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β-amyloid 42 (Aβ 42 ) in Alzheimer's disease (AD) and orexin in narcolepsy are considered crucial biomarkers for diagnosis and therapeutic targets. Recently, orexin and Aβ cerebral dynamics have been studied in both pathologies, but how they interact with each other remains further to be known. In this study, we investigated the reliability of using the correlation between orexin-A and Aβ 42 CSF levels as a candidate marker to explain the chain of events leading to narcolepsy or AD pathology. In order to test the correlation between these biomarkers, patients diagnosed with AD (n = 76), narcolepsy type 1 (NT1, n = 17), narcolepsy type 2 (NT2, n = 23) and healthy subjects (n = 91) were examined. Patients and healthy subjects underwent lumbar puncture between 8:00 and 10:00 am at the Neurology Unit of the University Hospital of Rome "Tor Vergata". CSF levels of Aβ 42 , total-tau, phosphorylated-tau, and orexin-A were assessed. The results showed that CSF levels of Aβ 42 were significantly lower (p < 0.001) in AD (332.28 ± 237.36 pg/mL) compared to NT1 (569.88 ± 187.00 pg/mL), NT2 (691.00 ± 292.63 pg/mL) and healthy subjects (943.68 ± 198.12 pg/mL). CSF orexin-A levels were statistically different (p < 0.001) between AD (148.01 ± 29.49 pg/mL), NT1 (45.94 ± 13.63 pg/mL), NT2 (104.92 ± 25.55 pg/mL) and healthy subjects (145.18 ± 27.01 pg/mL). Moderate-severe AD patients (mini mental state examination < 21) showed the highest CSF orexin-A levels, whereas NT1 patients showed the lowest CSF orexin-A levels. Correlation between CSF levels of Aβ 42 and orexin-A was found only in healthy subjects (r = 0.26; p = 0.01), and not in narcolepsy or AD patients. This lack of correlation in both diseases may be explained by the pathology itself since the correlation between these two biomarkers is evident only in the healthy subjects. This study adds to the present literature by further documenting the interplay between orexinergic neurotransmission and cerebral Aβ dynamics, possibly sustained by sleep., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Actigraphy has a consolidated role in Insomnia and Circadian Rhythm Sleep-Wake Disorders (CRSWD) and recent studies have highlighted the use of actigraphy for narcolepsy and REM sleep behaviour disorder (RBD). This review aims at summarising the results of studies published over the last decade regarding the use of actigraphy. Thirty-five studies proved eligible, and results were analysed separately for insomnia, narcolepsy and RBD. Actigraphy showed to consistently differentiate insomnia patients from healthy controls. Furthermore, the application of advanced analytical techniques has been shown to provide both unique insights into the physiology of insomnia and sleep misperception and to improve the specificity of actigraphy in detecting wakefulness within sleep periods. Regarding narcolepsy, several studies showed that actigraphy can detect peculiar sleep/wake disruption and the effects of pharmacological treatments. Finally, although the number of studies in RBD patients is still limited, the available evidence indicates a reduced amplitude of the activity pattern, sleep-wake rhythm dysregulation and daytime sleepiness. Therefore, the potential use of these markers as predictors of phenoconversion should be further explored. In conclusion, quantitative actigraphy presents a renewed interest when considering the possibility of using actigraphy in clinical sleep medicine to diagnose, monitor, and follow sleep disorders other than CRSWD., Competing Interests: Declaration of Competing interest Giuseppe Plazzi: UCB Pharma, Jazz pharmaceuticals, Bioprojet and Idorsia; Giancarlo Logroscino: Roche and Amplifon; Marco Zucconi: Jazz pharmaceuticals, Bioprojet and Idorsia; Luigi Ferini-Strambi: Jazz pharmaceuticals, Bioprojet, Idorsia, Angelini, Lundbeck, Valeas, Bayer and Italfarmaco. The other authors have no potential financial conflict of interest/competing interest to disclose., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

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., (© 2022. The Author(s).)

Neuropeptides orexin A and B (OX-A/B, also called hypocretin 1 and 2) are released selectively by a population of neurons which projects widely into the entire central nervous system but is localized in a restricted area of the tuberal region of the hypothalamus, caudal to the paraventricular nucleus. The OX system prominently targets brain structures involved in the regulation of wake-sleep state switching, and also orchestrates multiple physiological functions. The degeneration and dysregulation of the OX system promotes narcoleptic phenotypes both in humans and animals. Hence, this review begins with the already proven involvement of OX in narcolepsy, but it mainly discusses the new pre-clinical and clinical insights of the role of OX in three major neurological disorders characterized by sleep impairment which have been recently associated with OX dysfunction, such as Alzheimer's disease, stroke and Prader Willi syndrome, and have been emerged over the past 10 years to be strongly associated with the OX dysfunction and should be more considered in the future. In the light of the impairment of the OX system in these neurological disorders, it is conceivable to speculate that the integrity of the OX system is necessary for a healthy functioning body., (© 2020 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Purpose: To evaluate cardiovascular and sudomotor function during wakefulness and to assess autonomic symptoms in de novo patients with type 1 narcolepsy compared to healthy controls., Methods: De novo patients with type 1 narcolepsy (NT1) and healthy controls underwent cardiovascular function tests including head-up tilt test, Valsalva maneuver, deep breathing, hand grip, and cold face, and sudomotor function was assessed through Sudoscan. Autonomic symptoms were investigated using the Scales for Outcomes in Parkinson's Disease-Autonomic Dysfunction (SCOPA-AUT) questionnaire., Results: Twelve de novo patients with NT1 and 14 healthy controls were included. In supine rest condition and at 3 min and 10 min head-up tilt test, the systolic blood pressure values were significantly higher in the NT1 group than in controls (p < 0.05). A lower Valsalva ratio (p < 0.01), significantly smaller inspiratory-expiratory difference in deep breathing (p < 0.05), and lower delta heart rate in the cold face test (p < 0.01) were also observed in the NT1 group. The mean hand electrochemical skin conductance values were significantly lower (p < 0.05) and the mean SCOPA-AUT total scores were significantly higher in patients with NT1 than in healthy subjects (p < 0.001), with greater involvement of cardiovascular and thermoregulatory items., Conclusion: De novo patients with NT1 exhibit blunted parasympathetic activity during wakefulness, mild sudomotor dysfunction, and a large variety of autonomic symptoms.

Background: Endocannabinoids (ECs) modulate both excitatory and inhibitory components in the CNS. There is a growing body of evidence that shows ECs influence both hypothalamic orexinergic and histaminergic neurons involved in narcolepsy physiopathology. Therefore, ECs may influence sleep and sleep-wake cycle., Objective: To evaluate EC levels in the CSF of untreated narcoleptic patients to test whether ECs are dysregulated in Narcolepsy Type 1 (NT1) and Type 2 (NT2)., Methods: We compared CSF Anandamide (AEA), 2-Arachidonoylglycerol (2-AG) and orexin in narcoleptic drug-naïve patients and in a sample of healthy subjects., Results: We compared NT1 (n=6), NT2 (n=6), and healthy controls (n=6). We found significantly reduced AEA levels in NT1 patients compared to both NT2 and controls. No differences were found between AEA levels in NT2 versus controls and between 2-AG levels in all groups, although a trend toward a decrease in NT1 was evident. Finally, the CSF AEA level was related to CSF orexin levels in all subjects., Conclusion: We demonstrated that the EC system is dysregulated in NT1., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Purpose: The aim od this study is to test whether metabolism of beta-amyloid and tau proteins changes in narcolepsy along with the disease course., Methods: We analyzed a population of narcoleptic drug-naïve patients compared to a sample of healthy controls. Patients and controls underwent lumbar puncture for assessment of cerebrospinal fluid (CSF) beta-amyloid1-42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau) levels. Moreover, based on the median disease duration of the whole narcolepsy group, the patients were divided into two subgroups: patients with a short disease duration (SdN, <5 years) and patients with a long disease duration (LdN, >5 years)., Results: We found significantly lower CSF Aβ42 levels in the whole narcolepsy group with respect to controls. Taking into account the patient subgroups, we documented reduced CSF Aβ42 levels in SdN compared to both LdN and controls. Even LdN patients showed lower CSF Aβ42 levels with respect to controls. Moreover, we documented higher CSF p-tau levels in LdN patients compared to both SdN and controls. Finally, a significant positive correlation between CSF Aβ42 levels and disease duration was evident., Conclusions: We hypothesize that beta-amyloid metabolism and cascade may be impaired in narcolepsy not only at the onset but also along with the disease course, although they show a compensatory profile over time. Concurrently, also CSF biomarkers indicative of neural structure (p-tau) appear to be altered in narcolepsy patients with a long disease duration. However, the mechanism underlying beta-amyloid and tau metabolism impairment in narcolepsy remains still unclear and deserves to be better elucidated.

Narcolepsy is characterized by hypocretin deficiency due to the loss of hypothalamic orexinergic neurons, and is associated with both the human leucocyte antigen DQB1*06:02 and the T cell receptor polymorphism. The above relationship suggests autoimmune/inflammatory processes underlying the loss of orexinergic neurons in narcolepsy. To test the autoimmune/inflammatory hypothesis by means of cerebrospinal fluid (CSF) levels of beta-amyloid1-42 and/or total tau proteins in a sample of narcoleptic patients, we analysed 16 narcoleptic patients and 16 healthy controls. Beta-amyloid1-42 CSF levels were significantly lower in narcoleptic patients compared with healthy controls. We also documented pathologically low levels of CSF beta-amyloid1-42 (<500 pg mL(-1) ) in six of 16 narcoleptic patients (37.5%). We hypothesize that the significant decrease of the CSF beta-amyloid1-42 levels in narcoleptic patients may support both the inflammatory/autoimmune hypothesis as the basis of the pathogenesis of narcolepsy and the prevalence of an 'amyloidogenic' pathway caused by the deficiency of the alpha-secretases enzymes., (© 2014 European Sleep Research Society.)

Introduction: Autoimmune and inflammatory mechanisms are suggested as a possible cause of the hypocretin cell loss in human narcolepsy. Interestingly, decreased CSF levels of beta-amyloid1–42 (Abeta–42) are described related to brain inflammation. In fact the Abeta–42 metabolism is strongly regulated by inflammatory mechanisms and the inflammatory pathways of the immune system represent targets for modulating â-amyloid generation and accumulation. The aim of our study was to evaluate the CSF levels of Abeta–42, total-tau (t- tau) and phosphorylated-tau (ptau) in narcoleptic patients, compared with matched healthy controls, to test if the inflammatory pathways in narcolepsy may interfere with CSF Abeta–42 and/or tau metabolisms. Materials and methods: Lumbar CSF of patients with narcolepsy and healthy individuals was analyzed by ELISA tests in order to detect the CSF levels of orexin A, Abeta–42, t-tau and ptau proteins. Results: We analysed 15 narcoleptic patients and 15 sex and age-matched controls. More than one-and-a-half Abeta–42 CSF levels decrease was detected in narcoleptic patients compared with healthy controls. Moreover in 5 narcoleptic patients (33%) we documented pathological CSF Abeta–42 levels ( 500pg/ml) and 14 of the 15 narcoleptic subjects (93%) presented CSF Abeta–42 levels lower than the CSF Abeta–42 mean value of the matched controls. Conversely, CSF levels of t- tau and ptau proteins did not statistically differ between groups. Conclusion: We hypothesize that the significant decrease of the CSF Abeta–42 levels in narcoleptic patients may support the inflammatory/autoimmune hypothesis at the basis of the pathogenesis of narcolepsy. Therefore, our findings may be particularly appealing since narcolepsy is a neurological disorder caused by possible underlying autoimmune processes, aroused by viral or bacterial infections, responsible for the selective orexinergic neurons loss. In addition, a secondary explanation may be represented by the prevalence of an “amyloidogenic” pathway, due to the deficiency of the alpha-secretase ADAM10, previously described in narcolepsy, which cause the reduction of the CSF Abeta–42 levels in narcoleptic patients. Therefore, further studies are needed to better clarify the pathogenesis of narcolepsy, to understand the role of Abeta–42 and its links with degeneration and loss of the orexinergic neurons. Acknowledgements: We thank for their precious help and assistance: N.B. Mercuri, PhD, S. Bernardini, PhD, M. Nuccetelli, MD. [ABSTRACT FROM AUTHOR]