REM sleep is reduced in late middle-aged and older APOE4 allele carriers.

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. METHODS: 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: REM sleep percentage (F=9.95, p=0.002, ηp2=0.049) and duration (F=9.23, p=0.003, ηp2=0.047) were lower in APOE4 carriers. The results were replicated in a subsample of 112 participants without moderate-to-severe obstructive sleep apnea. There were no significant interactions between APOE4 status and age, sex, cognitive status and obstructive sleep apnea 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.

Longer sleep duration and neuroinflammation in at-risk elderly with a parental history of Alzheimer's disease.

STUDY OBJECTIVES: While short sleep could promote neurodegeneration, long sleep may be a marker of ongoing neurodegeneration, potentially as a result of neuroinflammation. The objective was to evaluate sleep patterns with age of expected Alzheimer's disease (AD) onset and neuroinflammation. METHODS: We tested 203 dementia-free participants (68.5±5.4y/o, 78M). The PREVENT-AD cohort includes older persons with a parental history of AD whose age was nearing their expected AD onset. We estimated expected years to AD onset by subtracting the participant's age from their parent's at AD dementia onset. We extracted actigraphy sleep variables of interest (times of sleep onset and morning awakening, time in bed, sleep efficiency, sleep duration) and general profiles (sleep fragmentation, phase delay, hypersomnia). CSF inflammatory biomarkers were assessed with OLINK multiplex technology. RESULTS: Proximity to, or exceeding, expected age of onset was associated with a sleep profile suggestive of hypersomnia (longer sleep, later morning awakening time). This hypersomnia sleep profile was associated with higher CSF neuroinflammatory biomarkers (IL-6, MCP-1, global score). Interactions analyses revealed that some of these sleep-neuroinflammation associations were present mostly in those closer/exceeding the age of expected AD onset, APOE4 carriers, and those with better memory performance. CONCLUSIONS: Proximity to, or exceeding, parental AD dementia onset was associated with a longer sleep pattern, which was related to elevated proinflammatory CSF biomarkers. We speculate that longer sleep may serve a compensatory purpose potentially triggered by neuroinflammation as individuals are approaching AD onset. Further studies should investigate whether neuroinflammatory-triggered long sleep duration could mitigate cognitive deficits.

Day-to-day sleep variability with Alzheimer's biomarkers in at-risk elderly.

INTRODUCTION: Measuring day-to-day sleep variability might reveal unstable sleep-wake cycles reflecting neurodegenerative processes. We evaluated the association between Alzheimer's disease (AD) fluid biomarkers with day-to-day sleep variability. METHODS: In the PREVENT-AD cohort, 203 dementia-free participants (age: 68.3 ± 5.4; 78 males) with a parental history of sporadic AD were tested with actigraphy and fluid biomarkers. Day-to-day variability (standard deviations over a week) was assessed for sleep midpoint, duration, efficiency, and nighttime activity count. RESULTS: Lower cerebrospinal fluid (CSF) ApoE, higher CSF p-tau181/amyloid-ß (Aß)42, and higher plasma p-tau231/Aß42 were associated with higher variability of sleep midpoint, sleep duration, and/or activity count. The associations between fluid biomarkers with greater sleep duration variability were especially observed in those that carried the APOE4 allele, mild cognitive impairment converters, or those with gray matter atrophy. DISCUSSION: Day-to-day sleep variability were associated with biomarkers of AD in at-risk individuals, suggesting that unstable sleep promotes neurodegeneration or, conversely, that AD neuropathology disrupts sleep-wake cycles.

99mTc-HMPAO SPECT Perfusion Signatures Associated With Clinical Progression in Patients With Isolated REM Sleep Behavior Disorder.

BACKGROUND AND OBJECTIVES: Idiopathic/isolated REM sleep behavior disorder (iRBD) is associated with dementia with Lewy bodies and Parkinson disease. Despite evidence of abnormal cerebral perfusion in iRBD, there is currently no pattern that can predict whether an individual will develop dementia with Lewy bodies or Parkinson disease. The objective was to identify a perfusion signature associated with conversion to dementia with Lewy bodies in iRBD. METHODS: Patients with iRBD underwent video-polysomnography, neurologic and neuropsychological assessments, and baseline 99mTc-HMPAO SPECT to assess relative cerebral blood flow. Partial least squares correlation was used to identify latent variables that maximized covariance between 27 clinical features and relative gray matter perfusion. Patient-specific scores on the latent variables were used to test the association with conversion to dementia with Lewy bodies compared with that with Parkinson disease. The signature's expression was also assessed in 24 patients with iRBD who underwent a second perfusion scan, 22 healthy controls, and 19 individuals with Parkinson disease. RESULTS: Of the 137 participants, 93 underwent SPECT processing, namely 52 patients with iRBD (67.9 years, 73% men), 19 patients with Parkinson disease (67.3 years, 37% men), and 22 controls (67.0 years, 73% men). Of the 47 patients with iRBD followed up longitudinally (4.5 years), 12 (26%) developed a manifest synucleinopathy (4 dementia with Lewy bodies and 8 Parkinson disease). Analysis revealed 2 latent variables between relative blood flow and clinical features: the first was associated with a broad set of features that included motor, cognitive, and perceptual variables, age, and sex; the second was mostly associated with cognitive features and RBD duration. When brought back into the patient's space, the expression of the first variable was associated with conversion to a manifest synucleinopathy, whereas the second was associated with conversion to dementia with Lewy bodies. The expression of the patterns changed over time and was associated with worse motor features. DISCUSSION: This study identified a brain perfusion signature associated with cognitive impairment in iRBD and transition to dementia with Lewy bodies. This signature, which can be derived from individual scans, has the potential to be developed into a biomarker that predicts dementia with Lewy bodies in at-risk individuals.

Association of Sleep Duration and Change Over Time With Imaging Biomarkers of Cerebrovascular, Amyloid, Tau, and Neurodegenerative Pathology.

BACKGROUND AND OBJECTIVES: Both short and long sleep duration were previously associated with incident dementia, but underlying mechanisms remain unclear. We evaluated how self-reported sleep duration and its change over time associate with (A)myloid, (T)au, (N)eurodegeneration, and (V)ascular neuroimaging markers of Alzheimer disease. METHODS: Two Framingham Heart Study overlapping samples were studied: participants who underwent 11C-Pittsburg Compound B amyloid and 18F-flortaucipir tau PET imaging and participants who underwent an MRI. MRI metrics estimated neurodegeneration (total brain volume) and cerebrovascular injuries (white matter hyperintensities [WMHs] volume, covert brain infarcts, free-water [FW] fraction). Self-reported sleep duration was assessed and split into categories both at the time of neuroimaging testing and approximately 13 years before: short ≤6 hours. average 7-8 hours, and long ≥9 hours. Logistic and linear regression models were used to examine sleep duration and neuroimaging metrics. RESULTS: The tested cohort was composed of 271 participants (age 53.6 ± 8.0 years; 51% male) in the PET imaging sample and 2,165 participants (age 61.3 ± 11.1 years; 45% male) in the MRI sample. No fully adjusted association was observed between cross-sectional sleep duration and neuroimaging metrics. In fully adjusted models compared with consistently sleeping 7-8 hours, groups transitioning to a longer sleep duration category over time had higher FW fraction (short to average ß [SE] 0.0062 [0.0024], p = 0.009; short to long ß [SE] 0.0164 [0.0076], p = 0.031; average to long ß [SE] 0.0083 [0.0022], p = 0.002), and those specifically going from average to long sleep duration also had higher WMH burden (ß [SE] 0.29 [0.11], p = 0.007). The opposite associations (lower WMH and FW) were observed in participants consistently sleeping ≥9 hours as compared with people consistently sleeping 7-8 hours in fully adjusted models (ß [SE] -0.43 [0.20], p = 0.028; ß [SE] -0.019 [0.004], p = 0.020). Each hour of increasing sleep (continuous, ß [SE] 0.12 [0.04], p = 0.003; ß [SE] 0.002 [0.001], p = 0.021) and extensive increase in sleep duration (≥2 hours vs 0 ± 1 hour change; ß [SE] 0.24 [0.10], p = 0.019; ß [SE] 0.0081 [0.0025], p = 0.001) over time was associated with higher WMH burden and FW fraction in fully adjusted models. Sleep duration change was not associated with PET amyloid or tau outcomes. DISCUSSION: Longer self-reported sleep duration over time was associated with neuroimaging biomarkers of cerebrovascular pathology as evidenced by higher WMH burden and FW fraction. A longer sleep duration extending over time may be an early change in the neurodegenerative trajectory.

Association of the Sleep Regularity Index With Incident Dementia and Brain Volume.

BACKGROUND AND OBJECTIVES: Irregular sleep may increase the risk of cardiometabolic conditions, but its association with incident dementia is unclear. The aim of this study was to assess the association between sleep regularity, that is, the day-to-day consistency in sleep-wake patterns and the risk of incident dementia and related brain MRI endophenotypes. METHODS: We used Cox proportional hazard models to investigate the relationships between sleep regularity and incident dementia in 88,094 UK Biobank participants. The sleep regularity index (SRI) was calculated as the probability of being in the same state (asleep/awake) at any 2 time points 24 hours apart, averaged over 7 days of accelerometry. RESULTS: The mean age of the sample was 62 years (SD = 8), 56% were women, and the median SRI was 60 (SD = 10). There were 480 cases of incident dementia over a median 7.2 years of follow-up. Following adjustments for demographic, clinical, and genetic confounders (APOE ε4), there was a nonlinear association between the SRI and dementia hazard (p [global test of spline term] < 0.001) with hazard ratios (HRs) following a U-shape pattern. HRs, relative to the median SRI, were 1.53 (95% CI 1.24-1.89) for participants with SRI at the 5th percentile (SRI = 41) and 1.16 (95% CI 0.89-1.50) for those with SRI at the 95th percentile (SRI = 71). In a subset with brain MRI (n = 15,263), gray matter and hippocampal volume tended to be lowest at the extremes of the SRI. DISCUSSION: Sleep regularity displayed a U-shaped association with risk of incident dementia. Irregular sleep may represent a novel dementia risk factor.

Association of plasma biomarkers with cognition, cognitive decline, and daily function across and within neurodegenerative diseases: Results from the Ontario Neurodegenerative Disease Research Initiative.

INTRODUCTION: We investigated whether novel plasma biomarkers are associated with cognition, cognitive decline, and functional independence in activities of daily living across and within neurodegenerative diseases. METHODS: Glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), phosphorylated tau (p-tau)181 and amyloid beta (Aß)42/40 were measured using ultra-sensitive Simoa immunoassays in 44 healthy controls and 480 participants diagnosed with Alzheimer's disease/mild cognitive impairment (AD/MCI), Parkinson's disease (PD), frontotemporal dementia (FTD) spectrum disorders, or cerebrovascular disease (CVD). RESULTS: GFAP, NfL, and/or p-tau181 were elevated among all diseases compared to controls, and were broadly associated with worse baseline cognitive performance, greater cognitive decline, and/or lower functional independence. While GFAP, NfL, and p-tau181 were highly predictive across diseases, p-tau181 was more specific to the AD/MCI cohort. Sparse associations were found in the FTD and CVD cohorts and for Aß42/40 . DISCUSSION: GFAP, NfL, and p-tau181 are valuable predictors of cognition and function across common neurodegenerative diseases, and may be useful in specialized clinics and clinical trials.

Sleep regularity and mortality: a prospective analysis in the UK Biobank.

Background: Irregular sleep-wake timing may cause circadian disruption leading to several chronic age-related diseases. We examined the relationship between sleep regularity and risk of all-cause, cardiovascular disease (CVD), and cancer mortality in 88,975 participants from the prospective UK Biobank cohort. Methods: The sleep regularity index (SRI) was calculated as the probability of an individual being in the same state (asleep or awake) at any two time points 24 hr apart, averaged over 7 days of accelerometry (range 0-100, with 100 being perfectly regular). The SRI was related to the risk of mortality in time-to-event models. Results: The mean sample age was 62 years (standard deviation [SD], 8), 56% were women, and the median SRI was 60 (SD, 10). There were 3010 deaths during a mean follow-up of 7.1 years. Following adjustments for demographic and clinical variables, we identified a non-linear relationship between the SRI and all-cause mortality hazard (p [global test of spline term]<0.001). Hazard ratios, relative to the median SRI, were 1.53 (95% confidence interval [CI]: 1.41, 1.66) for participants with SRI at the 5th percentile (SRI = 41) and 0.90 (95% CI: 0.81, 1.00) for those with SRI at the 95th percentile (SRI = 75), respectively. Findings for CVD mortality and cancer mortality followed a similar pattern. Conclusions: Irregular sleep-wake patterns are associated with higher mortality risk. Funding: National Health and Medical Research Council of Australia (GTN2009264; GTN1158384), National Institute on Aging (AG062531), Alzheimer's Association (2018-AARG-591358), and the Banting Fellowship Program (#454104).

Association Between Slow-Wave Sleep Loss and Incident Dementia.

Importance: Slow-wave sleep (SWS) supports the aging brain in many ways, including facilitating the glymphatic clearance of proteins that aggregate in Alzheimer disease. However, the role of SWS in the development of dementia remains equivocal. Objective: To determine whether SWS loss with aging is associated with the risk of incident dementia and examine whether Alzheimer disease genetic risk or hippocampal volumes suggestive of early neurodegeneration were associated with SWS loss. Design, Setting, and Participants: This prospective cohort study included participants in the Framingham Heart Study who completed 2 overnight polysomnography (PSG) studies in the time periods 1995 to 1998 and 2001 to 2003. Additional criteria for individuals in this study sample were an age of 60 years or older and no dementia at the time of the second overnight PSG. Data analysis was performed from January 2020 to August 2023. Exposure: Changes in SWS percentage measured across repeated overnight sleep studies over a mean of 5.2 years apart (range, 4.8-7.1 years). Main Outcome: Risk of incident all-cause dementia adjudicated over 17 years of follow-up from the second PSG. Results: From the 868 Framingham Heart Study participants who returned for a second PSG, this cohort included 346 participants with a mean age of 69 years (range, 60-87 years); 179 (52%) were female. Aging was associated with SWS loss across repeated overnight sleep studies (mean [SD] change, -0.6 [1.5%] per year; P < .001). Over the next 17 years of follow-up, there were 52 cases of incident dementia. In Cox regression models adjusted for age, sex, cohort, positivity for at least 1 APOE ε4 allele, smoking status, sleeping medication use, antidepressant use, and anxiolytic use, each percentage decrease in SWS per year was associated with a 27% increase in the risk of dementia (hazard ratio, 1.27; 95% CI, 1.06-1.54; P = .01). SWS loss with aging was accelerated in the presence of Alzheimer disease genetic risk (ie, APOE ε4 allele) but not hippocampal volumes measured proximal to the first PSG. Conclusions and Relevance: This cohort study found that slow-wave sleep percentage declined with aging and Alzheimer disease genetic risk, with greater reductions associated with the risk of incident dementia. These findings suggest that SWS loss may be a modifiable dementia risk factor.

Age- and sex-specific associations between obstructive sleep apnea risk and cognitive decline in middle-aged and older adults: A 3-year longitudinal analysis of the Canadian longitudinal study on aging.

BACKGROUND: Whether obstructive sleep apnea (OSA) increases the risk of cognitive decline and how sex and age influence this association is not clear. Here, we characterized the sex- and age-specific associations between OSA risk and 3-year cognitive change in middle-aged and older adults. METHODS: We included 24,819 participants aged 45-85 (52% women) from the Canadian Longitudinal Study on Aging. OSA risk was measured at baseline using the STOP combined to body mass index (STOP-B). Neuropsychological tests assessed memory, executive functioning, and psychomotor speed at baseline and at 3-year follow-up. We conducted age- and sex-specific linear mixed models to estimate the predictive role of baseline STOP-B score on 3-year cognitive change. RESULTS: Men at high-risk for OSA aged 45-59 years showed a steeper decline in psychomotor speed (+13.2 [95% CI: -1.6, 27.9]) compared to men at low-risk. Men at high-risk for OSA aged 60-69 showed a steeper decline in mental flexibility (-1.2 [-1.9, -0.5]) and processing speed (+0.6 [0.3, 0.9]) than those at low-risk. Women at high-risk for OSA aged 45-59 showed a steeper decline in processing speed (+0.1 [-0.2, 0.4]) than women at low-risk, while women at high-risk ≥70 years had a steeper decline in memory (-0.2 [-0.6, 0.1]) and processing speed (+1.0 [0.4, 1.5]). CONCLUSIONS: Associations between OSA risk and cognitive decline over 3 years depend on age and sex. Being at high-risk for OSA is associated with a generalized cognitive decline in attention and processing speed, while a memory decline is specific to older women (≥70 years).

Sleep Architecture, Obstructive Sleep Apnea, and Cognitive Function in Adults.

Importance: Good sleep is essential for health, yet associations between sleep and dementia risk remain incompletely understood. The Sleep and Dementia Consortium was established to study associations between polysomnography (PSG)-derived sleep and the risk of dementia and related cognitive and brain magnetic resonance imaging endophenotypes. Objective: To investigate association of sleep architecture and obstructive sleep apnea (OSA) with cognitive function in the Sleep and Dementia Consortium. Design, Setting, and Participants: The Sleep and Dementia Consortium curated data from 5 population-based cohorts across the US with methodologically consistent, overnight, home-based type II PSG and neuropsychological assessments over 5 years of follow-up: the Atherosclerosis Risk in Communities study, Cardiovascular Health Study, Framingham Heart Study (FHS), Osteoporotic Fractures in Men Study, and Study of Osteoporotic Fractures. Sleep metrics were harmonized centrally and then distributed to participating cohorts for cohort-specific analysis using linear regression; study-level estimates were pooled in random effects meta-analyses. Results were adjusted for demographic variables, the time between PSG and neuropsychological assessment (0-5 years), body mass index, antidepressant use, and sedative use. There were 5946 participants included in the pooled analyses without stroke or dementia. Data were analyzed from March 2020 to June 2023. Exposures: Measures of sleep architecture and OSA derived from in-home PSG. Main Outcomes and Measures: The main outcomes were global cognitive composite z scores derived from principal component analysis, with cognitive domains investigated as secondary outcomes. Higher scores indicated better performance. Results: Across cohorts, 5946 adults (1875 females [31.5%]; mean age range, 58-89 years) were included. The median (IQR) wake after sleep onset time ranged from 44 (27-73) to 101 (66-147) minutes, and the prevalence of moderate to severe OSA ranged from 16.9% to 28.9%. Across cohorts, higher sleep maintenance efficiency (pooled ß per 1% increase, 0.08; 95% CI, 0.03 to 0.14; P < .01) and lower wake after sleep onset (pooled ß per 1-min increase, -0.07; 95% CI, -0.13 to -0.01 per 1-min increase; P = .02) were associated with better global cognition. Mild to severe OSA (apnea-hypopnea index [AHI] ≥5) was associated with poorer global cognition (pooled ß, -0.06; 95% CI, -0.11 to -0.01; P = .01) vs AHI less than 5; comparable results were found for moderate to severe OSA (pooled ß, -0.06; 95% CI, -0.11 to -0.01; P = .02) vs AHI less than 5. Differences in sleep stages were not associated with cognition. Conclusions and Relevance: This study found that better sleep consolidation and the absence of OSA were associated with better global cognition over 5 years of follow-up. These findings suggest that the role of interventions to improve sleep for maintaining cognitive function requires investigation.

Altered resting-state functional connectivity patterns in late middle-aged and older adults with obstructive sleep apnea.

Introduction: Obstructive sleep apnea (OSA) is increasingly recognized as a risk factor for cognitive decline, and has been associated with structural brain alterations in regions relevant to memory processes and Alzheimer's disease. However, it is unclear whether OSA is associated with disrupted functional connectivity (FC) patterns between these regions in late middle-aged and older populations. Thus, we characterized the associations between OSA severity and resting-state FC between the default mode network (DMN) and medial temporal lobe (MTL) regions. Second, we explored whether significant FC changes differed depending on cognitive status and were associated with cognitive performance. Methods: Ninety-four participants [24 women, 65.7 ± 6.9 years old, 41% with Mild Cognitive Impairment (MCI)] underwent a polysomnography, a comprehensive neuropsychological assessment and a resting-state functional magnetic resonance imaging (MRI). General linear models were conducted between OSA severity markers (i.e., the apnea-hypopnea, oxygen desaturation and microarousal indices) and FC values between DMN and MTL regions using CONN toolbox. Partial correlations were then performed between OSA-related FC patterns and (i) OSA severity markers in subgroups stratified by cognitive status (i.e., cognitively unimpaired versus MCI) and (ii) cognitive scores in the whole sample. All analyzes were controlled for age, sex and education, and considered significant at a p < 0.05 threshold corrected for false discovery rate. Results: In the whole sample, a higher apnea-hypopnea index was significantly associated with lower FC between (i) the medial prefrontal cortex and bilateral hippocampi, and (ii) the left hippocampus and both the posterior cingulate cortex and precuneus. FC patterns were not associated with the oxygen desaturation index, or micro-arousal index. When stratifying the sample according to cognitive status, all associations remained significant in cognitively unimpaired individuals but not in the MCI group. No significant associations were observed between cognition and OSA severity or OSA-related FC patterns. Discussion: OSA severity was associated with patterns of lower FC in regions relevant to memory processes and Alzheimer's disease. Since no associations were found with cognitive performance, these FC changes could precede detectable cognitive deficits. Whether these FC patterns predict future cognitive decline over the long-term needs to be investigated.

Sleep Regularity and Mortality: A Prospective Analysis in the UK Biobank.

Background: Irregular sleep-wake timing may cause circadian disruption leading to several chronic age-related diseases. We examined the relationship between sleep regularity and risk of all-cause, cardiovascular disease (CVD), and cancer mortality in 88,975 participants from the prospective UK Biobank cohort. Methods: The sleep regularity index (SRI) was calculated as the probability of an individual being in the same state (asleep or awake) at any two time points 24 hours apart, averaged over 7-days of accelerometry (range 0-100, with 100 being perfectly regular). The SRI was related to the risk of mortality in time-to-event models. Findings: The mean sample age was 62 years (SD, 8), 56% were women, and the median SRI was 60 (SD, 10). There were 3010 deaths during a mean follow-up of 7.1 years. Following adjustments for demographic and clinical variables, we identified a non-linear relationship between the SRI and all-cause mortality hazard (p [global test of spline term] < 0·001). Hazard Ratios, relative to the median SRI, were 1·53 (95% confidence interval [CI]: 1·41, 1·66) for participants with SRI at the 5th percentile (SRI = 41) and 0·90 (95% CI: 0·81, 1·00) for those with SRI at the 95th percentile (SRI = 75), respectively. Findings for CVD mortality and cancer mortality followed a similar pattern. Conclusions: Irregular sleep-wake patterns are associated with higher mortality risk. Funding: National Health and Medical Research Council of Australia (GTN2009264; GTN1158384), National Institute on Aging (AG062531), Alzheimer's Association (2018-AARG-591358), and the Banting Fellowship Program (#454104).

The Putative Role of Neuroinflammation in the Interaction between Traumatic Brain Injuries, Sleep, Pain and Other Neuropsychiatric Outcomes: A State-of-the-Art Review.

Sleep disturbances are widely prevalent following a traumatic brain injury (TBI) and have the potential to contribute to numerous post-traumatic physiological, psychological, and cognitive difficulties developing chronically, including chronic pain. An important pathophysiological mechanism involved in the recovery of TBI is neuroinflammation, which leads to many downstream consequences. While neuroinflammation is a process that can be both beneficial and detrimental to individuals' recovery after sustaining a TBI, recent evidence suggests that neuroinflammation may worsen outcomes in traumatically injured patients, as well as exacerbate the deleterious consequences of sleep disturbances. Additionally, a bidirectional relationship between neuroinflammation and sleep has been described, where neuroinflammation plays a role in sleep regulation and, in turn, poor sleep promotes neuroinflammation. Given the complexity of this interplay, this review aims to clarify the role of neuroinflammation in the relationship between sleep and TBI, with an emphasis on long-term outcomes such as pain, mood disorders, cognitive dysfunctions, and elevated risk of Alzheimer's disease and dementia. In addition, some management strategies and novel treatment targeting sleep and neuroinflammation will be discussed in order to establish an effective approach to mitigate long-term outcomes after TBI.

Lighter sleep is associated with higher enlarged perivascular spaces burden in middle-aged and elderly individuals.

BACKGROUND: While healthy sleep is suggested to promote glymphatic clearance in the brain, poorer sleep may be associated with higher enlarged perivascular spaces (ePVS) burden, potentially representing impaired perivascular drainage. This study aims to evaluate the association between ePVS burden and polysomnographic sleep characteristics in a large community-based sample. METHODS: 552 dementia and stroke-free Framingham Heart Study participants (age: 58.6 ± 8.9 years; 50.4% men) underwent a full-night in-home polysomnography. Three years later on average, participants underwent a brain MRI. ePVS were rated in the basal ganglia and centrum semiovale, and dichotomized as low burden (<20 counts, grades 1 and 2) or high burden (>20 counts, grades 3 and 4). Logistic regression analyses relating sleep variables to subsequent ePVS burden were used, adjusted for age, sex, time interval between polysomnography and MRI, ApoE ε4 allele carrier status, hypertension, and smoking. RESULTS: Longer N1 sleep and shorter N3 sleep duration were associated with higher ePVS burden in the centrum semiovale. When stratifying these associations by subpopulations, longer N1 sleep duration with ePVS burden was observed especially in older individuals and hypertensive participants. Associations between ePVS burden and other sleep characteristics such as total sleep time and REM sleep duration varied according to ApoE ε4 allele carrier status. CONCLUSIONS: Lighter sleep, as characterized by longer N1 sleep and shorter slow-wave sleep, is associated with higher ePVS burden. These findings suggest that sleep architecture may be involved in glymphatic clearance and cerebral small vessel disease, which could be an important biological link between sleep and dementia risk.

Medial temporal lobe and obstructive sleep apnea: Effect of sex, age, cognitive status and free-water.

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.

Self-reported sleepiness associates with greater brain and cortical volume and lower prevalence of ischemic covert brain infarcts in a community sample.

STUDY OBJECTIVES: We evaluated if self-reported sleepiness was associated with neuroimaging markers of brain aging and ischemic damage in a large community-based sample. METHODS: Participants from the Framingham Heart Study Offspring cohort (n = 468, 62.5 ± 8.7 years old, 49.6%M) free of dementia, stroke, and neurological diseases, completed sleep questionnaires and polysomnography followed by magnetic resonance imaging (MRI), 3 years later on average. We used linear and logistic regression models to evaluate the associations between Epworth Sleepiness Scale (ESS) scores and total brain, cortical and subcortical gray matter, and white matter hyperintensities volumes, and the presence of covert brain infarcts. RESULTS: Higher sleepiness scores were associated with larger total brain volume, greater cortical gray matter volume, and a lower prevalence of covert brain infarcts, even when adjusting for a large array of potential confounders, including demographics, sleep profiles and disorders, organic health diseases, and proxies for daytime cognitive and physical activities. Interactions indicated that more sleepiness was associated with larger cortical gray matter volume in men only and in APOE ε4 noncarriers, whereas a trend for smaller cortical gray matter volume was observed in carriers. In longitudinal analyses, those with stable excessive daytime sleepiness over time had greater total brain and cortical gray matter volumes, whereas baseline sleepiness scores were not associated with subsequent atrophy or cognitive decline. CONCLUSION: Our findings suggest that sleepiness is not necessarily a marker of poor brain health when not explained by diseases or sleep debt and sleep disorders. Rather, sleepiness could be a marker of preserved sleep-regulatory processes and brain health in some cases.

Sleep from acute to chronic traumatic brain injury and cognitive outcomes.

STUDY OBJECTIVES: Traumatic brain injuries (TBIs) cause persistent cerebral damage and cognitive deficits. Because sleep may be a critical factor for brain recovery, we characterized the sleep of patients with TBI from early hospitalization to years post-injury and explored the hypothesis that better sleep during hospitalization predicts more favorable long-term cognitive outcomes. METHODS: We tested patients with moderate-to-severe TBI in the hospitalized (n = 11) and chronic (n = 43) stages using full-night polysomnography, with 82% of the hospitalized group being retested years post-injury. Hospitalized patients with severe orthopedic and/or spinal cord injury (n = 14) and healthy participants (n = 36) were tested as controls for the hospitalized and chronic TBI groups, respectively. Groups had similar age and sex and were compared for sleep characteristics, including slow waves and spindles. For patients with TBI, associations between sleep during hospitalization and long-term memory and executive function were assessed. RESULTS: Hospitalized patients with TBI or orthopedic injuries had lower sleep efficiency, higher wake after sleep onset, and lower spindle density than the chronic TBI and healthy control groups, but only hospitalized patients with brain injury had an increased proportion of slow-wave sleep. During hospitalization for TBI, less fragmented sleep, more slow-wave sleep, and higher spindle density were associated to more favorable cognitive outcomes years post-injury, while injury severity markers were not associated with these outcomes. CONCLUSION: These findings highlight the importance of sleep following TBI, as it could be a strong predictor of neurological recovery, either as a promoter or an early marker of cognitive outcomes.

Insomnia symptom severity and cognitive performance: Moderating role of APOE genotype.

INTRODUCTION: We evaluated whether insomnia symptom severity was associated with cognitive function, and whether this relationship was modified by biomarkers associated with Alzheimer's disease risk. METHODS: We examined insomnia symptoms and neuropsychological performance 3.4 years later in 511 dementia-free Framingham Heart Study participants (62.65 ± 8.7 years, 50.9% male). Additionally, we explored insomnia symptoms combined with self-reported short habitual sleep duration and effect modification by apolipoprotein E (APOE) ε4 allele status. RESULTS: More severe insomnia symptoms were associated with lower performance on global cognition, and immediate and delayed Logical Memory recall, especially when insomnia symptoms were combined with short sleep duration. The association between insomnia symptoms and poorer memory recall was more pronounced in APOE ε4 allele carriers. DISCUSSION: Insomnia symptom severity was associated with worse subsequent global cognitive and memory performance, which was especially apparent in APOE ε4 allele carriers, suggesting that poor sleep might be particularly detrimental when the brain is already vulnerable to neurodegeneration.

Autonomic Modulation During Baseline and Recovery Sleep in Adult Sleepwalkers.

Sleepwalking has been conceptualized as deregulation between slow-wave sleep and arousal, with its occurrence in predisposed patients increasing following sleep deprivation. Recent evidence showed autonomic changes before arousals and somnambulistic episodes, suggesting that autonomic dysfunctions may contribute to the pathophysiology of sleepwalking. We investigated cardiac autonomic modulation during slow-wave sleep in sleepwalkers and controls during normal and recovery sleep following sleep deprivation. Fourteen adult sleepwalkers (5M; 28.1 ± 5.8 years) and 14 sex- and age-matched normal controls were evaluated by video-polysomnography for one baseline night and during recovery sleep following 25 h of sleep deprivation. Autonomic modulation was investigated with heart rate variability during participants' slow-wave sleep in their first and second sleep cycles. 5-min electrocardiographic segments from slow-wave sleep were analyzed to investigate low-frequency (LF) and high-frequency (HF) components of heart rate spectral decomposition. Group (sleepwalkers, controls) X condition (baseline, recovery) ANOVAs were performed to compare LF and HF in absolute and normalized units (nLF and nHF), and LF/HF ratio. When compared to controls, sleepwalkers' recovery slow-wave sleep showed lower LF/HF ratio and higher nHF during the first sleep cycle. In fact, compared to baseline recordings, sleepwalkers, but not controls, showed a significant decrease in nLF and LF/HF ratio as well as increased nHF during recovery slow-wave sleep during the first cycle. Although non-significant, similar findings with medium effect sizes were observed for absolute values (LF, HF). Patterns of autonomic modulation during sleepwalkers' recovery slow-wave sleep suggest parasympathetic dominance as compared to baseline sleep values and to controls. This parasympathetic predominance may be a marker of abnormal neural mechanisms underlying, or interfere with, the arousal processes and contribute to the pathophysiology of sleepwalking.