mRNA expression profiling of mitochondrial subunits in subjects with Parkinson's disease.

Introduction: Parkinson's disease (PD) is a common adult-onset neurodegenerative disorder caused by a progressive loss of dopaminergic neurons due to the accumulation of α-synuclein in the substantia nigra. Mitochondria are known to play a key role in cell respiratory function and bioenergetics. Indeed, mitochondrial dysfunction causes insufficient energy production required to satisfy the needs of several organs, especially the nervous system. However, the profiling of messenger RNA (mRNA) expression of mitochondrial subunits in PD has not been systematically investigated yet. Material and methods: We explored the mRNA expression of mitochondrial DNA (mtDNA) encoded respiratory chain (RC) subunits in 43 PD patients and 43 normal controls (NC). Next generation sequencing analysis (NGS) was used and quantitative real-time polymerase chain reaction (qRT-PCR) assay was used for confirmation of the NGS results. Results: All tested mitochondrial RC subunits were significantly over-expressed in subjects with PD compared to NC. In qRT-PCR the mean expression of all mitochondrial subunits had an expression level of at least 7 times compared to NC. Conclusions: The over-expression of mitochondrial subunits in PD subjects with respect to NC might be secondary to a degeneration-related alteration of the mitochondrial structure and/or dynamics, or to the occurrence of a compensatory mechanism. The study of specific mRNA by peripheral blood mononuclear cells may provide a further diagnostic frame for early detection PD patients.

Repetitive transcranial magnetic stimulation in primary sleep disorders.

Repetitive transcranial magnetic stimulation (rTMS) is a widely used non-invasive neuromodulatory technique. When applied in sleep medicine, the main hypothesis explaining its effects concerns the modulation of synaptic plasticity and the strength of connections between the brain areas involved in sleep disorders. Recently, there has been a significant increase in the publication of rTMS studies in primary sleep disorders. A multi-database-based search converges on the evidence that rTMS is safe and feasible in chronic insomnia, obstructive sleep apnea syndrome (OSAS), restless legs syndrome (RLS), and sleep deprivation-related cognitive deficits, whereas limited or no data are available for narcolepsy, sleep bruxism, and REM sleep behavior disorder. Regarding efficacy, the stimulation of the dorsolateral prefrontal cortex bilaterally, right parietal cortex, and dominant primary motor cortex (M1) in insomnia, as well as the stimulation of M1 leg area bilaterally, left primary somatosensory cortex, and left M1 in RLS reduced subjective symptoms and severity scale scores, with effects lasting for up to weeks; conversely, no relevant effect was observed in OSAS and narcolepsy. Nevertheless, several limitations especially regarding the stimulation protocols need to be considered. This review should be viewed as a step towards the further contribution of individually tailored neuromodulatory techniques for sleep disorders.

Reduced Intracortical Facilitation to TMS in Both Isolated REM Sleep Behavior Disorder (RBD) and Early Parkinson's Disease with RBD.

BACKGROUND: a reduced intracortical facilitation (ICF), a transcranial magnetic stimulation (TMS) measure largely mediated by glutamatergic neurotransmission, was observed in subjects affected by isolated REM sleep behavior disorder (iRBD). However, direct comparison between iRBD and Parkinson's disease (PD) with RBD is currently lacking. METHODS: resting motor threshold, contralateral cortical silent period, amplitude and latency of motor evoked potentials, short-interval intracortical inhibition, and intracortical facilitation (ICF) were recorded from 15 drug-naïve iRBD patients, 15 drug-naïve PD with RBD patients, and 15 healthy participants from the right First Dorsal Interosseous muscle. REM sleep atonia index (RAI), Mini Mental State Examination (MMSE), Geriatric Depression Scale (GDS), and Epworth Sleepiness Scale (ESS) were assessed. RESULTS: Groups were similar for sex, age, education, and patients for RBD duration and RAI. Neurological examination, MMSE, ESS, and GDS were normal in iRBD patients and controls; ESS scored worse in PD patients, but with no difference between groups at post hoc analysis. Compared to controls, both patient groups exhibited a significantly decreased ICF, without difference between them. CONCLUSIONS: iRBD and PD with RBD shared a reduced ICF, thus suggesting the involvement of glutamatergic transmission both in subjects at risk for degeneration and in those with an overt α-synucleinopathy.

Post-stroke aphasia at the time of COVID-19 pandemic: a telerehabilitation perspective.

We report on our remote speech therapy experience in post-stroke aphasia. The aim was to test the feasibility and utility of telerehabilitation to support future randomized controlled trials. Post-stroke aphasia is a common and disabling speech disorder, which significantly affects patients' and caregivers' health and quality of life. Due to COVID-19 pandemic, most of the conventional speech therapy approaches had to stop or "switch" into telerehabilitation procedures to ensure the safety of patients and operators but, concomitantly, the best rehabilitation level possible. Here, we planned a 5-month telespeech therapy programme, twice per week, of a patient with non-fluent aphasia following an intracerebral haemorrhage. Overall, treatment adherence based on the operator's assessments was high, and incomplete adherence for technical problems occurred very rarely. In line with the patient's feedback, acceptability was also positive, since he was constantly motivated during the sessions and the exercises performed autonomously, as confirmed by the speech therapist and caregiver, respectively. Moreover, despite the sequelae from the cerebrovascular event, evident in some writing tests due to the motor deficits in his right arm and the disadvantages typical of all telepractices, more relevant results were achieved during the telerehabilitation period compared to those of the "face-to-face" therapy before the COVID-19 outbreak. The telespeech therapy performed can be considered successful and the patient was able to return to work. Concluding, we support it as a feasible approach offering patients and their families the opportunity to continue the speech and language rehabilitation pathway, even at the time of pandemic.

A Transcriptome Analysis of mRNAs and Long Non-Coding RNAs in Patients with Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative disorder. The number of cases of PD is expected to double by 2030, representing a heavy burden on the healthcare system. Clinical symptoms include the progressive loss of dopaminergic neurons in the substantia nigra of the midbrain, which leads to striatal dopamine deficiency and, subsequently, causes motor dysfunction. Certainly, the study of the transcriptome of the various RNAs plays a crucial role in the study of this neurodegenerative disease. In fact, the aim of this study was to evaluate the transcriptome in a cohort of subjects with PD compared with a control cohort. In particular we focused on mRNAs and long non-coding RNAs (lncRNA), using the Illumina NextSeq 550 DX System. Differential expression analysis revealed 716 transcripts with padj ≤ 0.05; among these, 630 were mRNA (coding protein), lncRNA, and MT_tRNA. Ingenuity pathway analysis (IPA, Qiagen) was used to perform the functional and pathway analysis. The highest statistically significant pathways were: IL-15 signaling, B cell receptor signaling, systemic lupus erythematosus in B cell signaling pathway, communication between innate and adaptive immune cells, and melatonin degradation II. Our findings further reinforce the important roles of mitochondria and lncRNA in PD and, in parallel, further support the concept of inverse comorbidity between PD and some cancers.

Role and Dysregulation of miRNA in Patients with Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative synucleinopathy that has a not yet fully understood molecular pathomechanism behind it. The role of risk genes regulated by small non-coding RNAs, or microRNAs (miRNAs), has also been highlighted in PD, where they may influence disease progression and comorbidities. In this case-control study, we analyzed miRNAs on peripheral blood mononuclear cells by means of RNA-seq in 30 participants, with the aim of identifying miRNAs differentially expressed in PD compared to age-matched healthy controls. Additionally, we investigated the pathways influenced by differentially expressed miRNAs and assessed whether a specific pathway could potentially be associated with PD susceptibility (enrichment analyses performed using the Ingenuity Pathway Analysis tools). Overall, considering that the upregulation of miRNAs might be related with the downregulation of their messenger RNA targets, and vice versa, we found several putative targets of dysregulated miRNAs (i.e., upregulated: hsa-miR-1275, hsa-miR-23a-5p, hsa-miR-432-5p, hsa-miR-4433b-3p, and hsa-miR-4443; downregulated: hsa-miR-142-5p, hsa-miR-143-3p, hsa-miR-374a-3p, hsa-miR-542-3p, and hsa-miR-99a-5p). An inverse connection between cancer and neurodegeneration, called "inverse comorbidity", has also been noted, showing that some genes or miRNAs may be expressed oppositely in neurodegenerative disorders and in some cancers. Therefore, it may be reasonable to consider these miRNAs as potential diagnostic markers and outcome measures.

Increased Serum Prolactin and Excessive Daytime Sleepiness: An Attempt of Proof-of-Concept Study.

The objectives of this study were: (1) to identify subjects with hyperprolactinemia in a clinical sample of patients; (2) to compare the neurologic, psychiatric, and sleep conditions found in patients subgrouped by excessive daytime sleepiness (EDS) and hyperprolactinemia; and (3) to identify patients with hyperprolactinemia and EDS not supported by the presence of any other neurologic, psychiatric, or sleep disorder, or substance/medication use. A retrospective chart review of inpatients was carried out in order to identify all patients in whom the prolactin (PRL) serum levels were determined. A total of 130 subjects were retrieved: 55 had increased levels of PRL, while the remaining 75 participants had normal PRL levels. EDS was reported by 32 (58.2%) participants with increased PRL and 34 (45.3%) with normal PRL. Obstructive sleep apnea or other sleep or neurologic/psychiatric conditions could explain EDS in all participants with normal PRL. Among subjects with increased PRL, eight had no other neurologic/psychiatric or sleep disorder (or drug) potentially causing EDS; these participants, at polysomnography, had time in bed, sleep period time, and total sleep time longer than those with EDS associated to another condition. These findings can be considered as a preliminary indication of a role of hyperprolactinemia in EDS and represent a basis for future controlled studies able to test this hypothesis in a reliable, objective, and methodologically more appropriate way.

Cognitive Impairment in Inpatients with Prurigo Nodularis and Psychiatric Comorbidities.

BACKGROUND: Prurigo nodularis (PN) is a chronic refractory itchy dermatosis. Although psychiatric comorbidity is known, research in cognitive impairment is lacking. We evaluated the occurrence and types of cognitive impairment in a series of inpatients with PN. METHODS: This was a retrospective chart review of all the patients with PN admitted to a referral neurological institute from September 2018 to March 2021. Any neurological and psychiatric disorder, along with neuroactive drugs taken, were concomitantly assessed. RESULTS: A total of 16 patients with PN (median age: 70 years, two males) were selected from a total of 1806 hospital admissions. Most of them had a neurodegenerative cognitive disorder, from mild cognitive impairment (8) to Alzheimer's disease (1), followed by mixed disorder (degenerative and vascular) in six and vascular dementia in one. Comorbid psychiatric diseases (anxiety and depression) were more common than either individual condition, followed by bipolar disorder, whereas two patients did not show psychiatric manifestations. Most patients were on combined treatment with benzodiazepines and antidepressants. CONCLUSION: Cognitive impairment can be observed in PN. In addition to screening for psychiatric comorbidity and initiating appropriate treatment or referral, clinicians may also consider the presence of cognitive impairment in PN of both degenerative and vascular origin.

Searching for Novel Candidate Biomarkers of RLS in Blood by Proteomic Analysis.

PURPOSE: We performed comparative proteomic analyses of blood of patients with RLS and healthy individuals aiming to identify potential biomarker and therapeutic target candidate for RLS. PATIENTS AND METHODS: Blood serum samples from 12 patients with a clinical diagnosis of RLS (8 females and 4 males, with a mean age of 68.52 years) and 10 healthy controls (5 females and 5 males, with a mean age of 67.61 years) underwent proteomic profiling by liquid chromatography coupled with tandem mass spectrometry. Pathway analysis incorporating protein-protein interaction networks was carried out to identify pathological processes linked to the differentially expressed proteins. RESULTS: We quantified 272 proteins in patients with RLS and healthy controls, of which 243 were shared. Five proteins - apolipoprotein C-II, leucine-rich alpha-2-glycoprotein 1, FLJ92374, extracellular matrix protein 1, and FLJ93143 - were substantially increased in RLS patients, whereas nine proteins - vitamin D-binding protein, FLJ78071, alpha-1-antitrypsin, CD5 antigen-like, haptoglobin, fibrinogen alpha chain, complement factor H-related protein 1, platelet factor 4, and plasma protease C1 inhibitor - were decreased. Bioinformatics analyses revealed that these proteins were linked to 1) inflammatory and immune response, and complement activation, 2) brain-related development, cell aging, and memory disorders, 3) pregnancy and associated complications, 4) myocardial infarction, and 5) reactive oxygen species generation and subsequent diabetes mellitus. CONCLUSION: Our findings shed light on the multifactorial nature of RLS and identified a set of circulating proteins that may have clinical importance as biomarkers and therapeutic targets.

Narcolepsy type 1 features across the life span: age impact on clinical and polysomnographic phenotype.

STUDY OBJECTIVES: Narcolepsy type 1 (NT1) is a chronic neurological disorder typically arising during adolescence and young adulthood. Recent studies demonstrated that NT1 presents with age-specific features, especially in children. With this study we aimed to describe and to compare the clinical pictures of NT1 in different age groups. METHODS: In this cross-sectional, multicenter study, 106 untreated patients with NT1 enrolled at the time of diagnosis underwent clinical evaluation, a semistructured interview (including the Epworth Sleepiness Scale), nocturnal video-polysomnography, and the Multiple Sleep Latency Test. Patients were enrolled in order to establish 5 age-balanced groups (childhood, adolescence, adulthood, middle age, and senior). RESULTS: The Epworth Sleepiness Scale score showed a significant increase with age, while self-reported diurnal total sleep time was lower in older and young adults, with the latter also complaining of automatic behaviors in more than 90% of patients. Children reported the cataplexy attacks to be more frequent (> 1/d in 95% of patients). "Recalling an emotional event," "meeting someone unexpectedly," "stress," and "anger" were more frequently reported in adult and older adult patients as possible triggers of cataplexy. Neurophysiological data showed a higher number of sleep-onset rapid eye movement periods on the Multiple Sleep Latency Test in adolescent compared to senior patients and an age-progressive decline in sleep efficiency. CONCLUSIONS: Daytime sleepiness, cataplexy features and triggers, and nocturnal sleep structure showed age-related difference in patients with NT1; this variability may contribute to diagnostic delay and misdiagnosis.

Uncharacterized RNAs in Plasma of Alzheimer's Patients Are Associated with Cognitive Impairment and Show a Potential Diagnostic Power.

Alzheimer's disease (AD) diagnosis is actually based on clinical evaluation and brain-imaging tests, and it can often be confirmed only post-mortem. Therefore, new non-invasive molecular biomarkers are necessary to improve AD diagnosis. As circulating microRNA biomarkers have been proposed for many diseases, including AD, we aimed to identify new diagnostic non-small RNAs in AD. Whole transcriptome analysis was performed on plasma samples of five AD and five unaffected individuals (CTRL) using the Clariom D Pico Assay, followed by validation in real-time PCR on 37 AD patients and 37 CTRL. Six differentially expressed (DE) transcripts were identified: GS1-304P7.3 (upregulated), NONHSAT090268, TC0100011037, TC0400008478, TC1400008125, and UBE2V1 (downregulated). Peripheral blood mononuclear cells (PBMCs) may influence the expression of circulating RNAs and their analysis has been proposed to improve AD clinical management. Accordingly, DE transcript expression was also evaluated in PBMCs, showing no difference between AD and CTRL. ROC (receiver operating characteristic) curve analysis was performed to evaluate the diagnostic accuracy of each DE transcript and a signature including all of them. A correlation between cognitive impairment and GS1-304P7.3, NONHSAT090268, TC0100011037, and TC0400008478 was detected, suggesting a potential association between their extracellular abundance and AD clinical phenotype. Finally, this study identified six transcripts showing altered expression in the plasma of AD patients. Given the need for new, accurate blood biomarkers for AD diagnosis, these transcripts may be considered for further analyses in larger cohorts, also in combination with other biomarkers, aiming to identify specific RNA-based biomarkers to be eventually applied to clinical practice.

A Customized Next-Generation Sequencing-Based Panel to Identify Novel Genetic Variants in Dementing Disorders: A Pilot Study.

Purpose: The advancements in the next-generation sequencing (NGS) techniques have allowed for rapid, efficient, and cost-time-effective genetic variant detection. However, in both clinical practice and research setting, sequencing is still often limited to the use of gene panels clinically targeted on the genes underlying the disease of interest. Methods: We performed a neurogenetic study through an ad hoc NGS-based custom sequencing gene panel in order to screen 16 genes in 8 patients with different types of degenerative cognitive disorders (Alzheimer's disease, mild cognitive impairment, frontotemporal dementia, and dementia associated with Parkinson's disease). The study protocol was based on previous evidence showing a high sensitivity and specificity of the technique even when the panel is limited to some hotspot exons. Results: We found variants of the TREM2 and APP genes in three patients; these have been previously identified as pathogenic or likely pathogenic and, therefore, considered "disease causing." In the remaining subjects, the pathogenicity was evaluated according to the guidelines of the American College of Medical Genetics (ACMG). In one patient, the p.R205W variant in the CHMP2B gene was found to be likely pathogenic of the disease. A variant in the CSF1R and SERPINI1 genes found in two patients was classified as benign, whereas the other two (in the GRN and APP genes) were classified as likely pathogenic according to the ACMG. Conclusions: Notwithstanding the preliminary value of this study, some rare genetic variants with a probable disease association were detected. Although future application of NGS-based sensors and further replication of these experimental data are needed, this approach seems to offer promising translational perspectives in the diagnosis and management of a wide range of neurodegenerative disorders.

Peculiar lifespan changes of periodic leg movements during sleep in restless legs syndrome.

The objective of this observational cohort study was to analyse the age-related changes of periodic leg movements during sleep using the newest international scoring rules, to expand past analyses, including patients in the paediatric age range, and also to analyse the changes of short-interval and isolated leg movements during sleep throughout the lifespan. One hundred and sixty-five patients (84 women) with restless legs syndrome were recruited in the following age groups: 16 preschoolers (≤5 years of age), 29 school-age children (6-12 years), 19 adolescents (13-17 years), 17 young adults (19-40 years), 47 adults (41-60 years) and 37 seniors (>60 years). Total, periodic, short-interval and isolated leg movements during sleep and periodicity indexes were obtained by polysomnography. The total index showed (quartic polynomial interpolation) a decrease before 10 years, followed by a steady increase up to 30 years, a relatively stable period until 60 years, and a final increase up to 80 years. This course was almost entirely due to changes in periodic movements. Isolated movements did not change significantly and short-interval movements showed only an increase in seniors. Our study indicates that, in restless legs syndrome, the total index shows a peculiar and unique course throughout the lifespan, mainly due to periodic movements. These age-related changes may mirror developmental changes in network complexity known to occur in dopaminergic circuits. These data further confirm the need to better assess the periodicity of leg movements in sleep during the human development period, in order to obtain clinically useful information.

Facilitatory/inhibitory intracortical imbalance in REM sleep behavior disorder: early electrophysiological marker of neurodegeneration?

STUDY OBJECTIVES: Previous studies found an early impairment of the short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) to transcranial magnetic stimulation (TMS) in Parkinson's disease. However, very little is known on the TMS correlates of rapid eye movement (REM) sleep behavior disorder (RBD), which can precede the onset of a α-synucleinopathy. METHODS: The following TMS measures were obtained from 14 de novo patients with isolated RBD and 14 age-matched healthy controls: resting motor threshold, cortical silent period, latency and amplitude of the motor evoked potentials, SICI, and ICF. A cognitive screening and a quantification of subjective sleepiness (Epworth Sleepiness Scale [ESS]) and depressive symptoms were also performed. RESULTS: Neurological examination, global cognitive functioning, and mood status were normal in all participants. ESS score was higher in patients, although not suggestive of diurnal sleepiness. Compared to controls, patients exhibited a significant decrease of ICF (median 0.8, range 0.5-1.4 vs. 1.9, range 1.4-2.3; p < 0.01) and a clear trend, though not significant, towards a reduction of SICI (median 0.55, range 0.1-1.4 vs. 0.25, range 0.1-0.3), with a large effect size (Cohen's d: -0.848). REM Sleep Atonia Index significantly correlated with SICI. CONCLUSIONS: In still asymptomatic patients for a parkinsonian syndrome or neurodegenerative disorder, changes of ICF and, to a lesser extent, SICI (which are largely mediated by glutamatergic and GABAergic transmission, respectively) might precede the onset of a future neurodegeneration. SICI was correlated with the muscle tone alteration, possibly supporting the proposed RBD model of retrograde influence on the cortex from the brainstem.

Dietary Inflammatory Index and Sleep Quality in Southern Italian Adults.

BACKGROUND: Current evidence supports the central role of a subclinical, low-grade inflammation in a number of chronic illnesses and mental disorders; however, studies on sleep quality are scarce. The aim of this study was to test the association between the inflammatory potential of the diet and sleep quality in a cohort of Italian adults. METHODS: A cross-sectional analysis of baseline data of the Mediterranean healthy Eating, Aging, and Lifestyle (MEAL) study was conducted on 1936 individuals recruited in the urban area of Catania during 2014-2015 through random sampling. A food frequency questionnaire and other validated instruments were used to calculate the dietary inflammatory index (DII®) and assess sleep quality (Pittsburg sleep quality index). Multivariable logistic regression analyses were performed to determine the association between exposure and outcome. RESULTS: Individuals in the highest quartile of the DII were less likely to have adequate sleep quality (odds ratio (OR) = 0.49, 95% CI: 0.31, 0.78). Among individual domains of sleep quality, an association with the highest exposure category was found only for sleep latency (OR = 0.60, 95% CI: 0.39, 0.93). CONCLUSIONS: The inflammatory potential of the diet appears to be associated with sleep quality in adults. Interventions to improve diet quality might consider including a dietary component that aims to lower chronic systemic inflammation to prevent cognitive decline and improve sleep quality.

Adherence to the Mediterranean Diet is Associated with Better Sleep Quality in Italian Adults.

BACKGROUND: Sleep quality has been associated with human health and diseases, including cognitive decline and dementia; however major determinants of sleep disorders are largely unknown. The aim of this study was to evaluate the association between sleep quality and adherence to the Mediterranean dietary pattern in a sample of Italian adults. METHODS: A total of 1936 individuals were recruited in the urban area of Catania during 2014-2015 through random sampling. A food frequency questionnaire and validated instruments were used to assess the adherence to the Mediterranean diet and sleep quality (Pittsburg sleep quality index). Multivariate logistic regressions were performed to determine the association between exposure and outcome. RESULTS: A total of 1314 individuals (67.9% of the cohort) reported adequate sleep quality: for each point increase of the Mediterranean diet score, individuals were 10% more likely to have adequate sleep quality. In an additional analysis stratifying the sample by weight status, the association between sleep quality and high adherence to the Mediterranean diet was observed only among normal/overweight individuals but not in obese participants. CONCLUSIONS: high adherence to a Mediterranean diet is associated with better sleep quality either toward direct effect on health or indirect effects through improvement of weight status.

Interpreting Genetic Variants: Hints from a Family Cluster of Parkinson's Disease.

Technological innovation related to the advent and development of the Next-Generation Sequencing (NGS) has provided significant advances in the diagnosis of disorders with genetic and phenotypic variability, such as neurodegenerative diseases. However, the interpretation of NGS data often remains challenging, although advanced prediction tools have contributed to primarily assess the impact of some missense variants. Here, we report a patient with Parkinson's disease (PD) and a family history of disease, in which a panel of 29 disease-causing or risk genes for PD were analyzed. We identified a new missense variant in the SNCA gene. Although this variant might be associated with PD in this family, it has been currently classified as a "Variant of Unknown Significance" because of the lack of segregation with disease. Indeed, we subsequently found the same mutation in an unaffected sister. Nevertheless, this finding may help clinicians and researchers in questioning the causative role of genetic variants within the daily clinical and diagnostic settings.

Novel biomarker signatures for idiopathic REM sleep behavior disorder: A proteomic and system biology approach.

OBJECTIVE: To perform a rigorous in-depth proteomics analysis to identify circulating biomarker signatures for idiopathic REM sleep behavior disorder (RBD), capable of providing new insights into the underlying pathogenic mechanisms and putative α-synuclein-related neurodegenerative processes. METHODS: Serum samples from patients with idiopathic RBD (n = 9) and healthy controls (n = 10) were subjected to a thorough liquid chromatography-mass spectrometry (MS)/MS proteomics analysis using ultimate 3,000 nanoLC interfaced to an ESI-orbitrap velos. Data were analyzed with a systems biology approach to identify altered pathways in RBD. RESULTS: We identified 259 proteins, 11 of which displayed significantly altered expression level in patients with RBD as compared to controls. Significant reduction in serum levels of dopamine ß-hydroxylase (DBH) and vitamin D binding protein (GC) were consistent with alterations in the norepinephrinergic (NErgic) and dopaminergic systems, respectively. Additional altered protein profiles indicated that immunity, inflammation, complement, and coagulation also play a role in RBD pathophysiology. CONCLUSIONS: Our results shed light on the protein signature profile, molecular pathways, and mechanisms involved in the pathogenesis of RBD and its clinical manifestation. This knowledge opens a new avenue towards more accurate and timely diagnosis and characterization of RBD, which might ultimately translate into new therapeutic strategies with disease-modifying effects. Further evaluation of the identified markers is required to confirm their diagnostic value and potential to guide clinical decision-making.

REM sleep without atonia with REM sleep-related motor events: broadening the spectrum of REM sleep behavior disorder.

Study Objectives: To assess the presence of increased REM-related motor activity during sleep, by questionnaires for REM sleep behavior disorder (RBD), in participants with "isolated" REM sleep without atonia (RWA). Participants and Methods: Two hundred forty-nine patients were consecutively enrolled, with age ≥18 years, sharing bedroom with a roommate, and without a severe health, neurological, or cognitive problem. Motor activity during sleep was assessed by means of the RBD Screening Questionnaire (RBDSQ) and the RBD questionnaire-Hong Kong (RBDQ-HK). A video-polysomnographic recording was obtained and the REM Atonia Index was computed. Thirteen participants were diagnosed to have RBD while the remaining 236 were subdivided into two subgroups: 34 participants with "low" (<0.8) and 202 participants with "high" Atonia Index (≥0.8). Results: RBDSQ and RBDQ-HK were both higher in participants with low Atonia Index than in those with high Atonia Index, as well as number of drugs taken and number of comorbidities. No effect of antidepressant use was found on Atonia Index and a multiple-regression analysis showed that Atonia Index was significantly (inversely) correlated only with the behavioral score obtained with the RBDQ-HK. Conclusions: Our study shows that individuals with isolated RWA have an increased motor activity/behavioral pattern during sleep, although this activity does not allow us to diagnose RBD. Our findings broaden the spectrum of RBD and the condition that we have identified should be better characterized in order to understand its eventual development into fully blown RBD or not.