A survey-based approach on restless legs syndrome: practices and perspectives among Italian neurologists.

INTRODUCTION: Restless Legs Syndrome (RLS) is a widely prevalent and complex neurological disorder. Despite notable advancements in managing RLS, the disorder continues to face challenges related to its recognition and management. OBJECTIVE: This study seeks to gain comprehensive insights into the knowledge and clinical practices among Italian neurologists regarding RLS diagnosis, management, and treatment, comparing approaches among general neurologists, movement disorder specialists, and sleep experts. METHODS: Members of the Italian Society of Neurology, the Italian Society of Parkinson and Movement Disorders, and the Italian Association of Sleep Medicine were invited to participate in a 19-question online survey. RESULTS: Among the 343 surveyed neurologists, 60% categorized RLS as a "sleep-related movement disorder." Forty% indicated managing 5-15 RLS patients annually, with sleep specialists handling the highest patient volume. Of note, only 34% adhered strictly to all five essential diagnostic criteria. The majority (69%) favored low-dosage dopamine agonists as their first-line treatment, with movement disorder specialists predominantly endorsing this approach, while sleep experts preferred iron supplementation. Regular screening for iron levels was widespread (91%), with supplementation typically guided by serum iron alterations. In cases of ineffective initial treatments, escalating dopamine agonist dosage was the preferred strategy (40%). CONCLUSIONS: These findings underscore a lack of a clear conceptualization of RLS, with a widespread misconception of the disorder as solely a movement disorder significantly influencing treatment approaches. Disparities in RLS understanding across neurology subspecialties underscore the necessity for improved diagnostic accuracy, targeted educational initiatives, and management guidelines to ensure consistent and effective RLS management.

Presynaptic Dopaminergic Imaging Characterizes Patients with REM Sleep Behavior Disorder Due to Synucleinopathy.

OBJECTIVE: To apply a machine learning analysis to clinical and presynaptic dopaminergic imaging data of patients with rapid eye movement (REM) sleep behavior disorder (RBD) to predict the development of Parkinson disease (PD) and dementia with Lewy bodies (DLB). METHODS: In this multicenter study of the International RBD study group, 173 patients (mean age 70.5 ± 6.3 years, 70.5% males) with polysomnography-confirmed RBD who eventually phenoconverted to overt alpha-synucleinopathy (RBD due to synucleinopathy) were enrolled, and underwent baseline presynaptic dopaminergic imaging and clinical assessment, including motor, cognitive, olfaction, and constipation evaluation. For comparison, 232 RBD non-phenoconvertor patients (67.6 ± 7.1 years, 78.4% males) and 160 controls (68.2 ± 7.2 years, 53.1% males) were enrolled. Imaging and clinical features were analyzed by machine learning to determine predictors of phenoconversion. RESULTS: Machine learning analysis showed that clinical data alone poorly predicted phenoconversion. Presynaptic dopaminergic imaging significantly improved the prediction, especially in combination with clinical data, with 77% sensitivity and 85% specificity in differentiating RBD due to synucleinopathy from non phenoconverted RBD patients, and 85% sensitivity and 86% specificity in discriminating PD-converters from DLB-converters. Quantification of presynaptic dopaminergic imaging showed that an empirical z-score cutoff of -1.0 at the most affected hemisphere putamen characterized RBD due to synucleinopathy patients, while a cutoff of -1.0 at the most affected hemisphere putamen/caudate ratio characterized PD-converters. INTERPRETATION: Clinical data alone poorly predicted phenoconversion in RBD due to synucleinopathy patients. Conversely, presynaptic dopaminergic imaging allows a good prediction of forthcoming phenoconversion diagnosis. This finding may be used in designing future disease-modifying trials. ANN NEUROL 2024.

Theory of Mind impairment in childhood narcolepsy type 1: a case-control study.

Narcolepsy type 1 is a central disorder of hypersomnolence characterized by excessive daytime sleepiness, cataplexy and other rapid eye movement sleep-related manifestations. Neurophysiological studies suggest that narcolepsy type 1 patients may experience impairment in emotional processing due to structural and functional changes in limbic structures and associated areas. However, the only study exploring narcolepsy behavioural responses found no impairment in the ability to recognize emotions, possibly due to compensatory mechanisms. The present study was designed to fill this gap in the literature by investigating the behavioural impairment related to emotional processing focusing on an advanced socio-cognitive skill, namely Theory of Mind, in paediatric narcolepsy type 1 patients. Twenty-two narcolepsy type 1 children and adolescents (six female; age range: 8.0-13.5) and 22 healthy controls matched for age and sex (six female; age range: 8.9-13.0) underwent a neuropsychological evaluation to assess socio-economic status, verbal abilities, working memory, social anxiety and Theory of Mind via a verbal task (i.e. Strange Stories task) and a visual task (i.e. Silent Films). Narcolepsy type 1 patients were also evaluated for disease severity. Patients exhibited impairment in Theory of Mind skills, as assessed both through both verbal (controls median = 8; patients median = 5; P = 0.009) and visual tasks (controls median = 8; patients median = 6; P = 0.003), compared to healthy controls. Correlation analyses showed that verbal and visual Theory of Mind was negatively related to narcolepsy severity (ρ = -0.45, P = 0.035 and ρ = -0.52, P = 0.012), and daytime sleepiness (ρ = -0.48, P = 0.025 and ρ = -0.45, P = 0.038). Our study shows a selective impairment in the Theory of Mind domain in children and adolescents with narcolepsy type 1. In addition, our results highlight a link between symptom severity and Theory of Mind, suggesting that lower Theory of Mind levels are associated with higher symptom severity. Further, longitudinal studies are needed to disentangle the direction of this relation and to disambiguate if narcolepsy severity impaired children's Theory of Mind or if Theory of Mind skills modulate the severity of narcolepsy symptoms by providing a greater ability to avoid cataplexy.

Estimation bias and agreement limits between two common self-report methods of habitual sleep duration in epidemiological surveys.

Accurate measurement of habitual sleep duration (HSD) is crucial for understanding the relationship between sleep and health. This study aimed to assess the bias and agreement limits between two commonly used short HSD self-report methods, considering sleep quality (SQ) and social jetlag (SJL) as potential predictors of bias. Data from 10,268 participants in the International COVID Sleep Study-II (ICOSS-II) were used. Method-Self and Method-MCTQ were compared. Method-Self involved a single question about average nightly sleep duration (HSDself), while Method-MCTQ estimated HSD from reported sleep times on workdays (HSDMCTQwork) and free days (HSDMCTQfree). Sleep quality was evaluated using a Likert scale and the Insomnia Severity Index (ISI) to explore its influence on estimation bias. HSDself was on average 42.41 ± 67.42 min lower than HSDMCTQweek, with an agreement range within ± 133 min. The bias and agreement range between methods increased with poorer SQ. HSDMCTQwork showed less bias and better agreement with HSDself compared to HSDMCTQfree. Sleep duration irregularity was - 43.35 ± 78.26 min on average. Subjective sleep quality predicted a significant proportion of variance in HSDself and estimation bias. The two methods showed very poor agreement and a significant systematic bias, both worsening with poorer SQ. Method-MCTQ considered sleep intervals without adjusting for SQ issues such as wakefulness after sleep onset but accounted for sleep irregularity and sleeping in on free days, while Method-Self reflected respondents' interpretation of their sleep, focusing on their sleep on workdays. Including an SQ-related question in surveys may help bidirectionally adjust the possible bias and enhance the accuracy of sleep-health studies.

Eating disorders in narcolepsy type 1: Evidence from a cross-sectional Italian study.

Narcolepsy type 1 is a chronic central disorder of hypersomnolence, and it is frequently accompanied by overweight, but the association between narcolepsy type 1 and eating disorders is controversial. Our study aims to compare patients with narcolepsy type 1 and controls on the symptomatology of eating disorders and to evaluate the association between clinical factors. This is a cross-sectional study, with consecutive recruitment of patients with narcolepsy type 1 attending the Outpatient Clinic for Narcolepsy at the IRCCS Istituto delle Scienze Neurologiche di Bologna (Italy) for routine follow-up visits. Healthy subjects from general populations were recruited as controls. Patients underwent a questionnaire-based assessment using the Eating Disorder Examination Questionnaire (EDE-Q), Binge Eating Scale (BES), Italian Night Eating Questionnaire (I-NEQ), Epworth Sleepiness Scale (ESS), and Narcolepsy Severity Scale (NSS). One hundred and thirty-eight patients with narcolepsy type 1 and 162 controls were enrolled. This study showed that individuals with narcolepsy type 1 reported higher scores on the EDE-Q, I-NEQ, and a higher body mass index (BMI) than the controls. The logistic regression analysis results, with EDE-Q positivity as a dependent variable, demonstrate a significant association with antidepressant drugs, female sex, and the use of sodium oxybate. We found an association between antidepressant drug consumption, the NSS total score, and female sex with BES positivity as the dependent variable. The logistic regression analysis for I-NEQ positivity found an association with antidepressant drug use. This study shows that patients with narcolepsy type 1 frequently present with comorbid eating disorder symptomatology, mainly night eating syndrome. Investigating the possible presence of eating disorders symptomatology through questionnaires is fundamental during the assessment of patients with narcolepsy type 1.

Long sleep time and excessive need for sleep: State of the art and perspectives.

The mechanisms underlying the individual need for sleep are unclear. Sleep duration is indeed influenced by multiple factors, such as genetic background, circadian and homeostatic processes, environmental factors, and sometimes transient disturbances such as infections. In some cases, the need for sleep dramatically and chronically increases, inducing a daily-life disability. This "excessive need for sleep" (ENS) was recently proposed and defined in a European Position Paper as a dimension of the hypersomnolence spectrum, "hypersomnia" being the objectified complaint of ENS. The most severe form of ENS has been described in Idiopathic Hypersomnia, a rare neurological disorder, but this disabling symptom can be also found in other hypersomnolence conditions. Because ENS has been defined recently, it remains a symptom poorly investigated and understood. However, protocols of long-term polysomnography recordings have been reported by expert centers in the last decades and open the way to a better understanding of ENS through a neurophysiological approach. In this narrative review, we will 1) present data related to the physiological and pathological variability of sleep duration and their mechanisms, 2) describe the published long-term polysomnography recording protocols, and 3) describe current neurophysiological tools to study sleep microstructure and discuss perspectives for a better understanding of ENS.

Sex disparities in clinical features and burden of narcolepsy type 1.

To investigate potential sex-related differences in patients with narcolepsy type 1, we carried out an analysis of baseline data from 93 women and 89 men with narcolepsy type 1 who participated in the TElemedicine for NARcolepsy (TENAR) trial. The following data were considered: sociodemographics; diagnostic (disease history, polysomnography, orexin, human leukocyte antigen) and clinical features, including sleepiness (Epworth Sleepiness Scale), cataplexy and other narcolepsy symptoms; disease severity (Narcolepsy Severity Scale); pharmacological treatment; depressive symptoms (Beck Depression Inventory); and self-reported relevance of eight narcolepsy-related issues. We found that, compared with men, significantly more women reported automatic behaviours (55.4% versus 40%) and had higher Epworth Sleepiness Scale (median 10 versus 9) and Beck Depression Inventory scores (median 10.5 versus 5), and there was a trend for a higher Narcolepsy Severity Scale total score in women (median 19 versus 18, p = 0.057). More women than men were officially recognized as having a disability (38% versus 22.5%) and considered 5/8 narcolepsy-related issues investigated as a relevant problem. More severe sleepiness and a greater narcolepsy-related burden in women could mirror sex differences present in the general population, or may be related to suboptimal management of narcolepsy type 1 or to more severe depressive symptoms in women. Future studies and guidelines should address these aspects.

Disclosing the Risk Associated with Isolated REM Behavior Disorder: The Sleep Experts' Perspective.

BACKGROUND: Isolated rapid-eye-movement sleep behavior disorder (iRBD) is associated with a high risk for phenoconversion to a neurodegenerative disorder, but the optimal approach for disclosure of this risk to patients is still debated. OBJECTIVES: The aim of this study was to explore views and experiences of iRBD experts regarding risk disclosure. METHODS: In this qualitative study, semi-structured interviews with sleep experts caring for patients with iRBD were analyzed through a conventional content analysis approach. RESULTS: We interviewed 22 iRBD experts (eight female, average age of 51.8 years) from 18 Italian sleep centers; 21/22 regularly disclosed the risks associated with iRBD, usually after the video-polysomnography, and 8/22 regularly mentioned phenoconversion rates. Content analysis allowed us to identify three main themes. First, sleep experts reported several points in favor of risk disclosure, especially related to the principle of beneficence, but some highlighted the need for specific learning on the topic. Second, experts favored a patient-tailored disclosure that should not upset the patient unnecessarily, since phenoconversion is uncertain. Third, risk disclosure was seen by participants as a relational task that should be carried out in person in the context of a trusting patient-physician relationship, while they had contrasting views regarding patients' previous knowledge. CONCLUSIONS: Sleep experts generally preferred a tailored and reassuring approach to risk disclosure within a framework of relational autonomy. The results of this study indicate the need for specific education, training, and recommendations concerning risk disclosure that should also include patients' and families' preferences.

Biomarkers of neurodegeneration in isolated and antidepressant-related rapid eye movement sleep behavior disorder.

BACKGROUND AND PURPOSE: This study compared the features of isolated rapid eye movement (REM) sleep behavior disorder (iRBD) and antidepressant-related REM sleep behaviour disorder (RBD) with the aim of highlighting markers that might distinguish the two entities. METHODS: The observational cohort study included RBD patients with and without antidepressant use (antiD+ and antiD- patients, respectively), without cognitive impairment and parkinsonism. Clinical features of RBD, subtle motor and non-motor symptoms of parkinsonism, sleep architecture, REM atonia index, dopamine transporter-single photon emission computed tomography (DAT-SPECT) and skin biopsies for the intraneuronal alpha-synuclein (α-syn), were evaluated in the baseline work-up. RESULTS: Thirty-nine patients, 10 antiD+ and 29 antiD-, were included. AntiD+ patients (more frequently female) reported more psychiatric symptoms, less violent dream enactment, and less frequent hyposmia. Dermal α-syn was detected in 93.1% of antiD- versus 30% of antiD+ patients (p = 0.00024). No differences appeared in other motor and non-motor symptoms, Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III score, DAT-SPECT, or polysomnographic features. CONCLUSIONS: Patients with antidepressant-related RBD have clinical and neuropathological features suggesting a lower risk of evolution than those with iRBD.

Nightmare frequency is a risk factor for suicidal ideation during the COVID-19 pandemic.

The association between nightmare frequency (NMF) and suicidal ideation (SI) is well known, yet the impact of the COVID-19 pandemic on this relation is inconsistent. This study aimed to investigate changes in NMF, SI, and their association during the COVID-19 pandemic. Data were collected in 16 countries using a harmonised questionnaire. The sample included 9328 individuals (4848 women; age M[SD] = 46.85 [17.75] years), and 17.60% reported previous COVID-19. Overall, SI was significantly 2% lower during the pandemic vs. before, and this was consistent across genders and ages. Most countries/regions demonstrated decreases in SI during this pandemic, with Austria (-9.57%), Sweden (-6.18%), and Bulgaria (-5.14%) exhibiting significant declines in SI, but Italy (1.45%) and Portugal (2.45%) demonstrated non-significant increases. Suicidal ideation was more common in participants with long-COVID (21.10%) vs. short-COVID (12.40%), though SI did not vary by COVID-19 history. Nightmare frequency increased by 4.50% during the pandemic and was significantly higher in those with previous COVID-19 (14.50% vs. 10.70%), during infection (23.00% vs. 8.10%), and in those with long-COVID (18.00% vs. 8.50%). The relation between NMF and SI was not significantly stronger during the pandemic than prior (rs = 0.18 vs. 0.14; z = 2.80). Frequent nightmares during the pandemic increased the likelihood of reporting SI (OR = 1.57, 95% CI 1.20-2.05), while frequent dream recall during the pandemic served a protective effect (OR = 0.74, 95% CI 0.59-0.94). These findings have important implications for identifying those at risk of suicide and may offer a potential pathway for suicide prevention.

Role of Daytime Continuous Polysomnography in the Diagnosis of Pediatric Narcolepsy Type 1.

BACKGROUND AND OBJECTIVES: Narcolepsy type 1 (NT1) is still largely underdiagnosed or diagnosed too late in children. Difficulties in obtaining rapid and reliable diagnostic evaluations of the condition in clinical practice partially explain this problem. Predictors of NT1 include cataplexy and sleep-onset REM periods (SOREMPs), documented during nocturnal polysomnography (N-PSG) or through the multiple sleep latency test (MSLT), although low CSF hypocretin-1 (CSF hcrt-1) is the definitive biological disease marker. Obtaining reliable MSLT results is not always feasible in children; therefore, this study aimed to validate daytime continuous polysomnography (D-PSG) as an alternative diagnostic tool. METHODS: Two hundred consecutive patients aged younger than 18 years (112 with NT1; 25 with other hypersomnias, including narcolepsy type 2 and idiopathic hypersomnia; and 63 with subjective excessive daytime sleepiness) were randomly split into 2 groups: group 1 (n = 133) for the identification of diagnostic markers and group 2 (n = 67) for the validation of the detected markers. The D-PSG data collected included the number of spontaneous naps, total sleep time, and the number of daytime SOREMPs (d-SOREMP). D-PSG data were tested against CSF hcrt-1 deficiency (NT1 diagnosis) as the gold standard using receiver operating characteristic (ROC) curve analysis in group 1. ROC diagnostic performances of single and combined D-PSG parameters were tested in group 1 and validated in group 2. RESULTS: In group 1, the areas under the ROC curve (AUCs) were 0.91 (95% CI 0.86-0.96) for d-SOREMPs, 0.81 (95% CI 0.74-0.89) for the number of spontaneous naps, and 0.70 (95% CI 0.60-0.79) for total sleep time. A d-SOREMP count ≥1 (sensitivity of 95% and specificity of 72%), coupled with a diurnal total sleep time above 60 minutes (sensitivity of 89% and specificity of 91%), identified NT1 in group 1 with high reliability (area under the ROC curve of 0.93, 95% CI 0.88-0.97). These results were confirmed in the validation group with an AUC of 0.88 (95% CI 0.79-0.97). DISCUSSION: D-PSG recording is an easily performed, cost-effective, and reliable tool for identifying NT1 in children. Further studies should confirm its validity with home D-PSG monitoring. These alternative procedures could be used to confirm NT1 diagnosis and curtail diagnostic delay.

Effects of oxybate dose and regimen on disrupted nighttime sleep and sleep architecture.

Many components of sleep are disrupted in patients with narcolepsy, including sleep quality, sleep architecture, and sleep stability (ie, frequent awakenings/arousals and frequent shifts from deeper to lighter stages of sleep). Sodium oxybate, dosed twice nightly, has historically been used to improve sleep, and subsequent daytime symptoms, in patients with narcolepsy. Recently, new formulations have been developed to address the high sodium content and twice-nightly dosing regimen of sodium oxybate: low-sodium oxybate and once-nightly sodium oxybate. To date, no head-to-head trials have been conducted to compare the effects of each oxybate product. This review aims to give an overview of the existing scientific literature regarding the impact of oxybate dose and regimen on sleep architecture and disrupted nighttime sleep in patients with narcolepsy. Evidence from 5 key clinical trials, as well as supporting evidence from additional studies, suggests that sodium oxybate, dosed once- and twice-nightly, is effective in improving sleep, measures of sleep architecture, and disrupted nighttime sleep in patients with narcolepsy. Direct comparison of available efficacy and safety data between oxybate products is complicated by differences in trial designs, outcomes assessed, and statistical analyses; future head-to-head trials are needed to better understand the advantage and disadvantages of each agent.

Habitual short sleepers with pre-existing medical conditions are at higher risk of Long COVID.

STUDY OBJECTIVES: Preliminary evidence suggests that the risk of Long COVID is higher among people with pre-existing medical conditions. Based on its proven adjuvant role in immunity, habitual sleep duration may alter the risk of developing Long COVID. The objective of this study was to determine whether the odds of Long COVID are higher among those with pre-existing medical conditions, and whether the strength of this association varies by habitual sleep duration. METHODS: Using data from 13,461 respondents from 16 countries who participated in the 2021 survey-based International COVID Sleep Study II (ICOSS II), we studied the associations between habitual sleep duration, pre-existing medical conditions, and Long COVID. RESULTS: Of 2,508 individuals who had COVID-19, 61% reported at least 1 Long COVID symptom. Multivariable logistic regression analysis showed that the risk of having Long COVID was 1.8-fold higher for average-length sleepers (6-9 h/night) with pre-existing medical conditions compared with those without pre-existing medical conditions (adjusted odds ratio [aOR] 1.84 [1.18-2.90]; P = .008). The risk of Long COVID was 3-fold higher for short sleepers with pre-existing medical conditions (aOR 2.95 [1.04-8.4]; P = .043) and not significantly higher for long sleepers with pre-existing conditions (aOR 2.11 [0.93-4.77]; P = .073) compared with average-length sleepers without pre-existing conditions. CONCLUSIONS: Habitual short nighttime sleep duration exacerbated the risk of Long COVID in individuals with pre-existing conditions. Restoring nighttime sleep to average duration represents a potentially modifiable behavioral factor to lower the odds of Long COVID for at-risk patients. CITATION: Berezin L, Waseem R, Merikanto I, et al. Habitual short sleepers with pre-existing medical conditions are at higher risk of long COVID. J Clin Sleep Med. 2024;20(1):111-119.

Effect of sodium oxybate on body mass index in pediatric patients with narcolepsy.

STUDY OBJECTIVES: We examined body mass index (BMI) changes associated with sodium oxybate treatment (SXB) in pediatric patients with narcolepsy with cataplexy who participated in a double-blind, placebo-controlled, randomized withdrawal study and an open-label continuation period. METHODS: Participants were aged 7-16 years at screening. SXB-naive participants titrated to twice-nightly dosing of SXB then entered a 2-week stable-dose period; participants taking SXB at study entry entered a 3-week stable-dose period. After a 2-week randomized withdrawal period, all participants entered an open-label safety period (OLP; main study duration: ≤ 52 weeks). Participants who completed the OLP were allowed to enter the open-label continuation period (an additional 1-2 years). BMI percentile categories were defined as underweight (< 5th), normal (5th to < 85th), overweight (≥ 85th to < 95th), and obese (≥ 95th). RESULTS: Median BMI percentile decreased from baseline to OLP week 52 in SXB-naive participants who were normal weight at baseline (decreased from 77.0 to 35.0) or overweight/obese at baseline (98.0 to 86.7). Median BMI percentile decreased to a lesser extent in participants taking twice-nightly SXB at study entry who were normal weight at baseline (54.6 to 53.0) or overweight/obese at baseline (96.5 to 88.9). Shifts in BMI category from baseline to week 52 were sometimes noted. In SXB-naive participants, 9/10 (90.0%) who were overweight became normal weight, 7/25 (28.0%) who were obese became normal weight, 3/25 (12.0%) who were obese became overweight, and 1/16 (6.3%) who was normal weight became obese. In participants taking SXB at baseline, 5/8 (62.5%) who were overweight became normal weight, 3/6 (50.0%) who were obese became overweight, 1/14 (7.1%) who was normal weight became overweight, and 2/14 (14.3%) who were normal weight became underweight. Median BMI percentiles at months 6 and 12 of the open-label continuation period were similar to those at OLP end (OLP week 52). In SXB-naive participants, the evident BMI z-score decrease over time was relative to the screening values. CONCLUSIONS: Decreases in BMI percentile and z-score, and downward shifts in BMI category, were observed within 1 year of SXB treatment in pediatric participants with narcolepsy with cataplexy. BMI decreases plateaued after approximately 1 year. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: A Multicenter Study of the Efficacy and Safety of Xyrem With an Open-Label Pharmacokinetic Evaluation and Safety Extension in Pediatric Subjects With Narcolepsy With Cataplexy; URL: https://clinicaltrials.gov/study/NCT02221869; Identifier: NCT02221869. CITATION: Dauvilliers Y, Lammers GJ, Lecendreux M, et al. Effect of sodium oxybate on body mass index in pediatric patients with narcolepsy. J Clin Sleep Med. 2024;20(3):445-454.

Prodromal dementia with Lewy bodies in REM sleep behavior disorder: A multicenter study.

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

Suicidal ideation in female individuals with fibromyalgia and comorbid obesity: prevalence and association with clinical, pain-related, and psychological factors.

OBJECTIVE: Individuals with fibromyalgia report alarming levels of suicidal ideation, and comorbidity with other chronic health conditions such as obesity-a risk factor for suicidal ideation per se-could further complicate the clinical picture. The aim of this study is to determine, in a sample of women with fibromyalgia and comorbid obesity, the prevalence of suicidal ideation and to evaluate clinical, pain-related and psychological factors associated with suicidal ideation. METHODS: In total, 156 female individuals with fibromyalgia and obesity were recruited and completed a series of self-report measures that assessed (i) the level of pain intensity, (ii) depressive symptomatology, (iii) sleep quality, and (iv) pain catastrophizing. Suicidal ideation was evaluated by item #9 of the Beck Depression Inventory. In addition, information regarding previous suicide attempts and current opioid use was collected. RESULTS: 3n sum, 7.8% of participants reported presence of suicidal ideation. According to the results of the multiple logistic regression, depressive symptomatology, sleep quality, and pain catastrophizing were associated with the presence of suicidal ideation. DISCUSSION: The presence of suicidal ideation in our sample was significantly associated with depressive symptomatology, sleep quality, and pain catastrophizing. Our findings are the first to suggest a unique (ie, independent of depressive symptomatology, and sleep quality) association between pain catastrophizing and suicidal ideation in the context of fibromyalgia and comorbid obesity. In order to prevent and reduce suicidal ideation, these factors should be assessed and targeted in interventions for pain management. Future research should investigate the extent to which addressing depressive symptoms, sleep quality, and pain catastrophizing reduces suicidal ideation.

Connecting the dots: An updated review of the role of autoimmunity in narcolepsy and emerging immunotherapeutic approaches.

BACKGROUND: Narcolepsy type 1 (NT1) is a chronic disorder characterized by pathological daytime sleepiness and cataplexy due to the disappearance of orexin immunoreactive neurons in the hypothalamus. Genetic and environmental factors point towards a potential role for inflammation and autoimmunity in the pathogenesis of the disease. This study aims to comprehensively review the latest evidence on the autoinflammatory mechanisms and immunomodulatory treatments aimed at suspected autoimmune pathways in NT1. METHODS: Recent relevant literature in the field of narcolepsy, its autoimmune hypothesis, and purposed immunomodulatory treatments were reviewed. RESULTS: Narcolepsy is strongly linked to specific HLA alleles and T-cell receptor polymorphisms. Furthermore, animal studies and autopsies have found infiltration of T cells in the hypothalamus, supporting T cell-mediated immunity. However, the role of autoantibodies has yet to be definitively established. Increased risk of NT1 after H1N1 infection and vaccination supports the autoimmune hypothesis, and the potential role of coronavirus disease 2019 and vaccination in triggering autoimmune neurodegeneration is a recent finding. Alterations in cytokine levels, gut microbiota, and microglial activation indicate a potential role for inflammation in the disease's development. Reports of using immunotherapies in NT1 patients are limited and inconsistent. Early treatment with IVIg, corticosteroids, plasmapheresis, and monoclonal antibodies has seldomly shown some potential benefits in some studies. CONCLUSION: The current body of literature supports that narcolepsy is an autoimmune disorder most likely caused by T-cell involvement. However, the potential for immunomodulatory treatments to reverse the autoinflammatory process remains understudied. Further clinical controlled trials may provide valuable insights into this area.

Work productivity and activity impairment in patients with narcolepsy type 1.

The aim of this study was to assess work productivity and activity impairments and to explore their association with excessive daytime sleepiness, body mass index (BMI), depression, and anxiety in patients with narcolepsy type 1. We carried out a cross-sectional study in which patients with narcolepsy type 1 and matched controls for sex, age, and education were assessed for occupational features, EDS (Epworth Sleepiness Scale), BMI, depression (Beck Depression Inventory), anxiety (State-Trait Anxiety Inventory), and Work Productivity and Activity Impairment (WPAI). Different statistical approaches were used to investigate differences between groups and correlations between WPAI scores and clinical features. The 127 patients with narcolepsy type 1 (mean age 38.2 ± 15.5, 91.3% taking drugs for narcolepsy) and 131 controls (mean age of 37.4 ± 14.3) included did not differ in terms of occupational features, except for hours worked/week (29.9 in patients vs. 34.9 in controls) and officially recognised disability (30.7% vs. 5.3%). Impairment in all WPAI scores was approximately three times greater in patients. Narcolepsy was associated with work time missed in 27.4% of patients, while 93.2% to 95.5% of them had some impairment while working or during daily activities (vs. 37.5-46.8% of controls). Correlations with WPAI scores were found for excessive daytime sleepiness only in patients, and for both depression and anxiety in patients and controls, with a stronger correlation for activity impairment in patients. These results suggest that, despite treatment, narcolepsy type 1 was associated with extensive impairment especially regarding job effectiveness and daily activities. Future studies should investigate risk factors and effects of interventions on these outcomes.

LC-MS/MS Quantitation of HILIC-Enriched N-glycopeptides Derived from Low-Abundance Serum Glycoproteins in Patients with Narcolepsy Type 1.

Glycoproteomic analysis is always challenging because of low abundance and complex site-specific heterogeneity. Glycoproteins are involved in various biological processes such as cell signaling, adhesion, and cell-cell communication and may serve as potential biomarkers when analyzing different diseases. Here, we investigate glycoproteins in narcolepsy type 1 (NT1) disease, a form of narcolepsy characterized by cataplexy-the sudden onset of muscle paralysis that is typically triggered by intense emotions. In this study, 27 human blood serum samples were analyzed, 16 from NT1 patients and 11 from healthy individuals serving as controls. We quantified hydrophilic interaction liquid chromatography (HILIC)-enriched glycopeptides from low-abundance serum samples of controls and NT1 patients via LC-MS/MS. Twenty-eight unique N-glycopeptides showed significant changes between the two studied groups. The sialylated N-glycopeptide structures LPTQNITFQTESSVAEQEAEFQSPK HexNAc6, Hex3, Neu5Ac2 (derived from the ITIH4 protein) and the structure IVLDPSGSMNIYLVLDGSDSIGASNFTGAK HexNAc5, Hex4, Fuc1 (derived from the CFB protein), with p values of 0.008 and 0.01, respectively, were elevated in NT1 samples compared with controls. In addition, the N-glycopeptide protein sources Ceruloplasmin, Complement factor B, and ITH4 were observed to play an important role in the complement activation and acute-phase response signaling pathways. This may explain the possible association between the biomarkers and pathophysiological effects.