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.

Inflammation biomarkers in the intracranial blood are associated with outcome in patients with ischemic stroke.

BACKGROUND: Performing endovascular treatment (EVT) in patients with acute ischemic stroke (AIS) allows a port of entry for intracranial biological sampling. OBJECTIVE: To test the hypothesis that specific immune players are molecular contributors to disease, outcome biomarkers, and potential targets for modifying AIS. METHODS: We examined 75 subjects presenting with large vessel occlusion of the anterior circulation and undergoing EVT. Intracranial blood samples were obtained by microcatheter aspiration, as positioned for stent deployment. Peripheral blood samples were collected from the femoral artery. Plasma samples were quality controlled by electrophoresis and analyzed using a Mesoscale multiplex for targeted inflammatory and vascular factors. RESULTS: We measured 37 protein biomarkers in our sample cohort. Through multivariate analysis, adjusted for age, intravenous thrombolysis, pretreatment National Institutes of Health Stroke Scale and Alberta Stroke Program Early CT scores, we found that post-clot blood levels of interleukin-6 (IL-6) were significantly correlated (adjusted P value <0.05) with disability assessed by the modified Rankin Scale (mRS) score at 90 days, with medium effect size. Chemokine (C-C) ligand 17 CCL17/TARC levels were inversely correlated with the mRS score. Examination of peripheral blood showed that these correlations did not reach statistical significance after correction. Intracranial biomarker IL-6 level was specifically associated with a lower likelihood of favorable outcome, defined as a mRS score of 0-2. CONCLUSIONS: Our findings show a signature of blood inflammatory factors at the cerebrovascular occlusion site. The correlations between these acute-stage biomarkers and mRS score outcome support an avenue for add-on and localized immune modulatory strategies in AIS.

Continuous low-level dietary exposure to glyphosate elicits dose and sex-dependent synaptic and microglial adaptations in the rodent brain.

Prolonged exposure to low levels of dietary contaminants is a context in modern life that could alter organ physiology gradually. Here, we aimed to investigate the impact of continuous exposure to acceptable daily intake (ADI) and non-observable adverse effect level (NOAEL) of glyphosate from gestation to adulthood using C57BL/6J mice and incorporating these levels into their food pellets. From adulthood, we analyzed neurophysiological and neuro-glia cellular adaptations in male and female animals. Using ex-vivo hippocampal slice electrophysiology, we found a reduced efficacy of Schaffer collateral-to-CA1 excitatory synapses in glyphosate-exposed dietary conditions, with ADI and NOAEL dose-dependent effects. Short-term facilitation of excitatory synaptic transmission was specifically increased in NOAEL conditions, with a predominant influence in males, suggesting a reduced probability of neurotransmitter release. Long-term synaptic potentiation (LTP) was decreased in NOAEL-exposed mice. Next, we explore whether these neurophysiological modifications are associated with neuro-glia changes in the somatosensory cortex and hippocampus. High-resolution confocal microscopy analyses unveil a dose-dependent increased density of excitatory Vglut1+ Homer1+ synapses. Microglial Iba1+ cells displayed a shortening of their ramifications, a sign of cellular reactivity that was more pronounced in males at NOAEL levels. The morphology of GFAP+ astrocytes was generally not modified. Finally, we asked whether mouse-specific cross-correlations exist among all data sets generated. This examination included the novel object recognition (NOR) test performed before ex vivo functional and immunohistochemical examinations. We report a negative linear regression between the number of synapses and NOR or LTP maintenance when plotting ADI and NOAEL datasets. These results outline synaptic and microglial cell adaptations resulting from prenatal and continuous dietary low levels of glyphosate, discernible in, but not limited to, adult males exposed to the NOAEL. We discuss the potential significance of these findings to real-world consumer situations and long-term brain resilience.

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).

CAR Protects Females from Diet-Induced Steatosis and Associated Metabolic Disorders.

Non-Alcoholic Fatty Liver Disease (NAFLD) is the most common cause of chronic liver disease worldwide, affecting 70-90% of obese individuals. In humans, a lower NAFLD incidence is reported in pre-menopausal women, although the mechanisms affording this protection remain under-investigated. Here, we tested the hypothesis that the constitutive androstane nuclear receptor (CAR) plays a role in the pathogenesis of experimental NAFLD. Male and female wild-type (WT) and CAR knock-out (CAR-/-) mice were subjected to a high-fat diet (HFD) for 16 weeks. We examined the metabolic phenotype of mice through body weight follow-up, glucose tolerance tests, analysis of plasmatic metabolic markers, hepatic lipid accumulation, and hepatic transcriptome. Finally, we examined the potential impact of HFD and CAR deletion on specific brain regions, focusing on glial cells. HFD-induced weight gain and hepatic steatosis are more pronounced in WT males than females. CAR-/- females present a NASH-like hepatic transcriptomic signature suggesting a potential NAFLD to NASH transition. Transcriptomic correlation analysis highlighted a possible cross-talk between CAR and ERα receptors. The peripheral effects of CAR deletion in female mice were associated with astrogliosis in the hypothalamus. These findings prove that nuclear receptor CAR may be a potential mechanism entry-point and a therapeutic target for treating NAFLD/NASH.

Dual-Hit: Glyphosate exposure at NOAEL level negatively impacts birth and glia-behavioural measures in heterozygous shank3 mutants.

The omnipresence of environmental contaminants represents a health danger with ramifications for adverse neurological trajectories. Here, we tested the dual-hit hypothesis that continuous exposure to non-observable adverse effect level (NOAEL) glyphosate from pre-natal to adulthood represents a risk factor for neurological-associated adaptations when in the presence of the heterozygote or homozygote mutation of the Shank3 synaptic gene. Ultrasound analysis of pregnant dams revealed patterns of pre-natal mortality with effects dependent on wild-type, Shank3ΔC/+, or Shank3ΔC/ΔC genotypes exposed to NOAEL glyphosate (GLY) compared to unexposed conditions. The postnatal survival rate was negatively impacted, specifically in Shank3ΔC/+ exposed to GLY. Next, the resulting six groups of pups were tracked into adulthood and analyzed for signs of neuroinflammation and neurological adaptions. Sholl's analysis revealed cortical microgliosis across groups exposed to GLY, with Shank3ΔC/+ mice presenting the most significant modifications. Brain tissues were devoid of astrocytosis, except for the perivascular compartment in the cortex in response to GLY. Distinct behavioral adaptations accompanied these cellular modifications, as locomotion and social preference were decreased in Shank3ΔC/+ mice exposed to GLY. Notably, GLY exposure from weaning did not elicit glial or neurological adaptations across groups, indicating the importance of pre-natal contaminant exposure. These results unveil the intersection between continuous pre-natal to adulthood environmental input and a pre-existing synaptic mutation. In an animal model, NOAEL GLY predominantly impacted Shank3ΔC/+ mice, compounding an otherwise mild phenotype compared to Shank3ΔC/ΔC. The possible relevance of these findings to neurodevelopmental risk is critically discussed, along with avenues for future research.

PIEZO1 expression at the glio-vascular unit adjusts to neuroinflammation in seizure conditions.

Mechanosensors are emerging players responding to hemodynamic and physical inputs. Their significance in the central nervous system remains relatively uncharted. Using human-derived brain specimens or cells and a pre-clinical model of mesio-temporal lobe epilepsy (MTLE), we examined how the mRNA levels of the mechanosensitive channel PIEZO1 adjust to disease-associated pro-inflammatory trajectories. In brain tissue micro-punches obtained from 18 drug-resistant MTLE patients, PIEZO1 expression positively correlated with pro-inflammatory biomarkers TNFα, IL-1ß, and NF-kB in the epileptogenic hippocampus compared to the adjacent amygdala and temporal cortex tissues. In an experimental MTLE model, hippocampal Piezo1 and cytokine expression levels were increased post-status epilepticus (SE) and during epileptogenesis. Piezo1 expression positively correlated with Tnfα, Il1ß, and Nf-kb in the hippocampal foci. Next, by combining RNAscope with immunohistochemistry, we identified Piezo1 in glio-vascular cells. Post-SE and during epileptogenesis, ameboid IBA1 microglia, hypertrophic GFAP astrocytes, and damaged NG2DsRed pericytes exhibited time-dependent patterns of increased Piezo1 expression. Digital droplet PCR analysis confirmed the Piezo1 trajectory in isolated hippocampal microvessels in the ipsi and contralateral hippocampi. The combined examinations performed in this model showed Piezo1 expression returning towards basal levels after the epileptogenesis-associated peak inflammation. From these associations, we next asked whether pro-inflammatory players directly regulate PIEZO1 expression. We used human-derived brain cells and confirmed that endothelium, astrocytes, and pericytes expressed PIEZO1. Exposure to human recombinant TNFα or IL1ß upregulated NF-kB in all cells. Furthermore, TNFα induced PIEZO1 expression in a dose and time-dependent manner, primarily in astrocytes. This exploratory study describes a spatiotemporal dialogue between PIEZO1 brain cell-mechanobiology and neuro-inflammatory cell remodeling. The precise functional mechanisms regulating this interplay in disease conditions warrant further investigation.

Lower systemic nitric oxide bioactivity, cerebral hypoperfusion and accelerated cognitive decline in formerly concussed retired rugby union players.

NEW FINDINGS: What is the central question of this study? What are the molecular, cerebrovascular and cognitive biomarkers of retired rugby union players with concussion history? What is the main finding and its importance? Retired rugby players compared with matched controls exhibited lower systemic nitric oxide bioavailability accompanied by lower middle cerebral artery velocity and mild cognitive impairment. Retired rugby players are more susceptible to accelerated cognitive decline. ABSTRACT: Following retirement from sport, the chronic consequences of prior-recurrent contact are evident and retired rugby union players may be especially prone to accelerated cognitive decline. The present study sought to integrate molecular, cerebrovascular and cognitive biomarkers in retired rugby players with concussion history. Twenty retired rugby players aged 64 ± 5 years with three (interquartile range (IQR), 3) concussions incurred over 22 (IQR, 6) years were compared to 21 sex-, age-, cardiorespiratory fitness- and education-matched controls with no prior concussion history. Concussion symptoms and severity were assessed using the Sport Concussion Assessment Tool. Plasma/serum nitric oxide (NO) metabolites (reductive ozone-based chemiluminescence), neuron specific enolase, glial fibrillary acidic protein and neurofilament light-chain (ELISA and single molecule array) were assessed. Middle cerebral artery blood velocity (MCAv, doppler ultrasound) and reactivity to hyper/hypocapnia ( CVR CO 2 hyper ${\mathrm{CVR}}_{{\mathrm{CO}}_{\mathrm{2}}{\mathrm{hyper}}}$ / CVR CO 2 hypo ${\mathrm{CVR}}_{{\mathrm{CO}}_{\mathrm{2}}{\mathrm{hypo}}}$ ) were assessed. Cognition was determined using the Grooved Pegboard Test and Montreal Cognitive Assessment. Players exhibited persistent neurological symptoms of concussion (U = 109(41) , P = 0.007), with increased severity compared to controls (U = 77(41) , P < 0.001). Lower total NO bioactivity (U = 135(41) , P = 0.049) and lower basal MCAv were apparent in players (F2,39  = 9.344, P = 0.004). This was accompanied by mild cognitive impairment (P = 0.020, 95% CI, -3.95 to -0.34), including impaired fine-motor coordination (U = 141(41) , P = 0.021). Retired rugby union players with history of multiple concussions may be characterised by impaired molecular, cerebral haemodynamic and cognitive function compared to non-concussed, non-contact controls.

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.

Pesticides at brain borders: Impact on the blood-brain barrier, neuroinflammation, and neurological risk trajectories.

Pesticides are omnipresent, and they pose significant environmental and health risks. Translational studies indicate that acute exposure to high pesticide levels is detrimental, and prolonged contact with low concentrations of pesticides, as single and cocktail, could represent a risk factor for multi-organ pathophysiology, including the brain. Within this research template, we focus on pesticides' impact on the blood-brain barrier (BBB) and neuroinflammation, physical and immunological borders for the homeostatic control of the central nervous system (CNS) neuronal networks. We examine the evidence supporting a link between pre- and postnatal pesticide exposure, neuroinflammatory responses, and time-depend vulnerability footprints in the brain. Because of the pathological influence of BBB damage and inflammation on neuronal transmission from early development, varying exposures to pesticides could represent a danger, perhaps accelerating adverse neurological trajectories during aging. Refining our understanding of how pesticides influence brain barriers and borders could enable the implementation of pesticide-specific regulatory measures directly relevant to environmental neuroethics, the exposome, and one-health frameworks.

Effect of oxybutynin and reboxetine on obstructive sleep apnea: a randomized, placebo-controlled, double-blind, crossover trial.

STUDY OBJECTIVES: Although recent investigations combining noradrenergic and antimuscarinic drugs have shown promising short-term results to treat obstructive sleep apnea (OSA), the mid-term effect and optimal dosage remain uncertain. The present study aimed to evaluate the effect of 1 week of 5 mg oxybutynin and 6 mg reboxetine (oxy-reb) on OSA versus placebo. METHODS: We performed a randomized, placebo-controlled, double-blind, crossover trial comparing the effect of 1 week of oxy-reb versus 1 week of placebo on OSA severity. At-home polysomnography was performed at baseline and after each week of intervention. RESULTS: Fifteen participants (male 66.7%) aged 59 [44-62] years (median [interquartile range]) with a mean body mass index of 33.1 ± 6.6 kg/m2 were included. No significant difference in apnea-hypopnea index (AHI) was observed between conditions (estimated marginal means [95% confidence interval] at baseline: 39.7 [28.5-55.3]; oxy-reb: 34.5 [22.7-52.3]; placebo: 37.9 [27.1-52.9]; p = 0.652), but oxy-reb improved average oxygen desaturation (p = 0.016) and hypoxic burden (p = 0.011) and lowered sleep efficiency (p = 0.019) and rapid eye movement sleep (p = 0.002). Moreover, participants reported reduced sleep quality during the week of oxy-reb compared to the week of placebo (4.7 [3.5; 5.9] vs. 6.5 [5.5; 7.5] on a 0-10 visual analogic scale, respectively; p = 0.001). No significant differences in sleepiness, vigilance, and fatigue were observed. No serious adverse events occurred. CONCLUSIONS: Administration of oxybutynin 5 mg and reboxetine 6 mg did not improve OSA severity assessed by AHI, but did alter sleep architecture and sleep quality. Reduced average oxygen desaturation and hypoxic burden were also observed. CLINICAL TRIAL: ClinicalTrials.gov, https://clinicaltrials.gov, NCT04394143.

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.

Lifelong exposure to high-altitude hypoxia in humans is associated with improved redox homeostasis and structural-functional adaptations of the neurovascular unit.

High-altitude (HA) hypoxia may alter the structural-functional integrity of the neurovascular unit (NVU). Herein, we compared male lowlanders (n = 9) at sea level (SL) and after 14 days acclimatization to 4300 m (chronic HA) in Cerro de Pasco (CdP), Péru (HA), against sex-, age- and body mass index-matched healthy highlanders (n = 9) native to CdP (lifelong HA). Venous blood was assayed for serum proteins reflecting NVU integrity, in addition to free radicals and nitric oxide (NO). Regional cerebral blood flow (CBF) was examined in conjunction with cerebral substrate delivery, dynamic cerebral autoregulation (dCA), cerebrovascular reactivity to carbon dioxide (CVRCO2 ) and neurovascular coupling (NVC). Psychomotor tests were employed to examine cognitive function. Compared to lowlanders at SL, highlanders exhibited elevated basal plasma and red blood cell NO bioavailability, improved anterior and posterior dCA, elevated anterior CVRCO2 and preserved cerebral substrate delivery, NVC and cognition. In highlanders, S100B, neurofilament light-chain (NF-L) and T-tau were consistently lower and cognition comparable to lowlanders following chronic-HA. These findings highlight novel integrated adaptations towards regulation of the NVU in highlanders that may represent a neuroprotective phenotype underpinning successful adaptation to the lifelong stress of HA hypoxia. KEY POINTS: High-altitude (HA) hypoxia has the potential to alter the structural-functional integrity of the neurovascular unit (NVU) in humans. For the first time, we examined to what extent chronic and lifelong hypoxia impacts multimodal biomarkers reflecting NVU structure and function in lowlanders and native Andean highlanders. Despite lowlanders presenting with a reduction in systemic oxidative-nitrosative stress and maintained cerebral bioenergetics and cerebrovascular function during chronic hypoxia, there was evidence for increased axonal injury and cognitive impairment. Compared to lowlanders at sea level, highlanders exhibited elevated vascular NO bioavailability, improved dynamic regulatory capacity and cerebrovascular reactivity, comparable cerebral substrate delivery and neurovascular coupling, and maintained cognition. Unlike lowlanders following chronic HA, highlanders presented with lower concentrations of S100B, neurofilament light chain and total tau. These findings highlight novel integrated adaptations towards the regulation of the NVU in highlanders that may represent a neuroprotective phenotype underpinning successful adaptation to the lifelong stress of HA hypoxia.

Neurovascular hypoxia after mild traumatic brain injury in juvenile mice correlates with heart-brain dysfunctions in adulthood.

AIM: Retrospective studies suggest that mild traumatic brain injury (mTBI) in pediatric patients may lead to an increased risk of cardiac events. However, the exact functional and temporal dynamics and the associations between heart and brain pathophysiological trajectories are not understood. METHODS: A single impact to the left somatosensory cortical area of the intact skull was performed on juvenile mice (17 days postnatal). Cerebral 3D photoacoustic imaging was used to measure the oxygen saturation (sO2 ) in the impacted area 4 h after mTBI followed by 2D and 4D echocardiography at days 7, 30, 90, and 190 post-impact. At 8 months, we performed a dobutamine stress test to evaluate cardiac function. Lastly, behavioral analyses were conducted 1 year after initial injury. RESULTS: We report a rapid and transient decrease in cerebrovascular sO2 and increased hemoglobin in the impacted left brain cortex. Cardiac analyses showed long-term diastolic dysfunction and a diminished systolic strain response under stress in the mTBI group. At the molecular level, cardiac T-p38MAPK and troponin I expression was pathologic modified post-mTBI. We found linear correlations between brain sO2 measured immediately post-mTBI and long-term cardiac strain after 8 months. We report that initial cerebrovascular hypoxia and chronic cardiac dysfunction correlated with long-term behavioral changes hinting at anxiety-like and memory maladaptation. CONCLUSION: Experimental juvenile mTBI induces time-dependent cardiac dysfunction that corresponds to the initial neurovascular sO2 dip and is associated with long-term behavioral modifications. These imaging biomarkers of the heart-brain axis could be applied to improve clinical pediatric mTBI management.