Biofluid Detection of Pathological α-Synuclein in the Prodromal Phase of Synucleinopathies.

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.

Developing disease-modifying interventions in idiopathic REM sleep behavior disorder and early synucleinopathy.

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.

Sleep and sleep disorders in people with Parkinson's disease.

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.

REM sleep behavior disorder in Brunner syndrome.

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 REM sleep behavior disorder (RBD) 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 suffered from 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 RBD 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 RBD symptomatology. We conclude that RBD can be a manifestation of Brunner syndrome probably due to an increased monoaminergic neurotransmission occurring in this rare genetic disorder.

REM sleep and neurodegeneration.

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.

Upper airway manifestations of anti-IgLON5 disease: Otorhinolaryngological point of view.

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.

HLA-DQB1*05 subtypes and not DRB1*10:01 mediates risk in anti-IgLON5 disease.

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.

Development of a Composite Score for the Clinical Assessment of Anti-IgLON5 Disease.

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.

Microglial Activation and Progression of Nigrostriatal Dysfunction in Isolated REM Sleep Behavior Disorder.

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 Ki changes from baseline were evaluated with volumes-of-interest and voxel-based analyses. RESULTS: Significant 18 F-DOPA Ki 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 Ki 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.

Mitochondrial DNA deletions in the cerebrospinal fluid of patients with idiopathic REM sleep behaviour disorder.

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".

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

OBJECTIVE: To apply a machine learning analysis to clinical and presynaptic dopaminergic imaging data of patients with rapid eye movement (REM) sleep behavior disorder (RBD) to predict the development of Parkinson disease (PD) and dementia with Lewy bodies (DLB). METHODS: In this multicenter study of the International RBD study group, 173 patients (mean age 70.5 ± 6.3 years, 70.5% males) with polysomnography-confirmed RBD who eventually phenoconverted to overt alpha-synucleinopathy (RBD due to synucleinopathy) were enrolled, and underwent baseline presynaptic dopaminergic imaging and clinical assessment, including motor, cognitive, olfaction, and constipation evaluation. For comparison, 232 RBD non-phenoconvertor patients (67.6 ± 7.1 years, 78.4% males) and 160 controls (68.2 ± 7.2 years, 53.1% males) were enrolled. Imaging and clinical features were analyzed by machine learning to determine predictors of phenoconversion. RESULTS: Machine learning analysis showed that clinical data alone poorly predicted phenoconversion. Presynaptic dopaminergic imaging significantly improved the prediction, especially in combination with clinical data, with 77% sensitivity and 85% specificity in differentiating RBD due to synucleinopathy from non phenoconverted RBD patients, and 85% sensitivity and 86% specificity in discriminating PD-converters from DLB-converters. Quantification of presynaptic dopaminergic imaging showed that an empirical z-score cutoff of -1.0 at the most affected hemisphere putamen characterized RBD due to synucleinopathy patients, while a cutoff of -1.0 at the most affected hemisphere putamen/caudate ratio characterized PD-converters. INTERPRETATION: Clinical data alone poorly predicted phenoconversion in RBD due to synucleinopathy patients. Conversely, presynaptic dopaminergic imaging allows a good prediction of forthcoming phenoconversion diagnosis. This finding may be used in designing future disease-modifying trials. ANN NEUROL 2024;95:1178-1192.

Cortical Macro- and Microstructural Changes in Parkinson's Disease with Probable Rapid Eye Movement Sleep Behavior Disorder.

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.

Role of sleep in neurodegeneration: the consensus report of the 5th Think Tank World Sleep Forum.

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-ß (Aß) concentrations in the interstitial fluid of experimental animal models and in cerebrospinal fluid in humans, while increased sleep decreases Aß. 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.

Progression of brain cholinergic dysfunction in patients with isolated rapid eye movement sleep behavior disorder.

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.

Memory performance mediates subjective sleep quality associations with cerebrospinal fluid Alzheimer's disease biomarker levels and hippocampal volume among individuals with mild cognitive symptoms.

Sleep disturbances are prevalent in Alzheimer's disease (AD), affecting individuals during its early stages. We investigated associations between subjective sleep measures and cerebrospinal fluid (CSF) biomarkers of AD in adults with mild cognitive symptoms from the European Prevention of Alzheimer's Dementia Longitudinal Cohort Study, considering the influence of memory performance. A total of 442 participants aged >50 years with a Clinical Dementia Rating (CDR) score of 0.5 completed the Pittsburgh Sleep Quality Index questionnaire and underwent neuropsychological assessment, magnetic resonance imaging acquisition, and CSF sampling. We analysed the relationship of sleep quality with CSF AD biomarkers and cognitive performance in separated multivariate linear regression models, adjusting for covariates. Poorer cross-sectional sleep quality was associated with lower CSF levels of phosphorylated tau and total tau alongside better immediate and delayed memory performance. After adjustment for delayed memory scores, associations between CSF biomarkers and sleep quality became non-significant, and further analysis revealed that memory performance mediated this relationship. In post hoc analyses, poorer subjective sleep quality was associated with lesser hippocampal atrophy, with memory performance also mediating this association. In conclusion, worse subjective sleep quality is associated with less altered AD biomarkers in adults with mild cognitive symptoms (CDR score 0.5). These results could be explained by a systematic recall bias affecting subjective sleep assessment in individuals with incipient memory impairment. Caution should therefore be exercised when interpreting subjective sleep quality measures in memory-impaired populations, emphasising the importance of complementing subjective measures with objective assessments.

Is REM Sleep Behavior Disorder Changing? Secular Changes Versus Referral Patterns.

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.

Sleep Disturbances in Autoimmune Neurological Diseases.

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.

Prior exposure to concussions in patients with isolated REM sleep behavior disorder.

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.