Cholinergic activity supports cortical activation during REM sleep, while other neurotransmitter systems are almost silent. Here, we tested the long-standing hypothesis that early cholinergic denervation may be associated with REM sleep EEG slowing in older adults. Twenty-four older participants without dementia (mean age: 71.29 ± 4.85 years; 58.33% women; 25% participants with amnestic Mild Cognitive Impairment) underwent a night of in-laboratory polysomnography, comprehensive neuropsychological evaluation, structural MRI and molecular PET imaging with [18F]-Fluoroethoxybenzovesamicol (FEOBV) to quantify brain cholinergic innervation. Voxel-wise multiple regressions assessed the associations between REM sleep characteristics (i.e., REM sleep percentage, relative theta power and EEG slowing ratios, defined as [delta + theta]/[alpha + beta] power) and FEOBV-PET standard uptake value ratio maps, controlling for sex. Given that FEOBV uptake was higher in women compared to men, we also performed exploratory sex-stratified analyses adjusted for age. Higher REM sleep EEG slowing over frontal (F3-F4), central (C3-C4), parietal (P3-P4), occipital (O1-O2) and temporal (T5-T6) derivations was significantly associated with cortical cholinergic denervation, notably in fronto-parietal areas and the medial temporal lobe. Sex-stratified analyses showed that higher REM sleep EEG slowing ratios were associated with cholinergic denervation mainly in medial temporal regions in women, and neocortical regions in men. These findings suggest that global REM sleep EEG slowing may represent a sensitive marker of cortical cholinergic denervation in older adults without dementia, and may constitute a promising marker for early diagnosis and disease-modifying interventions in Alzheimer's disease.

Non-rapid eye movement sleep electroencephalographic activity has been proposed to provide helpful markers for the early detection of Alzheimer's disease. However, studies have produced mixed results regarding the impact of mild cognitive impairment-a prodromal stage-when using traditional spectral power analyses during this sleep phase. It is increasingly recognized that electrophysiological power spectra are composed of two components: a rhythmic part, which reflects oscillatory activity, and an arrhythmic part, which represents the balance of neuronal excitation and inhibition. In this cross-sectional study, our objective was thus to determine whether cognitive impairment is associated with the non-rapid eye movement sleep rhythmic and arrhythmic components in older adults. Fifty-six cognitively normal participants (68.3 ± 7.1 years old, 41% women) and 56 participants with amnestic mild cognitive impairment (69.9 ± 8.6 years old, 41% women) matched on multiple variables (age, sex, education, body mass index, apnoea-hypopnoea index) underwent a neuropsychological assessment and a night of polysomnography. Analyses focused on six channels of interest (F3, F4, C3, C4, P3 and P4). Significant between-group differences were observed for non-rapid eye movement sleep rhythmic and arrhythmic activity. Participants with amnestic mild cognitive impairment had lower rhythmic power in the fast-sigma/slow-beta range across all topographies investigated and higher gamma rhythmic power in the left parietal area. Participants with amnestic mild cognitive impairment also showed lower mean gamma aperiodic exponents-an arrhythmic activity measure-across all topographies. Frontal rhythmic power in the fast-sigma/slow-beta range predicted episodic memory in the amnestic mild cognitive impairment group. Our findings reveal alterations in both rhythmic and arrhythmic brain activity, indicating oscillatory changes and signs of hyperexcitability during non-rapid eye movement sleep in individuals with amnestic mild cognitive impairment.

Brain cholinergic denervation is among the earliest manifestations of Alzheimer's disease, and rapid eye movement (REM) sleep alterations have also been described early in the course of the disease. While cholinergic activity supports cortical activation during REM sleep, direct evidence for a link between cholinergic degeneration and early REM sleep alterations in humans is still lacking. Here, we tested the long-standing hypothesis that early cholinergic denervation may be associated with REM sleep EEG slowing in older adults with and without Mild Cognitive Impairment. Twenty-four older participants (mean [standard deviation] age: 71.29 [4.85] years; 58.33% women; 25% participants with amnestic Mild Cognitive Impairment) without dementia or moderate-to-severe obstructive sleep apnea underwent a night of in-laboratory polysomnography, comprehensive neuropsychological evaluation, structural MRI and molecular PET imaging with [18F]-Fluoroethoxybenzovesamicol (FEOBV), known for its sensitivity to quantify brain cholinergic innervation. Voxel-wise multiple regressions assessed the associations between REM sleep characteristics (i.e., REM sleep percentage, relative theta power and EEG slowing ratios, defined as [delta + theta]/[alpha + beta] power) and FEOBV-PET standard uptake value ratio maps corrected for partial volume effects, controlling for sex. Given that FEOBV uptake was higher in women compared to men, we also performed exploratory sex-stratified analyses adjusted for age. Higher REM sleep EEG slowing over frontal and parietal derivations was significantly associated with cortical cholinergic denervation, notably in fronto-parietal areas and the medial temporal lobe (P<0.005 level, combined with a cluster-level family-wise error correction). Exploratory sex-stratified analyses revealed that REM sleep EEG slowing was associated with cholinergic denervation in medial temporal regions in women, and neocortical regions in men. These findings provide the first direct in vivo evidence that REM sleep EEG slowing could represent a sensitive marker of cortical cholinergic denervation in older adults, prior to dementia onset. Thus, quantitative REM sleep EEG may constitute a promising marker for early diagnosis and disease-modifying interventions in Alzheimer's disease. ### Competing Interest Statement N.G. has received research grants, educational grants and sponsorship for the Weston Family Foundation, the American Academy of Sleep Medicine Foundation, Eisai, Jazz Pharmaceuticals, Idorsia, Paladin and Axsome, but none are related to the present project. The other authors report no competing interests. ### Funding Statement This study was funded by the Canadian Institutes of Health Research (CIHR) through a project grant (PJT153259), as well as a Foundation grant (FDN154291) and Operating grants (MOP123294 and MOP102631). C.A. was supported by a postdoctoral fellowship from the Fonds de Recherche du Quebec - Sante. N.A.M. was supported by the Swiss National Science Foundation Postdoc Mobility fellowship. N.G. holds a Canada Research Chair in sleep disorders and brain health. J.M. holds a Canada Research Chair in Sleep Medicine. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The protocol was approved by the ethics committee of the CIUSSS du Nord-de-l'Ile-de-Montreal (MP-32-2018-1537), and a written informed consent was obtained from each participant prior to the examinations, according to the declaration of Helsinki. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data used in the present study will be available upon request to the corresponding author.

This correlational study explores the relationship between sleep and inflammation in aged individuals. Cytokines are involved in various central nervous system processes, including wakefulness, appetite, mood regulation, sexual behaviors, and thermoregulation. Sleep disorders commonly associated with aging, such as insomnia, circadian disruptions, sleep apnea, and periodic leg movements, might have significant biological impacts on the inflammatory system and immune functions. Aging is also associated with increased levels of some inflammatory markers. 77 individuals (women: 51, men: 26) aged 60–87 years (mean age 69.8 ± 6.1 years) were recruited from the community. None were using psychoactive drugs. Participants underwent three nights of polysomnographic sleep recording in the laboratory: the first night served for adaptation and sleep disorder assessment, while nights two and three were for experimentation. A 19-channel EEG montage was used with additional sensors for eye movements, muscle activity, respiration, and leg movements. Fasting, resting venous blood was drawn in the morning upon awakening for further measurement of cytokine receptors IL-1α, IL-1β, IL-1RA, IL-6, IL-8, IL-10, TNFα and sTNFR1 in serum (Milliplex). Questionnaires assessed health (SF-36), sleep quality (PSQI), anxiety (BAI), and depressive symptoms (BDI, POMS). Periodic Leg Movement during Sleep (PLMS) was correlated to four inflammation markers (IL10 (.361), IL6 (.307), IL1B (.264) IL1A (.227)), the most of any other sleep variables, clearly indicating that PLMS is associated with a prolonged state of inflammation. sTNFR1 was the biomarker most associated with other variables (Micro-arousal (-.375), AHI (Apnea Hypopnea Index:.278), #Arousal (-.261), Stage1 (-.238), POMS (.401)). The first three variables are sleep disrupters and Stage1 augments when there is less of deeper sleep states, it seems counterintuitive that they would consistently negatively correlate with an anti-inflammatory marker. AHI was further correlated with IL1RA (.277). Correlations are modest but many and significant, pointing toward a definite role of sleep in inflammatory processes. The signaling relevance of biomarkers, being pro, anti or both, depending on circumstances, remains ambiguous.

OBJECTIVE:Attention deficit disorder with or without hyperactivity (ADHD) has negative consequences for children. The effectiveness of medical interventions and educational outcomes are strongly influenced by expectations, which can be modulated by nocebo effects. The aims of this study were to compare the nocebo effect on pain perception and attention in children with and without ADHD as well as to characterize the associations of the nocebo effect with personal variables, such as anxiety, sleep, and pain catastrophizing. METHODS:Data were collected from 30 children with and without ADHD. The nocebo effect was induced using an inactive pill, "increasing" pain perception and attention deficits. Experimental thermal pain was evoked using a thermode and recorded using a computerized visual analog scale. Attention abilities were measured with the Stop-Signal Task. We also used questionnaires to measure personal variables. RESULTS:When combining groups, the nocebo treatment led to comparable nocebo effects for pain (increased pain perception) and attention (increased time needed for inhibition). When comparing groups, the nocebo effect on pain perception was similar for children with and without ADHD. Inattention, learning problems, anxiety, and sleep problems were associated with the nocebo response for pain and attention. CONCLUSION:This exploratory study conducted in an experimental setting emphasizes the importance of managing children's expectations for pain perception and attention as well as the potentially deleterious impact of negative suggestions on elementary school children.

Study Objectives Apolipoprotein E ɛ4 (APOE4) is the strongest genetic risk factor for Alzheimer’s disease (AD). In addition, APOE4 carriers may exhibit sleep disturbances, but conflicting results have been reported, such that there is no clear consensus regarding which aspects of sleep are impacted. Our objective was to compare objective sleep architecture between APOE4 carriers and non-carriers, and to investigate the modulating impact of age, sex, cognitive status, and obstructive sleep apnea (OSA). Methods A total of 198 dementia-free participants aged >55 years old (mean age: 68.7 ± 8.08 years old, 40.91% women, 41 APOE4 carriers) were recruited in this cross-sectional study. They underwent polysomnography, APOE4 genotyping, and a neuropsychological evaluation. ANCOVAs assessed the effect of APOE4 status on sleep architecture, controlling for age, sex, cognitive status, and the apnea–hypopnea index. Interaction terms were added between APOE4 status and covariates. Results Rapid eye movement (REM) sleep percentage (F = 9.95, p = .002, ηp2 = 0.049) and duration (F = 9.23, p = .003, ηp2 = 0.047) were lower in APOE4 carriers. The results were replicated in a subsample of 112 participants without moderate-to-severe OSA. There were no significant interactions between APOE4 status and age, sex, cognitive status, and OSA in the whole sample. Conclusions Our results show that APOE4 carriers exhibit lower REM sleep duration, including in cognitively unimpaired individuals, possibly resulting from early neurodegenerative processes in regions involved in REM sleep generation and maintenance.

INTRODUCTION:The limbic system is critical for memory function and degenerates early in the Alzheimer's disease continuum. Whether obstructive sleep apnea (OSA) is associated with alterations in the limbic white matter tracts remains understudied. METHODS:Polysomnography, neurocognitive assessment, and brain magnetic resonance imaging (MRI) were performed in 126 individuals aged 55-86 years, including 70 cognitively unimpaired participants and 56 participants with mild cognitive impairment (MCI). OSA measures of interest were the apnea-hypopnea index and composite variables of sleep fragmentation and hypoxemia. Microstructural properties of the cingulum, fornix, and uncinate fasciculus were estimated using free water-corrected diffusion tensor imaging. RESULTS:Higher levels of OSA-related hypoxemia were associated with higher left fornix diffusivities only in participants with MCI. Microstructure of the other white matter tracts was not associated with OSA measures. Higher left fornix diffusivities correlated with poorer episodic verbal memory. DISCUSSION:OSA may contribute to fornix damage and memory dysfunction in MCI. HIGHLIGHTS:Sleep apnea-related hypoxemia was associated with altered fornix integrity in MCI. Altered fornix integrity correlated with poorer memory function. Sleep apnea may contribute to fornix damage and memory dysfunction in MCI.

Study Objectives: Apolipoprotein E epsilon 4 (APOE4) is the strongest genetic risk factor for Alzheimer's disease (AD). In addition, APOE4 carriers may exhibit sleep disturbances, but conflicting results have been reported, such that there is no clear consensus regarding which aspects of sleep are impacted. Our objective was to compare objective sleep architecture between APOE4 carriers and non-carriers, and to investigate the modulating impact of age, sex, cognitive status, and obstructive sleep apnea (OSA). Methods: A total of 198 dementia-free participants aged >55 years old (mean age: 68.7 +/- 8.08 years old, 40.91% women, 41 APOE4 carriers) were recruited in this cross-sectional study. They underwent polysomnography, APOE4 genotyping, and a neuropsychological evaluation. ANCOVAs assessed the effect of APOE4 status on sleep architecture, controlling for age, sex, cognitive status, and the apnea-hypopnea index. Interaction terms were added between APOE4 status and covariates. Results: Rapid eye movement (REM) sleep percentage (F = 9.95, p = .002, eta p2 = 0.049) and duration (F = 9.23, p = .003, eta p2 = 0.047) were lower in APOE4 carriers. The results were replicated in a subsample of 112 participants without moderate-to-severe OSA. There were no significant interactions between APOE4 status and age, sex, cognitive status, and OSA in the whole sample. Conclusions: Our results show that APOE4 carriers exhibit lower REM sleep duration, including in cognitively unimpaired individuals, possibly resulting from early neurodegenerative processes in regions involved in REM sleep generation and maintenance.

Rapid-eye movement (REM) sleep highly depends on the activity of cholinergic basal forebrain (BF) neurons and is reduced in Alzheimer’s disease. Here, we investigated the associations between the volume of BF nuclei and REM sleep characteristics, and the impact of cognitive status on these links, in late middle-aged and older participants. Thirty-one cognitively healthy controls (66.8 ± 7.2 years old, 13 women) and 31 participants with amnestic Mild Cognitive Impairment (aMCI) (68.3 ± 8.8 years old, 7 women) were included in this cross-sectional study. All participants underwent polysomnography, a comprehensive neuropsychological assessment and Magnetic Resonance Imaging examination. REM sleep characteristics (i.e., percentage, latency and efficiency) were derived from polysomnographic recordings. T1-weighted images were preprocessed using CAT12 and the DARTEL algorithm, and we extracted the gray matter volume of BF regions of interest using a probabilistic atlas implemented in the JuBrain Anatomy Toolbox. Multiple linear regressions were performed between the volume of BF nuclei and REM sleep characteristics controlling for age, sex and total intracranial volume, in the whole cohort and in subgroups stratified by cognitive status. In the whole sample, lower REM sleep percentage was significantly associated to lower nucleus basalis of Meynert (Ch4) volume (β = 0.32, p = 0.009). When stratifying the cohort according to cognitive status, lower REM sleep percentage was significantly associated to both lower Ch4 (β = 0.48, p = 0.012) and total BF volumes (β = 0.44, p = 0.014) in aMCI individuals, but not in cognitively unimpaired participants. No significant associations were observed between the volume of the BF and wake after sleep onset or non-REM sleep variables. These results suggest that REM sleep disturbances may be an early manifestation of the degeneration of the BF cholinergic system before the onset of dementia, especially in participants with mild memory deficits.

Medial temporal structures, namely the hippocampus, the entorhinal cortex and the parahippocampal gyrus, are particularly vulnerable to Alzheimer's disease and hypoxemia. Here, we tested the associations between obstructive sleep apnea (OSA) severity and medial temporal lobe volumes in 114 participants aged 55-86 years (35 % women). We also investigated the impact of sex, age, cognitive status, and free-water fraction correction on these associations. Increased OSA severity was associated with larger hippocampal and entorhinal cortex volumes in women, but not in men. Greater OSA severity also correlated with increased hippocampal volumes in participants with amnestic mild cognitive impairment, but not in cognitively unimpaired participants, regardless of sex. Using free-water corrected volumes eliminated all significant associations with OSA severity. Therefore, the increase in medial temporal subregion volumes may possibly be due to edema. Whether these structural manifestations further progress to neuronal death in non-treated OSA patients should be investigated.

Determining the prevalence and characteristics of individuals susceptible to present with obstructive sleep apnea (OSA) is essential for developing targeted and efficient prevention and screening strategies. We included 27,210 participants aged ≥45 years old (50.3% women) from the Canadian Longitudinal Study on Aging. Using the STOP questionnaire combined to the percentage of body fat (%BF), we estimated the prevalence of individuals at high-risk for OSA in a sex and age-specific manner, and tested the relation with comorbidities, menopause and systemic inflammation. The prevalence was 17.5%, and was lower in women (13.1%) than in men (21.9%). A high level of high-sensitivity C-reactive protein was the strongest factor associated with OSA risk and this association was 1.3–2.3 times higher in women than in men. OSA risk increased with age, cardiovascular diseases, diabetes mellitus, anxio-depressive symptoms, asthma and arthritis. In women, post-menopausal status was associated with a high OSA risk. Nearly 1 adult out of 5 older than 45 is at risk for OSA in Canada. Comorbidities, menopause and systemic inflammation, more than age, explain increased OSA prevalence. Considering this high prevalence and associations with medical and mental comorbidities, health care practitioners should incorporate systematic OSA screening in their clinical procedures.

The basal forebrain cholinergic system (BFCS) degenerates in Alzheimer’s disease (AD) before the onset of dementia. Interestingly, rapid-eye movement (REM) sleep is highly dependent on cholinergic activity. In AD patients, REM sleep duration is reduced but the underlying brain mechanisms are still unclear. Our objective was to investigate the associations between REM-sleep quantity and BFCS integrity in participants with amnestic mild cognitive impairment (aMCI) compared to healthy controls. Sixty-two participants (31 cognitively healthy: 66.8 ± 7.2 years old, 13 women; 31 aMCI: 68.3 ± 8.8 years old, 7 women) underwent polysomnography and structural magnetic resonance imaging examinations. REM sleep duration (number of minutes) and proportion (%) were computed. All participants had a REM sleep apnea-hypopnea index <15. T1-weighted images were preprocessed using CAT12 and the DARTEL algorithm, and the mean intensity of BFCS subregions (i.e., Ch1-2-3, Ch4 and total BFCS) was extracted using the JuBrain Anatomy Toolbox. Multiple regressions were performed between BFCS subregional intensities and REM sleep indices controlling for age, sex and total intracranial volume, in the whole cohort and in the two groups separately. In the whole cohort, REM sleep duration and proportion were positively associated with Ch4 intensity (duration: r = 0.31, p = 0.017; proportion: r = 0.35, p = 0.007; Figure 1A and B) and total BFCS intensity (duration: r = 0.31, p = 0.016; proportion: r = 0.29, p = 0.024). Analyses stratified by cognitive status showed the same pattern in aMCI participants: REM sleep duration and proportion were positively associated with both Ch4 intensity (duration: r = 0.44, p = 0.018; proportion: r = 0.49, p = 0.009; Figure 1C and D) and total BFCS intensity (duration: r = 0.46, p = 0.014; proportion: r = 0.46, p = 0.013). No significant association, nor trend, was found in cognitively healthy participants (Figure 1C and D). In aMCI participants, lower REM sleep duration and proportion were associated with a decreased integrity of the BFCS, especially the Nucleus Basalis of Meynert. Our results support the notion that REM sleep alterations are an early marker of the degeneration of the BFCS in prodromal AD, before the onset of dementia.

The progressive histopathological sequence over the first 3 hr after a 400 g-cm blunt injury to the spinal cord of catecholamine (CA)-intact and CA-depleted cats is described. Norepinephrine levels were measured in all animals. The experiments were designed to determine the role of CA in progressive hemorrhagic necrosis of the spinal cord by removing CA from one group of animals prior to trauma. A second group of CA-intact animals was subjected to identical experimentally-induced trauma. Upon analysis of the histopathological changes, it appears that the sequential nature of the development of hemorrhagic necrosis is both qualitatively and quantitatively similar in both experimental groups. The general conclusion is drawn that catecholamines in greater than normal amounts are present at the lesion site after trauma, but these catecholamines are probably not involved in the process of central hemorrhagic necrosis.