Impact of Sleep Disorders and Disturbed Sleep on Brain Health: A Scientific Statement From the American Heart Association.

Accumulating evidence supports a link between sleep disorders, disturbed sleep, and adverse brain health, ranging from stroke to subclinical cerebrovascular disease to cognitive outcomes, including the development of Alzheimer disease and Alzheimer disease-related dementias. Sleep disorders such as sleep-disordered breathing (eg, obstructive sleep apnea), and other sleep disturbances, as well, some of which are also considered sleep disorders (eg, insomnia, sleep fragmentation, circadian rhythm disorders, and extreme sleep duration), have been associated with adverse brain health. Understanding the causal role of sleep disorders and disturbances in the development of adverse brain health is complicated by the common development of sleep disorders among individuals with neurodegenerative disease. In addition to the role of sleep disorders in stroke and cerebrovascular injury, mechanistic hypotheses linking sleep with brain health and biomarker data (blood-based, cerebrospinal fluid-based, and imaging) suggest direct links to Alzheimer disease-specific pathology. These potential mechanisms and the increasing understanding of the "glymphatic system," and the recognition of the importance of sleep in poststroke recovery, as well, support a biological basis for the indirect (through the worsening of vascular disease) and direct (through specific effects on neuropathology) connections between sleep disorders and brain health. Given promising evidence for the benefits of treatment and prevention, sleep disorders and disturbances represent potential targets for early treatment that may improve brain health more broadly. In this scientific statement, we discuss the evidence supporting an association between sleep disorders and disturbances and poor brain health ranging from stroke to dementia and opportunities for prevention and early treatment.

The stability of slow-wave sleep and EEG oscillations across two consecutive nights of laboratory polysomnography in cognitively normal older adults.

Laboratory polysomnography provides gold-standard measures of sleep physiology, but multi-night investigations are resource intensive. We assessed the night-to-night stability via reproducibility metrics for sleep macrostructure and electroencephalography oscillations in a group of cognitively normal adults attending two consecutive polysomnographies. Electroencephalographies were analysed using an automatic algorithm for detection of slow-wave activity, spindle and K-complex densities. Average differences between nights for sleep macrostructure, electroencephalography oscillations and sleep apnea severity were assessed, and test-retest reliability was determined using two-way intraclass correlations. Agreement was calculated using the smallest real differences between nights for all measures. Night 2 polysomnographies showed significantly greater time in bed, total sleep time (6.3 hr versus 6.8 hr, p < 0.001) and percentage of rapid eye movement sleep (17.5 versus 19.7, p < 0.001). Intraclass correlations were low for total sleep time, percentage of rapid eye movement sleep and sleep efficiency, moderate for percentage of slow-wave sleep and percentage of non-rapid eye movement 2 sleep, good for slow-wave activity and K-complex densities, and excellent for spindles and apnea-hypopnea index with hypopneas defined according to 4% oxygen desaturation criteria only. The smallest real difference values were proportionally high for most sleep macrostructure measures, indicating moderate agreement, and proportionally lower for most electroencephalography microstructure variables. Slow waves, K-complexes, spindles and apnea severity indices are highly reproducible across two consecutive nights of polysomnography. In contrast, sleep macrostructure measures all demonstrated poor reproducibility as indicated by low intraclass correlation values and moderate agreement. Although there were average differences in percentage of rapid eye movement sleep and total sleep time, these were numerically small and perhaps functionally or clinically less significant. One night of in-laboratory polysomnography is enough to provide stable, reproducible estimates of an individual's sleep concerning measures of slow-wave activity, spindles, K-complex densities and apnea severity.

The neutrophil to lymphocyte ratio associates with markers of Alzheimer's disease pathology in cognitively unimpaired elderly people.

BACKGROUND: An elevated neutrophil-lymphocyte ratio (NLR) in blood has been associated with Alzheimer's disease (AD). However, an elevated NLR has also been implicated in many other conditions that are risk factors for AD, prompting investigation into whether the NLR is directly linked with AD pathology or a result of underlying comorbidities. Herein, we explored the relationship between the NLR and AD biomarkers in the cerebrospinal fluid (CSF) of cognitively unimpaired (CU) subjects. Adjusting for sociodemographics, APOE4, and common comorbidities, we investigated these associations in two cohorts: the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the M.J. de Leon CSF repository at NYU. Specifically, we examined associations between the NLR and cross-sectional measures of amyloid-ß42 (Aß42), total tau (t-tau), and phosphorylated tau181 (p-tau), as well as the trajectories of these CSF measures obtained longitudinally. RESULTS: A total of 111 ADNI and 190 NYU participants classified as CU with available NLR, CSF, and covariate data were included. Compared to NYU, ADNI participants were older (73.79 vs. 61.53, p < 0.001), had a higher proportion of males (49.5% vs. 36.8%, p = 0.042), higher BMIs (27.94 vs. 25.79, p < 0.001), higher prevalence of hypertensive history (47.7% vs. 16.3%, p < 0.001), and a greater percentage of Aß-positivity (34.2% vs. 20.0%, p = 0.009). In the ADNI cohort, we found cross-sectional associations between the NLR and CSF Aß42 (ß = -12.193, p = 0.021), but not t-tau or p-tau. In the NYU cohort, we found cross-sectional associations between the NLR and CSF t-tau (ß = 26.812, p = 0.019) and p-tau (ß = 3.441, p = 0.015), but not Aß42. In the NYU cohort alone, subjects classified as Aß + (n = 38) displayed a stronger association between the NLR and t-tau (ß = 100.476, p = 0.037) compared to Aß- subjects or the non-stratified cohort. In both cohorts, the same associations observed in the cross-sectional analyses were observed after incorporating longitudinal CSF data. CONCLUSIONS: We report associations between the NLR and Aß42 in the older ADNI cohort, and between the NLR and t-tau and p-tau in the younger NYU cohort. Associations persisted after adjusting for comorbidities, suggesting a direct link between the NLR and AD. However, changes in associations between the NLR and specific AD biomarkers may occur as part of immunosenescence.

Antidepressant exposure and long-term dementia risk in a nationwide retrospective study on US veterans with midlife major depressive disorder.

INTRODUCTION: The use of antidepressants in major depressive disorder (MDD) has been reported to influence long-term risk of Alzheimer's disease (AD) and AD-related dementias (AD/ADRD), but studies are conflicting. METHODS: We used inverse probability weighted (IPW) Cox models with time-varying covariates in a retrospective cohort study among midlife veterans with MDD within the US Veterans Affairs healthcare system from January 1, 2000 to June 1, 2022. RESULTS: A total of 35,200 patients with MDD were identified. No associations were seen regarding the effect of being exposed to any antidepressant versus no exposure on AD/ADRD risk (events = 1,056, hazard ratio = 0.94, 95% confidence interval: 0.81 to 1.09) or the exposure to specific antidepressant classes versus no exposure. A risk reduction was observed for female patients in a stratified analysis; however, the number of cases was small. DISCUSSION: Our study suggests that antidepressant exposure has no effect on AD/ADRD risk. The association in female patients should be interpreted with caution and requires further attention. HIGHLIGHTS: We studied whether antidepressant use was associated with future dementia risk. We specifically focused on patients after their first-ever diagnosis of depression. We used IPW Cox models with time-varying covariates and a large observation window. Our study did not identify an effect of antidepressant use on dementia risk. A risk reduction was observed in female patients, but the number of cases was small.

Association between lower body temperature and increased tau pathology in cognitively normal older adults.

BACKGROUND: Preclinical studies suggest body temperature (Tb) and consequently brain temperature has the potential to bidirectionally interact with tau pathology in Alzheimer's Disease (AD). Tau phosphorylation is substantially increased by a small (<1 °C) decrease in temperature within the human physiological range, and thermoregulatory nuclei are affected by tau pathology early in the AD continuum. In this study we evaluated whether Tb (as a proxy for brain temperature) is cross-sectionally associated with clinically utilized markers of tau pathology in cognitively normal older adults. METHODS: Tb was continuously measured with ingestible telemetry sensors for 48 h. This period included two nights of nocturnal polysomnography to delineate whether Tb during waking vs sleep is differentially associated with tau pathology. Tau phosphorylation was assessed with plasma and cerebrospinal fluid (CSF) tau phosphorylated at threonine 181 (P-tau), sampled the day following Tb measurement. In addition, neurofibrillary tangle (NFT) burden in early Braak stage regions was imaged with PET-MR using the [18F]MK-6240 radiotracer on average one month later. RESULTS: Lower Tb was associated with increased NFT burden, as well as increased plasma and CSF P-tau levels (p < 0.05). NFT burden was associated with lower Tb during waking (p < 0.05) but not during sleep intervals. Plasma and CSF P-tau levels were highly correlated with each other (p < 0.05), and both variables were correlated with tau tangle radiotracer uptake (p < 0.05). CONCLUSIONS: These results, the first available for human, suggest that lower Tb in older adults may be associated with increased tau pathology. Our findings add to the substantial preclinical literature associating lower body and brain temperature with tau hyperphosphorylation. CLINICAL TRIAL NUMBER: NCT03053908.

Sleep apnoea in the elderly: a great challenge for the future.

Due in part to overall improvements in health, the population of elderly individuals is increasing rapidly. Similarly, obstructive sleep apnoea (OSA) is both gaining increased recognition and also increasing due to the worldwide obesity epidemic. The overlap of OSA and ageing is large, but there is strong plausibility for causation in both directions: OSA is associated with pathological processes that may accelerate ageing and ageing-related processes; ageing may cause physical and neurological changes that predispose to obstructive (and central) apnoea. In addition, the common symptoms (e.g. excessive daytime sleepiness, and defects in memory and cognition), possible physiological consequences of OSA (e.g. accelerated cardiovascular and cerebrovascular atherosclerosis), and changes in metabolic and inflammatory markers overlap with the symptoms and associated conditions seen in ageing. There is also the possibility of synergy in the effects of these symptoms and conditions on quality of life, as well as a need to separate treatable consequences of OSA from age-related complaints. Taken together, the aforementioned considerations make it essential to review the interaction of OSA and ageing, both proven and suspected. The present review examines some aspects of what is known and points to the need for further investigation of the relationships, given the large number of potentially affected subjects.

Endotyping Sleep Apnea One Breath at a Time: An Automated Approach for Separating Obstructive from Central Sleep-disordered Breathing.

Rationale: Determining whether an individual has obstructive or central sleep apnea is fundamental to selecting the appropriate treatment. Objectives: Here we derive an automated breath-by-breath probability of obstruction, as a surrogate of gold-standard upper airway resistance, using hallmarks of upper airway obstruction visible on clinical sleep studies. Methods: From five nocturnal polysomnography signals (airflow, thoracic and abdominal effort, oxygen saturation, and snore), nine features were extracted and weighted to derive the breath-by-breath probability of obstruction (Pobs). A development and initial test set of 29 subjects (development = 6, test = 23) (New York, NY) and a second test set of 39 subjects (Solingen, Germany), both with esophageal manometry, were used to develop Pobs and validate it against gold-standard upper airway resistance. A separate dataset of 114 subjects with 2 consecutive nocturnal polysomnographies (New York, NY) without esophageal manometry was used to assess the night-to-night variability of Pobs. Measurements and Main Results: A total of 1,962,229 breaths were analyzed. On a breath-by-breath level, Pobs was strongly correlated with normalized upper airway resistance in both test sets (set 1: cubic adjusted [adj.] R2 = 0.87, P < 0.001, area under the receiver operating characteristic curve = 0.74; set 2: cubic adj. R2 = 0.83, P < 0.001, area under the receiver operating characteristic curve = 0.7). On a subject level, median Pobs was associated with the median normalized upper airway resistance (set 1: linear adj. R2 = 0.59, P < 0.001; set 2: linear adj. R2 = 0.45, P < 0.001). Median Pobs exhibited low night-to-night variability [intraclass correlation(2, 1) = 0.93]. Conclusions: Using nearly 2 million breaths from 182 subjects, we show that breath-by-breath probability of obstruction can reliably predict the overall burden of obstructed breaths in individual subjects and can aid in determining the type of sleep apnea.

Clinical and biomarker changes of Alzheimer's disease in adults with Down syndrome: a cross-sectional study.

BACKGROUND: Alzheimer's disease and its complications are the leading cause of death in adults with Down syndrome. Studies have assessed Alzheimer's disease in individuals with Down syndrome, but the natural history of biomarker changes in Down syndrome has not been established. We characterised the order and timing of changes in biomarkers of Alzheimer's disease in a population of adults with Down syndrome. METHODS: We did a dual-centre cross-sectional study of adults with Down syndrome recruited through a population-based health plan in Barcelona (Spain) and through services for people with intellectual disabilities in Cambridge (UK). Cognitive impairment in participants with Down syndrome was classified with the Cambridge Cognitive Examination for Older Adults with Down Syndrome (CAMCOG-DS). Only participants with mild or moderate disability were included who had at least one of the following Alzheimer's disease measures: apolipoprotein E allele carrier status; plasma concentrations of amyloid ß peptides 1-42 and 1-40 and their ratio (Aß1-42/1-40), total tau protein, and neurofilament light chain (NFL); tau phosphorylated at threonine 181 (p-tau), and NFL in cerebrospinal fluid (CSF); and one or more of PET with 18F-fluorodeoxyglucose, PET with amyloid tracers, and MRI. Cognitively healthy euploid controls aged up to 75 years who had no biomarker abnormalities were recruited from the Sant Pau Initiative on Neurodegeneration. We used a first-order locally estimated scatterplot smoothing curve to determine the order and age at onset of the biomarker changes, and the lowest ages at the divergence with 95% CIs are also reported where appropriate. FINDINGS: Between Feb 1, 2013, and June 28, 2019 (Barcelona), and between June 1, 2009, and Dec 31, 2014 (Cambridge), we included 388 participants with Down syndrome (257 [66%] asymptomatic, 48 [12%] with prodromal Alzheimer's disease, and 83 [21%] with Alzheimer's disease dementia) and 242 euploid controls. CSF Aß1-42/1-40 and plasma NFL values changed in individuals with Down syndrome as early as the third decade of life, and amyloid PET uptake changed in the fourth decade. 18F-fluorodeoxyglucose PET and CSF p-tau changes occurred later in the fourth decade of life, followed by hippocampal atrophy and changes in cognition in the fifth decade of life. Prodromal Alzheimer's disease was diagnosed at a median age of 50·2 years (IQR 47·5-54·1), and Alzheimer's disease dementia at 53·7 years (49·5-57·2). Symptomatic Alzheimer's disease prevalence increased with age in individuals with Down syndrome, reaching 90-100% in the seventh decade of life. INTERPRETATION: Alzheimer's disease in individuals with Down syndrome has a long preclinical phase in which biomarkers follow a predictable order of changes over more than two decades. The similarities with sporadic and autosomal dominant Alzheimer's disease and the prevalence of Down syndrome make this population a suitable target for Alzheimer's disease preventive treatments. FUNDING: Instituto de Salud Carlos III, Fundació Bancaria La Caixa, Fundació La Marató de TV3, Medical Research Council, and National Institutes of Health.

ENIGMA-Sleep: Challenges, opportunities, and the road map.

Neuroimaging and genetics studies have advanced our understanding of the neurobiology of sleep and its disorders. However, individual studies usually have limitations to identifying consistent and reproducible effects, including modest sample sizes, heterogeneous clinical characteristics and varied methodologies. These issues call for a large-scale multi-centre effort in sleep research, in order to increase the number of samples, and harmonize the methods of data collection, preprocessing and analysis using pre-registered well-established protocols. The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) consortium provides a powerful collaborative framework for combining datasets across individual sites. Recently, we have launched the ENIGMA-Sleep working group with the collaboration of several institutes from 15 countries to perform large-scale worldwide neuroimaging and genetics studies for better understanding the neurobiology of impaired sleep quality in population-based healthy individuals, the neural consequences of sleep deprivation, pathophysiology of sleep disorders, as well as neural correlates of sleep disturbances across various neuropsychiatric disorders. In this introductory review, we describe the details of our currently available datasets and our ongoing projects in the ENIGMA-Sleep group, and discuss both the potential challenges and opportunities of a collaborative initiative in sleep medicine.

Contribution of pulmonary diseases to COVID-19 mortality in a diverse urban community of New York.

We examined the relative contribution of pulmonary diseases (chronic obstructive pulmonary disease, asthma and sleep apnea) to mortality risks associated with Coronavirus Disease (COVID-19) independent of other medical conditions, health risks, and sociodemographic factors. Data were derived from a large US-based case series of patients with COVID-19, captured from a quaternary academic health network covering New York City and Long Island. From March 2 to May 24, 2020, 11,512 patients who were hospitalized were tested for COVID-19, with 4,446 (38.62%) receiving a positive diagnosis for COVID-19. Among those who tested positive, 959 (21.57%) died of COVID-19-related complications at the hospital. Multivariate-adjusted Cox proportional hazards modeling showed mortality risks were strongly associated with greater age (HR = 1.05; 95% CI: 1.04-1.05), ethnic minority (Asians, Non-Hispanic blacks, and Hispanics) (HR = 1.26; 95% CI, 1.10-1.44), low household income (HR = 1.29; 95% CI: 1.11, 1.49), and male sex (HR = 0.85; 95% CI: 0.74, 0.97). Higher mortality risks were also associated with a history of COPD (HR = 1.27; 95% CI: 1.02-1.58), obesity (HR = 1.19; 95% CI: 1.04-1.37), and peripheral artery disease (HR = 1.33; 95% CI: 1.05-1.69). Findings indicate patients with COPD had the highest odds of COVID-19 mortality compared with patients with pre-existing metabolic conditions, such as obesity, diabetes and hypertension. Sociodemographic factors including increased age, male sex, low household income, ethnic minority status were also independently associated with greater mortality risks.

Obstructive Sleep Apnea and Its Treatment in Aging: Effects on Alzheimer's disease Biomarkers, Cognition, Brain Structure and Neurophysiology.

Here we review the impact of obstructive sleep apnea (OSA) on biomarkers of Alzheimer's disease (AD) pathogenesis, neuroanatomy, cognition and neurophysiology, and present the research investigating the effects of continuous positive airway pressure (CPAP) therapy. OSA is associated with an increase in AD markers amyloid-ß and tau measured in cerebrospinal fluid (CSF), by Positron Emission Tomography (PET) and in blood serum. There is some evidence suggesting CPAP therapy normalizes AD biomarkers in CSF but since mechanisms for amyloid-ß and tau production/clearance in humans are not completely understood, these findings remain preliminary. Deficits in the cognitive domains of attention, vigilance, memory and executive functioning are observed in OSA patients with the magnitude of impairment appearing stronger in younger people from clinical settings than in older community samples. Cognition improves with varying degrees after CPAP use, with the greatest effect seen for attention in middle age adults with more severe OSA and sleepiness. Paradigms in which encoding and retrieval of information are separated by periods of sleep with or without OSA have been done only rarely, but perhaps offer a better chance to understand cognitive effects of OSA than isolated daytime testing. In cognitively normal individuals, changes in EEG microstructure during sleep, particularly slow oscillations and spindles, are associated with biomarkers of AD, and measures of cognition and memory. Similar changes in EEG activity are reported in AD and OSA, such as "EEG slowing" during wake and REM sleep, and a degradation of NREM EEG microstructure. There is evidence that CPAP therapy partially reverses these changes but large longitudinal studies demonstrating this are lacking. A diagnostic definition of OSA relying solely on the Apnea Hypopnea Index (AHI) does not assist in understanding the high degree of inter-individual variation in daytime impairments related to OSA or response to CPAP therapy. We conclude by discussing conceptual challenges to a clinical trial of OSA treatment for AD prevention, including inclusion criteria for age, OSA severity, and associated symptoms, the need for a potentially long trial, defining relevant primary outcomes, and which treatments to target to optimize treatment adherence.

Cerebral white matter diffusion properties and free-water with obstructive sleep apnea severity in older adults.

Characterizing the effects of obstructive sleep apnea (OSA) on the aging brain could be key in our understanding of neurodegeneration in this population. Our objective was to assess white matter properties in newly diagnosed and untreated adults with mild to severe OSA. Sixty-five adults aged 55 to 85 were recruited and divided into three groups: control (apnea-hypopnea index ≤5/hr; n = 18; 65.2 ± 7.2 years old), mild (>5 to ≤15 hr; n = 27; 64.2 ± 5.3 years old) and moderate to severe OSA (>15/hr; n = 20; 65.2 ± 5.5 years old). Diffusion tensor imaging metrics (fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity, and mean diffusivity) were compared between groups with Tract-Based Spatial Statistics within the white matter skeleton created by the technique. Groups were also compared for white matter hyperintensities volume and the free-water (FW) fraction. Compared with controls, mild OSA participants showed widespread areas of lower diffusivity (p < .05 corrected) and lower FW fraction (p < .05). Participants with moderate to severe OSA showed lower AD in the corpus callosum compared with controls (p < .05 corrected). No between-group differences were observed for FA or white matter hyperintensities. Lower white matter diffusivity metrics is especially marked in mild OSA, suggesting that even the milder form may lead to detrimental outcomes. In moderate to severe OSA, competing pathological responses might have led to partial normalization of diffusion metrics.

Gray matter volume and estimated brain age gap are not linked with sleep-disordered breathing.

Alzheimer's disease (AD) and sleep-disordered breathing (SDB) are prevalent conditions with a rising burden. It is suggested that SDB may contribute to cognitive decline and advanced aging. Here, we assessed the link between self-reported SDB and gray matter volume in patients with AD, mild cognitive impairment (MCI) and healthy controls (HCs). We further investigated whether SDB was associated with advanced brain aging. We included a total of 330 participants, divided based on self-reported history of SDB, and matched across diagnoses for age, sex and presence of the Apolipoprotein E4 allele, from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Gray-matter volume was measured using voxel-wise morphometry and group differences in terms of SDB, cognitive status, and their interaction were assessed. Further, using an age-prediction model fitted on gray-matter data of external datasets, we predicted study participants' age from their structural images. Cognitive decline and advanced age were associated with lower gray matter volume in various regions, particularly in the bilateral temporal lobes. Brains age was well predicted from the morphological data in HCs and, as expected, elevated in MCI and particularly in AD subjects. However, there was neither a significant difference between regional gray matter volume in any diagnostic group related to the SDB status, nor in SDB-by-cognitive status interaction. Moreover, we found no difference in estimated chronological age gap related to SDB, or by-cognitive status interaction. Contrary to our hypothesis, we were not able to find a general or a diagnostic-dependent association of SDB with either gray-matter volumetric or brain aging.

Self-reported obstructive sleep apnea, amyloid and tau burden, and Alzheimer's disease time-dependent progression.

INTRODUCTION: Obstructive sleep apnea (OSA) is associated with Alzheimer's disease (AD) biomarkers in cognitively normal (CN) and mild cognitive impaired (MCI) participants. However, independent and combined effects of OSA, amyloid beta (Aß) and tau-accumulation on AD time-dependent progression risk is unclear. METHODS: Study participants grouped by biomarker profile, as described by the A/T/N scheme, where "A" refers to aggregated Aß, "T" aggregated tau, and "N" to neurodegeneration, included 258 CN (OSA-positive [OSA+] [A+TN+ n = 10, A+/TN- n = 6, A-/TN+ n = 10, A-/TN- n = 6 and OSA-negative [OSA-] [A+TN+ n = 84, A+/TN- n = 11, A-/TN+ n = 96, A-/TN- n = 36]) and 785 MCI (OSA+ [A+TN+ n = 35, A+/TN- n = 15, A-/TN+ n = 25, A-/TN- n = 16] and OSA- [A+TN+ n = 388, A+/TN- n = 28, A-/TN+ n = 164, A-/TN- n = 114]) older-adults from the Alzheimer's Disease Neuroimaging Initiative cohort. Cox proportional hazards regression models estimated the relative hazard of progression from CN-to-MCI and MCI-to-AD, among baseline OSA CN and MCI patients, respectively. Multi-level logistic mixed-effects models with random intercept and slope investigated the synergistic associations of self-reported OSA, Aß, and tau burden with prospective cognitive decline. RESULTS: Independent of TN-status (CN and MCI), OSA+/Aß+ participants were approximately two to four times more likely to progress to MCI/AD (P < .001) and progressed 6 to 18 months earlier (P < .001), compared to other participants combined (ie, OSA+/Aß-, OSA-/Aß+, and OSA-/Aß-). Notably, OSA+/Aß- versus OSA-/Aß- (CN and MCI) and OSA+/TN- versus OSA-/TN- (CN) participants showed no difference in the risk and time-to-MCI/AD progression. Mixed effects models demonstrated OSA synergism with Aß (CN and MCI [ß = 1.13, 95% confidence interval (CI), 0.74 to 1.52, and ß = 1.18, 95%CI, 0.82 to 1.54]) respectively, and with tau (MCI [ß = 1.31, 95% CI, 0.87 to 1.47]), P < .001 for all. DISCUSSION: OSA acts in synergism with Aß and with tau, and all three acting together result in synergistic neurodegenerative mechanisms especially as Aß and tau accumulation becomes increasingly abnormal, thus leading to shorter progression time to MCI/AD in CN and MCI-OSA patients, respectively.

The prevalence of obstructive sleep apnea in mild cognitive impairment: a systematic review.

BACKGROUND: Previous studies have shown that obstructive sleep apnea (OSA) is associated with a higher risk of cognitive impairment or dementia in the elderly, leading to deleterious health effects and decreasing quality of life. This systematic review aims to determine the prevalence of OSA in patients with mild cognitive impairment (MCI) and examine whether an association between OSA and MCI exists. METHODS: We searched Medline, PubMed, Embase, Cochrane Central, Cochrane Database of Systematic Reviews, PsychINFO, Scopus, the Web of Science, ClinicalTrials.gov and the International Clinical Trials Registry Platform for published and unpublished studies. We included studies in adults with a diagnosis of MCI that reported on the prevalence of OSA. Two independent reviewers performed the abstract and full-text screening, data extraction and the study quality critical appraisal. RESULTS: Five studies were included in the systematic review. Overall, OSA prevalence rates in patients with MCI varied between 11 and 71% and were influenced by OSA diagnostic methods and patient recruitment locations (community or clinic based). Among studies using the following OSA diagnostic measures- self-report, Home Sleep Apnea Testing, Berlin Questionnaire and polysomnography- the OSA prevalence rates in MCI were 11, 27, 59 and 71%, respectively. In a community-based sample, the prevalence of OSA in patients with and without MCI was 27 and 26%, respectively. CONCLUSIONS: Based on limited evidence, the prevalence of OSA in patients with MCI is 27% and varies based upon OSA diagnostic methods and patient recruitment locations. Our findings provide an important framework for future studies to prospectively investigate the association between OSA and MCI among larger community-based cohorts and implement a standardized approach to diagnose OSA in memory clinics. PROSPERO REGISTRATION: CRD42018096577.

Obstructive Sleep Apnea Severity Affects Amyloid Burden in Cognitively Normal Elderly. A Longitudinal Study.

RATIONALE: Recent evidence suggests that obstructive sleep apnea (OSA) may be a risk factor for developing mild cognitive impairment and Alzheimer's disease. However, how sleep apnea affects longitudinal risk for Alzheimer's disease is less well understood. OBJECTIVES: To test the hypothesis that there is an association between severity of OSA and longitudinal increase in amyloid burden in cognitively normal elderly. METHODS: Data were derived from a 2-year prospective longitudinal study that sampled community-dwelling healthy cognitively normal elderly. Subjects were healthy volunteers between the ages of 55 and 90, were nondepressed, and had a consensus clinical diagnosis of cognitively normal. Cerebrospinal fluid amyloid ß was measured using ELISA. Subjects received Pittsburgh compound B positron emission tomography scans following standardized procedures. Monitoring of OSA was completed using a home sleep recording device. MEASUREMENTS AND MAIN RESULTS: We found that severity of OSA indices (AHIall [F1,88 = 4.26; P < 0.05] and AHI4% [F1,87 = 4.36; P < 0.05]) were associated with annual rate of change of cerebrospinal fluid amyloid ß42 using linear regression after adjusting for age, sex, body mass index, and apolipoprotein E4 status. AHIall and AHI4% were not associated with increases in ADPiB-mask (Alzheimer's disease vulnerable regions of interest Pittsburg compound B positron emission tomography mask) most likely because of the small sample size, although there was a trend for AHIall (F1,28 = 2.96, P = 0.09; and F1,28 = 2.32, not significant, respectively). CONCLUSIONS: In a sample of cognitively normal elderly, OSA was associated with markers of increased amyloid burden over the 2-year follow-up. Sleep fragmentation and/or intermittent hypoxia from OSA are likely candidate mechanisms. If confirmed, clinical interventions for OSA may be useful in preventing amyloid build-up in cognitively normal elderly.

Structural correlates of apathy in Alzheimer's disease: a multimodal MRI study.

OBJECTIVE: Apathy is one of the most frequent symptoms of dementia, whose underlying neurobiology is not well understood. The objective was to analyze the correlations of apathy and its dimensions with gray and white matter damage in the brain of patients with advanced Alzheimer's disease (AD). METHODS: The setting of the study was at the Alzheimer Center Reina Sofía Foundation Research Unit. Participants include 37 nursing home patients with moderate to severe AD, 78.4% were women, and mean Standard Deviation (SD) age is 82.7 (5.8). Several measurements were taken: severe mini-mental state examination and Global Deterioration Scale for cognitive and functional status, Neuropsychiatric Inventory for behavioral problems, and Apathy In Dementia-Nursing Home Version Scale for apathy, including total score and subscores of emotional blunting, deficit of thinking, and cognitive inertia. 3T magnetic resonance imaging measures (voxel-based morphometry, fluid-attenuated inversion recovery, and diffusion tensor imaging) were also conducted. RESULTS: Moderate levels of apathy (mean Apathy In Dementia-Nursing Home Version Scale: 31.1 ± 18.5) were found. Bilateral damage to the corpus callosum and internal capsule was associated with apathy severity (cluster size 2435, p < 0.0005, family-wise error [FWE]-corrected). A smaller and more anteriorly located region of the right internal capsule and corpus callosum was associated with higher emotional blunting (cluster size 334, p < 0.0005, FWE-corrected). Ischemic damage in the right periventricular frontal region was associated with higher deficit of thinking (cluster size 3805, p < 0.005, FWE-corrected). CONCLUSIONS: Brain damage related to apathy may have different features in the advanced stages of AD and differs between the three apathy dimensions. Besides atrophy, brain connectivity and vascular lesions are relevant in the study of apathy, especially in the more severe stages of dementia. Further magnetic resonance imaging studies should include multimodal techniques. Copyright © 2016 John Wiley & Sons, Ltd.