Altered fornix integrity is associated with sleep apnea-related hypoxemia in mild cognitive impairment.

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.

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.

Obstructive sleep apnea and cognitive functioning in the older general population: The moderating effect of age, sex, ApoE4, and obesity.

Research on the relationship between obstructive sleep apnea and cognitive functioning has yielded conflicting results, particularly in the older population, and moderators of this association have rarely been studied. Here we investigated the cross-sectional association between obstructive sleep apnea and cognitive functioning as well as the moderating effect of age, sex, apolipoprotein E4, and obesity on this association among community-dwelling older people. We analysed data from 496 participants (71.4 ± 4.4 years; 45.6% men) of the HypnoLaus study who underwent polysomnography and a battery of neuropsychological tests. The sample was categorised as no-to-mild obstructive sleep apnea (apnea-hypopnea index 0-14.9/h; reference), moderate obstructive sleep apnea (apnea-hypopnea index 15.0-29.9/h), or severe obstructive sleep apnea (apnea-hypopnea index ≥30/h). Regression and moderation analyses were performed with adjustment for confounders. Apolipoprotein E4 and obesity moderated the association between severe obstructive sleep apnea and processing speed, whereas no moderating effects were found for age and sex. In apolipoprotein E4 carriers only, severe obstructive sleep apnea was associated with lower performance in Stroop condition 1 (B = 3.13, p = 0.024). In obese participants only, severe obstructive sleep apnea was associated with lower performance in Stroop condition 1 (B = 3.02, p = 0.025) and Stroop condition 2 (B = 3.30, p = 0.034). Severe obstructive sleep apnea was also associated with lower executive function in the whole sample according to Stroop condition 3 (B = 3.44, p = 0.020) and Stroop interference score (B = 0.24, p = 0.006). Our findings support associations of severe obstructive sleep apnea (but not moderate obstructive sleep apnea) with lower performance in processing speed and executive function in the older general population. Apolipoprotein E4 and obesity appear to be vulnerability factors that strengthen the association between severe obstructive sleep apnea and lower performance in processing speed.

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).

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.

Periodic leg movements during sleep and cognitive functioning in the older general population.

OBJECTIVE: The current evidence of a relationship between periodic leg movements during sleep (PLMS) and cognitive functioning is limited and inconsistent. This cross-sectional study assessed associations between PLMS and cognitive functioning among community-dwelling older adults. METHODS: We included community-dwelling older adults who underwent a polysomnography and a cognitive assessment. The PLMS index (PLMI) and PLMS arousal index (PLMAI) were categorized into tertiles: PLMI <5/h (reference), 5-29.9/h, ≥30/h; and PLMAI <1/h (reference), 1-4.9/h, ≥5/h. The cognitive assessment consisted of ten scores covering the main cognitive domains: global cognition, processing speed, executive function, language, episodic verbal memory, and visuospatial function. Associations between PLMI, PLMAI, and cognitive scores were assessed using regression unadjusted and adjusted models. RESULTS: A total of 579 individuals without dementia were included (mean age: 71.5 ± 4.4 years; men 45.4%). The number of participants in the high-PLMI categories, 5-29.9/h and ≥30/h, was 185 (32.0%) and 171 (29.5%), respectively. Participants in the high-PLMI categories showed no significant difference compared to the reference group regarding their cognitive performance according to the unadjusted and adjusted models. Similarly, we found no association between PLMAI severity and cognitive functioning. CONCLUSIONS: This study shows no cross-sectional association between PLMS severity and cognitive functioning among community-dwelling older adults. However, given the paucity of data in this field, further studies are needed to clarify the relationship between PLMS and cognitive functioning.

Objective polysomnography-based sleep features and major depressive disorder subtypes in the general population.

Insomnia and its opposite hypersomnia are part of the diagnostic criteria for major depressive disorder (MDD). However, no study has investigated whether the postulated sleep alterations in clinical subtypes of MDD are reflected in polysomnography (PSG)-derived objective sleep measures. The objective of this study was to establish associations between the melancholic, atypical and unspecified subtypes of MDD and objective PSG-based sleep features. This cross-sectional analysis included 1820 community-dwelling individuals who underwent PSG and a semi-structured psychiatric interview to elicit diagnostic criteria for MDD and its subtypes. Adjusted robust linear regression was used to assess associations between MDD subtypes and PSG-derived objective sleep measures. Current melancholic MDD was significantly associated with decreased absolute delta power and sleep efficiency and with increased wake after sleep onset. Remitted unspecified MDD was significantly associated with increased rapid eye movements density. No other significant associations were identified. Our findings reflect that some PSG-based sleep features differed in MDD subtypes compared with no MDD. The largest number of significant differences were observed for current melancholic MDD, whereas only rapid eye movements density could represent a risk factor for MDD as it was the only sleep measure that was also associated with MDD in remitted participants.

Pulse Wave Amplitude Drops Index: A Biomarker of Cardiovascular Risk in Obstructive Sleep Apnea.

Rationale: It is currently unclear which patients with obstructive sleep apnea (OSA) are at increased cardiovascular risk. Objective: To investigate the value of pulse wave amplitude drops (PWADs), reflecting sympathetic activations and vasoreactivity, as a biomarker of cardiovascular risk in OSA. Methods: PWADs were derived from pulse oximetry-based photoplethysmography signals in three prospective cohorts: HypnoLaus (N = 1,941), the Pays-de-la-Loire Sleep Cohort (PLSC; N = 6,367), and "Impact of Sleep Apnea syndrome in the evolution of Acute Coronary syndrome. Effect of intervention with CPAP" (ISAACC) (N = 692). The PWAD index was the number of PWADs (>30%) per hour during sleep. All participants were divided into subgroups according to the presence or absence of OSA (defined as ⩾15 or more events per hour or <15/h, respectively, on the apnea-hypopnea index) and the median PWAD index. Primary outcome was the incidence of composite cardiovascular events. Measurements and Main Results: Using Cox models adjusted for cardiovascular risk factors (hazard ratio; HR [95% confidence interval]), patients with a low PWAD index and OSA had a higher incidence of cardiovascular events compared with the high-PWAD and OSA group and those without OSA in the HypnoLaus cohort (HR, 2.16 [1.07-4.34], P = 0.031; and 2.35 [1.12-4.93], P = 0.024) and in the PLSC (1.36 [1.13-1.63], P = 0.001; and 1.44 [1.06-1.94], P = 0.019), respectively. In the ISAACC cohort, the low-PWAD and OSA untreated group had a higher cardiovascular event recurrence rate than that of the no-OSA group (2.03 [1.08-3.81], P = 0.028). In the PLSC and HypnoLaus cohorts, every increase of 10 events per hour in the continuous PWAD index was negatively associated with incident cardiovascular events exclusively in patients with OSA (HR, 0.85 [0.73-0.99], P = 0.031; and HR, 0.91 [0.86-0.96], P < 0.001, respectively). This association was not significant in the no-OSA group and the ISAACC cohort. Conclusions: In patients with OSA, a low PWAD index reflecting poor autonomic and vascular reactivity was independently associated with a higher cardiovascular risk.

Obstructive sleep apnoea and 5-year cognitive decline in the elderly.

BACKGROUND: The relationship between obstructive sleep apnoea (OSA) and cognitive decline remains controversial, especially in the elderly population. We used data from the HypnoLaus study to assess associations between OSA and longitudinal cognitive changes in a sample of community-dwelling elderly individuals. METHODS: We studied associations between polysomnographic OSA parameters (of breathing/hypoxaemia and sleep fragmentation) and cognitive changes over a 5-year period, after adjustment for potential confounders. The primary outcome was the annual change in cognitive scores. The moderating effects of age, sex and apolipoprotein E4 (ApoE4) status were also examined. RESULTS: 358 elderly individuals without dementia were included (mean±sd age 71.0±4.2 years; 42.5% males). A lower mean peripheral oxygen saturation (S pO2 ) during sleep was associated with a steeper decline in Mini-Mental State Examination (B= -0.12, p=0.004), Stroop test condition 1 (B=0.53, p=0.002) and Free and Cued Selective Reminding Test delayed free recall (B= -0.05, p=0.008). A longer time spent asleep with S pO2 <90% was associated with a steeper decline in Stroop test condition 1 (B=0.47, p=0.006). Moderation analysis showed that apnoea-hypopnoea index and oxygen desaturation index were associated with a steeper decline in global cognitive function, processing speed and executive function only in older participants, men and ApoE4 carriers. CONCLUSIONS: Our results provide evidence of the contribution of OSA and nocturnal hypoxaemia to cognitive decline in the elderly population.

Association Between Sleep Microstructure and Incident Hypertension in a Population-Based Sample: The HypnoLaus Study.

Background Poor sleep quality is associated with increased incident hypertension. However, few studies have investigated the impact of objective sleep structure parameters on hypertension. This study investigated the association between sleep macrostructural and microstructural parameters and incident hypertension in a middle- to older-aged sample. Methods and Results Participants from the HypnoLaus population-based cohort without hypertension at baseline were included. Participants had at-home polysomnography at baseline, allowing assessment of sleep macrostructure (nonrapid eye movement sleep stages 1, 2, and 3; rapid eye movement sleep stages; and total sleep time) and microstructure including power spectral density of electroencephalogram in nonrapid eye movement sleep and spindles characteristics (density, duration, frequency, amplitude) in nonrapid eye movement sleep stage 2. Associations between sleep macrostructure and microstructure parameters at baseline and incident clinical hypertension over a mean follow-up of 5.2 years were assessed with multiple-adjusted logistic regression. A total of 1172 participants (42% men; age 55±10 years) were included. Of these, 198 (17%) developed hypertension. After adjustment for confounders, no sleep macrostructure features were associated with incident hypertension. However, low absolute delta and sigma power were significantly associated with incident hypertension where participants in the lowest quartile of delta and sigma had a 1.69-fold (95% CI, 1.00-2.89) and 1.72-fold (95% CI, 1.05-2.82) increased risk of incident hypertension, respectively, versus those in the highest quartile. Lower spindle density (odds ratio, 0.87; 95% CI, 0.76-0.99) and amplitude (odds ratio, 0.98; 95% CI, 0.95-1.00) were also associated with higher incident hypertension. Conclusions Sleep microstructure is associated with incident hypertension. Slow-wave activity and sleep spindles, 2 hallmarks of objective sleep continuity and quality, were inversely and consistently associated with incident hypertension. This supports the protective role of sleep continuity in the development of hypertension.

Abnormal brain iron accumulation in obstructive sleep apnea: A quantitative MRI study in the HypnoLaus cohort.

Obstructive sleep apnea syndrome (OSA) may be a risk factor for Alzheimer's disease. One of the hallmarks of Alzheimer's disease is disturbed iron homeostasis leading to abnormal iron deposition in brain tissue. To date, there is no empirical evidence to support the hypothesis of altered brain iron homeostasis in patients with obstructive sleep apnea as well. Data were analysed from 773 participants in the HypnoLaus study (mean age 55.9 ± 10.3 years) who underwent polysomnography and brain MRI. Cross-sectional associations were tested between OSA parameters and the MRI effective transverse relaxation rate (R2*) - indicative of iron content - in 68 grey matter regions, after adjustment for confounders. The group with severe OSA (apnea-hypopnea index ≥30/h) had higher iron levels in the left superior frontal gyrus (F3,760  = 4.79, p = 0.003), left orbital gyri (F3,760  = 5.13, p = 0.002), right and left middle temporal gyrus (F3,760  = 4.41, p = 0.004 and F3,760  = 13.08, p < 0.001, respectively), left angular gyrus (F3,760  = 6.29, p = 0.001), left supramarginal gyrus (F3,760  = 4.98, p = 0.003), and right cuneus (F3,760  = 7.09, p < 0.001). The parameters of nocturnal hypoxaemia were all consistently associated with higher iron levels. Measures of sleep fragmentation had less consistent associations with iron content. This study provides the first evidence of increased brain iron levels in obstructive sleep apnea. The observed iron changes could reflect underlying neuropathological processes that appear to be driven primarily by hypoxaemic mechanisms.

Mean Oxygen Saturation during Sleep Is Related to Specific Brain Atrophy Pattern.

OBJECTIVE: There is much controversy about the neurobiological mechanisms underlying the effects of sleep-disordered breathing on the brain. The aim of this study was to investigate the association between markers of sleep-related hypoxemia and brain anatomy. METHODS: We used data from a large-scale cohort from the general population (n = 775, 50.6% males, age range = 45-86 years, mean age = 60.3 ± 9.9) that underwent full polysomnography and brain magnetic resonance imaging to correlate respiratory variables with regional brain volume estimates. RESULTS: After adjusting for age, gender, and cardiovascular risk factors, only mean oxygen saturation during sleep was associated with bilateral volume of hippocampus (right: p = 0.001; left: p < 0.001), thalamus (right: p < 0.001; left: p < 0.001), putamen (right: p = 0.001; left: p = 0.001), and angular gyrus (right: p = 0.011; left: p = 0.001). We observed the same relationship in left hemispheric amygdala (p = 0.010), caudate (p = 0.008), inferior frontal gyrus (p = 0.004), and supramarginal gyrus (p = 0.003). The other respiratory variables-lowest oxygen saturation, percentage of sleep time with oxygen saturation < 90%, apnea-hypopnea index, and oxygen desaturation index-did not show any significant association with brain volumes. INTERPRETATION: Lower mean oxygen saturation during sleep was associated with atrophy of cortical and subcortical brain areas known for high sensitivity to oxygen supply. Their vulnerability to hypoxemia may contribute to behavioral phenotype and cognitive decline in patients with sleep-disordered breathing. ANN NEUROL 2020;87:921-930.