Sleep‐related hypermotor epilepsy and non‐rapid eye movement parasomnias: Differences in the periodic and aperiodic component of the electroencephalographic power spectra

Over the last two decades, our understanding of clinical and pathophysiological aspects of sleep-related epileptic and non-epileptic paroxysmal behaviours has improved considerably, although it is far from complete. Indeed, even if many core characteristics of sleep-related hypermotor epilepsy and non-rapid eye movement parasomnias have been clarified, some crucial points remain controversial, and the overlap of the behavioural patterns between these disorders represents a diagnostic challenge. In this work, we focused on segments of multichannel sleep electroencephalogram free from clinical episodes, from two groups of subjects affected by sleep-related hypermotor epilepsy (N = 15) and non-rapid eye movement parasomnias (N = 16), respectively. We examined sleep stages N2 and N3 of the first part of the night (cycles 1 and 2), and assessed the existence of differences in the periodic and aperiodic components of the electroencephalogram power spectra between the two groups, using the Fitting Oscillations & One Over f (FOOOF) toolbox. A significant difference in the gamma frequency band was found, with an increased relative power in sleep-related hypermotor epilepsy subjects, during both N2 (p < .001) and N3 (p < .001), and a significant higher slope of the aperiodic component in non-rapid eye movement parasomnias, compared with sleep-related hypermotor epilepsy, during N3 (p = .012). We suggest that the relative power of the gamma band and the slope extracted from the aperiodic component of the electroencephalogram signal may be helpful to characterize differences between subjects affected by non-rapid eye movement parasomnias and those affected by sleep-related hypermotor epilepsy

Considering REM Sleep Behavior Disorder in the Management of Parkinson's Disease

Rapid eye movement (REM) sleep behavior disorder (RBD) is the result of the loss of physiological inhibition of muscle tone during REM sleep, characterized by dream-enacting behavior and widely recognized as a prodromal manifestation of alpha-synucleinopathies. Indeed, patients with isolated RBD (iRBD) have an extremely high estimated risk to develop a neurodegenerative disease after a long follow up. Nevertheless, in comparison with PD patients without RBD (PDnoRBD), the occurrence of RBD in the context of PD (PDRBD) seems to identify a unique, more malignant phenotype, characterized by a more severe burden of disease in terms of both motor and non-motor symptoms and increased risk for cognitive decline. However, while some medications (eg, melatonin, clonazepam, etc.) and non-pharmacological options have been found to have some therapeutic benefits on RBD there is no available treatment able to modify the disease course or, at least, slow down the neurodegenerative process underlying phenoconversion. In this scenario, the long prodromal phase may allow an early therapeutic window and, therefore, the identification of multimodal biomarkers of disease onset and progression is becoming increasingly crucial. To date, several clinical (motor, cognitive, olfactory, visual, and autonomic features) neurophysiological, neuroimaging, biological (biofluids or tissue biopsy), and genetic biomarkers have been identified and proposed, also in combination, as possible diagnostic or prognostic markers, along with a potential role for some of them as outcome measures and index of treatment response. In this review, we provide an insight into the present knowledge on both existing and future biomarkers of iRBD and highlight the difference with PDRBD and PDnoRBD, including currently available treatment options

Preliminary finding of a randomized, double-blind, placebo-controlled, crossover study to evaluate the safety and efficacy of 5-hydroxytryptophan on REM sleep behavior disorder in Parkinson's disease

Altered serotonergic neurotransmission may contribute to the non-motor features commonly associated with Parkinson's disease (PD) such as sleep disorders. The 5-hydroxytryptophan (5-HTP) is the intermediate metabolite of L-tryptophan in the production of serotonin and melatonin. The purpose of this study was to compare the effects of 5-HTP to placebo on REM sleep behavior disorder (RBD) status in patients with PD

Prevalence of sleep disruption and determinants of sleepiness in a cohort of Italian hospital physicians: The PRESOMO study

Nightshift work can cause daytime somnolence and decreased alertness, and can increase risk of medical errors, occupational injuries and car accidents. We used a structured questionnaire, including the Epworth Sleepiness Scale (ESS), to assess the prevalence and the determinants of sleep disruption in 268 Italian University hospital physicians from Cagliari (N = 57), Milan (N = 180) and Pisa (N = 31), who participated in the multicentre study on the prevalence of sleep disturbance among hospital physicians (PRESOMO); 198 of them (74%) were engaged in nightshift work. We explored the association between history of nightshift work and poor sleep quality and daytime somnolence with multivariate logistic regression, adjusting by personal and lifestyle covariates. Age, female gender, taking medication interfering with sleep and an elevated ESS score were significant predictors of poor sleep quality and daytime somnolence. Nightshift work was associated with a higher prevalence of unrestful sleep (84% versus 70%; odds ratio [OR] = 2.4, 95% confidence interval [CI] 1.18-5.05) and daytime dozing (57% versus 35%; OR = 1.9, 95% CI 1.03-3.64), with an upward trend by years of engagement in nightshift work for both conditions (p = .043 and 0.017, respectively), and by number of nightshifts/year for unrestful sleep (p = .024). Such an association was not detected with the ESS scale. Our results suggest that nightshift work significantly affects sleep quality and daytime somnolence in hospital physicians, who might underestimate their daytime dozing problem, when asked to subjectively scale it

Oligomeric Alpha-Synuclein and STX-1A from Neural-Derived Extracellular Vesicles (NDEVs) as Possible Biomarkers of REM Sleep Behavior Disorder in Parkinson's Disease: A Preliminary Cohort Study

REM sleep behavior disorder (RBD) has a tighter link with synucleinopathies than other neurodegenerative disorders. Parkinson's Disease (PD) patients with RBD have a more severe motor and cognitive impairment; biomarkers for RBD are currently unavailable. Synaptic accumulation of α-Syn oligomers and their interaction with SNARE proteins is responsible for synaptic dysfunction in PD. We verified whether oligomeric α-Syn and SNARE components in neural-derived extracellular vesicles (NDEVs) in serum could be biomarkers for RBD. Forty-seven PD patients were enrolled, and the RBD Screening Questionnaire (RBDSQ) was compiled. A cut-off score > 6 to define probable RBD (p-RBD) and probable non-RBD (p non-RBD) was used. NDEVs were isolated from serum by immunocapture, and oligomeric α-Syn and SNARE complex components VAMP-2 and STX-1 were measured by ELISA. NDEVs' STX-1A resulted in being decreased in p-RBD compared to p non-RBD PD patients. A positive correlation between NDEVs' oligomeric α-Syn and RBDSQ total score was found (p = 0.032). Regression analysis confirmed a significant association between NDEVs' oligomeric α-Syn concentration and RBD symptoms (p = 0.033) independent from age, disease duration, and motor impairment severity. Our findings suggest that synuclein-mediated neurodegeneration in PD-RBD is more diffuse. NDEVs' oligomeric α-Syn and SNARE complex components' serum concentrations could be regarded as reliable biomarkers for the RBD-specific PD endophenotype

Clinical and dopaminergic imaging characteristics of the FARPRESTO cohort of trial-ready idiopathic rapid eye movement sleep behavior patients

Introduction: Idiopathic/isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is considered the prodromal stage of alpha-synucleinopathies. Thus, iRBD patients are the ideal target for disease-modifying therapy. The risk FActoRs PREdictive of phenoconversion in iRBD Italian STudy (FARPRESTO) is an ongoing Italian database aimed at identifying risk factors of phenoconversion, and eventually to ease clinical trial enrollment of well-characterized subjects.Methods: Polysomnography-confirmed iRBD patients were retrospectively and prospectively enrolled. Baseline harmonized clinical and nigrostriatal functioning data were collected at baseline. Nigrostriatal functioning was evaluated by dopamine transporter-single-photon emission computed tomography (DaT-SPECT) and categorized with visual semi-quantification. Longitudinal data were evaluated to assess phenoconversion. Cox regressions were applied to calculate hazard ratios.Results: 365 patients were enrolled, and 289 patients with follow-up (age 67.7 & PLUSMN; 7.3 years, 237 males, mean follow-up 40 & PLUSMN; 37 months) were included in this study. At follow-up, 97 iRBD patients (33.6%) phenoconverted to an overt synucleinopathy. Older age, motor and cognitive impairment, constipation, urinary and sexual dysfunction, depression, and visual semi-quantification of nigrostriatal functioning predicted phenoconversion. The remaining 268 patients are in follow-up within the FARPRESTO project.Conclusions: Clinical data (older age, motor and cognitive impairment, constipation, urinary and sexual dysfunction, depression) predicted phenoconversion in this multicenter, longitudinal, observational study. A standardized visual approach for semi-quantification of DaT-SPECT is proposed as a practical risk factor for phenoconversion in iRBD patients. Of note, non-converted and newly diagnosed iRBD patients, who represent a trial-ready cohort for upcoming disease-modification trials, are currently being enrolled and followed in the FARPRESTO study. New data are expected to allow better risk characterization

Clinical characteristics of a large cohort of patients with narcolepsy candidate for pitolisant: a cross-sectional study from the Italian PASS Wakix® Cohort

Introduction Narcolepsy is a chronic and rare hypersomnia of central origin characterized by excessive daytime sleepiness and a complex array of symptoms as well as by several medical comorbidities. With growing pharmacological options, polytherapy may increase the possibility of a patient-centered management of narcolepsy symptoms. The aims of our study are to describe a large cohort of Italian patients with narcolepsy who were candidates for pitolisant treatment and to compare patients' subgroups based on current drug prescription (drug-naive patients in whom pitolisant was the first-choice treatment, switching to pitolisant from other monotherapy treatments, and adding on in polytherapy). Methods We conducted a cross-sectional survey based on Italian data from the inclusion visits of the Post Authorization Safety Study of pitolisant, a 5-year observational, multicenter, international study. Results One hundred ninety-one patients were enrolled (76.4% with narcolepsy type 1 and 23.6% with narcolepsy type 2). Most patients (63.4%) presented at least one comorbidity, mainly cardiovascular and psychiatric. Pitolisant was prescribed as an add-on treatment in 120/191 patients (62.8%), as switch from other therapies in 42/191 (22.0%), and as a first-line treatment in 29/191 (15.2%). Drug-naive patients presented more severe sleepiness, lower functional status, and a higher incidence of depressive symptoms. Conclusion Our study presents the picture of a large cohort of Italian patients with narcolepsy who were prescribed with pitolisant, suggesting that polytherapy is highly frequent to tailor a patient-centered approach

The double-sided of human leukocyte antigen-G molecules in type 1 autoimmune hepatitis

The immunomodulatory effects of HLA-G expression and its role in cancers, human liver infections and liver transplantation are well documented, but so far, there are only a few reports addressing autoimmune liver diseases, particularly autoimmune hepatitis (AIH). Method and materialsWe analyzed the genetic and phenotypic characteristics of HLA-G in 205 type 1 AIH patients (AIH-1) and a population of 210 healthy controls from Sardinia (Italy). ResultsAnalysis of the HLA-G locus showed no substantial differences in allele frequencies between patients and the healthy control population. The HLA-G UTR-1 haplotype was the most prevalent in both AIH-1 patients and controls (40.24% and 34.29%). Strong linkage was found between the HLA-G UTR-1 haplotype and HLA-DRB1*03:01 in AIH-1 patients but not controls (D' = 0.92 vs D' = 0.50 respectively; P = 1.3x10(-8)). Soluble HLA-G (sHLA-G) levels were significantly lower in AIH-1 patients compared to controls [13.9 (11.6 - 17.4) U/mL vs 21.3 (16.5 - 27.8) U/mL; P = 0.011]. Twenty-four patients with mild or moderate inflammatory involvement, as assessed from liver biopsy, showed much higher sHLA-G levels compared to the 28 patients with severe liver inflammation [33.5 (23.6 - 44.8) U/mL vs 8.8 (6.1 - 14.5) U/mL; P = 0.003]. Finally, immunohistochemistry analysis of 52 liver biopsies from AIH-1 patients did not show expression of HLA-G molecules in the liver parenchyma. However, a percentage of 69.2% (36/52) revealed widespread expression of HLA-G both in the cytoplasm and the membrane of plasma cells labeled with anti-HLA-G monoclonal antibodies. ConclusionThis study highlights the positive immunomodulatory effect of HLA-G molecules on the clinical course of AIH-1 and how this improvement closely correlates with plasma levels of sHLA-G. However, our results open the debate on the ambiguous role of HLA-G molecules expressed by plasma cells, which are pathognomonic features of AIH-1

GBA variants in REM sleep behavior disorder: a multicenter study

To study the role of GBA variants in the risk for isolated rapid-eye-movement (REM)-sleep behavior disorder (iRBD) and conversion to overt neurodegeneration

Genome-wide association study of REM sleep behavior disorder identifies polygenic risk and brain expression effects

Rapid-eye movement (REM) sleep behavior disorder (RBD), enactment of dreams during REM sleep, is an early clinical symptom of alpha-synucleinopathies and defines a more severe subtype. The genetic background of RBD and its underlying mechanisms are not well understood. Here, we perform a genome-wide association study of RBD, identifying five RBD risk loci near SNCA, GBA, TMEM175, INPP5F, and SCARB2. Expression analyses highlight SNCA-AS1 and potentially SCARB2 differential expression in different brain regions in RBD, with SNCA-AS1 further supported by colocalization analyses. Polygenic risk score, pathway analysis, and genetic correlations provide further insights into RBD genetics, highlighting RBD as a unique alpha-synucleinopathy subpopulation that will allow future early intervention