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High-altitude (HA) exposure may stimulate significant physiological and molecular changes, resulting in HA-related illnesses. HA may impact oxidative stress, antioxidant capacity, and iron homeostasis, yet it is unclear how both repeated exposure and HA acclimatization may modulate such effects. Therefore, we assessed the effects of weeklong repeated daily HA exposure (2,900–5,050 m) in altitude-naïve individuals ( n = 21 individuals, 13 females, mean ± SD, 25.3 ± 3.7 yr) to mirror the working schedule of HA workers ( n = 19 individuals, all males, 41.1 ± 9.4 yr) at the Atacama Large Millimeter Array (ALMA) Observatory (San Pedro de Atacama, Chile). Markers of oxidative stress, antioxidant capacity, and iron homeostasis were measured in blood plasma. Levels of protein oxidation ( P < 0.001) and catalase activity ( P = 0.023) increased and serum iron ( P < 0.001), serum ferritin ( P < 0.001), and transferrin saturation ( P < 0.001) levels decreased with HA exposure in both groups. HA workers had lower levels of oxidative stress, and higher levels of antioxidant capacity, iron supply, and hemoglobin concentration as compared with altitude-naïve individuals. On a second week of daily HA exposure, changes in levels of protein oxidation, glutathione peroxidase, and nitric oxide metabolites were lower as compared with the first week in altitude-naïve individuals. These results indicate that repeated exposure to HA may significantly alter oxidative stress and iron homeostasis, and the degree of such changes may be dependent on if HA is visited naïvely or routinely. Further studies are required to fully elucidate differences in HA-induced changes in oxidative stress and iron homeostasis profiles among visitors of HA.

Background and Purpose: We investigated the effect of higher therapeutic exercise doses on walking during inpatient rehabilitation, typically commencing 1 to 4 weeks poststroke. Methods: This phase II, blinded-assessor, randomized controlled trial recruited from 6 Canadian inpatient rehabilitation units, between 2014 and 2018. Subjects (n=75; 25/group) were randomized into: control (usual care) physical therapy: typically, 1 hour, 5 days/week; Determining Optimal Post-Stroke Exercise (DOSE1): 1 hour, 5 days/week, more than double the intensity of Control (based on aerobic minutes and walking steps); and DOSE2: 2 hours, 5 days/week, more than quadruple the intensity of Control, each for 4 weeks duration. The primary outcome, walking endurance at completion of the 4-week intervention (post-evaluation), was compared across these groups using linear regression. Secondary outcomes at post-evaluation, and longitudinal outcomes at 6 and 12-month evaluations, were also analyzed. Results: Both DOSE1 (mean change 61 m [95% CI, 9–113], P =0.02) and DOSE2 (mean change 58 m, 6–110, P =0.03) demonstrated greater walking endurance compared with Control at the post-evaluation. Significant improvements were also observed with DOSE2 in gait speed (5-m walk), and both DOSE groups in quality of life (EQ-5D-5 L) compared with Control. Longitudinal analyses revealed that improvements in walking endurance from the DOSE intervention were retained during the 1-year follow-up period over usual care. Conclusions: This study provides the first preliminary evidence that patients with stroke can improve their walking recovery and quality of life with higher doses of aerobic and stepping activity within a critical time period for neurological recovery. Furthermore, walking endurance benefits achieved from a 4-week intervention are retained over the first-year poststroke. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01915368.

Oxidative stress may be involved in disease pathology and dependent on both modifiable and nonmodifiable factors. This study aimed to assess exercise-induced changes in markers of oxidative stress among older, sedentary adults and to determine the effects of metabolic syndrome (MetS) status, aerobic capacity, age, sex, and weight on these biomarkers. Two hundred and six participants (means ± SE; 66.8 ± 6.4 yr, 104 women) of the Brain in Motion study underwent a 6-mo aerobic exercise intervention. At three time points, venous blood samples were collected and analyzed for markers of oxidative stress [advanced oxidation protein products (AOPP), malondialdehyde (MDA), 3-nitrotyrosine (3-NT) and antioxidant status: catalase, uric acid (UA), superoxide dismutase (SOD), and ferric-reducing ability of plasma (FRAP)]. AOPP levels significantly decreased after 6 mo of aerobic exercise ( P = 0.003). This decrease was not modified by MetS status ( P = 0.183). Subjects with MetS possessed significantly higher levels of AOPP ( P < 0.001), MDA ( P = 0.004), and FRAP ( P = 0.049) across the intervention ( months 0–6). Men possessed significantly higher levels of FRAP ( P < 0.001), catalase ( P = 0.023), and UA ( P = 0.037) across the intervention ( months 0–6). Sex-MetS status interaction analyses revealed that the effect of MetS is highly sex dependent. These findings are multifaceted because the effect of MetS status seems distinctly different between sexes, pointing to the importance of acknowledging modifiable and nonmodifiable factor differences in individuals who possess conditions where oxidative stress may be part of the etiology. NEW & NOTEWORTHY Oxidative stress is implicated in a myriad of conditions, namely cardiovascular disease risk factors. This article details the effect of aerobic exercise, sex, and metabolic syndrome on markers of oxidative stress. We conclude that 6 mo of aerobic exercise significantly decreased oxidative stress, and further, that there is an effect of metabolic syndrome status on oxidative stress and antioxidant status levels, which are highly dependent on the sex of the individual.

Background: Toxic amyloid-β (Aβ) peptides aggregate into higher molecular weight assemblies and accumulate not only in the extracellular space, but also in the walls of blood vessels in the brain, increasing their permeability, and promoting immune cell migration and activation. Given the prominent role of the immune system, phagocytic blood cells may contact pathological brain materials. Objective: To develop a novel method for early Alzheimer’s disease (AD) detection, we used blood leukocytes, that could act as “sentinels” after trafficking through the brain microvasculature, to detect pathological amyloid by labelling with a conformationally-sensitive fluorescent amyloid probe and imaging with confocal spectral microscopy. Methods: Formalin-fixed peripheral blood mononuclear cells (PBMCs) from cognitively healthy control (HC) subjects, mild cognitive impairment (MCI) and AD patients were stained with the fluorescent amyloid probe K114, and imaged. Results were validated against cerebrospinal fluid (CSF) biomarkers and clinical diagnosis. Results: K114-labeled leukocytes exhibited distinctive fluorescent spectral signatures in MCI/AD subjects. Comparing subjects with single CSF biomarker-positive AD/MCI to negative controls, our technique yielded modest AUCs, which improved to the 0.90 range when only MCI subjects were included in order to measure performance in an early disease state. Combining CSF Aβ42 and t-Tau metrics further improved the AUC to 0.93. Conclusion: Our method holds promise for sensitive detection of AD-related protein misfolding in circulating leukocytes, particularly in the early stages of disease.

Impairments of cognitive function during alterations in arterial blood gases (e.g., high‐altitude hypoxia) may result from the disruption of neurovascular coupling; however, the link between changes in arterial blood gases, cognition, and cerebral blood flow (CBF) is poorly understood. To interrogate this link, we developed a multimodal empirical strategy capable of monitoring neural correlates of cognition and CBF simultaneously. Human participants performed a sustained attention task during hypoxia, hypercapnia, hypocapnia, and normoxia while electroencephalographic (EEG) activity and CBF (middle and posterior cerebral arteries; transcranial Doppler ultrasound) were simultaneously measured. The protocol alternated between rest and engaging in a visual target detection task that required participants to monitor a sequence of brief‐duration colored circles and detect infrequent, longer duration circles (targets). The target detection task was overlaid on a large, circular checkerboard that provided robust visual stimulation. Spectral decomposition and event‐related potential (ERP) analyses were applied to the EEG data to investigate spontaneous and task‐specific fluctuations in neural activity. There were three main sets of findings: (1) spontaneous alpha oscillatory activity was modulated as a function of arterial CO2 (hypocapnia and hypercapnia), (2) task‐related neurovascular coupling was disrupted by all arterial blood gas manipulations, and (3) changes in task‐related alpha and theta band activity and attenuation of the P3 ERP component amplitude were observed during hypocapnia. Since alpha and theta are linked with suppression of visual processing and executive control and P3 amplitude with task difficulty, these data suggest that transient arterial blood gas changes can modulate multiple stages of cognitive information processing., Changes in arterial blood gases (e.g., from high‐altitude exposure) are associated with impairments of a variety of cognitive functions, potentially via disruption of how blood flow responds to brain activity. We used a novel multimodal approach to simultaneously measure human brain electrical activity using electroencephalography and blood flow using transcranial Doppler ultrasound, while participants performed a demanding sustained attention task at varying levels of arterial oxygen and carbon dioxide (CO2). We observed changes in both spontaneous and task‐related brain activity as a function of changes in arterial CO2 as well as disruptions in neurovascular coupling, suggesting that transient changes in arterial CO2 can affect multiple stages of cognitive processing.

Evidence from both preclinical and clinical studies suggests aerobic exercise may dampen age-related decline in cognitive performance. Alterations in hypothalamic-pituitary-adrenal (HPA) axis function and reactivity may be a mechanism by which aerobic exercise benefits cognitive performance, and reduces perceived stress. This investigation was completed as an ancillary investigation of the Brain in Motion (BIM) study, a 6-month supervised aerobic exercise intervention. Participants were generally healthy and screened for inclusion/exclusion criteria for the parent study. Thirty-eight participants were recruited (Mean age = 65.0 [SD = 5.1]; 60% female) and the final longitudinal sample was 32 participants. Participants provided a passive drool sample at: waking, 15, 30, and 45 min post-waking to assess the cortisol awakening response (CAR) and 3, 6, 9, and 12 h post-waking to assess daily area under the curve for cortisol. Salivary cortisol was quantified by liquid chromatography coupled to tandem mass spectrometry. The exercise intervention increased CAR but no differences were observed in daily AUC. In addition, larger increases in CAR were positively associated with greater decreases in subjective stress. Thus, aerobic exercise improved the CAR in otherwise healthy, but sedentary older adults and greater improvements in CAR were associated with greater reductions in perceived stress.

NEW FINDINGS What is the central question of this study? Does treatment of obstructive sleep apnoea (OSA) with nocturnal oxygen or continuous positive airway pressure (CPAP) improve hypoxic vascular responses, which are reportedly impaired in OSA? What is the main finding and its importance? Cerebrovascular and cardiovascular hypoxic responses were not impaired in OSA patients free of overt cardiovascular disease and known risk factors, and were not altered by nocturnal oxygen or CPAP treatment. We conclude that this OSA patient phenotype has normal vascular responses to hypoxia and is unlikely to obtain long term cardiovascular benefits from nocturnal oxygen or CPAP therapy. ABSTRACT Cerebral blood flow (CBF) and cardiovascular responses to hypoxia are reportedly impaired in obstructive sleep apnoea (OSA) patients and corrected by continuous positive airway pressure (CPAP), beneficial effects that are ascribed to correction of OSA-related intermittent hypoxia (IH). However, CPAP corrects both IH and ancillary OSA features (i.e. intermittent hypercapnia, sympathetic activation, blood pressure surges, negative intrathoracic pressure swings and sleep fragmentation). Whether correction of these ancillary OSA features contribute to CPAP's beneficial effects on vascular hypoxic responses is unknown. Nocturnal oxygen corrects OSA-induced IH, but apnoeas and ancillary features persist. Thus, we examined the effects of nocturnal oxygen and CPAP on cerebrovascular and cardiovascular hypoxic responses in untreated OSA patients. Responses were assessed in 52 OSA patients free of overt cardiovascular disease and known risk factors at baseline, after 2 weeks of nocturnal oxygen (n = 26) or no treatment (n = 26), and after ∼4 weeks of CPAP treatment (n = 40). Twenty-two age-matched controls were assessed at baseline and follow-up visits. Resting, isocapnic euoxia mean blood pressure was decreased following nocturnal oxygen (-3.6 ± 6.0 mmHg; P = 0.006) and CPAP (-4.5 ± 7.5 mmHg; P

ABSTRACT Cerebral autoregulation (CA) is impaired during acute high-altitude (HA) exposure and effects of acclimatization and re-exposure on CA are unknown. In 18 healthy lowlanders (11 women), we hypothesized that the cerebral autoregulation index (ARI) assessed by the percentage change in middle cerebral artery peak blood flow velocity (Δ%MCAv)/percentage change in mean arterial blood pressure (Δ%MAP) induced by a sit-to-stand maneuver, is i) reduced on Day1 at 5050m compared to 520m, ii) is improved after 6 days at 5050m, and iii) is less impaired during re-exposure to 5050m after 7 days at 520m compared to Cycle1. Participants spent 4-8h/day at 5050m and slept at 2900m similar to real-life working shifts. High/low ARI indicate impaired/intact CA, respectively. With the sit-to-stand at 520m, mean(95%CI) in ΔMAP and ΔMCAv were -26%(-41 to -10) and -13%(-19 to -7); mean±SE in ARI was 0.58±0.63Δ%/Δ%, respectively. On Day1 at 5050m, ARI worsened compared to 520m (3.29±0.70Δ%/Δ%), but improved with acclimatization (1.44±0.65Δ%/Δ%, P

Background High-altitude pulmonary edema is associated with elevated systolic pulmonary artery pressure (sPAP) and increased extravascular lung water (EVLW). We investigated sPAP and EVLW during repeated exposures to high altitude (HA). Methods Healthy lowlanders underwent two identical 7-day HA-cycles, where subjects slept at 2900 m and spent 4–8 h daily at 5050 m, separated by a weeklong break at low altitude (LA). Echocardiography and EVLW by B-lines were measured at 520 m (baseline, LA1), on day one, two and six at 5050 m (HA1–3) and after descent (LA2). Results We included 21 subjects (median 25 years, body mass index 22 kg/m2, SpO2 98%). SPAP rose from 21 mmHg at LA1 to 38 mmHg at HA1, decreased to 30 mmHg at HA3 (both p Conclusions Exposure to 5050 m induced a rapid increase in sPAP. B-lines rose during prolonged exposures to 5050 m, despite gradual decrease in sPAP, indicating excessive hydrostatic pressure might not be solely responsible for EVLW-development. Repeated HA-exposure had no acclimatization effect on EVLW. This may affect workers needing repetitive ascents to altitude and could indicate greater B-line development upon repeated exposure.

BackgroundHaemorheological alterations are reported in obstructive sleep apnoea (OSA) and reversed with continuous positive airway pressure (CPAP), observations potentially explained by intermittent hypoxia (IH)-induced oxidative stress. Our objective was to investigate whether IH causes haemorheological alterations via oxidative stress.MethodsWistar rats were exposed to normoxia (n=7) or IH (n=8) for 14 days. 23 moderate-to-severe OSA patients were assessed at three time-points: baseline, after randomisation to either 2 weeks of nocturnal oxygen (n=13) or no treatment (n=10) and after 1 month of CPAP treatment (n=17). Furthermore, an OSA-free control group (n=13) was assessed at baseline and after time-matched follow-up. We measured haemorheological parameters (haematocrit, blood viscosity, plasma viscosity (rats only), erythrocyte aggregation and deformability (humans only)) and redox balance (superoxide dismutase (SOD), glutathione peroxidase, protein oxidation (advanced oxidation protein products (AOPPs)) and lipid peroxidation (malondialdehyde)). We also tested the haemorheological sensitivity of erythrocytes to reactive oxygen species (ROS) in our human participants using the oxidant t-butyl hydroperoxide (TBHP).ResultsIn rats, IH increased blood viscosity by increasing haematocrit without altering the haemorheological properties of erythrocytes. IH also reduced SOD activity and increased AOPPs. In humans, baseline haemorheological properties were similar between patients and control participants, and properties were unaltered following oxygen and CPAP, except erythrocyte deformability was reduced following oxygen therapy. Redox balance was comparable between patients and control participants. At baseline, TBHP induced a greater reduction of erythrocyte deformability in patients while CPAP reduced TBHP-induced increase in aggregation strength.ConclusionsIH and OSA per se do not cause haemorheological alterations despite the presence of oxidative stress or higher sensitivity to ROS, respectively.

The clinical presentation of COVID‐19 due to infection with SARS‐CoV‐2 is highly variable with the majority of patients having mild symptoms while others develop severe respiratory failure. The reason for this variability is unclear but is in critical need of investigation. Some COVID‐19 patients have been labelled with ‘happy hypoxia’, in which patient complaints of dyspnoea and observable signs of respiratory distress are reported to be absent. Based on ongoing debate, we highlight key respiratory and neurological components that could underlie variation in the presentation of silent hypoxaemia and define priorities for subsequent investigation.

A primary characteristic of obstructive sleep apnea (OSA) is chronic exposure to intermittent hypoxia (IH) due to repeated upper airway obstruction. Chronic IH exposure is believed to increase OSA severity over time by enhancing the acute ventilatory response to hypoxia (AHVR), thus promoting ventilatory overshoot when apnea ends and perpetuation of apnea during sleep. Continuous positive airway pressure (CPAP), the gold-standard treatment of OSA, reduces the AHVR, believed to result from correction of IH. However, CPAP also corrects ancillary features of OSA such as intermittent hypercapnia, negative intrathoracic pressure and surges in sympathetic activity, which may also contribute to the reduction in AHVR. Therefore, the objective of this study was to investigate the impact of nocturnal oxygen therapy (to remove IH only) and CPAP (to correct IH and ancillary features of OSA) on AHVR in newly diagnosed OSA patients. Fifty-two OSA patients and twenty-two controls were recruited. The AHVR was assessed using a 5 min iscopanic-hypoxic challenge before, and after, treatment of OSA by nocturnal oxygen therapy and CPAP. Following baseline measurements, OSA patients were randomly assigned to nocturnal oxygen therapy (Oxygen, n = 26) or no treatment (Air; n = 26). The AHVR was re-assessed following two weeks of oxygen therapy or no treatment, after which all patients were treated with CPAP. The AHVR was quantified following ~4 weeks of adherent CPAP therapy (n = 40). Both nocturnal oxygen and CPAP treatments improved hypoxemia (p 0.05), and, as expected, nocturnal oxygen therapy did not completely abolish respiratory events (i.e., apneas/hypopneas). Averaged across all OSA patients, nocturnal oxygen therapy did not change AHVR from baseline to post-oxygen therapy. Similarly, the AHVR was not altered pre- and post-CPAP (p 0.05). However, there was a significant decrease in AHVR with both nocturnal oxygen therapy and CPAP in patients in the highest OSA severity quartile (p 0.05). Nocturnal oxygen therapy and CPAP both reduce the AHVR in patients with the most severe OSA. Therefore, IH appears to be the primary mechanism producing ventilatory instability in patients with severe OSA via enhancement of the AHVR.

Background There remains no effective intervention capable of reversing most cases of dementia. Current research is focused on prevention by addressing risk factors that are shared between cardiovascular disease and dementia (e.g., hypertension) before the cognitive, functional, and behavioural symptoms of dementia manifest. A promising preventive treatment is exercise. This study describes the methods of a randomized controlled trial (RCT) that assesses the effects of aerobic exercise and behavioural support interventions in older adults at increased risk of dementia due to genetic and/or cardiovascular risk factors. The specific aims are to determine the effect of aerobic exercise on cognitive performance, explore the biological mechanisms that influence cognitive performance after exercise training, and determine if changes in cerebrovascular physiology and function persist 1 year after a 6-month aerobic exercise intervention followed by a 1-year behavioural support programme (at 18 months). Methods We will recruit 264 participants (aged 50–80 years) at elevated risk of dementia. Participants will be randomly allocated into one of four treatment arms: (1) aerobic exercise and health behaviour support, (2) aerobic exercise and no health behaviour support, (3) stretching-toning and health behaviour support, and (4) stretching-toning and no health behaviour support. The aerobic exercise intervention will consist of three supervised walking/jogging sessions per week for 6 months, whereas the stretching-toning control intervention will consist of three supervised stretching-toning sessions per week also for 6 months. Following the exercise interventions, participants will receive either 1 year of ongoing telephone behavioural support or no telephone support. The primary aim is to determine the independent effect of aerobic exercise on a cognitive composite score in participants allocated to this intervention compared to participants allocated to the stretching-toning group. The secondary aims are to examine the effects of aerobic exercise on a number of secondary outcomes and determine whether aerobic exercise-related changes persist after a 1-year behavioural support programme (at 18 months). Discussion This study will address knowledge gaps regarding the underlying mechanisms of the pro-cognitive effects of exercise by examining the potential mediating factors, including cerebrovascular/physiological, neuroimaging, sleep, and genetic factors that will provide novel biologic evidence on how aerobic exercise can prevent declines in cognition with ageing. Trial registration ClinicalTrials.gov NCT03035851. Registered on 30 January 2017

Exposure to intermittent hypoxia (IH) ≥15 times per hour is believed to be the primary mechanism for the increased risk of cerebrovascular and cardiovascular disease in patients with moderate to severe sleep apnea. Human experimental models of IH used to investigate this link have been predominantly employed during wakefulness, which limits extrapolation of findings to sleep apnea where IH occurs during sleep. Moreover, how IH impacts vascular regulation during sleep has not been measured quantitatively. Therefore, the objective of this study was to assess the impact sleep accompanied by IH on vascular responses to hypoxia and hypercapnia during sleep. Ten males performed two randomly scheduled 6-h overnight sleep studies. One sleep study was performed in room air (normoxia) and the other sleep study was performed during isocapnic IH (60 s hypoxia-60 s normoxia). On each night, cerebrovascular (peak blood velocity through the middle cerebral artery ( V ¯ P ); transcranial Doppler ultrasound) and cardiovascular (blood pressure, heart rate) responses to hypoxia and hypercapnia were measured before sleep onset (PM-Awake), within the first 2 h of sleep (PM-Asleep), in the 5th (out of 6) hours of sleep (AM-Asleep) and after being awoken in the morning (AM-Awake). Sleep accompanied by IH had no impact on the V ¯ P and blood pressure responses to hypoxia and hypercapnic at any timepoint (p ≥ 0.103 for all responses). However, the AM-Awake heart rate response to hypoxia was greater following sleep in IH compared to sleep in normoxia. Independent of the sleep environment, the V ¯ P response to hypoxia and hypercapnia were reduced during sleep. In conclusion, cerebral blood flow responses are reduced during sleep compared to wakefulness, but 6 h of sleep accompanied by IH does not alter cerebrovascular and cardiovascular response to hypoxia and hypercapnia during wakefulness or sleep in healthy young humans. However, it is likely that longer exposure to IH during sleep (i.e., days-to-weeks) is required to better elucidate IH's impact on vascular regulation in humans.

ObjectiveTo test the hypothesis that aerobic exercise is associated with improvements in cognition and cerebrovascular regulation, we enrolled 206 healthy low-active middle-aged and older adults (mean ± SD age 65.9 ± 6.4 years) in a supervised 6-month aerobic exercise intervention and assessed them before and after the intervention.MethodsThe study is a quasi-experimental single group pre/postintervention study. Neuropsychological tests were used to assess cognition before and after the intervention. Transcranial Doppler ultrasound was used to measure cerebral blood flow velocity. Cerebrovascular regulation was assessed at rest, during euoxic hypercapnia, and in response to submaximal exercise. Multiple linear regression was used to examine the association between changes in cognition and changes in cerebrovascular function.ResultsThe intervention was associated with improvements in some cognitive domains, cardiorespiratory fitness, and cerebrovascular regulation. Changes in executive functions were negatively associated with changes in cerebrovascular resistance index (CVRi) during submaximal exercise (β = −0.205,p= 0.013), while fluency improvements were positively associated with changes in CVRi during hypercapnia (β = 0.106,p =0.03).ConclusionThe 6-month aerobic exercise intervention was associated with improvements in some cognitive domains and cerebrovascular regulation. Secondary analyses showed a novel association between changes in cognition and changes in cerebrovascular regulation during euoxic hypercapnia and in response to submaximal exercise.

PURPOSE Exercise intervention studies for brain health can be difficult to interpret due to heterogeneity in exercise intensity, exercise duration, and in adherence to the exercise intervention. This study aimed to characterize heterogeneity in these components in a cohort of healthy middle-age and older adults who participated in a prescribed 6-month supervised aerobic exercise intervention as part of the Brain in Motion study. METHODS AND RESULTS Group-based multitrajectory analysis (GBMTA) was used to characterize variation in the trajectory of exercise intensity and duration for male and female participants in the first 3 months of the exercise program. The GBMTA for males and females revealed two distinct trajectory subgroups, namely, "high-increasing" (HI) and "low-increasing" (LI). Logistic regression was used to assess the association between the identified latent subgroups and (i) demographic characteristics; (ii) physiological characteristics, including cardiovascular and cerebrovascular function; (iii) genetic characteristics; and (iv) adherence with American College of Sports Medicine guidelines on exercise for older adults. Of the 196 participants, 54.1% met the American College of Sports Medicine aerobic exercise targets for intensity and duration during the intervention. Aerobic fitness (maximal oxygen uptake; odds ratio, 1.27; P < 0.01) was significantly different between these trajectory subgroups in males, and cerebrovascular function (cerebrovascular resistance; odds ratio, 0.14; P < 0.01) was significantly different between these trajectory subgroups in females. CONCLUSION This novel approach to tracking a prespecified exercise program highlights that there are individual and group-specific variations within a prescribed exercise intervention. Characterizing exercise adherence in this way holds promise in developing optimized exercise prescriptions tailored to individual baseline characteristics, and additionally highlighting those participants at greatest risk of not meeting minimum dosage requirements for physiological and/or cognitive health.

To determine the relationship between sleep spindle characteristics (density, power and frequency), executive functioning and cognitive decline in older adults, we studied a convenience subsample of healthy middle-aged and older participants of the Brain in Motion study. Participants underwent a single night of unattended in-home polysomnography with neurocognitive testing carried out shortly afterwards. Spectral analysis of the EEG was performed to derive spindle characteristics in both central and frontal derivations during non-rapid eye movement (NREM) Stage 2 and 3. Multiple linear regressions were used to examine associations between spindle characteristics and cognitive outcomes, with age, body mass index (BMI), periodic limb movements index (PLMI) and apnea hypopnea index (AHI) as covariates. NREM Stage 2 total spindle density was significantly associated with executive functioning (central: β = .363, p = .016; frontal: β = .408, p = .004). NREM Stage 2 fast spindle density was associated with executive functioning (central: β = .351, p = .022; frontal: β = .380, p = .009) and Montreal Cognitive Assessment score (MoCA, central: β = .285, p = .037; frontal: β = .279, p = .032). NREM Stage 2 spindle frequency was also associated with MoCA score (central: β = .337, p = .013). Greater spindle density and fast spindle density were associated with better executive functioning and less cognitive decline in our study population. Our cross-sectional design cannot infer causality. Longitudinal studies will be required to assess the ability of spindle characteristics to predict future cognitive status.

Oxidative stress may be involved in disease pathology and dependent on both modifiable and nonmodifiable factors. This study aimed to assess exercise-induced changes in markers of oxidative stress among older, sedentary adults and to determine the effects of metabolic syndrome (MetS) status, aerobic capacity, age, sex, and weight on these biomarkers. Two hundred and six participants (means ± SE; 66.8 ± 6.4 yr, 104 women) of the

Background Sleep disturbances have been shown to be associated with the presence of the apolipoprotein (APOE) ɛ4 allele, the well-known genetic risk factor for late-onset sporadic Alzheimer's disease (AD). Objective This study quantifies the effects of a six-month aerobic exercise intervention on objective and subjective sleep quality in middle-aged to older individuals including those at increased genetic risk for late-onset sporadic Alzheimer's disease (AD), who carry the apolipoprotein (APOE) ɛ4 risk allele. Methods 199 sedentary men and women without significant cognitive impairments were enrolled in the Brain in Motion study, a quasi-experimental single group pre-test/post-test study with no control group. Participants completed a six-month aerobic exercise intervention and consented to genetic testing. Genotyping of APOE confirmed that 54 individuals were carriers of the ɛ4 allele. Participants' subjective quality of sleep was assessed with the Pittsburgh Sleep Quality Index (PSQI) pre- and post-intervention. A convenience sample of participants (n = 29, APOE ɛ4+ = 7) consented to undergo two nights of in-home polysomnography (PSG) pre- and post intervention. Sleep architecture and respiratory variables were assessed. Results The six-month aerobic exercise intervention significantly improved participants' total PSQI score, sleep efficiency, and sleep latency in the full sample (n = 199). PSG results showed that total sleep time and sleep onset latency significantly improved over the course of the exercise intervention only in individuals who carried the APOE ɛ4 allele. These results are, however, exploratory and need to be carefully interpreted due to the rather small number of APOE ɛ4+ in the PSG subgroup. Conclusions The six-month aerobic exercise intervention significantly improved participants' sleep quality with beneficial effects on PSG shown in individuals at increased genetic risk for late-onset sporadic AD.

Summary Background Impaired glucose tolerance is a risk factor for non-age-related cognitive decline and is also associated with measures of physical activity (PA) and cardiorespiratory fitness (CRF). A low glycemic load (GL) diet can aid in the management of blood glucose levels, but little is known about its effect on cognition with poor glucoregulation. Objective We assessed the relation between GL and cognitive function by glucoregulation and possible mediatory effects by CRF and PA in older adults from the Brain in Motion Study. Design A cross-sectional analysis of 194 cognitively healthy adults aged ≥55 years (mean = 65.7, SD = 6.1) was conducted. GL was assessed using a quantitative food frequency questionnaire, and glucoregulation was characterized on the HOMA-IR index. Subjects also completed a cognitive assessment, CRF testing, a validated self-reported PA questionnaire, and a blood draw. Multiple linear regression models adjusted for significant covariates were used to evaluate the relation between GL and cognition, and mediation by CRF and PA was also assessed. Results GL was inversely associated with global cognition (β = −0.014; 95% CI −0.024, −0.004) and figural memory (β = −0.035; 95% CI −0.052, −0.018) in subjects with poor glucoregulation. Neither CRF nor PA mediated these relations. In subjects with good glucoregulation, no association was found between GL and cognitive function (p > 0.05). Conclusions A low GL diet is associated with better cognitive function in older adults with poor glucoregulation. This study provides supportive evidence for the role of GL in maintaining better cognitive function during the aging process.

Accelerated trajectories of cognitive decline in older adults may increase the risk of developing Alzheimer disease and related dementias (ADRD). Physical activity has potential modifying effects on these changes that could prevent or delay ADRD. This review explores the hypothesis that multiple, mutually complimentary, and interacting factors explain the positive association between exercise and the optimization of cognition in older adults.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is associated with increased cardiovascular risk. The effect of OSA treatment with continuous positive airway pressure (CPAP) on the cardiovascular response to a stressor is unknown. We sought to determine the effect of CPAP therapy on heart rate variability (HRV) and arterial stiffness, at baseline, in response to, and recovery from a physiological stressor, Angiotensin II (AngII), in humans with OSA. METHODS: Twenty-five incident healthy subjects (32% female; 49 ± 2 years) with moderate-severe OSA and nocturnal hypoxia were studied in high-salt balance, a state of maximal renin-angiotensin system (RAS) suppression, before CPAP, and after 4 weeks of effective CPAP therapy (usage > 4 h/night) in a second identical study day. HRV was calculated by spectral power and time domain analysis. Aortic augmentation index (AIx) and carotid-femoral pulse-wave velocity (PWV(cf)) were measured by applanation tonometry. HRV and arterial stiffness were measured at baseline and in response to AngII challenge (3 ng/ kg/min·30 minutes, 6 ng/kg/min·30 minutes, recovery·30 minutes). The primary outcome was the association between CPAP treatment and HRV and arterial stiffness responses to, and recovery from, AngII challenge. In an exploratory analysis subjects were stratified by sex. RESULTS: CPAP corrected OSA and nocturnal hypoxemia. CPAP treatment was associated with increased sensitivity and delayed recovery from AngII (Δln HF [high frequency; recovery: −0.09 ± 0.19 versus −0.59 ± 0.17 ms(2), P = .042; ΔrMSSD [root mean successive differences; recovery: −0.4 ± 2.0 versus −7.2 ± 1.9 ms, P = .001], ΔpNN50 [percentage of normal waves differing ≥ 50 ms compared to the preceding wave; AngII: 1.3 ± 2.3 versus −3.0 ± 2.4%, P = .043; recovery: −0.4 ± 1.4 versus −6.0 ± 1.9%, P = .001], all values pre-CPAP versus post-CPAP treatment). No differences were observed by sex. There was increased AIx sensitivity to AngII after CPAP among men (8.2 ± 1.7 versus 11.9 ± 2.2%, P = .046), but not women (11.4 ± 1.5 versus 11.6 ± 2.1%, P = .4). No change in PWV(cf) sensitivity was observed in either sex. CONCLUSIONS: CPAP therapy was associated with delayed cardiovagal reactivation after a stressor and down-regulation of the arterial RAS. These findings may have important implications in mitigating cardiovascular risk in both men and women with OSA. CITATION: Nicholl DD, Hanly PJ, Zalucky AA, Mann MC, MacRae JM, Poulin MJ, Handley GB, Sola DY, Ahmed SB. CPAP therapy delays cardiovagal reactivation and decreases arterial renin-angiotensin system activity in humans with obstructive sleep apnea. J Clin Sleep Med. 2018;14(9):1509–1520.

Rationale A top priority in stroke rehabilitation research is determining the appropriate exercise dose to optimize recovery. Although more intensive rehabilitation very early after stroke may be deleterious to recovery, inpatient rehabilitation, occurring after acute care, may be a more appropriate setting to assess therapeutic dose on neurological recovery. Hypothesis Individuals receiving higher intensity and dose exercise programs will yield greater improvements in walking ability over usual inpatient physical therapy care. Methods and design Seventy-five individuals across seven inpatient rehabilitation sites in Canada will be randomized into one of three treatment programs, each 5 days/week, for four weeks and monitored for exertion (heart rate) and repetitions (step count). Study outcomes The primary outcome measure is the 6 min walk and secondary outcomes include functional independence, cognitive, and quality-of-life measures. Outcome data will be assessed at four time points. Summary This trial will contribute to our knowledge of the therapeutic intensity and dose necessary to maximize functional recovery at a very important stage of rehabilitation and neural recovery poststroke.

Background: Effects of hypobaric hypoxia at altitude on exercise performance of lowlanders with chronic obstructive pulmonary disease (COPD) have not been studied in detail. Objectives: To quantify changes in exercise performance and associated physiologic responses in lowlanders with COPD travelling to moderate altitude. Methods: A total of 31 COPD patients with a median age (quartiles) of 66 years (59; 69) and FEV1 of 56% predicted (49; 69) living below 800 m performed a constant-load bicycle exercise to exhaustion at 60% of the maximal work rate at 490 m (Zurich) and at an identical work rate at 2,590 m (Davos) in randomized order. Pulmonary gas exchange, pulse oximetry (SpO2), cerebral tissue oxygenation (CTO; near-infrared spectroscopy), and middle cerebral artery peak blood flow velocity (MCAv) by Doppler ultrasound during 30 s at end exercise were compared between altitudes. Results: With ascent from 490 to 2,590 m, the median endurance time (quartiles) was reduced from 500 s (256; 795) to 205 s (139; 297) by a median (95% CI) of 303 s (150–420) (p < 0.001). End exercise SpO2 decreased from 92% (89; 94) to 81% (77; 84) and CTO from 62% (56; 66) to 55% (50; 60); end exercise minute ventilation increased from 40.6 L/min (35.5; 47.8) to 47.2 L/min (39.6; 58.7) (p < 0.05; all comparisons 2,590 vs. 490 m). MCAv increased similarly from rest to end exercise at 490 m (+25% [17; 36]) and at 2,590 m (+21% [14; 30]). However, the ratio of MCAv increase to SpO2 drop during exercise decreased from +6%/% (3; 12) at 490 m to +3%/% (2; 5) at 2,590 m (p < 0.05). Conclusions: In lowlanders with COPD travelling to 2,590 m, exercise endurance is reduced by more than half compared to 490 m in association with reductions in systemic and cerebral oxygen availability.

The brain is a vital organ that relies on a constant and adequate blood flow to match oxygen and glucose delivery with the local metabolic demands of active neurons. Thus exquisite regulation of cerebral blood flow (CBF) is particularly important under hypoxic conditions to prevent a detrimental decrease in the partial pressure of oxygen within the brain tissues. Cerebrovascular sensitivity to hypoxia, assessed as the change in CBF during a hypoxic challenge, represents the capacity of cerebral vessels to respond to, and compensate for, a reduced oxygen supply, and has been shown to be impaired or blunted in a number of conditions. For instance, this is observed with aging, and in clinical conditions such as untreated obstructive sleep apnea (OSA) and in healthy humans exposed to intermittent hypoxia. This review will 1) provide a brief overview of cerebral blood flow regulation and results of pharmacological intervention studies which we have performed to better elucidate the basic mechanisms of cerebrovascular regulation in humans; and 2) present data from studies in clinical and healthy populations, using a translational physiology approach, to investigate human CBF control during hypoxia. Results from studies in patients with chronic obstructive pulmonary disease and OSA will be presented to identify the effects of the disease processes on cerebrovascular sensitivity to hypoxia. Data emerging from experimental human models of intermittent hypoxia during wakefulness will also be reviewed to highlight the effects of intermittent hypoxia on the brain.

Obstructive sleep apnoea (OSA) is associated with increased risk of cardiovascular and cerebrovascular disease, a consequence attributed in part to chronic intermittent hypoxia (IH) resulting from repetitive apnoeas during sleep. Although findings from experimental animal, and human, models have shown that IH is detrimental to vascular regulation, the severity of IH used in many of these animal studies (e.g. inspired fraction of oxygen (FIO2) = 2–3%; oxygen desaturation index (ODI) = 120 events h−1) is considerably greater than that observed in the majority of patients with OSA. This may also explain disparities between animal and recently developed human models of IH, where IH severity is, by necessity, less severe (e.g. FIO2 = 10–12%; ODI = 15–30 events h−1). In this review, we highlight the current knowledge regarding the impact of OSA and IH on cardiovascular and cerebrovascular regulation. In addition, we critically discuss the recent notion that OSA and IH may have hormetic effects on vascular health depending on conditions such as OSA severity, IH intensity and duration, and age. In general, data supports an independent causal link between OSA and vascular disease, particularly for patients with severe OSA. However, the data are equivocal for older OSA patients and patients with mild OSA as advanced age and short duration, low intensity IH have been reported to provide a degree of protection against IH and ischaemic events such as myocardial infarction and stroke, respectively. Overall, additional studies are needed to further investigate the beneficial/detrimental effects of mild OSA on the various vascular beds. This article is protected by copyright. All rights reserved

Key points Altered cerebral autoregulation (CA) in obstructive sleep apnoea (OSA) patients may contribute to increased stroke risk in this population; the gold standard treatment for OSA is continuous positive airway pressure, which improves cerebrovascular regulation and may decrease the risk of stroke. Isocapnic-hypoxia impairs CA in healthy subjects, but it remains unknown in OSA whether impaired CA is further exacerbated by isocapnic-hypoxia and whether it is improved by treatment with continuous positive airway pressure. During normoxia, CA was altered in the more severe but not in the less severe OSA patients, while, in contrast, during isocapnic-hypoxia, CA was similar between groups and tended to improve in patients with more severe OSA compared to normoxia. From a clinical perspective, one month of continuous positive airway pressure treatment does not improve CA. From a physiological perspective, this study suggests that sympathetic overactivity may be responsible for altered CA in the more severe OSA patients. Abstract Cerebral autoregulation (CA) impairment may contribute to the increased risk of stroke associated with obstructive sleep apnoea (OSA). It is unknown if impaired CA is further exacerbated by isocapnic-hypoxia and whether it is improved by treatment of OSA with continuous positive airway pressure (CPAP). CA was assessed during wakefulness in 53 OSA patients (50.3 ± 9.3 years) and 21 controls (49.8 ± 8.6 years) at baseline and following a minimum of 1 month of effective CPAP therapy (OSA patients, n = 40). Control participants (n = 21) performed a follow-up visit to control for time effects within OSA patients between baseline and the post-CPAP visit. Beat-by-beat middle cerebral artery blood flow velocity and mean arterial blood pressure (MBP), and breath-by-breath end-tidal partial pressure of CO2 (P ET ,CO2) were monitored. CA was determined during normoxia and isocapnic-hypoxia using transfer function (phase and gain) and coherence analysis (including multiple and partial coherence (using MBP and P ET ,CO2 as inputs)) in the very low frequency range (0.03–0.07 Hz). OSA patients were divided into two subgroups (less severe and more severe) based upon the median respiratory disturbance index (RDI). During normoxia, the more severe OSA patients (RDI 45.9 ± 10.3) exhibited altered CA compared to controls and the less severe OSA patients (RDI 24.5 ± 5.9). In contrast, during isocapnic-hypoxia, CA was similar between groups. CPAP had no effect on CA. In conclusion, CA is altered in the more severe OSA patients during normoxia but not during isocapnic-hypoxia and CPAP treatment does not impact CA.

AB Purpose: Chronic obstructive pulmonary disease (COPD) is associated with vascular dysfunction, possibly related to increased oxidative stress. Exercise hyperemia may similarly be impaired, which could have implications for exercise limitations in COPD. We tested if brachial blood flow (BBF) was reduced during handgrip exercise in COPD and if this response would be improved after vitamin C infusion. Methods: Doppler ultrasound was used to measure brachial blood flow and vascular conductance (BBF and BVC, respectively) during mild, rhythmic handgrip exercise (EX) under conditions of sham-saline and vitamin C. Measures of flow-mediated dilation (FMD) and nitroglycerine-mediated dilation were used to assess endothelial-dependent and independent dilation, respectively. Biomarkers of antioxidants (vitamin C, superoxide dismutase [SOD], catalase), oxidative stress (malondialdehyde [MDA], advanced oxidation protein products [AOPP]), and nitric oxide metabolism (NOx) were measured in blood plasma. Results: Ten COPD patients with moderate COPD and 10 healthy age-matched controls participated. COPD patients had similar increases in BBF and BVC during EX, compared with controls. Vitamin C was not found to have an effect on blood flow parameters during exercise (P > 0.05). Markers of endothelial-dependent dilation (FMD) and nitroglycerin-mediated dilation were similar between groups at baseline; FMD improved similarly in both groups after vitamin C. Conclusions: Moderate COPD patients have a preserved BBF response during handgrip exercise and do not exhibit endothelial dysfunction. Despite an increase in endothelial-dependent dilation after vitamin C, BBF remained unchanged, suggesting a limited impact of endothelial-derived NO in determining the blood flow response to handgrip exercise in older individuals. COPD patients of moderate severity, screened for cardiovascular disease, do not exhibit endothelial dysfunction and have similar exercise blood flow responses to healthy controls

Background: Sleep disturbances have been shown to be associated with the presence of the apolipoprotein (APOE) ɛ4 allele, the well-known genetic risk factor for late-onset sporadic Alzheimer’s disease (AD). Objective: This study quantifies the effects of a six-month aerobic exercise intervention on objective and subjective sleep quality in middle-aged to older individuals including those at increased genetic risk for late-onset sporadic Alzheimer’s disease (AD), who carry the apolipoprotein (APOE) ɛ4 risk allele. Methods: 199 sedentary men and women without significant cognitive impairments were enrolled in the Brain in Motion study, a quasi-experimental single group pre-test/post-test study with no control group. Participants completed a six-month aerobic exercise intervention and consented to genetic testing. Genotyping of APOE confirmed that 54 individuals were carriers of the ɛ4 allele. Participants’ subjective quality of sleep was assessed with the Pittsburgh Sleep Quality Index (PSQI) pre- and post-intervention. A convenience sample of participants (n = 29, APOE ɛ4+ = 7) consented to undergo two nights of in-home polysomnography (PSG) pre- and post intervention. Sleep architecture and respiratory variables were assessed. Results: The six-month aerobic exercise intervention significantly improved participants’ total PSQI score, sleep efficiency, and sleep latency in the full sample (n = 199). PSG results showed that total sleep time and sleep onset latency significantly improved over the course of the exercise intervention only in individuals who carried the APOE ɛ4 allele. These results are, however, exploratory and need to be carefully interpreted due to the rather small number of APOE ɛ4+ in the PSG subgroup. Conclusions: The six-month aerobic exercise intervention significantly improved participants’ sleep quality with beneficial effects on PSG shown in individuals at increased genetic risk for late-onset sporadic AD.