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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.
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Disfunção Cognitiva , Demência , Doenças Neurodegenerativas , Transtornos Parkinsonianos , Transtorno do Comportamento do Sono REM , Humanos , Transtorno do Comportamento do Sono REM/diagnóstico , Disfunção Cognitiva/diagnósticoRESUMO
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.
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Anti-IgLON5 disease is a unique condition that bridges autoimmunity and neurodegeneration. Since its initial description 10 years ago, an increasing number of autopsies has led to the observation of a broader spectrum of neuropathologies underlying a particular constellation of clinical symptoms. In this study, we describe the neuropathological findings in 22 patients with anti-IgLON5 disease from 9 different European centers. In 15 patients (68%), we observed a hypothalamic and brainstem-predominant tauopathy of varying severity in which the original research neuropathological criteria were readily applicable. This pathology was observed in younger patients (median age at onset 61 years) with a long disease duration (median 9 years). In contrast, in 7 (32%) patients, the originally described brainstem tauopathy was nearly absent or only minimal in the form of delicate threads, despite mild-to-moderate neurodegenerative features, consistent clinical symptoms and the presence of anti-IgLON5 antibodies in CSF and serum. These patients were older at onset (median 79 years) and had shorter disease duration (median < 1 year). Overall, about one-third of the patients showed concomitant TDP-43 pathology within the regions affected by tau pathology and/or neurodegeneration. Based on these observations and in view of the spectrum of the tau burden in the core regions involved in the disease, we propose a simple staging system: stage 1 mild neurodegeneration without overt or only minimal tau pathology, stage 2 moderate neurodegeneration and mild/ moderate tauopathy and stage 3 prominent neurodegeneration and tau pathology. This staging intends to reflect a potential (age- and time-dependent) progression of tau pathology, supporting the current notion that tau accumulation is a secondary phenomenon related to the presence of anti-IgLON5 antibodies in the CNS. Finally, we adapt the original research criteria of the anti-IgLON5 disease-related tauopathy to include the spectrum of pathologies observed in this larger postmortem series.
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Tronco Encefálico , Moléculas de Adesão Celular Neuronais , Tauopatias , Proteínas tau , Humanos , Tauopatias/patologia , Tauopatias/imunologia , Pessoa de Meia-Idade , Tronco Encefálico/patologia , Tronco Encefálico/metabolismo , Tronco Encefálico/imunologia , Masculino , Feminino , Idoso , Idoso de 80 Anos ou mais , Proteínas tau/metabolismo , Proteínas tau/imunologia , Moléculas de Adesão Celular Neuronais/metabolismo , Moléculas de Adesão Celular Neuronais/imunologia , Adulto , Autoanticorpos/imunologia , Proteínas de Ligação a DNA/metabolismoRESUMO
BACKGROUND: Early studies in cellular models suggested an iron accumulation in Friedreich's ataxia (FA), yet findings from patients are lacking. OBJECTIVES: The objective is to characterize systemic iron metabolism, body iron storages, and intracellular iron regulation in FA patients. METHODS: In FA patients and matched healthy controls, we assessed serum iron parameters, regulatory hormones as well as the expression of regulatory proteins and iron distribution in peripheral blood mononuclear cells (PBMCs). We applied magnetic resonance imaging with R2*-relaxometry to quantify iron storages in the liver, spleen, and pancreas. Across all evaluations, we assessed the influence of the genetic severity as expressed by the length of the shorter GAA-expansion (GAA1). RESULTS: We recruited 40 FA patients (19 women). Compared to controls, FA patients displayed lower serum iron and transferrin saturation. Serum ferritin, hepcidin, mean corpuscular hemoglobin and mean corpuscular volume in FA inversely correlated with the GAA1-repeat length, indicating iron deficiency and restricted availability for erythropoiesis with increasing genetic severity. R2*-relaxometry revealed a reduction of splenic and hepatic iron stores in FA. Liver and spleen R2* values inversely correlated with the GAA1-repeat length. FA PBMCs displayed downregulation of ferritin and upregulation of transferrin receptor and divalent metal transporter-1 mRNA, particularly in patients with >500 GAA1-repeats. In FA PBMCs, intracellular iron was not increased, but shifted toward mitochondria. CONCLUSIONS: We provide evidence for a previously unrecognized iron starvation signature at systemic and cellular levels in FA patients, which is related to the underlying genetic severity. These findings challenge the use of systemic iron lowering therapies in FA. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Ataxia de Friedreich , Ferro , Humanos , Ataxia de Friedreich/genética , Ataxia de Friedreich/sangue , Ataxia de Friedreich/metabolismo , Feminino , Masculino , Adulto , Ferro/metabolismo , Fígado/metabolismo , Fígado/patologia , Pessoa de Meia-Idade , Imageamento por Ressonância Magnética , Adulto Jovem , Baço/metabolismo , Leucócitos Mononucleares/metabolismo , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/metabolismo , Ferritinas/sangue , Ferritinas/metabolismo , Hepcidinas/genética , Hepcidinas/sangue , Hepcidinas/metabolismo , Pâncreas/metabolismo , Pâncreas/patologiaRESUMO
Previous studies indicated that patients with isolated rapid eye movement (REM) sleep behaviour disorder (iRBD) exhibit alterations in spectral electroencephalographic (EEG), spindle, and slow-wave features. As it is currently unknown how these EEG features evolve over time, this study aimed to evaluate their temporal progression in patients with iRBD in comparison to controls. We included 23 patients with iRBD and 23 controls. Two polysomnographies (baseline and follow-up) were recorded with a mean (standard deviation) interval of 4.0 (2.5) years and were automatically analysed for sleep stages, spectral bandpower, spindles, and slow waves. We used linear models to evaluate differences at each time point, and linear mixed-effects models to analyse differences in temporal progression between the groups. At baseline, patients with iRBD presented EEG slowing both in REM (expressed as significantly reduced α-bandpower and increased δ-bandpower in frontal channels) and in non-REM (NREM) sleep (significantly increased slow-to-fast ratio in central channels). These differences vanished at follow-up. In both REM and NREM sleep, γ-bandpower was increased at follow-up in patients with iRBD, resulting in significantly different temporal progression between groups (in occipital channels during REM sleep and frontal channels during NREM sleep). Relative power of sleep spindles was significantly higher at baseline in patients with iRBD in frontal channels, but we observed a significant reduction over time in central channels. Finally, slow waves were significantly shorter in patients with iRBD at both time-points. Our results underscore the need of considering longitudinal data when analysing sleep EEG features in patients with iRBD. The observed temporal changes as markers of progression of neurodegeneration require further investigations.
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The aim of the present study was to examine gender and age-specific effects on subjective daytime sleepiness (as measured by the Epworth Sleepiness Scale), body weight and eating behaviour in patients with central disorders of hypersomnolence. Based on the European Narcolepsy Network database, we compared 1035 patients with narcolepsy type I and 505 patients with other central disorders of hypersomnolence ("narcoleptic borderland"), including narcolepsy type II (N = 308) and idiopathic hypersomnia (N = 174), using logistic regression and general linear models. In the entire study population, the Epworth Sleepiness Scale was higher in women (N = 735, mean age = 30 years, mean Epworth Sleepiness Scale = 16.6 ± SD 3.9) than in men (N = 805, mean age = 32 years, mean Epworth Sleepiness Scale = 15.8 ± SD 4.4). In women with narcolepsy type I (N = 475), both Epworth Sleepiness Scale and body mass index increased in parallel with age. In women of the narcoleptic borderland (N = 260), the Epworth Sleepiness Scale markedly peaked in their early 30s, while body mass index only started to rise at that age. This rise in body mass index following the Epworth Sleepiness Scale peak cannot be explained by sleepiness-induced uncontrolled eating, as self-reported uncontrolled eating was negatively associated with the Epworth Sleepiness Scale in this group. We propose that the narcoleptic borderland harbours a unique cluster of women in their fertile years with an unexplored aetiology requiring further investigation towards tailored interventions.
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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.
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Doença por Corpos de Lewy , Doença de Parkinson , Transtorno do Comportamento do Sono REM , Humanos , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico , Doença por Corpos de Lewy/diagnóstico , Transtorno do Comportamento do Sono REM/diagnóstico , Estudos Prospectivos , Progressão da Doença , Biomarcadores , Sintomas ProdrômicosRESUMO
Kleine-Levin syndrome (KLS) is a rare disorder characterized by severe episodic hypersomnia, with cognitive impairment accompanied by apathy or disinhibition. Pathophysiology is unknown, although imaging studies indicate decreased activity in hypothalamic/thalamic areas during episodes. Familial occurrence is increased, and risk is associated with reports of a difficult birth. We conducted a worldwide case-control genome-wide association study in 673 KLS cases collected over 14 y, and ethnically matched 15,341 control individuals. We found a strong genome-wide significant association (rs71947865, Odds Ratio [OR] = 1.48, P = 8.6 × 10-9) within the 3'region of TRANK1 gene locus, previously associated with bipolar disorder and schizophrenia. Strikingly, KLS cases with rs71947865 variant had significantly increased reports of a difficult birth. As perinatal outcomes have dramatically improved over the last 40 y, we further stratified our sample by birth years and found that recent cases had a significantly reduced rs71947865 association. While the rs71947865 association did not replicate in the entire follow-up sample of 171 KLS cases, rs71947865 was significantly associated with KLS in the subset follow-up sample of 59 KLS cases who reported birth difficulties (OR = 1.54, P = 0.01). Genetic liability of KLS as explained by polygenic risk scores was increased (pseudo R2 = 0.15; P < 2.0 × 10-22 at P = 0.5 threshold) in the follow-up sample. Pathway analysis of genetic associations identified enrichment of circadian regulation pathway genes in KLS cases. Our results suggest links between KLS, circadian regulation, and bipolar disorder, and indicate that the TRANK1 polymorphisms in conjunction with reported birth difficulties may predispose to KLS.
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Citocinas/genética , Suscetibilidade a Doenças , Variação Genética , Síndrome de Kleine-Levin/complicações , Síndrome de Kleine-Levin/genética , Complicações do Trabalho de Parto/epidemiologia , Complicações do Trabalho de Parto/etiologia , Transtorno Bipolar/etiologia , Distúrbios do Sono por Sonolência Excessiva/etiologia , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Síndrome de Kleine-Levin/epidemiologia , Masculino , Razão de Chances , Polimorfismo Genético , Gravidez , Medição de Risco , Fatores de RiscoRESUMO
OBJECTIVE: This study was undertaken to follow up predictive factors for α-synuclein-related neurodegenerative diseases in a multicenter cohort of idiopathic/isolated rapid eye movement sleep behavior disorder (iRBD). METHODS: Patients with iRBD from 12 centers underwent a detailed assessment for potential environmental and lifestyle risk factors via a standardized questionnaire at baseline. Patients were then prospectively followed and received assessments for parkinsonism or dementia during follow-up. The cumulative incidence of parkinsonism or dementia was estimated with competing risk analysis. Cox regression analyses were used to evaluate the predictive value of environmental/lifestyle factors over a follow-up period of 11 years, adjusting for age, sex, and center. RESULTS: Of 319 patients who were free of parkinsonism or dementia, 281 provided follow-up information. After a mean follow-up of 5.8 years, 130 (46.3%) patients developed neurodegenerative disease. The overall phenoconversion rate was 24.2% after 3 years, 44.8% after 6 years, and 67.5% after 10 years. Patients with older age (adjusted hazard ratio [aHR] = 1.05) and nitrate derivative use (aHR = 2.18) were more likely to phenoconvert, whereas prior pesticide exposure (aHR = 0.21-0.64), rural living (aHR = 0.53), lipid-lowering medication use (aHR = 0.59), and respiratory medication use (aHR = 0.36) were associated with lower phenoconversion risk. Risk factors for those converting to primary dementia and parkinsonism were generally similar, with dementia-first converters having lower coffee intake and beta-blocker intake, and higher occurrence of family history of dementia. INTERPRETATION: Our findings elucidate the predictive values of environmental factors and comorbid conditions in identifying RBD patients at higher risk of phenoconversion. ANN NEUROL 2022;91:404-416.
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Demência/epidemiologia , Doenças Neurodegenerativas/epidemiologia , Transtorno do Comportamento do Sono REM/complicações , Idoso , Demência/etiologia , Progressão da Doença , Seguimentos , Humanos , Incidência , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Doenças Neurodegenerativas/etiologia , Fatores de Risco , Inquéritos e QuestionáriosRESUMO
Anti-IgLON5 disease is a rare neurological, probably autoimmune, disorder associated in many cases with a specific tauopathy. Only a few post-mortem neuropathological studies have been reported so far. Little is known about the pathogenic mechanisms that result in neurodegeneration. We investigated the neuropathology of anti-IgLON5 disease and characterized cellular and humoral inflammation. We included nine cases (six of them previously published). Median age of patients was 71 years (53-82 years), the median disease duration was 6 years (0.5-13 years), and the female to male ratio was 5:4. Six cases with a median disease duration of 9 years presented a prominent tauopathy. Five of them had a classical anti-IgLON5-related brainstem tauopathy and another presented a prominent neuronal and glial 4-repeat tauopathy, consistent with progressive supranuclear palsy (PSP). Three cases with short disease duration (median 1.25 years) only showed a primary age-related neurofibrillary pathology. Inflammatory infiltrates of T and B cells were mild to moderate and did not significantly differ between anti-IgLON5 disease cases with or without tauopathy. In contrast, we found an extensive neuropil deposition of IgG4 in the tegmentum of the brainstem, olivary nucleus, and cerebellar cortex that was most prominent in two patients with short disease duration without the typical IgLON5-related tauopathy. The IgG4 deposits were particularly prominent in the cerebellar cortex and in these regions accompanied by mild IgG1 deposits. Activated complement deposition (C9neo) was absent. Our study indicates that IgLON5-related tau pathology occurs in later disease stages and may also present a PSP-phenotype with exclusively 4-repeat neuronal and glial tau pathology. The prominent deposition of anti-IgLON5 IgG4 at predilection sites for tau pathology suggests that anti-IgLON5 antibodies precede the tau pathology. Early start of immunotherapy might prevent irreversible neuronal damage and progression of the disease, at least in a subgroup of patients.
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Encefalite , Doença de Hashimoto , Proteínas tau , Idoso , Feminino , Humanos , Masculino , Autopsia , Encefalite/patologia , Doença de Hashimoto/patologia , Imunoglobulina G , Moléculas de Adesão Celular Neuronais , Proteínas tau/análiseRESUMO
BACKGROUND: As opposed to other neurobehavioral disorders, epigenetic analyses and biomarkers are largely missing in the case of idiopathic restless legs syndrome (RLS). OBJECTIVES: Our aims were to develop a biomarker for RLS based on DNA methylation in blood and to examine DNA methylation in brain tissues for dissecting RLS pathophysiology. METHODS: Methylation of blood DNA from three independent cohorts (n = 2283) and post-mortem brain DNA from two cohorts (n = 61) was assessed by Infinium EPIC 850 K BeadChip. Epigenome-wide association study (EWAS) results of individual cohorts were combined by random-effect meta-analysis. A three-stage selection procedure (discovery, n = 884; testing, n = 520; validation, n = 879) established an epigenetic risk score including 30 CpG sites. Epigenetic age was assessed by Horvath's multi-tissue clock and Shireby's cortical clock. RESULTS: EWAS meta-analysis revealed 149 CpG sites linked to 136 genes (P < 0.05 after Bonferroni correction) in blood and 23 CpG linked to 18 genes in brain (false discovery rate [FDR] < 5%). Gene-set analyses of blood EWAS results suggested enrichments in brain tissue types and in subunits of the kainate-selective glutamate receptor complex. Individual candidate genes of the brain EWAS could be assigned to neurodevelopmental or metabolic traits. The blood epigenetic risk score achieved an area under the curve (AUC) of 0.70 (0.67-0.73) in the validation set, comparable to analogous scores in other neurobehavioral disorders. A significant difference in biological age in blood or brain of RLS patients was not detectable. CONCLUSIONS: DNA methylation supports the notion of altered neurodevelopment in RLS. Epigenetic risk scores are reliably associated with RLS but require even higher accuracy to be useful as biomarkers. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Epigênese Genética , Síndrome das Pernas Inquietas , Humanos , Epigênese Genética/genética , Síndrome das Pernas Inquietas/genética , Metilação de DNA/genética , DNA , Estudo de Associação Genômica Ampla/métodos , Biomarcadores , Ilhas de CpG/genéticaRESUMO
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.
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Doença de Parkinson , Transtorno do Comportamento do Sono REM , Masculino , Humanos , Pessoa de Meia-Idade , Feminino , Transtorno do Comportamento do Sono REM/diagnóstico , Estudos Prospectivos , Doença de Parkinson/diagnóstico , Polissonografia/métodos , Inquéritos e QuestionáriosRESUMO
Excessive fragmentary myoclonus (EFM) is a frequent finding during routine video-polysomnography (VPSG). We aimed to automatically measure the prevalence of EFM according to current American Academy of Sleep Medicine (AASM) criteria, and the fragmentary myoclonus index (FMI) in sleep stage N1, N2, N3, rapid eye movement (REM) sleep and wake in a large patient population. A total of 500 VPSG recordings of patients admitted to the Sleep Laboratory, Department of Neurology, Medical University of Innsbruck, Austria, between May 1, 2022 and February 28, 2023, were included. EFM according to AASM criteria and FMI were computed by applying a previously validated algorithm. EFM was automatically detected in 121 of the 500 Sleep Laboratory patients (24.2%, 95% confidence interval 20.1%-28.9%). FMI increased with age, male gender, apnea-hypopnea-index (AHI), oxygen desaturation index (ODI), and periodic leg movements of sleep (PLMS) index. FMI was highest in REM sleep behaviour disorder (RBD), followed by neurodegenerative and internal medicine diseases, but the increase in the FMI was not explained by the disease itself but rather by the age and sex of the patients. Almost a quarter of our patient population had EFM. However, the prevalence of EFM does not allow the drawing of any conclusions about the pathophysiology of EFM or even the determination of a pathological FMI cut-off value. Associations of the FMI with age, sex, AHI, ODI and PLMS are in line with previous studies, but the FMI needs to be evaluated in different disease entities to learn more about its pathophysiology.
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Excessive fragmentary myoclonus (EFM) is an incidental polysomnographic finding requiring documentation of ≥20 minutes of NREM sleep with ≥5 fragmentary myoclonus (FM) potentials per minute. Manual FM scoring is time-consuming and prone to inter-rater variability. This work aimed to validate an automatic algorithm to score FM in whole-night recordings. One expert scorer manually scored FM in the anterior tibialis muscles in 10 polysomnographies of as many subjects. The algorithm consisted of two steps. First, parameters of the automatic leg movement identification algorithm of the BrainRT software (OSG, Belgium) were modified to identify FM-like activity. Second, a post-processing algorithm was implemented to remove FM activity not meeting sufficient amplitude criteria. The parameter choice and the post-processing were optimised with leave-one-out cross-validation. Agreement with the human scorer was measured with Cohen's kappa (k) and correlation between manual and automatic FM indices in different sleep stages was evaluated. Agreement in identifying patients with EFM was computed. The algorithm showed substantial agreement (average k > 0.62) for all sleep stages, except for W, where a moderate agreement was observed (average k = 0.58). Nonetheless, the agreement between human scorer and the algorithm was similar to previously reported values of inter-rater variability for FM scoring. Correlation coefficients were over 0.96 for all sleep stages. Furthermore, the presence/absence of EFM was correctly identified in 80% of the subjects. In conclusion, this work presents a reliable algorithm for automatic scoring of FM and EFM. Future studies will apply it to objectively and consistently evaluate FM indices and the presence of EFM in large populations.
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Mioclonia , Humanos , Mioclonia/diagnóstico , Reprodutibilidade dos Testes , Polissonografia , Fases do Sono/fisiologia , Algoritmos , EletroencefalografiaRESUMO
BACKGROUND AND PURPOSE: Automatic 3D video analysis of the lower body during rapid eye movement (REM) sleep has been recently proposed as a novel tool for identifying people with isolated REM sleep behavior disorder (iRBD), but, so far, it has not been validated on unseen subjects. This study aims at validating this technology in a large cohort and at improving its performances by also including an analysis of movements in the head, hands and upper body. METHODS: Fifty-three people with iRBD and 128 people without RBD (of whom 89 had sleep disorders considered RBD differential diagnoses) were included in the study. An automatic algorithm identified movements from 3D videos during REM sleep in four regions of interest (ROIs): head, hands, upper body and lower body. The movements were divided into categories according to duration: short (0.1-2 s), medium (2-15 s) and long (15-300 s). For each ROI and duration range, features were obtained from the identified movements. Logistic regression models using as predictors the features from one single ROI or a combination of ROIs were trained and tested in a 10-runs 10-fold cross-validation scheme on the task of differentiating people with iRBD from people without RBD. RESULTS: The best differentiation was achieved using short movements in all four ROIs (test accuracy 0.866 ± 0.007, test F1 score = 0.783 ± 0.010). Single group analyses showed that people with iRBD were distinguished successfully from subjects with RBD differential diagnoses. CONCLUSIONS: Automatic 3D video analysis might be implemented in clinical routine as a supportive screening tool for identifying people with RBD.
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Transtorno do Comportamento do Sono REM , Humanos , Transtorno do Comportamento do Sono REM/diagnóstico , Movimento , Sono REM , PolissonografiaRESUMO
Alpha-synucleinopathies can be identified in their prodromal phase, raising several ethical issues. In this review, we first provide definitions of prodromal α-synucleinopathies and discuss the importance of distinguishing between prodromes and risk factors. Next, we discuss the implications of a diagnosis of prodromal α-synucleinopathy and considerations regarding prognostic counseling in both clinical and research settings. We review available data on patient preferences regarding disclosure as well as providers' perspectives. We examine the pros and cons of disclosing a diagnosis of prodromal α-synucleinopathy, taking into consideration the differences between clinical and research settings. Asking about willingness to know in clinical and research settings and the shared decision-making process applied to prognostic counseling is discussed. Concerning research settings, ethical aspects regarding clinical trials are addressed. Availability of direct-to-consumer technologies will likely lead to novel contexts requiring prognostic counseling, and future neuroprotective or neuromodulating treatments may require further considerations on the timing, role, and importance of prognostic counseling. Recommendations on how to address ethical gaps should be a priority for patients, medical professional societies, and research workgroups. Ethical issues must be considered as an integral part of the overall clinical and research approach to prodromal synucleinopathies.
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Sinucleinopatias , Humanos , Prognóstico , Aconselhamento , Aconselhamento Genético , RevelaçãoRESUMO
OBJECTIVE: This multilanguage study used simple speech recording and high-end pattern analysis to provide sensitive and reliable noninvasive biomarkers of prodromal versus manifest α-synucleinopathy in patients with idiopathic rapid eye movement sleep behavior disorder (iRBD) and early-stage Parkinson disease (PD). METHODS: We performed a multicenter study across the Czech, English, German, French, and Italian languages at 7 centers in Europe and North America. A total of 448 participants (337 males), including 150 with iRBD (mean duration of iRBD across language groups 0.5-3.4 years), 149 with PD (mean duration of disease across language groups 1.7-2.5 years), and 149 healthy controls were recorded; 350 of the participants completed the 12-month follow-up. We developed a fully automated acoustic quantitative assessment approach for the 7 distinctive patterns of hypokinetic dysarthria. RESULTS: No differences in language that impacted clinical parkinsonian phenotypes were found. Compared with the controls, we found significant abnormalities of an overall acoustic speech severity measure via composite dysarthria index for both iRBD (p = 0.002) and PD (p < 0.001). However, only PD (p < 0.001) was perceptually distinct in a blinded subjective analysis. We found significant group differences between PD and controls for monopitch (p < 0.001), prolonged pauses (p < 0.001), and imprecise consonants (p = 0.03); only monopitch was able to differentiate iRBD patients from controls (p = 0.004). At the 12-month follow-up, a slight progression of overall acoustic speech impairment was noted for the iRBD (p = 0.04) and PD (p = 0.03) groups. INTERPRETATION: Automated speech analysis might provide a useful additional biomarker of parkinsonism for the assessment of disease progression and therapeutic interventions. ANN NEUROL 2021;90:62-75.
Assuntos
Doença de Parkinson/diagnóstico , Transtorno do Comportamento do Sono REM/diagnóstico , Fala/fisiologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Progressão da Doença , Europa (Continente) , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/fisiopatologia , Sintomas Prodrômicos , Transtorno do Comportamento do Sono REM/fisiopatologiaRESUMO
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.
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Síndrome das Pernas Inquietas , Feminino , Humanos , Idioma , Masculino , Estudos Prospectivos , Fatores SexuaisRESUMO
This manuscript presents an overview of REM sleep behaviour disorder (RBD) with a special focus on European contributions. After an introduction examining the history of the disorder, we address the pathophysiological and clinical aspects, as well as the diagnostic issues. Further, implications of RBD diagnosis and biomarkers are discussed. Contributions of European researchers to this field are highlighted.
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Transtorno do Comportamento do Sono REM , Humanos , Polissonografia , Transtorno do Comportamento do Sono REM/diagnóstico , Sono REM/fisiologiaRESUMO
BACKGROUND AND PURPOSE: Augmentation is a paradoxical reaction mainly to dopaminergic medication in patients with restless legs syndrome (RLS), but the exact pathomechanism remains unclear. The aim of this study was to identify factors associated with augmentation in RLS patients. METHODS: RLS patients with and without current or previous augmentation were recruited. Demographic characteristics, history of smoking, questionnaires for depression, alexithymia, and impulsivity, and RLS severity were obtained. RESULTS: We included 122 patients, of whom half had a history of augmentation. Patients with augmentation had a longer disease duration (p = 0.001), had higher RLS severity scores (p = 0.013), had higher levodopa equivalent doses (p < 0.001), had higher scores for alexithymia (p = 0.028), had higher prevalence of impulse control disorders (p < 0.001), more often had a history of smoking (p = 0.039), were more often currently smoking (p = 0.015), and had more average pack-years (p = 0.016). CONCLUSIONS: Here, we describe several factors commonly associated with augmentation in RLS. These may help clinicians to screen and treat patients carefully to avoid the challenging side effect of augmentation.