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Introduction Brunner syndrome is a recessive X-linked disorder characterized by impulsive aggressiveness and mild mental retardation associated with Monoamine Oxidase – A (MAOA) deficiency (Brunner et al. Science 1993; 262 578-580). Objectives To present a REM sleep behavior disorder (RBD) case in a patient with Brunner syndrome. Methods The present study is a case report of a patient followed in our hospital’s outpatient care. We also searched for previous case reports of sleep disorders and other clinical features in Brunner syndrome using a pubmed query. Results A 46-year-old Spanish male, diagnosed with Brunner syndrome due to the mutation c.1438A>G/iVS14-2 A>G, a loss-of-function mutation in the X-linked MAOA gene. He suffers from mild mental retardation and psychotic disturbances treated with SSRI and antipsychotic drugs. The patient was referred to our outpatient care to assess his sleep abnormal behaviors. He had been presenting with episodes of sleep-related vocalization and complex motor behaviors during sleep for the last 3 years, correlating with dream mentation. His relatives recounted episodes of talking, screaming, gesturing, kicking, falling out of bed and crying during sleep. Dream content referred by the patient was often related to persecutions, attacks and fights. Polysomnography revealed vocalization and gesticulation during REM sleep compatible with the diagnosis of RBD. The addition of clonazepam to his treatment at doses of 1-3 mg per day achieved significant clinical response of the sleep disorder. Conclusions The clinical presentation suggested the diagnosis of RBD case in a patient with Brunner syndrome. Although sleep disorders are not one of the most important or frequent clinical features in Brunner syndrome, they are described in the literature and can significantly affect the patient’s quality of life. To our knowledge, this is the first report about clinical management of RBD case in Brunner syndrome. Disclosure of Interest None Declared

Background: Resting-state functional MRI has been proposed as a new biomarker of prodromal neurodegenerative disorders, but it has been poorly investigated in the idiopathic form of rapid-eye-movement sleep behavior disorder (IRBD), a clinical harbinger of subsequent synucleinopathy. Particularly, a complex-network approach has not been tested to study brain functional connectivity in IRBD patients. Objectives: The aim of the current work is to characterize resting-state functional connectivity in IRBD patients using a complex-network approach and to determine its possible relation to cognitive impairment. Method: Twenty patients with IRBD and 27 matched healthy controls (HC) underwent resting-state functional MRI with a 3T scanner and a comprehensive neuropsychological battery. The functional connectome was studied using threshold-free network-based statistics. Global and local network parameters were calculated based on graph theory and compared between groups. Head motion, age and sex were introduced as covariates in all analyses. Results: IRBD patients showed reduced cortico-cortical functional connectivity strength in comparison with HC in edges located in posterior regions (p

Background: Idiopathic Rapid eye movement sleep behavior disorder (IRBD) is recognized as the prodromal stage of the alpha-Synucleinopathies. Although some studies have addressed the characterization of brain structure in IRBD, little is known about its progression. Objective: The present work aims at further characterizing gray matter progression throughout IRBD relative to normal aging and investigating how these changes are associated with cognitive decline. Methods: Fourteen patients with polysomnography-confirmed IRBD and 18 age-matched healthy controls (HC) underwent neuropsychological, olfactory, motor, and T1-weighted MRI evaluation at baseline and follow-up. We compared the evolution of cortical thickness (CTh), subcortical volumes, smell, motor and cognitive performance in IRBD and HC after a mean of 1.6 years. FreeSurfer was used for CTh and volumetry preprocessing and analyses. The symmetrized percent of change (SPC) of the CTh was correlated with the SPC of motor and neuropsychological performance. Results: IRBD and HC differed significantly in the cortical thinning progression in regions encompassing bilateral superior parietal and precuneus, the right cuneus, the left occipital pole and lateral orbitofrontal gyri (FWE corrected, p

Resumen: Introducción: El objetivo de nuestro trabajo es describir 4 casos de sexsomnia, una parasomnia caracterizada por conductas sexuales durante el sueño. Método: Historia clínica y registro videopolisomnográfico de pacientes identificados en la unidad multidisciplinaria del sueño del Hospital Clínic de Barcelona. Resultados: Tres varones y una mujer entre 28 y 43 años de edad referían conductas sexuales durante el sueño de entre 9 meses y 7 años de evolución. Consistían en la masturbación sin buscar la participación de la pareja, que dormía en la misma cama (2 casos), e intentar el coito con vigorosidad conductual y verbal inapropiada e inhabitual (3 casos). La frecuencia era variable entre 4 únicos episodios y 2-3 semanales. Los pacientes presentaban amnesia completa de los eventos y sorpresa cuando se les explicaba lo que habían hecho. Había antecedentes de sonambulismo (un caso), despertares confusos (2 casos) y somniloquia (un caso). Los registros polisomnográficos con vídeo no detectaron conductas sexuales pero registraron apneas (2 casos) y movimientos periódicos de las piernas (un caso). En el único paciente en que se probó clonacepam la frecuencia de la sexsomnia y los despertares confusos disminuyó. Conclusión: La sexsomnia aparece en el adulto joven, consiste en intentar consumar de forma inapropiada el coito o masturbarse durante el sueño, con amnesia posterior de lo ocurrido. Puede coexistir con otras parasomnias, como sonambulismo y despertares confusos. Otros trastornos del sueño, como las apneas y los movimientos periódicos de las piernas, podrían desencadenar los episodios de sexsomnia. Abstract: Introduction: The purpose of our study is to describe 4 cases of sexsomnia, a form of parasomnia characterised by sexual behaviour during sleep. Methods: Clinical history and video-polysomnography recordings from patients diagnosed with sexsomnia in the Multidisciplinary Sleep Unit at Hospital Clínic in Barcelona. Results: Three men and one woman between 28 and 43 years of age reported sexual behaviours during sleep with progression times ranging from 9 months to 7 years. Episodes consisted of masturbation without seeking the participation of a sleeping partner (2 cases) and attempts at sexual intercourse with inappropriate and uncharacteristic vocalizations and behaviours (3 cases). The frequency of the episodes ranged from 4 isolated episodes to 2-3 per week. Patients were amnestic of these events and surprised by their partners’ accounts of their behaviour. Medical histories revealed that 1 patient was a somnambulist, 2 had confusional arousals, and 1 experienced somniloquy. Video-polysomnography did not disclose sexual behaviours during sleep but revealed sleep apnoea in 2 cases and periodic leg movements in sleep in another. The only patient treated with clonazepam reported decreased frequency of both confusional arousals and sexsomnia episodes. Conclusions: Sexsomnia occurs in young adults and is characterised by masturbation and inappropriate attempts at achieving sexual intercourse followed by total amnesia of the events. It can be associated with other parasomnias such as sleepwalking and confusional arousals. Other sleep disorders, including sleep apnoea and periodic leg movement disorder, may trigger episodes of sexsomnia. Palabras clave: Sexsomnia, Parasomnia, Masturbación, Coito, Amnesia y sueño, Keywords: Sexsomnia, Parasomnia, Masturbation, Intercourse, Amnesia and sleep

Introduction: The purpose of our study is to describe 4 cases of sexsomnia, a form of parasomnia characterised by sexual behaviour during sleep. Methods: Clinical history and video-polysomnography recordings from patients diagnosed with sexsomnia in the Multidisciplinary Sleep Unit at Hospital Clínic in Barcelona. Results: Three men and one woman between 28 and 43 years of age reported sexual behaviours during sleep with progression times ranging from 9 months to 7 years. Episodes consisted of masturbation without seeking the participation of a sleeping partner (2 cases) and attempts at sexual intercourse with inappropriate and uncharacteristic vocalisations and behaviours (3 cases). The frequency of the episodes ranged from 4 isolated episodes to 2-3 per week. Patients were amnestic of these events and surprised by their partners’ accounts of their behaviour. Medical histories revealed that 1 patient was a somnambulist, 2 had confusional arousals, and 1 experienced somniloquy. Video-polysomnography did not disclose sexual behaviours during sleep but revealed sleep apnoea in 2 cases and periodic leg movements in sleep in another. The only patient treated with clonazepam reported decreased frequency of both confusional arousals and sexsomnia episodes. Conclusions: Sexsomnia occurs in young adults and is characterised by masturbation and inappropriate attempts at achieving sexual intercourse followed by total amnesia of the events. It can be associated with other parasomnias such as sleepwalking and confusional arousals. Other sleep disorders, including sleep apnoea and periodic leg movement disorder, may trigger episodes of sexsomnia. Resumen: Introducción: El objetivo de nuestro trabajo es describir 4 casos de sexsomnia, una parasomnia caracterizada por conductas sexuales durante el sueño. Método: Historia clínica y registro videopolisomnográfico de pacientes identificados en la unidad multidisciplinaria del sueño del Hospital Clínic de Barcelona. Resultados: Tres varones y una mujer entre 28 y 43 años de edad referían conductas sexuales durante el sueño de entre 9 meses y 7 años de evolución. Consistían en la masturbación sin buscar la participación de la pareja, que dormía en la misma cama (2 casos), e intentar el coito con vigorosidad conductual y verbal inapropiada e inhabitual (3 casos). La frecuencia era variable entre 4 únicos episodios y 2-3 semanales. Los pacientes presentaban amnesia completa de los eventos y sorpresa cuando se les explicaba lo que habían hecho. Había antecedentes de sonambulismo (un caso), despertares confusos (2 casos) y somniloquia (un caso). Los registros polisomnográficos con vídeo no detectaron conductas sexuales pero registraron apneas (2 casos) y movimientos periódicos de las piernas (un caso). En el único paciente en que se probó clonacepam la frecuencia de la sexsomnia y los despertares confusos disminuyó. Conclusión: La sexsomnia aparece en el adulto joven, consiste en intentar consumar de forma inapropiada el coito o masturbarse durante el sueño, con amnesia posterior de lo ocurrido. Puede coexistir con otras parasomnias, como sonambulismo y despertares confusos. Otros trastornos del sueño, como las apneas y los movimientos periódicos de las piernas, podrían desencadenar los episodios de sexsomnia. Keywords: Sexsomnia, Parasomnia, Masturbation, Intercourse, Amnesia and sleep, Palabras clave: Sexsomnia, Parasomnia, Masturbación, Coito, Amnesia y sueño

Current environmental issues that have been made unavoidable by environmental regulations have become new constraints for industrial companies. In this paper, we consider a joint production-location problem for supply chains under a carbon tax policy on transport-related carbon emissions. We characterize the relationship that links the production level to the input quantities by considering a production function, namely, constant elasticity of substitution (CES) function. Our study focuses on the potential impact of increased transportation costs due to carbon taxation on the joint production-location decision. We find that the location-production configuration differs according to the degree of substitutability among the raw material quantities. More importantly, we observe that a higher carbon tax is more likely to cause a significant jump in firm location choice and a considerable change in production decisions when a firm has high flexibility in its ability to substitute among input quantities.

Dans cet article, nous analysons trois territoires à haute densité animale, différentiés par le contexte de production (densité et diversité des élevages), la sensibilité des milieux et les choix stratégiques et technologiques mis en oeuvre pour la gestion des effluents : i) la Bretagne, un territoire de polyculture-polyélevage avec une forte densité d'élevages et des zones particulièrement sensibles sur le plan environnemental, ii) l'Allemagne, avec la particularité d'un très fort développement de la méthanisation à des fins de production d'énergie renouvelable et iii) la Catalogne, un territoire marqué par un développement récent et très rapide de la production porcine dans un milieu où les surfaces agricoles disponibles pour l'épandage sont limitées. Ces systèmes se caractérisent par une production élevée par unité de surface et par unité de travail, à des coûts relativement bas, avec un recours important à des intrants, principalement pour l’alimentation des animaux. Malgré des progrès significatifs, les impacts environnementaux locaux, eutrophisation et acidification, constituent une limite importante dans ces systèmes. À l'inverse, les impacts globaux, comme l'émission de gaz à effet de serre sont faibles par unité de produit, compte tenu du type d'élevage et de l'intensité de production. Ils sont encore réduits avec la méthanisation. Ces systèmes font face à une remise en cause du modèle socio-économique dans lequel ils s’inscrivent avec des questions autour de la faible rémunération des éleveurs et du bien-être animal. Différents leviers d'action spécifiques à ces territoires à haute densité animale ont été identifiés pour mieux gérer les compromis entre les différents services.

Si les différents gains associés à la concentration spatiale au sein d’une même filière animale sont relativement bien identifiés, les combinaisons des différentes filières animales au niveau des territoires en Europe sont rarement étudiées. Cet article vise i) à réaliser un état des lieux de la co-localisation des différentes filières animales au sein des territoires européens, à partir d’un indicateur statistique mesurant la spécialisation des territoires, et ii) à discuter le lien entre la nature des spécialisations et les densités animales à travers une analyse économétrique. À l’échelle du territoire, cette étude met en avant que de nombreux territoires des grands pays producteurs de l’UE sont spécialisés dans une unique production animale. Ceci suggère que les gains à la co-agglomération de différentes productions animales sont relativement faibles. En France, les modalités d’application des politiques agricoles, environnementales et même foncières semblent agir comme des freins au processus de mono-spécialisation des territoires d’élevage dans les filières avicoles, laitières et porcines.

Cet article porte sur l’évolution récente (depuis 2000) de la localisation des productions animales (lait de vache, viande bovine, porcs et volailles) au sein des Etats membres de l’Union Européenne. En utilisant les dernières données statistiques disponibles à un niveau géographique fin, une analyse est conduite sur les processus de concentration géographique et de spécialisation productive des territoires. Les forces qui influent sur ces processus ne sont pas nouvelles et ont déjà fait l’objet de nombreux travaux d’économistes au fil du temps. Elles concernent principalement les avantages comparatifs, les économies d’échelle et d’agglomération ainsi que la qualité de la structuration industrielle et commerciale. Si les normes environnementales (directive Nitrates, Natura 2000…) et les mesures du développement rural (soutiens spécifiques aux agricultures des zones défavorisées) constituent un levier pour freiner voire diminuer la concentration animale, force est de constater que leur influence est souvent moins grande que les forces évoquées ci-dessus. La spécialisation productive des territoires demeure cependant un processus complexe. Une analyse de la co-localisation des productions animales met en évidence le fait que les productions de granivores (volailles et porcs) ont tendance à se localiser dans les zones géographiques similaires. Cependant, l’association porcs et vaches laitières est la plus fréquente dans les zones les plus denses en cheptel total. Le cheptel de vaches allaitantes a quant à lui tendance à être repoussé dans les zones défavorisées où les autres productions animales ont des difficultés à s’implanter ou à se maintenir.

Depuis plusieurs décennies, on assiste à un double mouvement de concentration industrielle et spatiale dans les filières animales en France, comme dans de nombreux pays d’Europe et d’Amérique du Nord. La baisse du prix relatif de l’énergie, la présence d’économies d’échelle aux différents stades des filières, les gains économiques liés à la proximité géographique entre les éleveurs et les industries amont et aval constituent des facteurs importants de ce processus de concentration spatiale des productions animales. Cette agglomération se traduit cependant par une concentration des effluents d’élevage, dont l’épandage a des conséquences environnementales souvent néfastes. Des mesures de régulation environnementale ont vu le jour, notamment au travers de la Directive Nitrates de 1991. La question de la localisation des productions agricoles et notamment de sa dispersion a été évoquée comme un levier possible pour réduire les problèmes environnementaux, mais il apparaît que les mesures actuelles sont insuffisantes pour contrecarrer les facteurs d’agglomération à l’origine des excès d’azote dans les territoires spécialisés dans les productions animales. Plusieurs arguments peuvent en revanche être avancés montrant qu’il pourrait être plus efficace d’appliquer des régulations au niveau des filières plutôt que seulement sur les éleveurs.

Background: Isolated rapid-eye movement (REM) sleep behavior disorder (iRBD) is characterized by abnormal behaviors in REM sleep and is considered as a prodromal symptom of alpha-synucleinopathies. Resting-state functional magnetic resonance imaging (rsfMRI) studies have unveiled altered functional connectivity (rsFC) in patients with iRBD. However, the associations between intra- and inter-network rsFC with clinical symptoms and neuropsychological functioning in iRBD remain unclear., Objective: To characterize intra- and inter-network rsFC in iRBD patients using a data-driven approach and to assess its associations with clinical features and cognitive functioning., Methods: Forty-two patients with iRBD and 45 healthy controls (HC) underwent rsfMRI and comprehensive neuropsychological testing. Resting-state networks were characterized using independent component analyses. Group differences in intra- and inter-network rsFC and their associations with clinical and neuropsychological data were studied. A threshold of corrected P < 0.05 was used in all the analyses., Results: iRBD patients displayed lower intra-network rsFC within basal ganglia, visual, sensorimotor, and cerebellar networks, relative to HC. Mean rsFC strength within the basal ganglia network positively correlated with processing speed and negatively with the non-motor symptoms in iRBD patients. Reduced inter-network rsFC between sensorimotor and visual medial networks was observed in iRBD patients, which was associated with global cognitive status., Conclusions: iRBD is characterized by both reductions in intra-network rsFC in cortical and subcortical networks and inter-network dysconnectivity between sensorimotor and visual networks. Abnormalities in intra- and inter-network rsFC are associated with cognitive performance and non-motor symptoms, suggesting the utility of both rsFC measures as imaging markers in prodromal alpha-synucleinopathies. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: The diagnosis of isolated REM sleep behavior disorder (IRBD) requires video polysomnography (V-PSG) showing increased muscle activity and abnormal behaviors in REM sleep., Objective: To describe in IRBD the behavioral manifestations occurring during REM sleep in the diagnostic V-PSG., Methods: This is a systematic audiovisual V-PSG analysis of consecutive IRBD patients. According to the International RBD Study Group recommendations, REM sleep movements and vocalizations were classified into categories and severity., Results: We analyzed the V-PSG of 62 IRBD patients with a mean age of 67.6 ± 8.1 years. Of 6,330 30-s epochs of REM sleep, 55.1% epochs exhibited motor events, 5.5% contained vocalizations and 39.4% were silent. Among the epochs with motor manifestations, 66.1% contained simple minor movements, 25.0% simple major and 8.9% complex movements. Motor severity of the epochs was mild in 82.2%, moderate in 13.2% and severe in 4.6%. Most movements were bilateral (62.4%) and located in the upper limbs (42.5%). Of the epochs with vocalizations, 61.5% were simple minor, 20.7% complex and 17.8% simple major of mild (72.7%), moderate (23.0%) and severe (4.3%) severity. Complex movements occurred in 87.1% of the patients and complex vocalizations in 38.7%., Conclusions: In IRBD, the most common manifestations in REM sleep are simple minor movements and vocalizations of mild intensity. Complex movements are observed during REM sleep in most patients but are much less frequent than simple minor and major motor events. These findings should be considered for the routine diagnosis of IRBD when reviewing the V-PSG studies., Competing Interests: Declarations. Conflicts of interest: The authors had no financial disclosures and no conflict of interests concerning the research related to the current study. Ethics approval: The ethical committee of the Hospital Clinic de Barcelona approved this study (HCB/2023/0962)., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Anti-IgLON5 disease was identified 10 years ago, thanks to the discovery of IgLON5 antibodies and the joint effort of specialists in sleep medicine, neuroimmunology, and neuropathology. Without this collaboration, it would have been impossible to untangle fundamental aspects of this disease. After the seminal description in 2014, today there is growing evidence that most patients present a chronic progressive course with gait instability, abnormal movements, bulbar dysfunction, and a sleep disorder characterized by nonrapid eye movement and REM parasomnias, and obstructive sleep apnea with stridor. Unlike other autoimmune encephalitides, the response to immunotherapy is suboptimal. Neuropathologic studies in patients with a prolonged clinical course showed a novel 3-repeat and 4-repeat neuronal tauopathy mainly involving the hypothalamus and tegmentum of the brainstem. The absence of tau deposits in the brain of patients who died early, the demonstration that IgLON5 antibodies cause an irreversible decrease in cell-surface levels of IgLON5, and a disorganization of the neuronal cytoskeleton suggest that the disease is primarily autoimmune and the tauopathy a secondary event. After a decade, we now know the disease much better, but important issues still need to be addressed. We have to gather more information on the natural course of the disease, develop better treatments, and identify robust predictors of outcome. More basic research is needed on the physiology of IgLON5, how antibodies disrupt its function, and the downstream effects leading to neurodegeneration. Finally, better designed passive transfer and active immunization models are needed to confirm the pathogenic effect of IgLON5 antibodies.

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 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.)

Anti-IgLON5 disease is a rare neurological disease, identified just ten years ago, where autoimmunity and neurodegeneration converge. The heterogeneity of symptoms, sometimes mimicking pure neurodegenerative diseases or motor neuron diseases, in addition to lack of awareness, represents a diagnostic challenge. Biomarkers of neuronal damage in combination with in vivo visualization of tau deposition using positron emission tomography (PET) scanning could represent a major advance in monitoring disease progression. Recent studies with more autopsies available have helped refine the knowledge of the pathological features of the disease and strengthen the autoimmune hypothesis of the disease. Although the pathogenesis of anti-IgLON5 disease remains unclear, the irreversible antibody-mediated decrease of IgLON5 clusters from the cell surface and alterations produced in the cytoskeleton, as well as the behavioural abnormalities and signs of neuroinflammation and neurodegeneration observed in the brains of animals infused with antibodies from patients by passive transfer, which have recently been published, support the autoimmune hypothesis of the disease. This review aims to summarize these important aspects and recent advances in the pathophysiology of anti-IgLON5 disease., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

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.)

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.)

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.)

Purpose of Review: Anti-IgLON5 disease is characterized by a distinctive sleep disorder, associated with a heterogeneous spectrum of neurological symptoms. Initial autopsies showed a novel neuronal tauopathy predominantly located in the tegmentum of the brainstem. Recently, new diagnostic red flags, biomarkers predictors of response to immunotherapy, and novel insights into the autoimmune pathogenesis of the disease have been reported., Recent Findings: Patients with diagnosis of neurodegenerative dementia, progressive supranuclear palsy (PSP) or with motor-neuron disease (MND)-like syndrome have been reported to have IgLON5 antibodies, which are the hallmark of anti-IgLON5 disease. Second, low levels of neurofilament light chain in serum and cerebrospinal fluid of patients at disease onset could be a predictor of immunotherapy response. Recent neuropathological studies indicate that the neuronal tau deposits occur late in the course of the disease. Moreover, IgLON5 antibodies induce cytoskeletal changes in cultured hippocampal neurons suggesting that the tauopathy could be secondary of the IgLON5 antibody effects., Summary: Anti-IgLON5 disease can mimic and should be considered in atypical presentations of MND, neurodegenerative dementia and PSP. Neurofilament light chain levels seem promising biomarker for disease prognosis. Finally, the neuropathological and in vitro experimental studies strengthen the autoimmune hypothesis of the disease., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

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: Anti-IgLON5 disease is a rare chronic autoimmune disorder characterized by IgLON5 autoantibodies predominantly of the IgG4 subclass. Distinct pathogenic effects were described for anti-IgLON5 IgG1 and IgG4, however, with uncertain clinical relevance., Methods: IgLON5-specific IgG1-4 levels were measured in 46 sera and 20 cerebrospinal fluid (CSF) samples from 13 HLA-subtyped anti-IgLON5 disease patients (six females, seven males) using flow cytometry. Intervals between two consecutive serum or CSF samplings (31 and 10 intervals, respectively) were categorized with regard to the immunomodulatory treatment active at the end of the interval, changes of anti-IgLON5 IgG1 and IgG4 levels, and disease severity. Intrathecal anti-IgLON5 IgG4 synthesis (IS) was assessed using a quantitative method., Results: The median age at onset was 66 years (range: 54-75), disease duration 10 years (range: 15-156 months), and follow-up 25 months (range: 0-83). IgLON5-specific IgG4 predominance was observed in 38 of 46 (83%) serum and 11 of 20 (55%) CSF samples. Anti-IgLON5 IgG4 levels prior clinical improvement in CSF but not serum were significantly lower than in those prior stable/progressive disease. Compared to IgLON5 IgG4 levels in serum, CSF levels in HLA-DRB1*10:01 carriers were significantly higher than in non-carriers. Indeed, IgLON5-specific IgG4 IS was demonstrated not only in four of five HLA-DRB1*10:01 carriers but also in one non-carrier. Immunotherapy was associated with decreased anti-IgGLON5 IgG serum levels. In CSF, lower anti-IgLON5 IgG was associated with immunosuppressive treatments used in combination, that is, corticosteroids and/or azathioprine plus intravenous immunoglobulins or rituximab., Conclusion: Our findings might indicate that CSF IgLON5-specific IgG4 is frequently produced intrathecally, especially in HLA-DRB1*10:01 carriers. Intrathecally produced IgG4 may be clinically relevant. While many immunotherapies reduce serum IgLON5 IgG levels, more intense immunotherapies induce clinical improvement and may be able to target intrathecally produced anti-IgLON5 IgG. Further studies need to confirm whether anti-IgLON5 IgG4 IS is a suitable prognostic and predictive biomarker in anti-IgLON5 disease., Competing Interests: TS-H reports travel grants and speaker honoraria from Roche. MBr has received honoraria for speaking from Sanofi. No conflict of interest with respect to the present study. AH reports speaker honoraria for UCB, Bioprojet, Servier, Medice, Jazz Pharmaceuticals BH reports speaker honoraria Jazz and Abbvie and advisor feed from Lundbeck. MS reports personal fees and grants from Merck Healthcare Deutschland and Bayer Vital GmbH and grant support from the University of Greifswald Gerhard-Domagk fellowship. HT reports speaker honoraria from Jansen, UCB and Zambon. TB has participated in meetings sponsored by and received honoraria lectures, advisory boards, consultations from pharmaceutical companies marketing treatments for MS: Allergan, Biogen, Biologix, Bionorica, BMS/Celgene, Eisei, Janssen-Cilag, MedDay, Merck, Novartis, Roche, Sandoz, Sanofi-Genzyme, Teva, UCB. His institution has received financial support in the past 12 months by unrestricted research grants Bayer, Biogen, BMS/Celgene, Merck, Novartis, Roche, Sanofi-Genzyme, Teva and for participation in clinical trials in multiple sclerosis sponsored by Alexion, Bayer, Biogen, BMS/Celgene, Merck, Novartis, Roche, Sanofi-Aventis, Teva. JL reports travel honoraria and speakers fees from the Cure Huntington’s Disease Initiative CHDI, the Movement Disorders Society as the German Society for Cerebrospinal Fluid Diagnostic and Clinical Neurochemistry DGLN. His institution received financial compensation for clinical trials with JL as principal investigator from CHDI. He is member of the executive board of the DGLN. He received research funding from the German Federal Ministry of Education and Research BMBF. RH reports speaker honoraria from UCB and Biogen. The Medical University of Vienna Austria; employer of RH receives payment for antibody assays and for antibody validation experiments organized by Euroimmun Lübeck, Germany. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Koneczny, Macher, Hutterer, Seifert-Held, Berger-Sieczkowski, Blaabjerg, Breu, Dreyhaupt, Dutra, Erdler, Fae, Fischer, Frommlet, Heidbreder, Högl, Klose, Klotz, Liendl, Nissen, Rahimi, Reinecke, Ricken, Stefani, Süße, Teive, Weis, Berger, Sabater, Gaig, Lewerenz and Höftberger.)

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.

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.)

Background: Anti-leucine-rich glioma-inactivated protein 1 (LGI1) encephalitis is an autoimmune disorder that can be treated with immunotherapy, but the symptoms that remain after treatment have not been well described. We aimed to characterise the clinical features of patients with anti-LGI1 encephalitis for 1 year starting within the first year after initial immunotherapy., Methods: For this prospective cohort study, we recruited patients with anti-LGI1 encephalitis as soon as possible after they had received conventional immunotherapy for initial symptoms; patients were recruited from 21 hospitals in Spain. Patients were excluded if they had an interval of more than 1 year since initial immunotherapy, had pre-existing neurodegenerative or psychiatric disorders, or were unable to travel to Hospital Clínic de Barcelona (Barcelona, Spain). Patients visited Hospital Clínic de Barcelona on three occasions-the first at study entry (visit 1), the second 6 months later (visit 2), and the third 12 months after the initial visit (visit 3). They underwent neuropsychiatric and videopolysomnography assessments at each visit. Healthy participants who were matched for age and sex and recruited from Hospital Clínic de Barcelona underwent the same investigations at study entry and at 12 months. Cross-sectional comparisons of clinical features between groups were done with conditional logistic regression, and binary logistic regression was used to assess associations between cognitive outcomes at 12 months and clinical features before initial immunotherapy and at study entry., Findings: Between May 1, 2019, and Sept 30, 2022, 42 participants agreed to be included in this study. 24 (57%) participants had anti-LGI1 encephalitis (mean age 63 years [SD 12]; 13 [54%] were female and 11 [46%] were male) and 18 (43%) were healthy individuals (mean age 62 years [10]; 11 [61%] were female and seven [39%] were male). At visit 1 (median 88 days [IQR 67-155] from initiation of immunotherapy), all 24 patients had one or more symptoms; 20 (83%) patients had cognitive deficits, 20 (83%) had psychiatric symptoms, 14 (58%) had insomnia, 12 (50%) had rapid eye movement (REM)-sleep behaviour disorder, nine (38%) had faciobrachial dystonic seizures, and seven (29%) had focal onset seizures. Faciobrachial dystonic seizures were unnoticed in four (17%) of 24 patients and focal onset seizures were unnoticed in five (21%) patients. At visit 1, videopolysomnography showed that 19 (79%) patients, but no healthy participants, had disrupted sleep structure (p=0·013); 15 (63%) patients and four (22%) healthy participants had excessive fragmentary myoclonus (p=0·039), and nine (38%) patients, but no healthy participants, had myokymic discharges (p=0·0051). These clinical and videopolysomnographic features led to additional immunotherapy in 15 (63%) of 24 patients, which resulted in improvement of these features in all 15 individuals. However, at visit 3, 13 (65%) of 20 patients continued to have cognitive deficits. Persistent cognitive deficits at visit 3 were associated with no use of rituximab before visit 1 (odds ratio [OR] 4·0, 95% CI 1·5-10·7; p=0·0015), REM sleep without atonia at visit 1 (2·2, 1·2-4·2; p=0·043), and presence of LGI1 antibodies in serum at visit 1 (11·0, 1·1-106·4; p=0·038)., Interpretation: Unsuspected but ongoing clinical and videopolysomnography alterations are common in patients with anti-LGI1 encephalitis during the first year or more after initial immunotherapy. Recognising these alterations is important as they are treatable, can be used as outcome measures in clinical trials, and might influence cognitive outcome., Funding: Fundació La Caixa., Competing Interests: Declaration of interests JD has patents for the use of Ma2, N-methyl-D-aspartate receptors, GABA(B) receptors, GABA(A) receptors, dipeptidyl-peptidase-like protein-6, and IgLON5 as autoantibody tests. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

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.)

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.)

Anti-IgLON5 disease is a rare neurological, probably autoimmune, disorder associated in many cases with a specific tauopathy. Only a few post-mortem neuropathological studies have been reported so far. Little is known about the pathogenic mechanisms that result in neurodegeneration. We investigated the neuropathology of anti-IgLON5 disease and characterized cellular and humoral inflammation. We included nine cases (six of them previously published). Median age of patients was 71 years (53-82 years), the median disease duration was 6 years (0.5-13 years), and the female to male ratio was 5:4. Six cases with a median disease duration of 9 years presented a prominent tauopathy. Five of them had a classical anti-IgLON5-related brainstem tauopathy and another presented a prominent neuronal and glial 4-repeat tauopathy, consistent with progressive supranuclear palsy (PSP). Three cases with short disease duration (median 1.25 years) only showed a primary age-related neurofibrillary pathology. Inflammatory infiltrates of T and B cells were mild to moderate and did not significantly differ between anti-IgLON5 disease cases with or without tauopathy. In contrast, we found an extensive neuropil deposition of IgG4 in the tegmentum of the brainstem, olivary nucleus, and cerebellar cortex that was most prominent in two patients with short disease duration without the typical IgLON5-related tauopathy. The IgG4 deposits were particularly prominent in the cerebellar cortex and in these regions accompanied by mild IgG1 deposits. Activated complement deposition (C9neo) was absent. Our study indicates that IgLON5-related tau pathology occurs in later disease stages and may also present a PSP-phenotype with exclusively 4-repeat neuronal and glial tau pathology. The prominent deposition of anti-IgLON5 IgG4 at predilection sites for tau pathology suggests that anti-IgLON5 antibodies precede the tau pathology. Early start of immunotherapy might prevent irreversible neuronal damage and progression of the disease, at least in a subgroup of patients., (© 2023. The Author(s).)

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.)

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.)

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.)

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 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.)