUTHOR]

Objective: This study assessed the relationship between speech and language impairment and outcome in a multicenter cohort of isolated/idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD)., Methods: Patients with iRBD from 7 centers speaking Czech, English, German, French, and Italian languages underwent a detailed speech assessment at baseline. Story-tale narratives were transcribed and linguistically annotated using fully automated methods based on automatic speech recognition and natural language processing algorithms, leading to the 3 distinctive linguistic and 2 acoustic patterns of language deterioration and associated composite indexes of their overall severity. Patients were then prospectively followed and received assessments for parkinsonism or dementia during follow-up. The Cox proportional hazard was performed to evaluate the predictive value of language patterns for phenoconversion over a follow-up period of 5 years., Results: Of 180 patients free of parkinsonism or dementia, 156 provided follow-up information. After a mean follow-up of 2.7 years, 42 (26.9%) patients developed neurodegenerative disease. Patients with higher severity of linguistic abnormalities (hazard ratio [HR = 2.35]) and acoustic abnormalities (HR = 1.92) were more likely to develop a defined neurodegenerative disease, with converters having lower content richness (HR = 1.74), slower articulation rate (HR = 1.58), and prolonged pauses (HR = 1.46). Dementia-first (n = 16) and parkinsonism-first with mild cognitive impairment (n = 9) converters had higher severity of linguistic abnormalities than parkinsonism-first with normal cognition converters (n = 17)., Interpretation: Automated language analysis might provide a predictor of phenoconversion from iRBD into synucleinopathy subtypes with cognitive impairment, and thus can be used to stratify patients for neuroprotective trials. ANN NEUROL 2024;95:530-543., (© 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Movements during sleep characterize sleep disorders, which can disturb sleep or its onset, impacting sleep quantity and quality. Video-polysomnography is the current gold standard to assess movements during sleep, but its availability is limited. Using data recorded with a 3D time of flight sensor, we developed a novel method of encoding temporal and spatial information of automatically identified movements during sleep. In a cohort of 20 insomnia patients and 18 controls, we showed that this novel method holds important information able to discriminate the groups. Future studies will explore the methodology in the context of other sleep disorders.

Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by dream enactment, abnormal jerks and movements during REM sleep. Isolated RBD (iRBD) is recognized as the early stage of alpha-synucleinopathies, i.e. dementia with Lewy bodies, Parkinson's disease and multiple system atrophy. The certain diagnosis of iRBD requires video-polysomnography, evaluated by experts with time-consuming visual analyses. In this study, we propose automatic analysis of movements detected with 3D contactless video as a promising technology to assist sleep experts in the identification of patients with iRBD. By using automatically detected upper and lower body movements occurring during REM sleep with a duration between 4s and 5s, we could discriminate 20 iRBD patients from 24 patients with sleep-disordered breathing with an accuracy of 0.91 and F1-score of 0.90. This pilot study shows that 3D contactless video can be successfully used as a non-invasive technology to assist clinicians in identifying abnormal movements during REM sleep, and therefore to recognize patients with iRBD. Future investigations in larger cohorts are needed to validate the proposed technology and methodology.