Cholinergic Markers and Cytokines in OSA Patients.

The role of inflammation and dysfunction of the cholinergic system in obstructive sleep apnea (OSA) has not exhaustively clarified. Thus, in this study, we explore the non-neuronal cholinergic system and the balance of T helper (Th) 17- and T regulatory (Treg)-related cytokines in OSA patients. The study includes 33 subjects with obstructive sleep apnea and 10 healthy controls (HC). The expression levels of cholinergic system component, RAR-related orphan receptor (RORc), transcription factor forkhead box protein 3 (Foxp3) and cytokines were evaluated. Th17- and Treg-related cytokines, choline levels and acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) activity were quantified in OSA and control subjects. AChE and nicotinic receptor α 7 subunit (α7nAChR) gene expression and serum levels of choline, AChE and BuChE were lower in OSA patients than in the HC group. Compared with the HC group, OSA patients exhibited an increased expression, secretion and serum levels of pro-inflammatory cytokines, a reduced expression, secretion and serum levels of transforming growth factor (TGF)ß and reduced Foxp3 mRNA levels. The Th17/Treg-related cytokine ratio was higher in the OSA group. Our results confirm and reinforce the hypothesis that OSA may be considered a systemic inflammatory disease, and that an imbalance of non-neuronal cholinergic and pro/anti-inflammatory cytokines may contribute to development and progression of comorbidities in OSA subjects. The evaluation of Th17/Treg-related cytokine may provide an additional explanation for OSA pathogenesis and clinical features, opening new directions for the OSA management.

Sleep and Cognitive Decline: A Strong Bidirectional Relationship. It Is Time for Specific Recommendations on Routine Assessment and the Management of Sleep Disorders in Patients with Mild Cognitive Impairment and Dementia.

BACKGROUND: Sleep disturbances and disruption of the neural regulation of the sleep-wake rhythm appear to be involved in the cellular and molecular mechanisms of cognitive decline. Although sleep problems are highly prevalent in mild cognitive impairment (MCI) and many types of dementia, they have not been systematically investigated in the clinical setting and are often only investigated by sleep specialists upon individual request. SUMMARY: This review discusses sleep disorders in the context of cognitive decline and provides an overview of the clinical diagnosis and management of these disorders in patients with dementia and MCI. Key Messages: Sleep disorders are largely underestimated and do not receive sufficient attention in the global management of dementia patients. Sleep disturbances have a significant impact on cognitive and physical functions in individuals with cognitive decline and may be associated with important psychological distress and depression. They are positively associated with the severity of behavioral problems and cognitive impairment. CLINICAL IMPLICATIONS: The recent recommendations by the Sleep Study Group of the Italian Dementia Research Association can be used as a guideline for the clinical assessment and management of sleep disorders in MCI and dementia patients. Sleep disorders should be carefully investigated using an in-depth sleep history, physical examination, questionnaires and clinical scales and should be validated with the support of a direct caregiver. The recommendations for older adults can be used as a framework to guide the diagnosis and treatment of sleep disorders in individuals with dementia and MCI. The management strategy should be based on the choice of different treatments for each sleep problem present in the same patient, while avoiding adverse interactions between treatments.

Sleep disturbances and cognitive decline: recommendations on clinical assessment and the management.

In 2004, in Genoa (Italy), the Italian Dementia Research Association (SINDem) was born. The first congress of this new scientific society took place in Rome in 2006. SINDem soon recognized the importance to investigate sleep problems in cognitive decline and created a national "sleep study group "composed by neurologists and sleep specialists. In 2012, The SINDem study group, in close relationship with the Italian Association of sleep medicine (AIMS), published the study "Prevalence of sleep disturbances in mild cognitive impairment and dementing disorders: a multicenter Italian clinical cross-sectional study on 431 patients ", confirming the high prevalence of sleep disturbances in a wide Italian population of persons with cognitive decline. The study was supported by a grant from the Italian Minister of Health and was conducted with the fundamental contribution of the Italian National Research Center (CNR). In 2014, the same group published the paper "Recommendations of the Sleep Study Group of the Italian Dementia Research Association (SINDem) on clinical assessment and management of sleep disorders in individuals with mild cognitive impairment and dementia: a clinical review". The recommendations are wide and directed to professionals (neurologists but not exclusively) to try to establish uniform levels of care, promote collaborative studies into areas of uncertainty, and define the qualitative characteristics of Dementia Reference Centers about sleep disturbances.

Sleep disorders in menopause: results from an Italian Multicentric Study.

Menopause in the female life cycle is a special period due to important hormonal, physical and psychological changes. Sleep disruption represents a common complaint for midlife and menopausal women, related to primary sleep disorders, including insomnia, sleep disordered breathing, restless legs syndrome (RLS), mood and anxiety disorder, other medical illness, hormonal-related vasomotor symptoms, and aging per se. Aims of our study were to evaluate the prevalence of sleep disorders in a sample of pre and post menopausal women, and to investigate the relationship between sleep and other medical disorders, and life habits. Among workers in the six participant centers, we enrolled 334 women, aged between 40 and 60 years, that completed a questionnaire that included screening on menarche, menstrual cycle, fertility, parity, menopause, life habits, personal medical and sleep history and related treatment, and self-administered scales for sleep quality (PSQI), excessive daytime sleepiness [Epworth Sleepiness Scale (ESS)], mood disorder [Beck Depression Inventory (BDI)], Berlin Questionnaire for sleep disordered breathing (SDB), IRLS diagnostic interview and Rating Scale. Menopausal and perimenopausal women showed an increased prevalence of poor sleep, high risk of SDB, and mood disorder; menopausal women also reported increased RLS severity. Mood disorder had a significant impact on night sleep measures and excessive daytime sleepiness, as well as on RLS severity, and had a greater prevalence in hypertensive women. Sleep disturbances are frequent in menopausal women. Their aetiology is unclear, but probably multifactorial, and many factors contribute to the sleep disruption. Our data suggest the importance of correctly investigate and address sleep problems associated with menopause, through sleep history, and a sleep study could be obtained if clinically warranted. Pharmacological and behavioural treatment strategies should then be aimed at improving sleep and life quality in perimenopausal and menopausal women.

Association of rs3027178 polymorphism in the circadian clock gene PER1 with susceptibility to Alzheimer's disease and longevity in an Italian population.

Many physiological processes in the human body follow a 24-h circadian rhythm controlled by the circadian clock system. Light, sensed by retina, is the predominant "zeitgeber" able to synchronize the circadian rhythms to the light-dark cycles. Circadian rhythm dysfunction and sleep disorders have been associated with aging and neurodegenerative diseases including mild cognitive impairment (MCI) and Alzheimer's disease (AD). In the present study, we aimed at investigating the genetic variability of clock genes in AD patients compared to healthy controls from Italy. We also included a group of Italian centenarians, considered as super-controls in association studies given their extreme phenotype of successful aging. We analyzed the exon sequences of eighty-four genes related to circadian rhythms, and the most significant variants identified in this first discovery phase were further assessed in a larger independent cohort of AD patients by matrix assisted laser desorption/ionization-time of flight mass spectrometry. The results identified a significant association between the rs3027178 polymorphism in the PER1 circadian gene with AD, the G allele being protective for AD. Interestingly, rs3027178 showed similar genotypic frequencies among AD patients and centenarians. These results collectively underline the relevance of circadian dysfunction in the predisposition to AD and contribute to the discussion on the role of the relationship between the genetics of age-related diseases and of longevity.

Sleep-disordered breathing and the risk of Alzheimer's disease.

Sleep-disordered breathing is highly prevalent in the elderly population. Obstructive sleep apnea (OSA) represents the most common sleep disorder among the adult and elderly population. Recently, OSA diagnosis has been associated with an increased risk of developing cognitive decline and dementia, including vascular dementia and Alzheimer's disease (AD). Subsequently, there have been studies on AD biomarkers investigating cerebrospinal fluid, blood, neuroimaging, and nuclear medicine biomarkers in patients with OSA. Furthermore, studies have attempted to assess the possible effects of continuous positive airway pressure (CPAP) treatment on the cognitive trajectory and AD biomarkers in patients with OSA. This review summarizes the findings of studies on each AD biomarker (cognitive, biofluid, neuroimaging, and nuclear medicine imaging) in patients with OSA, also accounting for the related effects of CPAP treatment. In addition, the hypothetical model connecting OSA to AD in a bi-directional interplay is analyzed. Finally, the sex-based differences in prevalence and clinical symptoms of OSA between men and women have been investigated in relation to AD risk. Further studies investigating AD biomarkers changes in patients with OSA and the effect of CPAP treatment should be auspicated in future for identifying strategies to prevent the development of AD.

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.

Multicenter Study on Sleep and Circadian Alterations as Objective Markers of Mild Cognitive Impairment and Alzheimer's Disease Reveals Sex Differences.

BACKGROUND: Circadian and sleep disturbances are associated with increased risk of mild cognitive impairment (MCI) and Alzheimer's disease (AD). Wearable activity trackers could provide a new approach in diagnosis and prevention. OBJECTIVE: To evaluate sleep and circadian rhythm parameters, through wearable activity trackers, in MCI and AD patients as compared to controls, focusing on sex dissimilarities. METHODS: Based on minute level data from consumer wearable devices, we analyzed actigraphic sleep parameters by applying an electromedical type I registered algorithm, and the corresponding circadian variables in 158 subjects: 86 females and 72 males (42 AD, 28 MCI, and 88 controls). Moreover, we used a confusion-matrix chart method to assess accuracy, precision, sensitivity, and specificity of two decision-tree models based on actigraphic data in predicting disease or health status. RESULTS: Wake after sleep onset (WASO) was higher (p < 0.001) and sleep efficiency (SE) lower (p = 0.003) in MCI, and Sleep Regularity Index (SRI) was lower in AD patients compared to controls (p = 0.004). SE was lower in male AD compared to female AD (p = 0.038) and SRI lower in male AD compared to male controls (p = 0.008), male MCI (p = 0.047), but also female AD subjects (p = 0.046). Mesor was significantly lower in males in the overall population. Age reduced the dissimilarities for WASO and SE but demonstrated sex differences for amplitude (p = 0.009) in the overall population, controls (p = 0.005), and AD subjects (p = 0.034). The confusion-matrices showed good predictive power of actigraphic data. CONCLUSION: Actigraphic data could help identify disease or health status. Sex (possibly gender) differences could impact on neurodegeneration and disease trajectory with potential clinical applications.

Kitten Scanner reduces the use of sedation in pediatric MRI.

The use of sedation before a magnetic resonance imaging (MRI) scan is a common practice to overcome motion artifacts and anxiety in children. However, this technique has its drawbacks. We retrospectively compared the number of children undergoing a brain MRI scan with or without sedation before and after the introduction of an educational training protocol using a toy scanner (the Philips Kitten Scanner) and we investigated the effectiveness of this training in relation to children's age and gender. We considered 1461 children between 4 years and 14 years. Of them, 158 had a diagnosis of autism spectrum disorder or attention-deficit hyperactivity disorder and were excluded from further analysis. After the introduction of the Kitten Scanner training protocol, the sedation need decreased by 30% in the total sample group and in children younger than 10 years in particular. Before the training, females were more likely to undergo the MRI examination without sedation as compared to males, while after its introduction this gender difference was no more visible.

Angiotensin converting enzyme insertion/deletion polymorphism in sporadic and familial Alzheimer's disease and longevity.

A recent, large meta-analysis has reproposed the role of the angiotensin converting enzyme (ACE) insertion/deletion (I/D) polymorphism as a risk factor for Alzheimer's disease (AD). To further investigate the proposed association and to better clarify the role of ACE as a risk factor for AD, we analyzed the genotype and allele frequency distribution of ACE I/D and apolipoprotein E (APOE) gene polymorphisms in 235 Italian patients with sporadic AD, 153 with familial AD (FAD), 192 healthy controls and 111 centenarians. Patients with AD were consecutively gathered from among the outpatients from the Neurology Department at the University of Florence. All 691 subjects were genotyped for ACE and APOE polymorphisms. There were no significant differences in ACE genotypes or allele frequencies in all the studied groups, even after stratification for APOE epsilon4 carrier status. Centenarians show the highest allele D frequency, although the value is not significant, thus suggesting a possible implication of the D allele as an epistatic allele that has pleiotropic age-dependent effects. In conclusion, our data suggest that the ACE allelic variant is not a susceptibility factor in sporadic and familial AD (FAD), nor does it mitigate the effect of the APOE epsilon4 allele in the risk of developing AD. Moreover, our data do not suggest a possible involvement of the D allele in longevity.

Assessing neuro-motor recovery in a stroke survivor with high-resolution EEG, robotics and Virtual Reality.

One post-stroke patient underwent neuro-motor rehabilitation of one upper limb with a novel system combining a passive robotic device, Virtual Reality training applications and high resolution electroencephalography (HR-EEG). The outcome of the clinical tests and the evaluation of the kinematic parameters recorded with the robotic device concurred to highlight an improved motor recovery of the impaired limb despite the age of the patient, his compromised motor function, and the start of rehabilitation at the 3rd week post stroke. The time frequency and functional source analysis of the HR-EEG signals permitted to quantify the functional changes occurring in the brain in association with the rehabilitation motor tasks, and to highlight the recovery of the neuro-motor function.

Monitoring Neuro-Motor Recovery From Stroke With High-Resolution EEG, Robotics and Virtual Reality: A Proof of Concept.

A novel system for the neuro-motor rehabilitation of upper limbs was validated in three sub-acute post-stroke patients. The system permits synchronized cortical and kinematic measures by integrating high-resolution EEG, passive robotic device and Virtual Reality. The brain functional re-organization was monitored in association with motor patterns replicating activities of daily living (ADL). Patients underwent 13 rehabilitation sessions. At sessions 1, 7 and 13, clinical tests were administered to assess the level of motor impairment, and EEG was recorded during rehabilitation task execution. For each session and rehabilitation task, four kinematic indices of motor performance were calculated and compared with the outcome of clinical tests. Functional source maps were obtained from EEG data and projected on the real patients' anatomy (MRI data). Laterality indices were calculated for hemispheric dominance assessment. All patients showed increased participation in the rehabilitation process. Cortical activation changes during recovery were detected in relation to different motor patterns, hence verifying the system's suitability to add quantitative measures of motor performance and neural recovery to classical tests. We conclude that this system seems a promising tool for novel robot-based rehabilitation paradigms tailored to individual needs and neuro-motor responses of the patients.