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Regression Analysis for Polysomnographic Respiratory Variables Predicting Regional Brain Volumes, after Adjusting for Age, Gender, Body Mass Index, Diabetes, Dyslipidemia, Hypertension, Smoking, and Alcohol Use
Source publication
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%...
Context in source publication
Context 1
... interaction between PSG respiratory variables and age was excluded from the model, given that the results were not significant (data not shown). Among the 5 PSG respiratory variables, only mean SaO2 was independently associated with volume of hippocampus (right: B = 0.013, p = 0.001; left: B = 0.014, p < 0. Table 2 and Supplementary Table 2). Figure 2 provides a 3D map of these brain structures. ...Citations
... Traditionally, studies pertaining to gray matter structure have been conducted using voxel-based morphometry (VBM), followed by the introduction of methods utilizing volumetric segmentation and cortical thickness assessment. [8,[27][28][29] A meta-analysis of VBM studies reported gray matter atrophy in the frontal, cingulate, and temporal cortex [27]; however, subsequent studies have reported conflicting results. Gray matter atrophy has been indicated to be associated with more severe hypoxemia states in large cohort studies, [29] while a study involving older patients with sleep-disordered breathing who were cognitively unimpaired also reported partial gray matter hypertrophy attributed to an increased amyloid β burden. ...
... [8,[27][28][29] A meta-analysis of VBM studies reported gray matter atrophy in the frontal, cingulate, and temporal cortex [27]; however, subsequent studies have reported conflicting results. Gray matter atrophy has been indicated to be associated with more severe hypoxemia states in large cohort studies, [29] while a study involving older patients with sleep-disordered breathing who were cognitively unimpaired also reported partial gray matter hypertrophy attributed to an increased amyloid β burden. [28] However, more recently, it has been increasingly recognized that gray matter atrophy or hypertrophy may not present conflicting results but rather indicate diverse patterns depending on factors such as the duration of OSA, patient age, and the presence of cognitive impairment. ...
Purpose
The objective of this research was to examine changes in the neural networks of both gray and white matter in individuals with obstructive sleep apnea (OSA) in comparison to those without the condition, employing a comprehensive multilayer network analysis.
Methods
Patients meeting the criteria for OSA were recruited through polysomnography, while a control group of healthy individuals matched for age and sex was also assembled. Utilizing T1-weighted imaging, a morphometric similarity network was crafted to represent gray matter, while diffusion tensor imaging provided structural connectivity for constructing a white matter network. A multilayer network analysis was then performed, employing graph theory methodologies.
Results
We included 40 individuals diagnosed with OSA and 40 healthy participants in our study. Analysis revealed significant differences in various global network metrics between the two groups. Specifically, patients with OSA exhibited higher average degree overlap and average multilayer clustering coefficient (28.081 vs. 23.407, p < 0.001; 0.459 vs. 0.412, p = 0.004), but lower multilayer modularity (0.150 vs. 0.175, p = 0.001) compared to healthy controls. However, no significant differences were observed in average multiplex participation, average overlapping strength, or average weighted multiplex participation between the patients with OSA and healthy controls. Moreover, several brain regions displayed notable differences in degree overlap at the nodal level between patients with OSA and healthy controls.
Conclusion
Remarkable alterations in the multilayer network, indicating shifts in both gray and white matter, were detected in patients with OSA in contrast to their healthy counterparts. Further examination at the nodal level unveiled notable changes in regions associated with cognition, underscoring the effectiveness of multilayer network analysis in exploring interactions across brain layers.
... One potential mechanism could be the detrimental effect of OSA-related hypoxemia, which could promote tissue alterations in AD-related brain regions. OSA-related hypoxemia has been associated with gray matter changes in the medial temporal lobe, including volume loss [14][15][16] and edema. 17 Yet, no study has extended these findings to assess the link between OSA and microstructural integrity of limbic white matter tracts that represent the main afferent and efferent pathways of the medial temporal lobe. ...
... Previous neuroimaging studies have found a correlation between the degree of nocturnal hypoxemia and morphometric changes in the brain, including in the medial temporal lobe. [14][15][16][17] Furthermore, hypoxemia, rather than sleep fragmentation, has been shown to predict greater cognitive decline in older adults with OSA in population-based cohort studies. [76][77][78] This study has strengths, including the diagnosis of OSA based on the gold standard PSG, the analysis of the moderating role of MCI, and the use of a FW-DTI approach. ...
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.
... Moderate to severe OSA is independently associated with white matter change; however, mild OSA does not seem to influence the occurrence of white matter change in middle-aged and older individuals (16). A cohort study revealed a correlation between hypoxia and subcortical, hippocampal, and frontal gray matter atrophy in patients with OSA (17). However, currently, no research has reported on the relationship between OSA and early brain perfusion imaging abnormalities in patients with cerebral infarction. ...
Purpose
To explore the relationship between obstructive sleep apnea (OSA) and hypoperfusion during ultra-early acute cerebral infarction.
Patients and methods
Data were retrospectively collected from patients admitted to our hospital with acute cerebral infarction between January 2020 and January 2022, who underwent comprehensive whole-brain computed tomography perfusion imaging and angiography examinations within 6 h of onset. The F-stroke software automatically assessed and obtained relevant data (Tmax). The patients underwent an initial screening for sleep apnea. Based on their Apnea-Hypopnea Index (AHI), patients were categorized into an AHI ≤15 (n = 22) or AHI >15 (n = 25) group. The pairwise difference of the time-to-maximum of the residue function (Tmax) > 6 s volume was compared, and the correlation between AHI, mean pulse oxygen saturation (SpO2), oxygen desaturation index (ODI), percentage of time with oxygen saturation < 90% (T90%), and the Tmax >6 s volume was analyzed.
Results
The Tmax >6 s volume in the AHI > 15 group was significantly larger than that in the AHI ≤ 15 group [109 (62–157) vs. 59 (21–106) mL, p = 0.013]. Spearman’s correlation analysis revealed Tmax >6 s volume was significantly correlated with AHI, mean SpO2, ODI, and T90% in the AHI > 15 group, however, no significant correlations were observed in the AHI ≤ 15 group. Controlling for the site of occlusion and Multiphase CT angiography (mCTA) score, AHI (β = 0.919, p < 0.001), mean SpO2 (β = −0.460, p = 0.031), ODI (β = 0.467, p = 0.032), and T90% (β =0.478, p = 0.026) remained associated with early hypoperfusion in the AHI > 15 group.
Conclusion
In patients with acute cerebral infarction and AHI > 15, AHI, mean SpO2, ODI and T90% were associated with early hypoperfusion. However, no such relationship exists among patients with AHI ≤ 15.
... For all analyses, a two-sided p < 0.05 was considered statistically significant. Based on reported practical considerations (Marchi et al., 2020;Sangal & Sudan, 2020) and the exploratory nature of the analyses, multiple comparison adjustments were not performed. ...
... Severe OSA (AHI ≥30 events/h) has also been associated with worse visual attention and processing speed (Martin et al., 2015). In contrast, in the Atherosclerosis Risk in Com- (Marchi et al., 2020;Sangal & Sudan, 2020;Shahveisi et al., 2018). Our association of a higher percentage of N1 sleep with better TMT-A performance also contrasts with the association in the older sample of men (aged ≥65 years) in our cross-sectional analysis, which suggested that greater light or fragmented sleep is associated with worse TMT-A performance (Parker, Appleton, et al., 2021). ...
Previous prospective studies examining associations of obstructive sleep apnea and sleep macroarchitecture with future cognitive function recruited older participants, many demonstrating baseline cognitive impairment. This study examined obstructive sleep apnea and sleep macroarchitecture predictors of visual attention, processing speed, and executive function after 8 years among younger community-dwelling men. Florey Adelaide Male Ageing Study participants (n = 477) underwent home-based polysomnography, with 157 completing Trail-Making Tests A and B and the Mini-Mental State Examination. Associations of obstructive sleep apnea (apnea-hypopnea index, oxygen desaturation index, and hypoxic burden index) and sleep macroarchitecture (sleep stage percentages and total sleep time) parameters with future cognitive function were examined using regression models adjusted for base-line demographic, biomedical, and behavioural factors, and cognitive task performance. The mean (standard deviation) age of the men at baseline was 58.9 (8.9) years, with severe obstructive sleep apnea (apnea-hypopnea index ≥30 events/h) in 9.6%. The median (interquartile range) follow-up was 8.3 (7.9-8.6) years. A minority of men (14.6%) were cognitively impaired at baseline (Mini-Mental State Examination score <28/30). A higher percentage of light sleep was associated with better Trail-Making Test A performance (B = À0.04, 95% confidence interval [CI] À0.06, À0.01; p = 0.003), whereas higher mean oxygen saturation was associated with worse performance (B = 0.11, 95% CI 0.02, 0.19; p = 0.012). While obstructive sleep apnea and sleep macroarchitecture might predict cognitive decline, future studies should Sarah L. Appleton and Robert J. Adams are co-senior authors.
... Therefore, part of the decline observed in attention and mental flexibility may be attributed to a decrease in processing speed. These cognitive functions also depend on the prefrontal cortex, which is highly vulnerable to OSA [27,49]. Specifically, sleep fragmentation and intermittent hypoxemia interfere with brain structure and function through oxidative stress and neuroinflammation, leading to neuronal death [41]. ...
... OSA prevalence in adults ranges from 6 to 17% but increases with aging, affecting up to 49% of the elderly population (2). By chronically fragmenting sleep and provoking intermittent episodes of hypoxemia, OSA may increase oxidative stress, neuroinflammation and cerebral edema, leading to complex and potentially non-linear changes in neuroimaging markers such as cerebral gray matter volume, metabolism, white matter diffusivity, as well as greater amyloid and tau levels (3)(4)(5)(6)(7)(8)(9)(10). Unsurprisingly, most epidemiological studies show that untreated OSA increases the risk of cognitive decline and dementia (11)(12)(13)(14)(15). ...
... Structural neuroimaging has been used to identify OSA-related brain changes suggestive of early neurodegenerative processes in late middleaged and older adults. Some brain regions appear to be particularly sensitive to the pathological consequences of OSA, such as the medial temporal lobe (MTL), and other hubs of the default mode network (DMN), such as the posterior cingulate cortex and the precuneus (4,5,7,9,10). Whether OSA is associated with functional connectivity (FC) abnormalities in older populations is unclear, as most studies have been performed in young and middle-aged adults, often in male participants only. Studies among 20-70 years old participants with moderate to severe OSA show that they have lower resting-state FC between the hippocampus and other DMN regions, such as the posterior cingular cortex (PCC), medial prefrontal cortex (mPFC) and parahippocampal region (PHC) compared to non-apneic participants (16,17). ...
... Hippocampal pyramidal neurons are especially vulnerable to hypoxia due to their large size, and their high pre-existing levels of reactive oxygen species (41)(42)(43). Consistently, studies in humans show that OSA is associated with hippocampal damage, with greater OSA severity being associated with lower hippocampal volume (9,44). Interestingly, the MTL is well known to be among the first cortical areas to accumulate tau pathology, a hallmark of AD which partly underlies neurodegeneration in this population (45,46). ...
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.
... As SDB has been associated with a greater risk of cognitive decline 4 , a number of studies investigated SDB-related brain alterations. Some studies have previously demonstrated that SDB is associated with hippocampal damage [11][12][13][14]40 . Our results demonstrate that MTL subregions particularly vulnerable to SDB, including the ERC and within the hippocampus, the subiculum, CA1 and DG subfields. ...
Background and objectives
Sleep-disordered breathing (SDB) has been related to amyloid deposition and increased dementia risk. However, how SDB relates to medial temporal lobe neurodegeneration and subsequent episodic memory impairment is unclear. Our objective was to investigate the impact of amyloid positivity on the associations between SDB severity, medial temporal lobe subregions and episodic memory performance in cognitively unimpaired older adults.
Methods
Data were acquired between 2016 and 2020 in the context of the Age-Well randomized controlled trial of the Medit-Ageing European project. Participants aged over 65 years old, free of neurological, psychiatric or chronic medical diseases were recruited from the community. They completed a neuropsychological evaluation, in-home polysomnography, a Florbetapir positron emission tomography and magnetic resonance imaging, including a specific high-resolution assessment of the medial temporal lobe and hippocampal subfields. Multiple linear regressions were conducted to test interactions between amyloid status and SDB severity on the volume of MTL subregions, controlling for age, sex, education and the ApoE4 status. Secondary analyses aimed at investigating the links between SDB, MTL subregional atrophy and episodic memory performance at baseline and at a mean follow up of 20.66 months in the whole cohort and in subgroups stratified according to amyloid status.
Results
We included 122 cognitively intact community-dwelling older adults (mean age ± SD: 69.40 ± 3.85 years, 77 women, 26 Aβ+ individuals) in baseline analyses and 111 at follow-up. The apnea-hypopnea index interacted with entorhinal (β=-0.81, p<0.001, pη ² =0.19), whole hippocampal (β=-0.61, p<0.001, pη ² =0.10), subiculum (β=-0.56, p=0.002, pη ² =0.08), CA1 (β=-0.55, p=0.002, pη ² =0.08) and DG (β=-0.53, p=0.003, pη ² =0.08) volumes, such that higher sleep apnea severity was related to lower MTL subregions volumes in amyloid-positive individuals, but not those who were amyloid-negative. In the whole cohort, lower whole hippocampal (r=0.27, p=0.005) and CA1 (r=0.28, p=0.003) volumes at baseline were associated with worse episodic memory performance at follow-up.
Discussion
Overall, we showed that SDB was associated with MTL atrophy in cognitively asymptomatic older adults engaged in the Alzheimer’s continuum, which may increase the risk of developing memory impairment over time.
Trial Registration Information
ClinicalTrials.gov Identifier: NCT02977819
... Diagnosis of cerebellar hemorrhage/infarction or brainstem hemorrhage/infarction was based on findings on CT and MRI examinations. Exclusion criteria included comorbidities that may cause brain atrophy such as cardiopulmonary arrest prior to admission or on arrival [18], hypoxemia (PaO 2 < 60 mmHg) at admission [23], status epilepticus [16], and hematological disease [28]; presence of a ventricular drain; hydrocephalus; inappropriate thickness (> 5 mm) of CT sections; and segmentation errors during image analysis. ...
Background
The effect of posterior cranial fossa stroke on changes in cerebral volume is not known. We assessed cerebral volume changes in patients with acute posterior fossa stroke using CT scans, and looked for risk factors for cerebral atrophy.
Methods
Patients with cerebellar or brainstem hemorrhage/infarction admitted to the ICU, and who underwent at least two subsequent inpatient head CT scans during hospitalization were included (n = 60). The cerebral volume was estimated using an automatic segmentation method. Patients with cerebral volume reduction > 0% from the first to the last scan were defined as the “cerebral atrophy group (n = 47),” and those with ≤ 0% were defined as the “no cerebral atrophy group (n = 13).”
Results
The cerebral atrophy group showed a significant decrease in cerebral volume (first CT scan: 0.974 ± 0.109 L vs. last CT scan: 0.927 ± 0.104 L, P < 0.001). The mean percentage change in cerebral volume between CT scans in the cerebral atrophy group was –4.7%, equivalent to a cerebral volume of 46.8 cm³, over a median of 17 days. The proportions of cases with a history of hypertension, diabetes mellitus, and median time on mechanical ventilation were significantly higher in the cerebral atrophy group than in the no cerebral atrophy group.
Conclusions
Many ICU patients with posterior cranial fossa stroke showed signs of cerebral atrophy. Those with rapidly progressive cerebral atrophy were more likely to have a history of hypertension or diabetes mellitus and required prolonged ventilation.
... A meta-analysis revealed a clear decrease in gray matter volume (GMV) in middle aged untreated patients with OSA (Shi et al., 2017). However, recently, using more advanced neuroimaging measures, Baril et al. (2017) found a consistent positive relationship between markers of OSA severity (hypoxemia, respiratory disturbances, and sleep structure alteration) and gray matter hypertrophy and thickening, while another large sample study observed lower mean oxygen saturation during sleep was associated with atrophy of both cortical and subcortical brain areas (Marchi et al., 2020). Furthermore, Cross et al. (2018) and his colleagues reported more complex results, that is, hypoxia metrices were shown to be associated with decreased cortical thickness, while sleep disturbance with increased thickness. ...
... Furthermore, Cross et al. (2018) and his colleagues reported more complex results, that is, hypoxia metrices were shown to be associated with decreased cortical thickness, while sleep disturbance with increased thickness. Although researchers have posited the presence of two counteracting mechanisms (One may indicate cellular damage, while the other may reflect transitory responses) to account for these seemingly contradictory results (Baril et al., 2021), no consensus on the exact pattern of OSA-induced gray matter changes can be drawn from the current literature (Baril et al., 2017;Cross et al., 2018;André et al., 2020;Marchi et al., 2020). ...
Background:
Obstructive Sleep Apnea (OSA) characteristically leads to nocturnal hypoxia and sleep disturbance. Despite clear evidence of OSA-induced cognitive impairments, the literature offers no consensus on the relationship between these pathophysiological processes and brain structure alterations in patients.
Objective:
This study leverages the robust technique of structural equation modeling to investigate how hypoxia and sleep disturbance exert differential effects on gray matter structures.
Methods:
Seventy-four Male participants were recruited to undergo overnight polysomnography and T1-weighted Magnetic Resonance Imaging. Four structural outcome parameters were extracted, namely, gray matter volume, cortical thickness, sulcal depth, and fractal dimension. Structural equation models were constructed with two latent variables (hypoxia, and sleep disturbance) and three covariates (age, body mass index, and education) to examine the association between gray matter structural changes in OSA and the two latent variables, hypoxia and sleep disturbance.
Results:
The structural equation models revealed hypoxia-associated changes in diverse regions, most significantly in increased gray matter volume, cortical thickness and sulcal depth. In contrast, sleep disturbance. Was shown to be largely associated with reduce gray matter volume and sulcal depth.
Conclusion:
This study provides new evidence showing significant effects of OSA-induced hypoxia and sleep disturbance on gray matter volume and morphology in male patients with obstructive sleep apnea. It also demonstrates the utility of robust structural equation models in examining obstructive sleep apnea pathophysiology.
... When compared with healthy controls, patients with obstructive sleep apnea show lower performance in memory, executive functions, attention, and processing speed (Stranks and Crowe 2016;Leng et al. 2017), along with reduced grey matter volume in the amygdala/hippocampus and insula (Tahmasian et al. 2016). These results are consistent with the finding that lower mean oxygen saturation during sleep relates to lower regional grey matter volume in subcortical areas, such as the hippocampus, thalamus, or dorsal striatum (Marchi et al. 2020). Recent findings stipulate an association with the glymphatic system that affect the normal "filtering" function through pressure gradient changes (Ju et al. 2016). ...
Across the lifespan, the human body and brain endure the impact of a plethora of exogenous and endogenous factors that modulate individuals' health outcome in old age. The overwhelming inter-individual variance spans between increased frailties with loss of autonomy to largely preserved physical, cognitive, and social functions. Understanding the mechanisms underlying the diverse aging trajectories can inform future strategies to maintain a healthy body and brain. Here we provide a comprehensive overview on the lifetime factors governing brain health. We summarise the evidence that unhealthy alimentary regime, sedentary behaviour, sleep pathologies, cardio-vascular risk factors, and chronic inflammation exert their harmful effects in a cumulative and gradual manner, and that timely and efficient intervention promotes successful aging. We discuss the main effects and interactions between these risk factors and the resulting brain health outcomes to follow with a description of current strategies aiming to eliminate, treat, or counteract the risk factors. We conclude that detailed insight about the modifiable risk factors should guide personalized approaches to maintain our brains healthy.
