Continuous positive airway pressure treatment improves bone mineral density in men affected by severe obstructive sleep apnea syndrome.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) and low bone mineral density (BMD) are 2 prevalent conditions with a significant negative impact on patients' well-being and quality of life. Recent research has shown low BMD at different bone sites in male patients with OSA. Although the efficacy of continuous positive airway pressure (CPAP) treatment for OSA has been widely demonstrated, the evidence for understanding its impact on BMD and other bone-related outcomes is insufficient. The aim of this observational study was to investigate the effect of 12 months of CPAP treatment on lumbar and femur BMD and bone-related serum biomarkers in male patients with severe OSA. METHODS: Sixty patients (mean age: 55.1 ± 9.9 years) were consecutively included and underwent BMD measurement with dual-energy x-ray absorptiometry at baseline and after 12 months of CPAP treatment. Vitamin D, parathyroid hormone, and calcium serum levels were examined at the same time points. RESULTS: A significant increase in BMD in the L1 (P < .001, d = 0.27) and L2 (P < .001, d = 0.26) vertebrae was observed after CPAP treatment, along with an increase in vitamin D (P < .001, d = 0.71) and calcium (P < .001, d = 0.73) levels and a decrease in parathyroid hormone levels (P < .001, d = 0.60). The increase in BMD in L1 was significantly correlated with the decrease in parathyroid hormone serum levels (r = -.50, P < .001). CONCLUSIONS: Overall, these findings showed that beneficial OSA treatment might restore bone health and support CPAP treatment as a feasible strategy to improve BMD in male patients with severe OSA. Accordingly, diagnosing and targeting OSA may be warranted in the treatment of male patients with undetermined osteopenia and osteoporosis. CITATION: Carpi M, Cordella A, Placidi F, et al. Continuous positive airway pressure treatment improves bone mineral density in men affected by severe obstructive sleep apnea syndrome. J Clin Sleep Med. 2024;20(1):67-73.

Cerebrospinal-fluid biomarkers for predicting phenoconversion in patients with isolated rapid-eye movement sleep behavior disorder.

STUDY OBJECTIVES: Patients with isolated rapid-eye-movement sleep behavior disorder (iRBD) have an increased risk of developing neurodegenerative diseases. This study assessed cerebrospinal-fluid (CSF) biomarkers of neurodegeneration and blood-brain barrier (BBB) alteration in patients with iRBD compared to controls and ascertain whether these biomarkers may predict phenoconversion to alpha-synucleinopathies (Parkinson's Disease (PD), Dementia with Lewy bodies (DLB), Multiple System Atrophy (MSA)). METHODS: Patients and controls underwent between 2012 and 2016 a neurological assessment, a lumbar puncture for CSF biomarker analysis (ß-amyloid42 - Aß42; total-tau, and phosphorylated tau), and BBB alteration (CSF/serum albumin ratio). All patients with iRBD were followed until 2021 and then classified into patients who converted to alpha-synucleinopathies (iRBD converters, cRBD) or not (iRBD non-converters, ncRBD). RESULTS: Thirty-four patients with iRBD (mean age 67.12 ±â€…8.14) and 33 controls (mean age 64.97 ±â€…8.91) were included. At follow-up (7.63 ±â€…3.40 years), eight patients were ncRBD and 33 patients were cRBD: eleven converted to PD, 10 to DLB, and two to MSA. Patients with iRBD showed lower CSF Aß42 levels and higher CSF/serum albumin ratio than controls. Cox regression analysis showed that the phenoconversion rate increases with higher motor impairment (hazard ratio [HR] = 1.23, p = 0.032). CSF Aß42 levels predicted phenoconversion to DLB (HR = 0.67, p = 0.038) and BBB alteration predicted phenoconversion to PD (HR = 1.20, p = 0.038). DISCUSSION: This study showed that low CSF Aß42 levels and high BBB alteration may predict the phenoconversion to DLB and PD in patients with iRBD, respectively. These findings highlight the possibility to discriminate phenoconversion in iRBD patients through CSF biomarkers; however, further studies are needed.

Brainstem impairment in obstructive sleep apnoea and the effect of CPAP treatment: an electrophysiological blink reflex study.

PURPOSE: This study aimed to evaluate the functionality of the brainstem structures through the blink reflex (BR) test in patients with obstructive sleep apnoea (OSA) and to assess the effects of continuous positive airway pressure (CPAP) treatment on BR responses. METHODS: Patients with moderate-severe OSA and controls underwent BR testing. Patients with OSA who were adherent to CPAP therapy repeated BR testing at 6 months follow-up. CPAP adherence was defined as CPAP use for ≥ 4 hour per night on > 5 nights per week with residual apnoea-hypopnea index less than 5 events per hour. RESULTS: A total of 22 patients with OSA (86% male, mean age 57.8 ± 10.6 years) and 20 controls (60% male, mean age 55.3 ± 9.3 years) were included. Patients with OSA showed longer right and left R1 latency, as well as delayed right ipsilateral and contralateral R2 latencies compared to controls. Patients with OSA who were compliant with CPAP treatment (n = 16; 88% men, mean age 58.8 ± 9.7 years) showed a significant decrease in latency of the right ipsilateral and contralateral R2 responses at 6 months. CONCLUSION: This study showed an abnormal pattern of BR responses in patients with OSA, consistent with a significant impairment of brainstem functionality in OSA. CPAP treatment partially improved the BR responses, suggesting the importance of treating OSA.

The Sleepiness-Depression Link in Obstructive Sleep Apnea: Preliminary Results on the Mediation of Impulsivity.

BACKGROUND: Emotional impulsivity has been found to be relevant in explaining the association between sleep problems and depressive symptoms, suggesting the potential role of impulsivity as a key underlying mechanism of this link. The objective of this study was to take a preliminary step in understanding the mediating role of impulsivity in the relation between excessive daytime sleepiness (EDS) and depression in patients with obstructive sleep apnea syndrome (OSAS) and to compare psychological and demographic characteristics between different levels of daytime sleepiness. METHODS: A total of 138 patients with OSAS underwent polygraphic cardiorespiratory monitoring and completed a series of questionnaires investigating perceived sleepiness, depression, impulsivity, and other psychological characteristics. A mediational model was tested in order to assess whether impulsivity mediated the relation between sleepiness and depressive symptoms while controlling for the effects of age, sex, BMI, and oxygen saturation parameters. RESULTS: the mediation model showed that there was a significant indirect effect of impulsivity in the sleepiness-depression link (αß = 0.084 [0.0243-0.1617]). CONCLUSIONS: The here-presented results showed that the sleepiness-depression link is not direct as previous studies asserted, but instead it may be better explained by impulsivity. Research and practical implications are discussed.

A preliminary study investigating the clinical potential of measuring cerebrospinal-fluid lactate levels in patients with narcolepsy type 1 and 2.

STUDY OBJECTIVES: Besides the quantification of orexin-A/hypocretin-1 cerebrospinal fluid (CSF) levels in narcolepsy for diagnostic purposes, several other CSF biomarkers have been evaluated, although with controversial results. Since CSF lactate concentrations fluctuate according to the sleep-wake cycle with higher levels during wakefulness and lower levels during sleep, as documented in animal model studies, the present study aimed at quantifying the CSF lactate levels in patients with narcolepsy type 1 (NT1) and 2 (NT2), which are two sleep disorders featured by excessive daytime sleepiness (EDS). METHODS: Patients with NT1 and NT2 were enrolled in this study and compared to a control group of similar age and sex. All the subjects included in the study underwent a polysomnographic study followed by lumbar puncture for the quantification of CSF lactate levels at awakening. RESULTS: 23 NT1 (43.5 % male; 36.43 ± 11.89 years) and 15 NT2 patients (46.7 % male; 37.8 ± 14.1 years) were compared to 17 controls (58.8 % male; 32.3 ± 8.4 years). CSF lactate concentrations were reduced in patients with NT1 and NT2 compared to controls but no differences were found between the two groups of patients. ROC curves analysis showed that CSF lactate ≤1.3 mmol/l had a sensitivity of 96.49 and a specificity of 82.35 % for discriminating patients with narcolepsy from controls. CONCLUSIONS: The present study showed a decrease in CSF lactate levels in patients with narcolepsy. Notably, the reduction of lactate levels was present in both NT1 and NT2 patients, independently of CSF orexin levels. Narcolepsy patients present EDS with daytime napping and REM-related episodes, possibly substantiating the CSF lactate levels reduction related to the impaired daytime wakefulness which was demonstrated in animal studies. Moreover, CSF lactate levels present a good sensitivity and adequate specificity for differentiating narcolepsy from controls. Further studies are needed to understand the role of CSF lactate and its usefulness for monitoring daytime vigilance in patients with narcolepsy.

Sleep Dysregulation Is Associated with 18F-FDG PET and Cerebrospinal Fluid Biomarkers in Alzheimer's Disease.

Background: Sleep impairment has been commonly reported in Alzheimer's disease (AD) patients. The association between sleep dysregulation and AD biomarkers has been separately explored in mild cognitive impairment (MCI) and AD patients. Objective: The present study investigated cerebrospinal-fluid (CSF) and 18F-fluoro-deoxy-glucose positron emission tomography (18F-FDG-PET) biomarkers in MCI and AD patients in order to explore their association with sleep parameters measured with polysomnography (PSG). Methods: MCI and AD patients underwent PSG, 18F-FDG-PET, and CSF analysis for detecting and correlating these biomarkers with sleep architecture. Results: Thirty-five patients were included in the study (9 MCI and 26 AD patients). 18F-FDG uptake in left Brodmann area 31 (owing to the posterior cingulate cortex) correlated negatively with REM sleep latency (p = 0.013) and positively with REM sleep (p = 0.033). 18F-FDG uptake in the hippocampus was negatively associated with sleep onset latency (p = 0.041). Higher CSF orexin levels were associated with higher sleep onset latency (p = 0.042), Non-REM stage 1 of sleep (p = 0.031), wake after sleep onset (p = 0.028), and lower sleep efficiency (p = 0.045). CSF levels of Aß42 correlated negatively with the wake bouts index (p = 0.002). CSF total-tau and phosphorylated tau levels correlated positively with total sleep time (p = 0.045) and time in bed (p = 0.031), respectively. Conclusion: Sleep impairment, namely sleep fragmentation, REM sleep dysregulation, and difficulty in initiating sleep correlates with AD biomarkers, suggesting an effect of sleep on the pathological processes in different AD stages. Targeting sleep for counteracting the AD pathological processes represents a timely need for clinicians and researchers.

Highly purified cannabidiol improves stability and postural tone in adult patients with Lennox-Gastaut syndrome: A case series.

Lennox-Gastaut syndrome (LGS) is a severe developmental epileptic encephalopathy associated with numerous neurological signs and symptoms. Altered postural tone and the need for a caregiver-assisted wheelchair are features characterizing patients with LGS. Highly purified cannabidiol (CBD) is a novel antiseizure medication (ASM) recommended for seizure treatment, in combination with clobazam, in patients with LGS. Adding CBD to the previous ASM treatment helps in reducing seizure frequency, specifically drop seizures, in patients with LGS in both clinical trials and real-world studies. However, no data about drug effects on postural tone, motor activity, gait, and stability are available. In this case series, three adult patients diagnosed with LGS were treated with CBD as an add-on. During the follow-up, a slight improvement in seizure frequency was observed. Unexpectedly, an amelioration in postural tone and stability, measured using the validated Gross Motor Function Classification System, was also detected. Our case series suggests that CBD may help in managing patients with LGS regarding seizure control and in improving other aspects of the clinical spectrum of the disease, such as postural tone and stability. The mechanisms at the basis of this improvement may be related, other than seizure reduction, to the drug's effect on the brain locomotor centers, as demonstrated in animal model studies.

The effect of lacosamide monotherapy on sleep architecture in patients with epilepsy: a preliminary evidence.

Lacosamide (LCM) is a third-generation antiseizure medication (ASM), and its effect on sleep architecture was supported by a few studies in patients with drug-resistant epilepsy in which LCM was used as an add-on treatment. To gather knowledge on ASMs effects on sleep, this study aimed at evaluating the effects of LCM monotherapy on sleep in patients with focal epilepsy. Ten patients diagnosed with epilepsy (mean age 58.00 ± 14.77, 60.0% female, mean monthly seizure frequency 1.20 ± 2.48) starting LCM as monotherapy were included. Sleep architecture was assessed through polysomnography at baseline and at the 6-month follow-up visit. A significant decrease was observed in seizure frequency (p = 0.004), being all patients seizure-free at follow-up. At baseline, eight patients had poor sleep efficiency (< 85%). Sleep efficiency increased at follow-up, with only three patients having an index < 85% (p = 0.022). From baseline to follow-up, a significant decrease was observed in sleep latency (p = 0.022) and wakefulness after sleep onset (p = 0.047). Moreover, a significant decrease was observed in the percentage of stage 1 (Md = 6.70 vs Md = 3.85, p = 0.005) and stage 3 (Md = 27.70 vs Md = 22.35, p = 0.01) of Non-REM sleep. This study suggests that LCM monotherapy may positively impact sleep architecture in patients with epilepsy. The sleep efficiency improvement and the decrease of sleep latency and wakefulness after sleep onset observed at follow-up highlight better sleep stability and continuity in patients treated with LCM. Notably, all patients were seizure-free at follow-up, and seizure freedom may also concur to sleep structure improvement.

Sleep architecture in drug-naïve adult patients with epilepsy: Comparison between focal and generalized epilepsy.

OBJECTIVE: Sleep impairment is one of the most common comorbidities affecting people with epilepsy (PWE). The bidirectional relation between epilepsy and sleep has been widely established. Several studies investigated subjective sleep quality and daytime vigilance in PWE, highlighting frequent complaints of sleep fragmentation, difficulties in falling asleep, and daytime sleepiness. The present study aimed to evaluate sleep structure in drug-naive PWE, distributed on the basis of epilepsy type, and compared with controls. METHODS: This observational study included adult patients newly diagnosed with epilepsy and drug-naive as well as a control group of healthy subjects. All PWE and controls underwent a dynamic 24-h EEG with signals for sleep recording to evaluate sleep architecture, structure, continuity, and fragmentation. RESULTS: Twenty-four PWE were included and distributed in two groups based on epilepsy type. Eleven patients were included in the generalized epilepsy group (63.6% male; 34.91 ± 9.80 years) and 13 patients in the focal epilepsy group (53.8% male; 38.69 ± 12.74 years). The control group included 16 subjects (56.3% male; 32.75 ± 12.19 years). Patients with generalized or focal epilepsy had a significantly lower sleep efficiency than controls. Moreover, both patient groups presented the alteration of markers of sleep fragmentation and loss of continuity, with higher indices of sleep stage transitions and arousal. Finally, the two patient groups presented less REM sleep than controls. SIGNIFICANCE: This study highlighted the alteration of sleep quality, continuity, and stability in both patients with focal or generalized epilepsy compared with controls, also in the absence of ictal events. This sleep impairment resulted in the reduction of REM sleep. Therefore, these findings may be explained by the increase in awakenings and sleep stage shifts, which may be attributed to both sleep networks impairment and neurotransmission dysfunction in PWE, and also possibly triggered by paroxysmal interictal abnormalities.

Sleep-wake cycle and daytime sleepiness in patients with epilepsy after initiating perampanel as adjunctive therapy.

BACKGROUND: Antiseizure medications (ASMs) may affect nocturnal sleep and daytime vigilance. Perampanel (PER), a third-generation ASM, showed to improve nocturnal sleep in patients with epilepsy (PWE). Although ASMs can have beneficial effects on nocturnal sleep and daytime sleepiness, no study investigated the effect of PER on both sleep-wake cycle and daytime sleepiness. Therefore, this study aimed to objectively evaluate the sleep-wake cycle and daytime sleepiness in PWE treated with PER as adjunctive therapy. METHODS: This prospective study included adult PWE who received PER as add-on treatment. Sleep-wake cycle was assessed through actigraphic monitoring and daytime sleepiness by the multiple sleep latency test (MSLT) performed at the end of the actigraphic recording. All patients performed both tests at baseline and at 6-month follow-up. RESULTS: Ten patients (mean age: 44.50 ± 22.71 years, 50.0% female) were included. The mean monthly seizure frequency was 3.20 ± 5.94. Six of ten patients started PER as a first add-on treatment. The final PER dose was 5.11 ± 2.02 mg/day, and nine of ten patients achieved seizure freedom at follow-up. There was a significant decrease in mean monthly seizure frequency from baseline to follow-up (p = 0.004). No significant changes were found in the sleep-wake cycle parameters. An increase in sleep latency mean was observed at MSLT at 6-month follow-up (p = 0.005). CONCLUSIONS: This study confirms that adjunctive PER is effective on seizures without pathologically change of the sleep-wake cycle in PWE and can even improve daytime sleepiness. This effect can be mediated by the achievement of seizure control. Therefore, PER may be promising in PWE with sleep disturbances and daytime sleepiness.

Derivation and Validation of a Phenoconversion-Related Pattern in Idiopathic Rapid Eye Movement Behavior Disorder.

BACKGROUND: Idiopathic rapid eye movement sleep behavior disorder (iRBD) represents the prodromal stage of α-synucleinopathies. Reliable biomarkers are needed to predict phenoconversion. OBJECTIVE: The aim was to derive and validate a brain glucose metabolism pattern related to phenoconversion in iRBD (iRBDconvRP) using spatial covariance analysis (Scaled Subprofile Model and Principal Component Analysis [SSM-PCA]). METHODS: Seventy-six consecutive iRBD patients (70 ± 6 years, 15 women) were enrolled in two centers and prospectively evaluated to assess phenoconversion (30 converters, 73 ± 6 years, 14 Parkinson's disease and 16 dementia with Lewy bodies, follow-up time: 21 ± 14 months; 46 nonconverters, 69 ± 6 years, follow-up time: 33 ± 19 months). All patients underwent [18 F]FDG-PET (18 F-fluorodeoxyglucose positron emitting tomography) to investigate brain glucose metabolism at baseline. SSM-PCA was applied to obtain the iRBDconvRP; nonconverter patients were considered as the reference group. Survival analysis and Cox regression were applied to explore prediction power. RESULTS: First, we derived and validated two distinct center-specific iRBDconvRP that were comparable and significantly able to predict phenoconversion. Then, SSM-PCA was applied to the whole set, identifying the iRBDconvRP. The iRBDconvRP included positive voxel weights in cerebellum; brainstem; anterior cingulate cortex; lentiform nucleus; and middle, mesial temporal, and postcentral areas. Negative voxel weights were found in posterior cingulate, precuneus, middle frontal gyrus, and parietal areas. Receiver operating characteristic analysis showed an area under the curve of 0.85 (sensitivity: 87%, specificity: 72%), discriminating converters from nonconverters. The iRBDconvRP significantly predicted phenoconversion (hazard ratio: 7.42, 95% confidence interval: 2.6-21.4). CONCLUSIONS: We derived and validated an iRBDconvRP to efficiently discriminate converter from nonconverter iRBD patients. [18 F]FDG-PET pattern analysis has potential as a phenoconversion biomarker in iRBD patients. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Alexithymia, impulsiveness, emotion, and eating dyscontrol: similarities and differences between narcolepsy type 1 and type 2.

Non-sleep symptoms, as depression, anxiety and overweight, are often encountered in narcoleptic patients. The purposes of this study are to evaluate mood, impulsiveness, emotion, alexithymia, and eating behavior in patients with narcolepsy type 1 (NT1) and narcolepsy type 2 (NT2) compared to healthy controls and to investigate possible correlations between clinical-demographic data, polysomnographic parameters, and subjective questionnaires. Consecutive patients affected by NT1 and NT2 underwent to Patient Health Questionnaire-9, Generalized Anxiety Disorder-7 Scale, Barratt Impulsivity Scale-11, Difficulties in Emotion Regulation Scale, Toronto Alexithymia Scale, and Eating Disorder Evaluation Questionnaire. Daytime sleepiness was assessed using Epworth sleepiness score. Data were compared with controls. Fourteen NT1, 10 NT2, and 24 healthy subjects were enrolled. Toronto Alexithymia Scale total score was significantly higher in NT1 than NT2. Compared to controls, NT1 patients exhibited significantly higher scores at Patient Health Questionnaire-9 and Difficulties in Emotion Regulation Scale. A positive correlation between hypnagogic hallucinations and Difficulties in emotion regulation was found. NT1 and NT2 share several psycho-emotional aspects, but whereas NT1 patients exhibit more depressive mood and emotion dysregulation compared to controls, alexithymic symptoms are more prominent in NT1 than NT2. Hypnagogic hallucinations, emotion dysregulation, and alexithymia appear to be correlated, supporting the hypothesis of mutual interaction of the above areas in narcolepsy.

Periodic sharp wave complexes identify a distinctive phenotype in Creutzfeldt-Jacob disease.

OBJECTIVE: The aim of our study was to evaluate the diagnostic and prognostic value of Electroencephalogram (EEG), brain Magnetic Resonance Imaging (MRI) and cerebrospinal fluid features, currently representing Creutzfeldt-Jacob Disease (CJD) diagnostic criteria. METHODS: A retrospective study on rapidly progressive dementia patients admitted at the Neurology Clinic of the University of Rome "Tor Vergata" between 2015 and 2020 was conducted. We evaluated clinical, EEG, cerebrospinal fluid and neuroradiological findings. RESULTS: Our analysis included 13 patients with probable CJD and 18 patients with non-CJD rapidly progressive dementia. Periodic sharp wave complexes were observed in 7/13 CJD and in 4/18 non-CJD patients (p =.151). The sub-analysis according to the EEG features revealed that CJD patients with earlier periodic sharp wave complexes had a significantly lower average survival time (p =.003), a shorter time to admission (p =.003) and lower levels of cerebrospinal fluid p-tau (p =.008) compared to CJD patients without periodic sharp wave complexes. Finally, they did not show signs of signal alteration on Fluid Attenuated Inversion Recovery images. CONCLUSIONS: Despite the lowest diagnostic specificity and sensibility among the CJD criteria, periodic sharp wave complexes could identify a distinctive phenotype hallmarked by a faster evolution, a reduced survival time and specific MRI and cerebrospinal fluid features. SIGNIFICANCE: The early presence of the typical EEG pattern may play a prognostic role in CJD.

Neuropsychiatric, neuropsychological, and neuroimaging features in isolated REM sleep behavior disorder: The importance of MCI.

BACKGROUND: Mild cognitive impairment (MCI) is frequently diagnosed in patients with isolated rapid eye movement (REM) sleep behavior disorder (iRBD), although the extent of MCI-associated neuropathology has not yet been quantified. The present study compared the differences in neuropsychiatric, neuropsychological, and neuroimaging markers of neurodegeneration in MCI-iRBD and iRBD patients with normal cognition. METHODS: Sixty-one patients with iRBD were included in the study: 30 patients were included in the MCI subgroup (RBD-MCI) and 31 in the normal cognition subgroup (RBD-NC). Both groups underwent neuropsychiatric and neuropsychological assessments to evaluate psychopathological symptoms and neuropsychological functions. Brain [18F]FDG PET and 123I-FP-CIT-SPECT were performed to evaluate brain glucose metabolism and nigrostriatal dopaminergic function in convenient subgroups of patients, respectively. RESULTS: Neuropsychological measures generally confirmed overall cognitive decline in patients with iRBD-MCI. Immediate long-term verbal memory and visuospatial functions, as well as attentional-executive impairment were evident in the MCI group compared to the NC group. Neuroimaging results indicated reduced brain glucose uptake in the bilateral posterior cingulate cortex and more evident nigrostriatal deafferentation in the RBD-MCI group. There were no differences in psychopathological symptoms between the two groups. CONCLUSIONS: This study confirmed that iRBD patients with MCI had a more impaired cognitive status that those with NC. Moreover, the MCI subgroup presented reduced cerebral glucose consumption in brain areas critical for cognition, and a more severe deafferentation of the nigro-striatal regions, highlighting the importance of identifying iRBD patients with MCI for urgent neuroprotective trials.

Comparative transcriptional analysis of satellite glial cell injury response.

Background: Satellite glial cells (SGCs) tightly surround and support primary sensory neurons in the peripheral nervous system and are increasingly recognized for their involvement in the development of neuropathic pain following nerve injury. SGCs are difficult to investigate due to their flattened shape and tight physical connection to neurons in vivo and their rapid changes in phenotype and protein expression when cultured in vitro. Consequently, several aspects of SGC function under normal conditions as well as after a nerve injury remain to be explored. The recent advance in single cell RNA sequencing (scRNAseq) technologies has enabled a new approach to investigate SGCs. Methods: In this study we used scRNAseq to investigate SGCs from mice subjected to sciatic nerve injury. We used a meta-analysis approach to compare the injury response with that found in other published datasets.  Furthermore, we also used scRNAseq to investigate how cells from the dorsal root ganglion (DRG) change after 3 days in culture. Results: From our meta-analysis of the injured conditions, we find that SGCs share a common signature of 18 regulated genes following sciatic nerve crush or sciatic nerve ligation, involving transcriptional regulation of cholesterol biosynthesis. We also observed a considerable transcriptional change when culturing SGCs, suggesting that some differentiate into a specialised in vitro state while others start resembling Schwann cell-like precursors. Conclusion: By using integrated analyses of new and previously published scRNAseq datasets, this study provides a consensus view of which genes are most robustly changed in SGCs after injury. Our results are available via the Broad Institute Single Cell Portal, so that readers can explore and search for genes of interest.

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

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

Cognitive functioning, cerebrospinal fluid Alzheimer's disease biomarkers and cerebral glucose metabolism in late-onset epilepsy of unknown aetiology: A prospective study.

Epilepsy is increasing, being more common in older adults, with more than 20% of late-onset cases with unknown aetiology (LOEU). Although epilepsy was associated with cognitive impairment, few studies evaluated the trajectories of cognitive decline in patients with LOEU. The present study aimed at assessing biomarkers of Alzheimer's disease (AD) in patients with LOEU and evaluating their cognitive performance for 12 months. For this study, 55 patients diagnosed with LOEU and 21 controls were included. Participants underwent cognitive evaluation and cerebrospinal fluid (CSF) biomarker analysis (ß-amyloid42 , tau proteins) before starting anti-seizure medication and then repeated the cognitive evaluation at the 12-month follow-up. A subgroup of LOEU patients and controls also performed 18 F-fluoro-2-deoxy-D-glucose positron emission tomography (18 F-FDG PET) before starting anti-seizure medication. At baseline, LOEU patients showed lower Mini-Mental State Examination (MMSE) score, worse cognitive performance in several domains, lower ß-amyloid42 and higher tau proteins CSF levels than controls. Significantly reduced glucose consumption was observed in the right posterior cingulate cortex and left praecuneus areas in LOEU patients than controls, and this finding correlated with memory impairment. In the longitudinal analysis, a significant decrease in MMSE and an increase in verbal fluency scores were found in LOEU patients. These findings evidence that LOEU patients have a significant cognitive impairment, and alteration of cerebral glucose consumption and CSF AD biomarkers than controls. Moreover, they showed a progressive global cognitive decline at follow-up, although verbal fluency was preserved. Further studies are needed to better understand the pathophysiological aspects of LOEU and its association with AD.

18F-FDG PET, cognitive functioning, and CSF biomarkers in patients with obstructive sleep apnoea before and after continuous positive airway pressure treatment.

INTRODUCTION: Dysregulation of cerebral glucose consumption, alterations in cerebrospinal fluid (CSF) biomarkers, and cognitive impairment have been reported in patients with obstructive sleep apnoea (OSA). On these bases, OSA has been considered a risk factor for Alzheimer's disease (AD). This study aimed to measure cognitive performance, CSF biomarkers, and cerebral glucose consumption in OSA patients and to evaluate the effects of continuous positive airway pressure (CPAP) treatment on these biomarkers over a 12-month period. METHODS: Thirty-four OSA patients and 34 controls underwent 18F-fluoro-2-deoxy-D-glucose positron emission tomography (18F-FDG PET), cognitive evaluation, and CSF analysis. A subgroup of 12 OSA patients treated with beneficial CPAP and performing the 12-month follow-up was included in the longitudinal analysis, and cognitive evaluation and 18F-FDG PET were repeated. RESULTS: Significantly reduced glucose consumption was observed in the bilateral praecuneus, posterior cingulate cortex, and frontal areas in OSA patients than controls. At baseline, OSA patients also showed lower ß-amyloid42 and higher phosphorylated-tau CSF levels than controls. Increased total tau and phosphorylated tau levels correlated with a reduction in brain glucose consumption in a cluster of different brain areas. In the longitudinal analysis, OSA patients showed an improvement in cognition and a global increase in cerebral 18F-FDG uptake. CONCLUSIONS: Cognitive impairment, reduced cerebral glucose consumption, and alterations in CSF biomarkers were observed in OSA patients, which may reinforce the hypothesis of AD neurodegenerative processes triggered by OSA. Notably, cognition and brain glucose consumption improved after beneficial CPAP treatment. Further studies are needed to evaluate the long-term effects of CPAP treatment on these AD biomarkers.

Nocturnal Hypoxia and Sleep Fragmentation May Drive Neurodegenerative Processes: The Compared Effects of Obstructive Sleep Apnea Syndrome and Periodic Limb Movement Disorder on Alzheimer's Disease Biomarkers.

BACKGROUND: Sleep disorders may cause dysregulation in cerebral glucose metabolism and synaptic functions, as well as alterations in cerebrospinal fluid (CSF) biomarker levels. OBJECTIVE: This study aimed at measuring sleep, CSF Alzheimer's disease (AD) biomarkers, and cerebral glucose consumption in patients with obstructive sleep apnea syndrome (OSAS) and patients with periodic limb movement disorder (PLMD), compared to controls. METHODS: OSAS and PLMD patients underwent 18F-fluoro-2-deoxy-D-glucose positron emission tomography (18F-FDG PET), polysomnographic monitoring, and lumbar puncture to quantify CSF levels of amyloid-ß42 (Aß42), total tau, and phosphorylated tau. All patients were compared to controls, who were not affected by sleep or neurodegenerative disorders. RESULTS: Twenty OSAS patients, 12 PLMD patients, and 15 controls were included. Sleep quality and sleep structure were altered in both OSAS and PLMD patients when compared to controls. OSAS and PLMD patients showed lower CSF Aß42 levels than controls. OSAS patients showed a significant increase in glucose uptake in a wide cluster of temporal-frontal areas and cerebellum, as well as a reduced glucose consumption in temporal-parietal regions compared to controls. PLMD patients showed increased brain glucose consumption in the left parahippocampal gyrus and left caudate than controls. CONCLUSION: Sleep dysregulation and nocturnal hypoxia present in OSAS patients, more than sleep fragmentation in PLMD patients, were associated with the alteration in CSF and 18F-FDG PET AD biomarkers, namely reduction of CSF Aß42 levels and cerebral glucose metabolism dysregulation mainly in temporal areas, thus highlighting the possible role of sleep disorders in driving neurodegenerative processes typical of AD pathology.

Generalized Fast Discharges Along the Genetic Generalized Epilepsy Spectrum: Clinical and Prognostic Significance.

Objective: To investigate the electroclinical characteristics and the prognostic impact of generalized fast discharges in a large cohort of genetic generalized epilepsy (GGE) patients studied with 24-h prolonged ambulatory electroencephalography (paEEG). Methods: This retrospective multicenter cohort study included 202 GGE patients. The occurrence of generalized paroxysmal fast activity (GPFA) and generalized polyspike train (GPT) was reviewed. GGE patients were classified as having idiopathic generalized epilepsy (IGE) or another GGE syndrome (namely perioral myoclonia with absences, eyelid myoclonia with absences, epilepsy with myoclonic absences, generalized epilepsy with febrile seizures plus, or GGE without a specific epilepsy syndrome) according to recent classification proposals. Results: GPFA/GPT was found in overall 25 (12.4%) patients, though it was significantly less frequent in IGE compared with other GGE syndromes (9.3 vs. 25%, p = 0.007). GPFA/GPT was found independently of seizure type experienced during history, the presence of mild intellectual disability/borderline intellectual functioning, or EEG features. At multivariable analysis, GPFA/GPT was significantly associated with drug resistance (p = 0.04) and with a higher number of antiseizure medications (ASMs) at the time of paEEG (p < 0.001) and at the last medical observation (p < 0.001). Similarly, GPFA/GPT, frequent/abundant generalized spike-wave discharges during sleep, and a higher number of seizure types during history were the only factors independently associated with a lower chance of achieving 2-year seizure remission at the last medical observation. Additionally, a greater number of GPFA/GPT discharges significantly discriminated between patients who achieved 2-year seizure remission at the last medical observation and those who did not (area under the curve = 0.77, 95% confidence interval 0.57-0.97, p = 0.02). Conclusion: We found that generalized fast discharges were more common than expected in GGE patients when considering the entire GGE spectrum. In addition, our study highlighted that GPFA/GPT could be found along the entire GGE continuum, though their occurrence was more common in less benign GGE syndromes. Finally, we confirmed that GPFA/GPT was associated with difficult-to-treat GGE, as evidenced by the multivariable analysis and the higher ASM load during history.