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Isolated rapid-eye-movement sleep behavior disorder (iRBD) is a strong predictor of Parkinson's disease and Dementia with Lewy bodies. Previous studies indicate that cortical atrophy in iRBD patients may be linked to cognitive impairment, but the pattern of atrophy is inconsistently reported. This study aimed to elucidate cortical atrophy patterns in a cognitively unimpaired iRBD cohort, focusing on regions associated with cognitive functions, particularly the cuneus/precuneus, and evaluated the predictive value for future phenoconversion. We conducted voxel-based morphometry and region of interest (ROI) analysis of structural MRI scans of 36 healthy controls and 19 iRBD patients, nine of whom also received a 3-year follow-up MRI scan. The iRBD patients were followed clinically for 8 years, and time-to-event analyses, using Cox regression, were performed based on baseline ROI volumes. The iRBD patients had lower gray-matter volume in the cuneus/precuneus region as well as in subcortical structures (caudate nuclei and putamen) compared to controls. Eight iRBD patients developed either Parkinson's disease (N = 4) or Dementia with Lewy bodies (N = 4) during the follow-up period. Time-to-event analyses showed that lower right cuneus volume was associated with a higher risk of phenoconversion to alpha-synuclein-linked Parkinsonism in the iRBD patients (Hazard ratio = 13.0, CI: 1.53-110), and correlated with shorter time to conversion. In addition, lower volumes of the bilateral precuneus trended to indicate a higher risk of phenoconversion. These findings suggest a potential predictive value of cuneus and precuneus volumes in identifying iRBD patients at risk of disease progression, even before the onset of cognitive impairment., Competing Interests: Declarations. Conflicts of interest: The authors declare that they have no conflicts of interests. Consent and ethics approval: Before enrollment in the study, all study participants gave written informed consent according to the Declaration of Helsinki. The study protocol was approved by the Central Denmark Region Committee on Health Research (M-2014–397-14) and the ethics committee of the Hospital Clínic de Barcelona (HCB/2015/0186)., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Idiopathic REM sleep behavior disorder (iRBD) is a prodromal marker of the alpha-synucleinopathies, in which autonomic nervous system (ANS) involvement may occur. We aimed to characterize the presence and severity of subjective and objective ANS dysfunction in iRBD and assess its capacity to predict short-term clinical progression to a synucleinopathy., Methods: Prospective study of patients with polysomnography-confirmed iRBD in whom symptomatic ANS involvement was assessed using the Composite Autonomic Symptom Score (COMPASS-31) and objective dysfunction with the Composite Autonomic Severity Score (CASS). Baseline ANS data were compared between those who later developed a synucleinopathy and those who did not., Results: We evaluated 25 subjects with iRBD without risk factors for autonomic neuropathy and at least 6 months of follow-up (mean: 19 months). At the end of the study, seven (28%) patients developed a synucleinopathy, namely Parkinson's disease (n = 5) and dementia with Lewy bodies (n = 2). 73.7% of patients had COMPASS-31 scores above the normal cut-off, while no score differences regarding phenoconversion status were observed. At baseline, 85.7% of the subjects who phenoconverted exhibited at least one abnormal result in the CASS score, compared to 38.9% of subjects who remained disease-free (p = 0.035). Adrenergic dysfunction evaluated by an impaired overshoot in Valsalva phase IV and by pressure recovery time was associated with the development of overt synucleinopathy (p = 0.032 and 0.033, respectively)., Conclusion: Symptomatic and subclinical ANS dysfunctions are common in iRBD. ANS dysfunction affecting mainly the adrenergic system seems to be a short-term risk for the development of a synucleinopathy., Competing Interests: Declarations. Conflict of interest: The authors have no competing interests to declare that are relevant to the content of this article. Ethical approval: The study received approval from the Ethics Committee of Hospital Clinic Barcelona (HCB/2020/0277) and was performed in accordance with the ethical standards as laid down in 1964 Declaration of Helsinski and its later amendments. Consent to participate: Informed consent was obtained from all individual participants included in the study., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Idiopathic rapid eye movement (REM) sleep behaviour disorder (IRBD) is thought to be an early stage of α-synuclein-related neurodegenerative diseases. Nevertheless, the definitive identification of its biological substrate can be determined only by post-mortem neuropathology. We aimed to describe the post-mortem neuropathology of individuals with IRBD who developed or did not develop a neurodegenerative disease before death., Methods: In this case series at the Hospital Clinic de Barcelona, Barcelona, Spain, we examined post-mortem brain tissue and spinal cords from individuals diagnosed with IRBD by video polysomnography who became donors to the Neurological Tissue Bank between May 28, 2005, and March 23, 2023. We performed post-mortem neuropathology to assess the presence and distribution of neuronal loss, gliosis, and protein aggregates using antibodies against α-synuclein, amyloid β, phosphorylated tau, three-repeat and four-repeat tau isoforms, and TDP-43. Comparative statistical analyses were not done because of the small sample size, but differences observed across the nuclei and brain structures were described., Findings: The brains and spinal cords of 20 individuals with IRBD were examined (19 [95%] men, one [5%] woman). Their clinical antemortem diagnoses were of IRBD without any other neurological disorder in three (15%), Parkinson's disease without dementia in two (10%), Parkinson's disease dementia (PDD) in three (15%), and dementia with Lewy bodies (DLB) in 12 (60%) individuals. Post-mortem neuropathological diagnoses were Lewy body disease in 19 (95%) and multiple system atrophy (MSA) in one (5%). All participants with Lewy body disease and MSA showed neuronal loss, gliosis, and α-synuclein deposits in neurons and astrocytes. In all participants, α-synuclein was found in the structures that regulate REM sleep atonia (eg, subcoeruleus nucleus, gigantocellular reticular nucleus, laterodorsal tegmentum, and amygdala). Coexistent pathologies were found in all participants, including Alzheimer's disease pathology (amyloid β plaques and neurofibrillary tangles) in 14 (70%), ageing-related tau astrogliopathy in 12 (60%), cerebral amyloid angiopathy in 11 (55%), argyrophilic grain disease in four (20%), limbic-predominant age-related TDP-43 encephalopathy in four (20%), and early changes indicative of progressive supranuclear palsy in three (15%). In individuals with IRBD without any other neurological disorder and in those who developed Parkinson's disease without dementia, α-synuclein was found in the brainstem and limbic system and rarely in the cortex, whereas coexisting proteinopathies were few and showed mild pathological burden. In contrast, in individuals who developed PDD or DLB, α-synuclein had diffuse distribution in the brainstem, limbic system, and cortex, and multiple comorbid pathologies were common, particularly those related to Alzheimer's disease., Interpretation: Although limited by a relatively small sample size, our observations provide strong neuropathological evidence that IRBD is an early stage of α-synuclein-related neurodegenerative disease. Concomitant pathologies are frequent and their role remains to be clarified: some might have contributed to the development of dementia, but some might be age-related changes. Our findings could inform the design of clinical trials of compounds that target specific pathological proteins (eg, α-synuclein and amyloid β) in people with IRBD., Funding: Fundación BBVA-Hospital Clínic de Barcelona., Competing Interests: Declaration of interests GM declares support for attending meetings or travel from Bioproject outside the submitted work. RS-V declares consulting fees from Ionis, AviadoBio, NovoNordisk, Pfizer, and UCB, outside the submitted work; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Neuraxpharma and Roche Diagnostics; support for attending meetings or travel from Esteve; and participation on a data safety monitoring board and advisory board from Wave Ph. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background and Purpose: Most patients with isolated rapid eye movement sleep behaviour disorder (iRBD) progress to a parkinsonian alpha-synucleinopathy. However, time to phenoconversion shows great variation. The aim of this study was to investigate whether cholinergic and dopaminergic dysfunction in iRBD patients was associated with impending phenoconversion., Methods: Twenty-one polysomnography-confirmed iRBD patients underwent baseline 11 C-donepezil and 6-Fluoro-( 18 F)-l-3,4-dihydroxyphenylalanine ( 18 F-DOPA) positron emission tomography (PET). Potential phenoconversion was monitored for up to 8 years. PET images were analysed according to patients' diagnoses after 3 and 8 years using linear regression. Time-to-event analysis was made with Cox regression, dividing patients into low and high tracer uptake groups., Results: Follow-up was accomplished in 17 patients. Eight patients progressed to either Parkinson's disease (n = 4) or dementia with Lewy bodies (n = 4), while nine remained non-phenoconverters. Compared with non-phenoconverters, 8-year phenoconverters had lower mean 11 C-donepezil uptake in the parietal (p = 0.032) and frontal cortex (p = 0.042), whereas mean 11 C-donepezil uptake in 3-year phenoconverters was lower in the parietal cortex (p = 0.005), frontal cortex (p = 0.025), thalamus (p = 0.043) and putamen (p = 0.049). Phenoconverters within 3 years and 8 years had lower 18 F-DOPA uptake in the putamen (p < 0.001). iRBD patients with low parietal 11 C-donepezil uptake had a 13.46 (95% confidence interval 1.42;127.21) times higher rate of phenoconversion compared with those with higher uptake (p = 0.023). iRBD patients with low 18 F-DOPA uptake in the most affected putamen were all phenoconverters with higher rate of phenoconversion (p = 0.0002)., Conclusions: These findings suggest that cortical cholinergic dysfunction, particularly within the parietal cortex, could be a biomarker candidate for predicting short-term phenoconversion in iRBD patients. This study aligns with previous reports suggesting dopaminergic dysfunction is associated with forthcoming phenoconversion., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Optimizing the use of existing high-voltage transmission lines demands real-time condition monitoring to ensure structural integrity and continuous service. Operating these lines at the current capacity is limited by safety margins based on worst-case weather scenarios, as exceeding these margins risks bringing conductors dangerously close to the ground. The integration of optical fibers within modern transmission lines enables the use of Distributed Fiber Optic Sensing (DFOS) technology, with Chirped-Pulse Phase-Sensitive Optical Time-Domain Reflectometry (CP-ΦOTDR) proving especially effective for this purpose. CP-ΦOTDR measures wind-induced vibrations along the conductor, allowing for an analysis of frequency-domain vibration modes that correlate with conductor length and sag across spans. This monitoring system, capable of covering distances up to 40 km from a single endpoint, enables dynamic capacity adjustments for optimized line efficiency. Beyond sag monitoring, CP-ΦOTDR provides robust detection of external threats, including environmental interference and mechanical intrusions, which could compromise cable stability. By simultaneously monitoring the Optical Phase Conductor (OPPC) and Optical Ground Wire (OPGW), this study offers the first comprehensive, real-time evaluation of both structural integrity and potential external aggressions on overhead transmission lines. The findings demonstrate that high-frequency data offer valuable insights for classifying mechanical intrusions and environmental interferences based on spectral content, while low-frequency data reveal the diurnal temperature-induced sag evolution, with distinct amplitude responses for each cable. These results affirm CP-ΦOTDR's unique capacity to enhance line safety, operational efficiency, and proactive maintenance by delivering precise, real-time assessments of both structural integrity and external threats.

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., (© 2024. The Author(s).)

Introduction: Anti-IgLON5 disease is a recently described neurological disorder with multisystemic features. The disease is characterized by the presence of IgLON5 antibodies in serum and cerebrospinal fluid. Our objective is to describe in detail the otorhinolaryngological manifestations of this disease, which are frequent and may include dysphagia, dysarthria, vocal cord paralysis and laryngospasm., Methods: In this study, we present a series of 9 patients with anti-IgLON5 disease and otolaryngological manifestations. Patients were evaluated between July 2012 and March 2022 by video-polysomnography, fiber-optic laryngoscopy, and functional endoscopic evaluation of swallowing., Results: The median age was 71 years, and 5 (56%) were female. Video-polysomnography showed a NREM/REM parasomnia in 6 patients (67%), obstructive sleep apnea in 8 (88%), stridor during sleep in 7 (78%) and central apneas in 1 (11%). Six out of the 9 patients (67%) presented episodes of acute respiratory failure that required mechanical ventilation, 6 had vocal fold palsy with 4 of them requiring tracheostomy (3 had to be performed on an emergency basis). Dysphagia occurred in 8 patients (89%). Prominent upper airway secretion and sialorrhea was also present in 3 cases., Conclusion: The anti-IgLON5 disease exhibits extensive otolaryngological symptoms, mainly affecting the upper airway. These symptoms affect the quality of life and can be life-threatening. Prompt acute management is essential for stridor, dyspnea, and dysphagia. Given the potential severity of the symptoms and rarity of the disease, it is important for otolaryngologists to be familiar with anti-IgLON5 disease., Level of Evidence: Level 4., (Copyright © 2024 Sociedad Española de Otorrinolaringología y Cirugía de Cabeza y Cuello. Published by Elsevier España, S.L.U. All rights reserved.)

Brunner syndrome is a recessive X-linked disorder characterized by intellectual disability and impulsive aggressiveness associated with monoamine oxidase A (MAOA) deficiency leading to increased monoaminergic activity. We report the presence of rapid eye movement (REM) sleep behavior disorder in a 46-year-old patient with Brunner syndrome due to a c.1438A > G/iVS14-2 A > G mutation of the MAOA gene. He has mild intellectual disability and psychotic disturbances. He presented a 15-year history of nightmares (chase, attacks, and fights), sleep-related vocalizations, and motor behaviors characterized by talking, screaming, crying, gesturing, punching, and kicking. Video polysomnography showed REM sleep behavior disorder characterized by excessive tonic and phasic muscle activity in the mentalis and limb muscles with dream-enacting behaviors during REM sleep. Clonazepam achieved a significant reduction of REM sleep behavior disorder symptomatology. We conclude that REM sleep behavior disorder can be a manifestation of Brunner syndrome, probably due to an increased monoaminergic neurotransmission occurring in this rare genetic disorder., Citation: Cesari E, Muñoz-Lopetegi A, Santamaria J, Iranzo A, Gaig C. REM sleep behavior disorder in Brunner syndrome. J Clin Sleep Med. 2024;20(9):1557-1560., (© 2024 American Academy of Sleep Medicine.)

Introduction: Early-onset Alzheimer's disease (EOAD) shows a higher burden of neuropsychiatric symptoms than late-onset Alzheimer's disease (LOAD). We aim to determine the differences in the severity of neuropsychiatric symptoms and locus coeruleus (LC) integrity between EOAD and LOAD accounting for disease stage., Methods: One hundred four subjects with AD diagnosis and 32 healthy controls were included. Participants underwent magnetic resonance imaging (MRI) to measure LC integrity, measures of noradrenaline levels in cerebrospinal fluid (CSF) and Neuropsychiatric Inventory (NPI). We analyzed LC-noradrenaline measurements and clinical and Alzheimer's disease (AD) biomarker associations., Results: EOAD showed higher NPI scores, lower LC integrity, and similar levels of CSF noradrenaline compared to LOAD. Notably, EOAD exhibited lower LC integrity independently of disease stage. LC integrity negatively correlated with neuropsychiatric symptoms. Noradrenaline levels were increased in AD correlating with AD biomarkers., Discussion: Decreased LC integrity negatively contributes to neuropsychiatric symptoms. The higher LC degeneration in EOAD compared to LOAD could explain the more severe neuropsychiatric symptoms in EOAD., Highlights: LC degeneration is greater in early-onset AD (EOAD) compared to late-onset AD. Tau-derived LC degeneration drives a higher severity of neuropsychiatric symptoms. EOAD harbors a more profound selective vulnerability of the LC system. LC degeneration is associated with an increase of cerebrospinal fluid noradrenaline levels in AD., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Sleep disorders are common in people with Parkinson's disease. These disorders, which increase in frequency throughout the course of the neurodegenerative disease and impair quality of life, include insomnia, excessive daytime sleepiness, circadian disorders, obstructive sleep apnoea, restless legs syndrome, and rapid eye movement (REM) sleep behaviour disorder. The causes of these sleep disorders are complex and multifactorial, including the degeneration of the neural structures that modulate sleep, the detrimental effect of some medications on sleep, the parkinsonian symptoms that interfere with mobility and comfort in bed, and comorbidities that disrupt sleep quality and quantity. The clinical evaluation of sleep disorders include both subjective (eg, questionnaires or diaries) and objective (eg, actigraphy or video polysomnography) assessments. The management of patients with Parkinson's disease and a sleep disorder is challenging and should be individualised. Treatment can include education aiming at changes in behaviour (ie, sleep hygiene), cognitive behavioural therapy, continuous dopaminergic stimulation at night, and specific medications. REM sleep behaviour disorder can occur several years before the onset of parkinsonism, suggesting that the implementation of trials of neuroprotective therapies should focus on people with this sleep disorder., Competing Interests: Declaration of interests MLF received a grant from Region AURA (France) Research and Development and the Société Française de Recherche et Médecine du Sommeil. MLF received a payment honoraria for lectures from Elvie, and financial support for attending meetings from Sos Oygène and Odalys Santé. LMT participated in the board of the American Academy of Sleep Medicine, American Academy of Sleep Medicine Foundation, and American Board of Sleep Medicine. All other authors report no conflict of interests regarding the content of this Review., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

We investigated the biomarker profile of neurodegeneration, Alzheimer's and Lewy body pathology in the CSF of 148 polysomnography-confirmed patients with isolated REM sleep behavior disorder (IRBD), a condition that precedes Parkinson's disease (PD) and dementia with Lewy bodies (DLB). We assessed misfolded α-synuclein (AS) by RT-QuIC assay, amyloid-beta peptides (Aβ 42 and Aβ 40 ), phosphorylated tau (p-tau), and total tau (t-tau) by CLEIA and neurofilament light chain (NfL) by ELISA. We detected AS in 75.3% of patients, pathologically decreased Aβ 42 /Aβ 40 ratio in 22.5%, increased p-tau in 15.5%, increased t-tau in 14.9%, and elevated NfL in 14.7%. After a mean follow-up of 2.48 ± 2.75 years, 47 (38.1%) patients developed PD (n = 24) or DLB (n = 23). At CSF collection, AS positivity [HR 4.05 (1.26-12.99), p = 0.019], mild cognitive impairment [3.86 (1.96-7.61), p < 0.001], and abnormal DAT-SPECT [2.31 (1.09-4.91), p < 0.030] were independent predictors of conversion to PD and DLB. Among the other CSF markers, only elevated p-tau/Aβ 42 was predictive of conversion, although only to DLB and not as an independent variable. In IRBD, CSF AS assessment by RT-QuIC provides an added value in defining the risk of short-term conversion to PD and DLB independent of clinical and instrumental investigations. Positive Alzheimer's disease (AD) pathology markers and elevated NfL occur in a subgroup of patients, but p-tau/Aβ 42 is the only marker that predicts short-term conversion to DLB. Longer follow-up is needed to assess if AD biomarkers predict the later development of PD and DLB in IRBD., (© 2024. The Author(s).)

Background: Using 11 C-(R)-PK11195-PET, we found increased microglia activation in isolated REM sleep behavior disorder (iRBD) patients. Their role remains to be clarified., Objectives: The objective is to assess relationships between activated microglia and progression of nigrostriatal dysfunction in iRBD., Methods: Fifteen iRBD patients previously scanned with 11 C-(R)-PK11195 and 18 F-DOPA-PET underwent repeat 18 F-DOPA-PET after 3 years. 18 F-DOPA K i changes from baseline were evaluated with volumes-of-interest and voxel-based analyses., Results: Significant 18 F-DOPA K i reductions were found in putamen and caudate. Reductions were larger and more widespread in patients with increased nigral microglia activation at baseline. Left nigral 11 C-(R)-PK11195 binding at baseline was a predictor of 18 F-DOPA K i reduction in left caudate (coef = -0.0426, P = 0.016)., Conclusions: Subjects with increased baseline 11 C-(R)-PK11195 binding have greater changes in nigrostriatal function, suggesting a detrimental rather than protective effect of microglial activation. Alternatively, both phenomena occur in patients with prominent nigrostriatal dysfunction without a causative link. The clinical and therapeutic implications of these findings need further elucidation. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Alpha-synucleinopathies are prevalent neurological disorders that cause significant disability, leading to progressive clinical deterioration that is currently managed solely through symptomatic treatment. Efforts to evaluate disease-modifying therapies during the established stage of the disease have not yielded positive outcomes in terms of clinical or imaging efficacy endpoints. However, alpha-synucleinopathies have a long prodromal phase that presents a promising opportunity for intervention with disease-modifying therapies. The presence of polysomnography-confirmed REM sleep behavior disorder (RBD) is the most reliable risk factor for identifying individuals in the prodromal stage of alpha-synucleinopathy. This paper discusses the rationale behind targeting idiopathic/isolated RBD in disease-modifying trials and outlines possible study designs, including strategies for patient stratification, selection of biomarkers to assess disease progression and patient eligibility, as well as the identification of suitable endpoints. Additionally, the potential targets for disease-modifying treatment in alpha-synucleinopathies are summarized., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dario Arnaldi reports financial support was provided by Italian ministry of health. Dario Arnaldi reports financial support was provided by Italian ministry of university and research. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Anti-IgLON5 disease is a rare and likely underdiagnosed subtype of autoimmune encephalitis. The disease displays a heterogeneous phenotype that includes sleep, movement and bulbar-associated dysfunction. The presence of IgLON5-antibodies in CSF/serum, together with a strong association with HLA-DRB1*10:01∼DQB1*05:01, supports an autoimmune basis. In this study, a multicentric human leukocyte antigen (HLA) study of 87 anti-IgLON5 patients revealed a stronger association with HLA-DQ than HLA-DR. Specifically, we identified a predisposing rank-wise association with HLA-DQA1*01:05∼DQB1*05:01, HLA-DQA1*01:01∼DQB1*05:01 and HLA-DQA1*01:04∼DQB1*05:03 in 85% of patients. HLA sequences and binding cores for these three DQ heterodimers were similar, unlike those of linked DRB1 alleles, supporting a causal link to HLA-DQ. This association was further reflected in an increasingly later age of onset across each genotype group, with a delay of up to 11 years, while HLA-DQ-dosage dependent effects were also suggested by reduced risk in the presence of non-predisposing DQ1 alleles. The functional relevance of the observed HLA-DQ molecules was studied with competition binding assays. These proof-of-concept experiments revealed preferential binding of IgLON5 in a post-translationally modified, but not native, state to all three risk-associated HLA-DQ receptors. Further, a deamidated peptide from the Ig2-domain of IgLON5 activated T cells in two patients, compared with one control carrying HLA-DQA1*01:05∼DQB1*05:01. Taken together, these data support a HLA-DQ-mediated T-cell response to IgLON5 as a potentially key step in the initiation of autoimmunity in this disease., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Several brainstem, subcortical and cortical areas are involved in the generation of rapid eye movement (REM) sleep. The alteration of these structures as a result of a neurodegenerative process may therefore lead to REM sleep anomalies. REM sleep behaviour disorder is associated with nightmares, dream-enacting behaviours and increased electromyographic activity in REM sleep. Its isolated form is a harbinger of synucleinopathies such as Parkinson's disease or dementia with Lewy bodies, and neuroprotective interventions are advocated. This link might also be present in patients taking antidepressants, with post-traumatic stress disorder, or with a history of repeated traumatic head injury. REM sleep likely contributes to normal memory processes. Its alteration has also been proposed to be part of the neuropathological changes occurring in Alzheimer's disease., (© 2024 European Sleep Research Society.)

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;95:1178-1192., (© 2024 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Evidence regarding cortical atrophy patterns in Parkinson's disease (PD) with probable rapid eye movement sleep behavior disorder (RBD) (PD-pRBD) remains scarce. Cortical mean diffusivity (cMD), as a novel imaging biomarker highly sensitive to detecting cortical microstructural changes in different neurodegenerative diseases, has not been investigated in PD-pRBD yet., Objectives: The aim was to investigate cMD as a sensitive measure to identify subtle cortical microstructural changes in PD-pRBD and its relationship with cortical thickness (CTh)., Methods: Twenty-two PD-pRBD, 31 PD without probable RBD (PD-nonpRBD), and 28 healthy controls (HC) were assessed using 3D T1-weighted and diffusion-weighted magnetic resonance imaging on a 3-T scanner and neuropsychological testing. Measures of cortical brain changes were obtained through cMD and CTh. Two-class group comparisons of a general linear model were performed (P < 0.05). Cohen's d effect size for both approaches was computed., Results: PD-pRBD patients showed higher cMD than PD-nonpRBD patients in the left superior temporal, superior frontal, and precentral gyri, precuneus cortex, as well as in the right middle frontal and postcentral gyri and paracentral lobule (d > 0.8), whereas CTh did not detect significant differences. PD-pRBD patients also showed increased bilateral posterior cMD in comparison with HCs (d > 0.8). These results partially overlapped with CTh results (0.5 < d < 0.8). PD-nonpRBD patients showed no differences in cMD when compared with HCs but showed cortical thinning in the left fusiform gyrus and lateral occipital cortex bilaterally (d > 0.5)., Conclusions: cMD may be more sensitive than CTh displaying significant cortico-structural differences between PD subgroups, indicating this imaging biomarker's utility in studying early cortical changes in PD. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

This dataset gathers the initial formation and the evolution of water content and distribution, as well as water evacuation, within a lung-inspired PEM (proton exchange membrane) fuel cell with a 50 cm 2 active area for various operating conditions such as cell pressure, relative humidity of the reactant (anode and cathode), temperature, and cell current density. Neutron imaging was used since it has been shown to be an effective technique for quantitative analysis of water distribution, obtaining the thickness of the water with the Lambert-Beer law, thus obtaining the numerical data that composes the tables and graphs in this dataset. A series of videos compiling the individual images obtained through neutron imaging, showing the water distribution evolution are presented. Numerical and graphical compilation of the amount of water in a cell through time in different regions of the cell and for a total of 10 experiments are provided. This dataset provides a deeper knowledge on the complex phenomena that liquid water is subjected to in fuel cells along time, as well as a basis for an experimental validation for Computational Fluid Dynamics (CFD) simulations., (© 2024 The Authors.)

Background and Objectives: To develop a composite score to assess the severity of the multiple symptoms present in anti-IgLON5 disease., Methods: The anti-IgLON5 disease composite score (ICS) was designed to evaluate 17 symptoms divided into 5 clinical domains (bulbar, sleep, movement disorders, cognition, and others). Each symptom was scored from 0 (absent/normal) to 3 or 6 (severe) depending on the contribution of the symptom to neurologic disability with a maximum ICS of 69. The ICS was tested in patients from 2 cohorts (Barcelona, Spain, and GENERATE, Germany) that included cases personally seen by the authors (internal) and patients whose ICS was obtained from information of questionnaires completed by the referring neurologists (external). Test-retest and interrater reliabilities of the ICS were assessed by the intraclass coefficient (ICC) and the correlation between the ICS and modified Rankin scale (mRS) with the nonparametric Spearman rank coefficient. The Wilcoxon signed rank test was used to compare the ICS at diagnosis of anti-IgLON5 disease and follow-up in a subset of patients with available clinical information., Results: A total of 86 patients (46 from Barcelona cohort; 40 from GENERATE cohort) were included. The median ICS was 15 (range 2-31). The ICS was higher in the Barcelona cohort than in the German cohort (18 vs 12, p < 0.001), due to higher partial scores in sleep and movement disorder domains. There were no significant differences in the ICS between internal and external patients (15 vs 14, p = 0.96). The ICS correlated with the mRS score ( r = 0.429, p < 0.001). Test-retest and interrater reliabilities were excellent with an ICC of 0.997 (95% CI 0.992-0.999) and 0.973 (95% CI 0.925-0.990), respectively. ICS was retested during follow-up in 27 patients, and it was similar to that at diagnosis in 10 clinically stable patients (median ICS at diagnosis 11.5 vs 11.5 at follow-up; p = 1), higher in 8 patients who worsened (12.5 vs 18; p = 0.012), and lower in 9 patients who improved after immunotherapy (14 vs 10; p = 0.007)., Discussion: The ICS is a valid method to assess the extension and severity of the different clinical manifestations of anti-IgLON5 disease.

A dataset from experimental tests of a proton exchange membrane fuel cell (PEMFC) with an active area of approximately 50 cm 2 , parallel-serpentine channels and cross-flow field distribution between anode and cathode is presented. Tests were performed for four different gas inlet and outlet configurations. In particular, tests were performed for the original configuration, hydrogen inlet and outlet reversed, air inlet and outlet reversed, and hoses reversed for both gases. The operating conditions for all gas configurations were: pressure of 0.5 bar, temperature of 65 °C, anode and cathode relative humidity of 60 %, and anode and cathode stoichiometry of 1.3 and 2.5 respectively. The tests performed were the polarization curve (PC) for each gas configuration and the dynamic load cycles (FC-DLC) also for each hose position. A current density mapping (CDM) sensor, capable of measuring both the current density distribution and the temperature distribution inside the cell, was inserted into the fuel cell system during all tests. The use of the sensor during the experiments makes it possible to know how these distributions behave and to observe whether or not there is homogeneity in its measurements, thus verifying that the design of the flow channels is adequate and fulfilling its function. The results can be used to investigate and compare other bipolar plates and channel designs, or to compare with results from other test benches and environmental conditions., (© 2024 The Authors.)

Background: Idiopathic rapid eye movement (REM) sleep behaviour disorder (IRBD) represents the prodromal stage of Lewy body disorders (Parkinson's disease (PD) and dementia with Lewy bodies (DLB)) which are linked to variations in circulating cell-free mitochondrial DNA (cf-mtDNA). Here, we assessed whether altered cf-mtDNA release and integrity are already present in IRBD., Methods: We used multiplex digital PCR (dPCR) to quantify cf-mtDNA copies and deletion ratio in cerebrospinal fluid (CSF) and serum in a cohort of 71 participants, including 1) 17 patients with IRBD who remained disease-free (non-converters), 2) 34 patients initially diagnosed with IRBD who later developed either PD or DLB (converters), and 3) 20 age-matched controls without IRBD or Parkinsonism. In addition, we investigated whether CD9-positive extracellular vesicles (CD9-EVs) from CSF and serum samples contained cf-mtDNA., Findings: Patients with IRBD, both converters and non-converters, exhibited more cf-mtDNA with deletions in the CSF than controls. This finding was confirmed in CD9-EVs. The high levels of deleted cf-mtDNA in CSF corresponded to a significant decrease in cf-mtDNA copies in CD9-EVs in both IRBD non-converters and converters. Conversely, a significant increase in cf-mtDNA copies was found in serum and CD9-EVs from the serum of patients with IRBD who later converted to a Lewy body disorder., Interpretation: Alterations in cf-mtDNA copy number and deletion ratio known to occur in Lewy body disorders are already present in IRBD and are not a consequence of Lewy body disease conversion. This suggests that mtDNA dysfunction is a primary molecular mechanism of the pathophysiological cascade that precedes the full clinical motor and cognitive manifestation of Lewy body disorders., Funding: Funded by Michael J. Fox Foundation research grant MJFF-001111. Funded by MICIU/AEI/10.13039/501100011033 "ERDF A way of making Europe", grants PID2020-115091RB-I00 (RT) and PID2022-143279OB-I00 (ACo). Funded by Instituto de Salud Carlos III and European Union NextGenerationEU/PRTR, grant PMP22/00100 (RT and ACo). Funded by AGAUR/Generalitat de Catalunya, grant SGR00490 (RT and ACo). MP has an FPI fellowship, PRE2018-083297, funded by MICIU/AEI/10.13039/501100011033 "ESF Investing in your future"., Competing Interests: Declaration of interests The authors have nothing to disclose., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Sleep abnormalities may represent an independent risk factor for neurodegeneration. An international expert group convened in 2021 to discuss the state-of-the-science in this domain. The present article summarizes the presentations and discussions concerning the importance of a strategy for studying sleep- and circadian-related interventions for early detection and prevention of neurodegenerative diseases. An international expert group considered the current state of knowledge based on the most relevant publications in the previous 5 years; discussed the current challenges in the field of relationships among sleep, sleep disorders, and neurodegeneration; and identified future priorities. Sleep efficiency and slow wave activity during non-rapid eye movement (NREM) sleep are decreased in cognitively normal middle-aged and older adults with Alzheimer's disease (AD) pathology. Sleep deprivation increases amyloid-β (Aβ) concentrations in the interstitial fluid of experimental animal models and in cerebrospinal fluid in humans, while increased sleep decreases Aβ. Obstructive sleep apnea (OSA) is a risk factor for dementia. Studies indicate that positive airway pressure (PAP) treatment should be started in patients with mild cognitive impairment or AD and comorbid OSA. Identification of other measures of nocturnal hypoxia and sleep fragmentation could better clarify the role of OSA as a risk factor for neurodegeneration. Concerning REM sleep behavior disorder (RBD), it will be crucial to identify the subset of RBD patients who will convert to a specific neurodegenerative disorder. Circadian sleep-wake rhythm disorders (CSWRD) are strong predictors of caregiver stress and institutionalization, but the absence of recommendations or consensus statements must be considered. Future priorities include to develop and validate existing and novel comprehensive assessments of CSWRD in patients with/at risk for dementia. Strategies for studying sleep-circadian-related interventions for early detection/prevention of neurodegenerative diseases are required. CSWRD evaluation may help to identify additional biomarkers for phenotyping and personalizing treatment of neurodegeneration., (© 2023. Fondazione Società Italiana di Neurologia.)

Synucleinopathies are disorders characterized by the aggregation and deposition of pathological α-synuclein conformers. The underlying neurodegenerative processes begin years or decades before the onset of cardinal motor symptoms. This prodromal phase may manifest with various signs or symptoms. However, there are no current standardized laboratory tests to ascertain the progression and conversion of prodromal conditions such as mild cognitive impairment, isolated REM sleep behavior disorder or pure autonomic failure. The aim of this systematic review was to evaluate the diagnostic possibilities using human biofluids as source material to detect pathological α-synuclein in the prodromal phase of synucleinopathies. Our review identified eight eligible studies, that investigated pathological α-synuclein conformers using cerebrospinal fluid from patients with prodromal signs of synulceinopathies to differentiate this patient group from non-synucleinopathies, while only one study investigated this aspect using blood as medium. While previous studies clearly demonstrated a high diagnostic performance of α-synuclein seed amplification assays for differentiating synucleinopathies with Lewy bodies from healthy controls, only few analyses were performed focussing on individuals with prodromal disease. Nevertheless, results for the early detection of α-synuclein seeds using α-synuclein seed amplification assays were promising and may be of particular relevance for future clinical trials and clinical practice.

Background: Reduced cortical acetylcholinesterase activity, as measured by 11 C-donepezil positron emission tomography (PET), has been reported in patients with isolated rapid eye movement (REM) sleep behavior disorder (iRBD). However, its progression and clinical implications have not been fully investigated. Here, we explored the relationship between longitudinal changes in brain acetylcholinesterase activity and cognitive function in iRBD., Methods: Twelve iRBD patients underwent 11 C-donepezil PET at baseline and after 3 years. PET images were interrogated with statistical parametric mapping (SPM) and a regions of interest (ROI) approach. Clinical progression was assessed with the Movement Disorder Society-Unified Parkinson's Disease Rating Scale-Part III (MDS-UPDRS-III). Cognitive function was rated using the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA)., Results: From baseline to follow-up, the mean 11 C-donepezil distribution volume ratio (DVR) decreased in the cortex (p = 0.006), thalamus (p = 0.013), and caudate (p = 0.013) ROI. Despite no significant changes in the group mean MMSE or MoCA scores being observed, individually, seven patients showed a decline in their scores on these cognitive tests. Subgroup analysis showed that only the subgroup of patients with a decline in cognitive scores had a significant reduction in mean cortical 11 C-donepezil DVR., Conclusions: Our results show that severity of brain cholinergic dysfunction in iRBD patients increases significantly over 3 years, and those changes are more severe in those with a decline in cognitive test scores., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Purpose of Review: To summarize the current evidence on the associations between autoimmune neurological diseases (e.g., multiple sclerosis, myasthenia gravis) and sleep disturbances (e.g., insomnia, parasomnias), as well as to review the main characteristics of sleep disorders with an immune-related pathophysiology (e.g., narcolepsy, anti-IgLON5 disease)., Recent Findings: An immune-mediated damage of the areas in the central nervous system that control sleep and wake functions (e.g., hypothalamus, brainstem) can lead to sleep disorders and sleep symptoms. Sleep disturbances are the reason to seek for medical attention in certain neuroimmunological conditions (e.g., narcolepsy, anti-IgLON5 disease) where sleep-related alterations are the main clinical feature. The assessment of sleep-related symptomatology and disorders should be included in the routine evaluation of patients with autoimmune neurological diseases. Clinicians should be aware of the typical clinical presentation of certain neuroimmunological disorders mainly affecting sleep., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Neurodegenerative diseases often alter sleep architecture, complicating the application of the standard sleep scoring rules. There are no recommendations to overcome this problem. Our aim was to develop a scoring method that incorporates the stages previously applied in dementia with Lewy Bodies (DLB), anti-IgLON5 disease, and fatal insomnia, and to test it in patients with alpha-synucleinopathies., Methods: Video-polysomnographies (VPSG) of nine patients (DLB:3, Parkinson's disease (PD):3, and multiple system atrophy (MSA):3) selected for their difficulty in applying standard rules were scored independently by two authors, using additional Sleep/Wake stages. These included Abnormal Wake, Subwake, Undifferentiated NREM sleep (UNREM), Poorly structured N2 (P-S N2) and abnormal REM sleep including REM without atonia (RWA), REM without low-amplitude, mixed-frequency EEG activity (RWL) and REM without rapid eye movements (RWR)., Results: Patients (4 females) had a median age of 74 (range 63-85). Six patients (all with PD or DLB) had abnormal EEG awake and Subwake stage. UNREM sleep was present in all patients, typically at sleep onset, and was the most common sleep stage in five. P-S N2 was recorded only in the three patients with MSA. Periods of normal and abnormal NREM coexisted in three patients. RWA was the predominant REM subtype, RWR occurred mainly in patients with MSA and RWL in those with DLB. Six patients had brief REM episodes into NREM sleep which we termed "Encapsulated RBD"., Conclusion: Our scoring system allows an accurate description of the complex sleep-wake changes in patients with alpha-synucleinopathies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: Traumatic brain injury is associated with the late development of neurodegenerative diseases such as the synucleinopathies. Isolated REM sleep behavior disorder (IRBD) constitutes an early manifestation of the synucleinopathies. We assessed whether lifetime history of concussive episodes is common in IRBD and examined its characteristics and clinical significance., Methods: Prior exposure to concussions was evaluated by interviewing polysomnographically-confirmed IRBD patients and controls without IRBD, and by the BRAIN-Q questionnaire., Results: We recruited 199 IRBD patients aged 73.2 ± 7.7 years and 168 age and sex matched controls. Previous history of concussion was more common in patients than in controls (21.1% versus 10.1%, p = 0.004). In patients, concussions occurred at the age of 24.7 ± 20.6 years. The interval between concussion and IRBD diagnosis was 43.0 ± 19.0 years. There were no differences between patients and controls in the causes of concussions (e.g., traffic accidents, sport practice), and number of events resulting in skull fractures, urgent medical assistance, and hospitalization. After a follow-up of 5.7 ± 4.7 years from IRBD diagnosis, 21.1% patients developed an overt synucleinopathy with an interval of 49.3 ± 24.2 years between concussion and synucleinopathy diagnosis. The risk to develop a synucleinopathy was similar between patients with and without concussions (p = 0.57)., Conclusions: Previous history of concussion is common in IRBD. Our observations may suggest that in individuals with increased susceptibility, early-life concussions may trigger a slow neurodegenerative process leading four decades later to IRBD. This study highlights the need for head injury prevention, particularly in early life., Competing Interests: Declaration of competing interest Authors declare none., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: Isolated REM sleep behavior disorder (IRBD) represents an early manifestation of the synucleinopathies Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Aggregation of abnormal α-synuclein and its increased expression in the brain is crucial in the development of the synucleinopathies. Whereas α-synuclein gene (SNCA) transcripts are overexpressed in brain, a concomitant reduction occurs in blood of DLB patients. We assessed whether this decrease is also detectable in IRBD., Methods: 108 IRBD patients and 149 controls were included of which 29 IRBD and 32 control cases were available for expression studies. Expression of SNCAtv1, SNCAtv2, SNCAtv3 and SNCA126 isoforms, and GBA were determined by real-time PCR. Genotype distribution of SNCA SNPs, rs356219 and rs2736990, and correlation with SNCA expression was analyzed., Results: Expression of all SNCA transcripts was reduced in IRBD blood whereas GBA expression did not change. SNCAtv3 expression correlated inversely with IRBD duration, being lower in patients with longer follow-up. Rs356219-AA genotype frequency was increased in IRBD patients who later developed PD and DLB. Rs2736990-CC frequency was increased among IRBD cases who remained disease-free. No correlation was observed between rs356219 and rs2736990 genotypes and SNCA transcript levels., Conclusion: SNCA transcript expression is decreased in blood in IRBD, and levels decrease with IRBD duration. Our findings indicate that changes in SNCA expression occur in the earliest stages of the synucleinopathies before motor and cognitive symptoms become apparent., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Since 2014, there has been increasing public outreach effort regarding isolated/idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) in Montreal., Objective: To assess if, over time, milder iRBD cases are presenting earlier., Methods: Disease-free survival was compared in two iRBD recruitment epochs: 2004 to 2013 ("earlier") versus 2014to 2022 ("later " ) and by referral type ("self-referral" vs. "conventional-referral") in three large centers., Results: In Montreal, among 209 subjects followed prospectively, shorter time to phenoconversion was observed in the earlier epoch (5-year phenoconversion = 42% earlier vs. 23% later); diagnosis before 2014 had a 1.8-fold phenoconversion hazard. However, no difference was observed in 248 subjects from Barcelona and 166 from Innsbruck. Analysis of Montreal data found that increased survival in the later epoch was driven by an increasing number of self-referrals, who phenoconverted at 1/3 the rate of physician-referred subjects., Conclusions: Increased patient awareness of iRBD results in earlier presentation to clinical attention, with a longer time to phenoconversion., (© 2023 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Gerstmann-Sträussler-Scheinker (GSS) is a rare prion disease with heterogeneous clinical presentation. Although sleep-related abnormalities are prominent and well-known in other prion diseases such as fatal familial insomnia and Creutzfeldt-Jakob disease, information on sleep is limited in GSS., Methods: We evaluated sleep in three genetically confirmed GSS cases using clinical history, sleep scales and video-polysomnography. In addition, patients underwent neurological assessment, neurological scales, neuropsychological testing, lumbar puncture, brain MRI and brain 18 F-FDG-PET., Results: Two patients reported sleep maintenance insomnia attributed to leg stiffness and back pain while the remaining patient did not report sleep problems. Video-polysomnography showed normal sleep staging in all of them. Findings such as reduced sleep efficiency in two patients, a confusional arousal in one patient, obstructive apneas in one patient, and periodic legs movements in sleep in two patients were observed., Conclusions: In contrast to fatal familial insomnia, the normal sleep staging in GSS may suggest dissimilar involvement of the neuronal structures that regulate sleep. We found non-specific sleep alterations in GSS such as obstructive apneas and periodic leg movements in sleep which are of unknown origin and of uncertain clinical relevance. Studies including a larger number of patients, serial sleep evaluations and incorporating neuropathological assessment will further help to understand sleep in GSS., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Competing Interests: Competing interests: None declared.

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., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Contact sports such as football are associated with late development of neurodegenerative diseases, in part due to the deleterious effect of repetitive head impacts during participation. Isolated REM sleep behavior disorder (IRBD) represents an early manifestation of neurodegenerative diseases including Parkinson disease (RBD) and dementia with Lewy bodies (DLB). We hypothesized that former professional football participation would be overrepresented in IRBD., Objective: To assess former participation in professional football as an occupation in IRBD., Methods: In a case-control retrospective study, having played football as a professional occupation in the Spanish Football Professional Leagues was examined interviewing polysomnographically confirmed IRBD patients and matched controls without IRBD., Results: Among 228 Caucasian Spanish IRBD patients with 68.5 ± 7.2 years, six (2.63%) were retired professional footballers. Length professional football career ranged between 11 and 16 years. Interval between football retirement and IRBD diagnosis was 39.5 ± 6.4 years. At IRBD diagnosis, the six footballers had synucleinopathy biomarkers including pathologic synuclein in the CSF and tissues, nigrostriatal dopaminergic deficit and hyposmia. Follow-up showed that three footballers developed PD and two DLB. None of the controls was a professional footballer. The percentage of professional footballers was higher in IRBD patients than in controls (2.63% versus 0.00%; p = 0.030) and among the general Spanish population (2.63% versus 0.62%; p < 0.0001)., Conclusion: We found an overrepresentation of former professional footballers in IRBD patients who later developed PD and DLB after four decades from professional retirement. In professional footballers the development of a neurodegenerative disease may be first manifested by IRBD. Screening for IRBD in former footballers might identify individuals with underlying synucleinopathies. Further studies with larger samples are needed to confirm our observations., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Narcolepsy type 1 (NT1) is caused by a loss of hypocretin/orexin transmission. Risk factors include pandemic 2009 H1N1 influenza A infection and immunization with Pandemrix®. Here, we dissect disease mechanisms and interactions with environmental triggers in a multi-ethnic sample of 6,073 cases and 84,856 controls. We fine-mapped GWAS signals within HLA (DQ0602, DQB1*03:01 and DPB1*04:02) and discovered seven novel associations (CD207, NAB1, IKZF4-ERBB3, CTSC, DENND1B, SIRPG, PRF1). Significant signals at TRA and DQB1*06:02 loci were found in 245 vaccination-related cases, who also shared polygenic risk. T cell receptor associations in NT1 modulated TRAJ*24, TRAJ*28 and TRBV*4-2 chain-usage. Partitioned heritability and immune cell enrichment analyses found genetic signals to be driven by dendritic and helper T cells. Lastly comorbidity analysis using data from FinnGen, suggests shared effects between NT1 and other autoimmune diseases. NT1 genetic variants shape autoimmunity and response to environmental triggers, including influenza A infection and immunization with Pandemrix®., (© 2023. The Author(s).)

Background and Objectives: Real-time quaking-induced conversion (RT-QuIC) assay detects misfolded α-synuclein (AS) in the skin and CSF of patients with the synucleinopathies Parkinson disease and dementia with Lewy bodies. Isolated REM sleep behavior disorder (IRBD) constitutes the prodromal stage of these synucleinopathies. We aimed to compare the ability of RT-QuIC to identify AS in the skin and CSF of patients with IRBD., Methods: This was a cross-sectional study where consecutive patients with polysomnographic-confirmed IRBD and age-matched controls without RBD underwent skin biopsy and lumbar puncture the same day. Three-millimeter skin punch biopsies were obtained bilaterally in the cervical region from dorsal C7 and C8 dermatomes and in distal legs. RT-QuIC assessed AS in these 6 skin sites and the CSF., Results: We recruited 91 patients with IRBD and 41 controls. In the skin, sensitivity to detect AS was 76.9% (95% CI 66.9-85.1), specificity 97.6% (95% CI 87.1-99.9) positive predictive value 98.6% (95% CI 91.0-99.8), negative predictive value 65.6% (95% CI 56.6-73.6), and accuracy 83.3% (95% CI 75.9-89.3). In the CSF, the sensitivity was 75.0% (95% CI 64.6-83.6), the specificity was 97.5% (95% CI 86.8-99.9), the positive predictive value was 98.5% (95% CI 90.5-99.8), the negative predictive value was 63.9% (95% CI 55.2-71.9), and the accuracy was 82.0% (95% CI 74.3-88.3). Results in the skin and CSF samples showed 99.2% agreement. Compared with negative patients, RT-QuIC AS-positive patients had a higher likelihood ratio of prodromal Parkinson disease ( p < 0.001) and showed more frequently hyposmia ( p < 0.001), dopamine transporter imaging single-photon emission CT deficit ( p = 0.002), and orthostatic hypotension ( p = 0.014). No severe or moderate adverse effects were reported. There was no difference between the percentage of participants reporting mild adverse events secondary to skin biopsy or lumbar puncture (9.1% vs 17.2%; p = 0.053). One hundred and ten (83%) and 104 (80%) participants, respectively, stated they would accept to undergo skin biopsy and lumbar puncture again for research purposes., Discussion: Our study in IRBD shows that (1) RT-QuIC detects AS in the skin and CSF with similar high sensitivity, specificity, and agreement, (2) AS RT-QuIC positivity is associated with supportive features and biomarkers of synucleinopathy, and (3) skin punch biopsy and lumbar puncture have comparable mild adverse effects, tolerance, and acceptance. RT-QuIC in the skin or CSF might represent a patient selection strategy for future neuroprotective trials targeting AS in IRBD., Classification of Evidence: This study provides Class III evidence that RT-QuIC-detected AS in the skin and CSF distinguishes patients with IRBD from controls., (© 2023 American Academy of Neurology.)

Purpose of Review: The aim of this review is to summarize the current evidence on the relationship between sleep and cognition and present available data reporting the impact that sleep alterations may have on cognitive functions., Recent Findings: Research findings support the idea that sleep is involved in cognitive processes and that altered sleep homeostasis or circadian rhythms may lead to clinical and biochemical changes associated with cognitive impairment. Evidence is particularly solid for the association between specific sleep architecture and circadian alterations and Alzheimer's disease. Sleep changes, as early manifestations or possible risk factors for neurodegeneration and cognitive decline, may be appropriate targets for interventions aiming to reduce the likelihood of dementia., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Study Objectives: To identify a fast and reliable method for rapid eye movement (REM) sleep without atonia (RWA) quantification., Methods: We analyzed 36 video-polysomnographies (v-PSGs) of isolated REM sleep behavior disorder (iRBD) patients and 35 controls' v-PSGs. Patients diagnosed with RBD had: i) RWA, quantified with a reference method, i.e. automatic and artifact-corrected 3-s Sleep Innsbruck Barcelona (SINBAR) index in REM sleep periods (RSPs, i.e. manually selected portions of REM sleep); and ii) v-PSG-documented RBD behaviors. We quantified RWA with other (semi)-automated methods requiring less human intervention than the reference one: the indices proposed by the SINBAR group (the 3-s and 30-s phasic flexor digitorum superficialis (FDS), phasic/"any"/tonic mentalis), and the REM atonia, short and long muscle activity indices (in mentalis/submentalis/FDS muscles). They were calculated in whole REM sleep (i.e. REM sleep scored following international guidelines), in RSPs, with and without manual artifact correction. Area under curves (AUC) discriminating iRBD from controls were computed. Using published cut-offs, the indices' sensitivity and specificity for iRBD identification were calculated. Apnea-hypopnea index in REM sleep (AHIREM) was considered in the analyses., Results: RWA indices from FDS muscles alone had the highest AUCs and all of them had 100% sensitivity. Without manual RSP selection and artifact correction, the "30-s phasic FDS" and the "FDS long muscle activity" had the highest specificity (85%) with AHIREM < 15/h. RWA indices were less reliable when AHIREM≥15/h., Conclusions: If AHIREM<15/h, FDS muscular activity in whole REM sleep and without artifact correction is fast and reliable to rule out RWA., (© Sleep Research Society 2022. Published by Oxford University Press on behalf of the Sleep Research Society.)

Introduction: The presence of ≥2 sleep onset REM periods (SOREMP) in the Multiple Sleep Latency Test (MSLT) and the previous night polysomnogram (PSG) is part of the diagnostic criteria of narcolepsy, with every SOREMP having the same diagnostic value, despite evidence suggesting that time of SOREMP appearance and their preceding sleep stage might be relevant. We studied the temporal distribution of SOREMPs and associated sleep stages in the MSLT of patients with narcolepsy type 1 (NT1) and other hypersomnias (OH)., Methods: We reviewed consecutive five-nap MSLTs and their preceding PSG from 83 untreated adult patients with hypersomnolence and ≥1 SOREMPs. Wake/N1(W/N1)-SOREMPs, N2-SOREMPs, and N3 sleep presence and time of appearance were analyzed., Results: Thirty-nine patients had NT1 and 44 OH. There were 183 (78%) SOREMPs in patients with NT1 and 83 (31%) in OH. Sixty-seven percent of SOREMPs in NT1 were from W/N1, and 20% -none from wake-in OH (p < 0.001). Most patients (94%) with ≥2 W/N1-SOREMPs had NT1 (specificity 95%, sensitivity 82%). In patients with NT1 but not in OH, W/N1-SOREMPs decreased throughout the day (from 79% in the 1st nap to 33% in the preceding night, p < 0.001), whereas N2-SOREMPs did not change. N3 sleep frequency in the 5th nap was higher in NT1 than in OH (28% vs. 7%, p:0.009). Nocturnal-SOREMP plus ≥4 daytime SOREMPs, Wake-REM transitions, and REM followed by N3 were only seen in NT1., Conclusion: Measuring the sleep stage sequence and temporal distribution of SOREMP helps to identify patients with narcolepsy in the MSLT., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Study Objectives: Fatal insomnia (FI) is a rare prion disease severely affecting sleep architecture. Breathing during sleep has not been systematically assessed. Our aim was to characterize the sleep architecture, respiratory patterns, and neuropathologic findings in FI., Methods: Eleven consecutive FI patients (ten familial, one sporadic) were examined with video-polysomnography (vPSG) between 2002 and 2017. Wake/sleep stages and respiration were evaluated using a modified scoring system. Postmortem neuropathology was assessed in seven patients., Results: Median age at onset was 48 years and survival after vPSG was 1 year. All patients had different combinations of breathing disturbances including increased respiratory rate variability (RRV; n = 7), stridor (n = 9), central sleep apnea (CSA) (n = 5), hiccup (n = 6), catathrenia (n = 7), and other expiratory sounds (n = 10). RRV in NREM sleep correlated with ambiguous and solitary nuclei degeneration (r = 0.9, p = 0.008) and reduced survival (r = -0.7, p = 0.037). Two new stages, Subwake1 and Subwake2, present in all patients, were characterized. NREM sleep (conventional or undifferentiated) was identifiable in ten patients but reduced in duration in eight. REM sleep occurred in short segments in nine patients, and their reduced duration correlated with medullary raphe nuclei degeneration (r = -0.9, p = 0.005). Seven patients had REM without atonia. Three vPSG patterns were identified: agitated, with aperiodic, manipulative, and finalistic movements (n = 4); quiet-apneic, with CSA (n = 4); and quiet-non-apneic (n = 3)., Conclusions: FI patients show frequent breathing alterations, associated with respiratory nuclei damage, and, in addition to NREM sleep distortion, have severe impairment of REM sleep, related with raphe nuclei degeneration. Brainstem impairment is crucial in FI., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Sleep abnormalities are prevalent in Alzheimer's disease, with sleep quality already impaired at its preclinical stage. Epidemiological and experimental data point to sleep abnormalities contributing to the risk of Alzheimer's disease. However, previous studies are limited by either a lack of Alzheimer's disease biomarkers, reduced sample size or cross-sectional design. Understanding if, when, and how poor sleep contributes to Alzheimer's disease progression is important so that therapies can be targeted to the right phase of the disease. Using the largest cohort to date, the European Prevention of Alzheimer's Dementia Longitudinal Cohort Study, we test the hypotheses that poor sleep is associated with core Alzheimer's disease CSF biomarkers cross-sectionally and predicts future increments of Alzheimer's disease pathology in people without identifiable symptoms of Alzheimer's disease at baseline. This study included 1168 adults aged over 50 years with CSF core Alzheimer's disease biomarkers (total tau, phosphorylated tau and amyloid-beta), cognitive performance, and sleep quality (Pittsburgh sleep quality index questionnaire) data. We used multivariate linear regressions to analyse associations between core Alzheimer's disease biomarkers and the following Pittsburgh sleep quality index measures: total score of sleep quality, binarized score (poor sleep categorized as Pittsburgh sleep quality index > 5), sleep latency, duration, efficiency and disturbance. On a subsample of 332 participants with CSF taken at baseline and after an average period of 1.5 years, we assessed the effect of baseline sleep quality on change in Alzheimer's disease biomarkers over time. Cross-sectional analyses revealed that poor sleep quality (Pittsburgh sleep quality index total > 5) was significantly associated with higher CSF t-tau; shorter sleep duration (<7 h) was associated with higher CSF p-tau and t-tau; and a higher degree of sleep disturbance (1-9 versus 0 and >9 versus 0) was associated with lower CSF amyloid-beta. Longitudinal analyses showed that greater sleep disturbances (1-9 versus 0 and >9 versus 0) were associated with a decrease in CSF Aβ42 over time. This study demonstrates that self-reported poor sleep quality is associated with greater Alzheimer's disease-related pathology in cognitively unimpaired individuals, with longitudinal results further strengthening the hypothesis that disrupted sleep may represent a risk factor for Alzheimer's disease. This highlights the need for future work to test the efficacy of preventive practices, designed to improve sleep at pre-symptomatic stages of disease, on reducing Alzheimer's disease pathology., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Purpose: To investigate the quantity and quality of sleep hours in young athletes in a professional football club, to study if there is a significant relationship with mood state and subjective well-being, and to identify the relationship between sleep and quarterly academic performance. We also explored the relationship between sleep and quarterly academic performance., Method: the study included 261 players of the various age group categories from football at Barcelona Football Club (average age:13.04 ± 3.16). Participants maintained a sleep diary and completed questionnaires on their mood state and the quantity and quality of their sleep., Results: 70% of the athletes slept less hours than recommended by the American National Sleep Foundation. Athletes with worse quantity and quality of sleep showed negative effects on academic results., Conclusions: The results show that the majority of young players sleep less than recommended and show that those who sleep more hours obtain better academic results.

Competing Interests: I declare no competing interests.

Background: Isolated rapid eye movement sleep behavior disorder (IRBD) is a well-established clinical risk factor for Lewy body diseases (LBDs), such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB)., Objective: To elucidate whether serum microRNA (miRNA) deregulation in IRBD can antedate the diagnosis of LBD by performing a longitudinal study in different progression stages of IRBD before and after LBD diagnosis and assessing the predictive performance of differentially expressed miRNAs by machine learning-based modeling., Methods: Using genome-wide miRNA analysis and real-time quantitative polymerase chain reaction validation, we assessed serum miRNA profiles from patients with IRBD stratified by dopamine transporter (DaT) single-photon emission computed tomography into DaT-negative IRBD (n = 17) and DaT-positive IRBD (n = 21), IRBD phenoconverted into LBD (n = 13), and controls (n = 20). Longitudinally, we followed up the IRBD cohort by studying three time point serum samples over 26 months., Results: We found sustained cross-sectional and longitudinal deregulation of 12 miRNAs across the RBD continuum, including DaT-negative IRBD, DaT-positive IRBD, and LBD phenoconverted IRBD (let-7c-5p, miR-19b-3p, miR-140, miR-22-3p, miR-221-3p, miR-24-3p, miR-25-3p, miR-29c-3p, miR-361-5p, miR-425-5p, miR-4505, and miR-451a) (false discovery rate P < 0.05). Age- and sex-adjusted predictive modeling based on the 12 differentially expressed miRNA biosignatures discriminated IRBD and PD or DLB from controls with an area under the curve of 98% (95% confidence interval: 89-99%)., Conclusions: Besides clinical diagnosis of IRBD or imaging markers such as DaT single-photon emission computed tomography, specific miRNA biosignatures alone hold promise as progression biomarkers for patients with IRBD for predicting PD and DLB clinical outcomes. Further miRNA studies in other PD at-risk populations, such as LRRK2 mutation asymptomatic carriers or hyposmic subjects, are warranted. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

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., (© 2022 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)

Sleep paralysis is rare in the elderly but may occur particularly in families suffering from this phenomenon. In a minority of patients with disorders of arousal, the episodes persist until the age of 70. Zolpidem and other medications may induce sleepwalking and sleep eating-related syndrome. Most patients with idiopathic REM sleep behavior disorder (RBD) eventually develop Parkinson disease and dementia with Lewy bodies. Anti-IgLON5 disease includes abnormal behaviors in both nonrapid eye movement sleep and rapid eye movement sleep (REM) sleep. Restless legs syndrome prevalence increases with age until the sixth decade. A severe form of periodic limb movements in sleep may clinically mimic REM sleep behavior disorder (RBD)., (Copyright © 2022 Elsevier Inc. All rights reserved.)