Sébastien Celle

Blood pressure levels and brain volume reduction: a systematic review and meta-analysis.

Objective: High blood pressure (BP) levels may be associated with brain volume reduction and may contribute to brain atrophy in key brain regions involved in cognition and susceptible to neurodegeneration in Alzheimers disease. The purpose of this work was to systematically review and quantitatively synthesize the association of BP levels with brain volume reduction in humans. Methods: An English Medline, Cochrane Library and PsycINFO search was conducted in June 2012 using the Medical Subject Heading terms ‘Blood pressure’, ‘Hypertension’, ‘Brain mapping’ and ‘Brain atrophy’. Results: Of the 609 screened abstracts, 28 studies (4.6%) were included in the qualitative analysis. Twenty-six studies (92.9%) showed a significant association of higher BP levels and/or hypertension with total and/or regional brain volume reduction, the frontal and temporal lobes being particularly affected. In addition, four other studies reported an association between lower BP levels and brain volume reduction. Due to the heterogeneity of methodology and outcomes, random-effects meta-analyses of the mean difference of brain volume could be performed on only seven studies, with a total of 709 cases with hypertension and 1001 controls without hypertension. The findings showed no between-group difference regarding the whole-gray matter volume (summary mean difference = 2.42 cm3 [95% confidence interval (CI): −2.13 to 6.96]). Conversely, cases with hypertension exhibited lower hippocampus volume compared with controls [summary mean difference = −0.10 cm3 (95% CI: −0.17 to −0.02)]. Conclusion: These findings provide evidence that high BP levels lead to brain volume reduction, specifically in hippocampus, and may be an important factor that contributes to neurodegeneration in Alzheimers disease.

Methods in Neuroepidemiology Autonomic Nervous System Activity and Decline as Prognostic Indicators of Cardiovascular and Cerebrovascular Events: The 'PROOF' Study Study Design and Population Sample. Associations with Sleep-Related Breathing Disorders: The 'SYNAPSE' Study

Background: Transversal studies have underlined the association between the decline in autonomic nervous system (ANS) activity and all-cause mortality. However, the predictive value of ANS has never been prospectively assessed in a general population-based cohort. Method: The PROOF (PROgnostic indicator OF cardiovascular and cerebrovascular events) cohort study was designed to prospectively assess the predictive value of ANS activity level in the general population, with regard to cardiovascular and cerebrovascular events, and death. This predictive power will be compared with the usual and newly discovered risk factors for the purposes of developing a risk model. Results: A prospective cohort of elderly subjects aged 65 years upon study entry were recruited from the electoral list of the city of Saint-Etienne, France. Three initial 2-year examination programs were scheduled for 7 years (2001–2007), followed by late events monitoring. At each examination, ANS activity was assessed along with clinical and biological cardiovascular risk factors, brain MRI, neuropsychological evaluation, physical activity profile, and sleep-related breathing disorders. The main study outcomes are stroke, myocardial infarction and death from any cause. A cohort consisting of 1,011 subjects aged 65.6 (0.8) years was constituted. Conclusion: Despite other selective characteristics, the associations between ANS activity and events will be applicable to other populations.Background: Transversal studies have underlined the association between the decline in autonomic nervous system (ANS) activity and all-cause mortality. However, the predictive value of ANS has never been prospectively assessed in a general population-based cohort. Method: The PROOF (PROgnostic indicator OF cardiovascular and cerebrovascular events) cohort study was designed to prospectively assess the predictive value of ANS activity level in the general population, with regard to cardiovascular and cerebrovascular events, and death. This predictive power will be compared with the usual and newly discovered risk factors for the purposes of developing a risk model. Results: A prospective cohort of elderly subjects aged 65 years upon study entry were recruited from the electoral list of the city of Saint-Etienne, France. Three initial 2-year examination programs were scheduled for 7 years (2001–2007), followed by late events monitoring. At each examination, ANS activity was assessed along with clinical and biological cardiovascular risk factors, brain MRI, neuropsychological evaluation, physical activity profile, and sleep-related breathing disorders. The main study outcomes are stroke, myocardial infarction and death from any cause. A cohort consisting of 1,011 subjects aged 65.6 (0.8) years was constituted. Conclusion: Despite other selective characteristics, the associations between ANS activity and events will be applicable to other populations.

Sympathetic overactivity due to sleep fragmentation is associated with elevated diurnal systolic blood pressure in healthy elderly subjects: the PROOF-SYNAPSE study

AIMS Sleep fragmentation is a landmark of sleep disorders, because microarousals are systematically associated with sympathetic surges (i.e., sympathetic arousals). However, the impact of sympathetic sleep fragmentation on blood pressure (BP) remains understudied. We assessed the relationships between 24 h ambulatory BP monitoring, the autonomic arousal index (AAI) derived from pulse transit time, and heart rate variability indices. We hypothesized that repeated sympathetic arousals during sleep are associated with elevated BP in a large population of elderly volunteers. METHODS AND RESULTS Volunteer subjects (n = 780, 57.4% women) with a mean age of 68.7 years and free of known sleep-disordered breathing, coronary heart diseases, and neurological disorders underwent polygraphy, 24 h ECG Holter monitoring, and 24 h ambulatory BP monitoring. Multivariate regressions showed that sleep fragmentation, expressed by AAI, was associated with elevated diurnal (P = 0.008) and 24 h (P = 0.005) systolic BP and higher risk for 24 h [odds ratio (OR): 1.70 (1.04-2.80), P = 0.036] systolic hypertension, independently of confounders such as sleep-disordered breathing, body mass index, sex, diabetes, hypercholesterolaemia, and self-reported sleep duration and quality. Increased AAI was associated with higher nocturnal and diurnal low-frequency power (P < 0.001) and low-to-high-frequency ratio (P < 0.001), suggesting nocturnal and diurnal sympathetic overactivity. CONCLUSION In healthy elderly subjects, repetitive sympathetic arousals during sleep are associated with elevated systolic BP and higher risk of hypertension, after controlling for confounders. Sympathetic overactivity is the proposed underlying mechanism. CLINICAL TRIAL REGISTRATION NCT00766584 and NCT00759304.

Obstructive sleep apnoea/hypopnea influences high-density lipoprotein cholesterol in the elderly

BACKGROUND AND PURPOSE An association between obstructive sleep apnoea/hypopnea (OSAH) and cardiovascular risk factors such as dyslipidemia has been described in adults and high-risk populations. PATIENTS AND METHODS We examined this association in a prospective cohort (SYNAPSE study) of 846 elderly (68.5+/-1.1 years) volunteers (41.6% of men). No subject presented with recognized OSAH syndrome, heart disease, or any neurological disorder. Unattended at-home polygraphy was done by all subjects. OSAH severity was defined as moderate (apnoea/hypopnea index: AHI>15/h) or severe (AHI>30/h). High-density lipoprotein cholesterol (HDL-c) was measured by immuno-separation-based homogenous assay. RESULTS The prevalence of severe cases reached 21.5% (AHI mean+/-SD: 43.5+/-11.9). Using univariate linear regression analysis, AHI (R=-0.172; p<0.0001), oxyhemoglobin desaturation index (ODI) (R=-0.108; p<0.002), mean SaO(2) (R=0.125; p<0.0003) and Nadir SaO(2) (R=0.094; p<0.007) were significantly associated with HDL-c. Multiple regression analysis demonstrated that male gender, BMI, waist to hip ratio, ODI, and AHI represent independent predictors of HDL-c. Logistic regression analysis showed a significant association between severe OSAH and low HDL-c serum levels (p<0.03) after adjustment for gender, BMI, hypertension, glycaemia, waist to hip ratio, alcohol intake and treated dyslipidemia. The association appears more evident in subjects free of lipid-lowering medications and beta-blockers (p<0.007). There was no independent association of OSAH syndrome with low-density lipoprotein (LDL) cholesterol. CONCLUSION Unrecognized moderate to severe apnoea/hypopnea syndrome was independently associated with low HDL-c serum levels in the present cross-sectional based elderly population. This could explain the deleterious effect of OSAH syndrome on cardiovascular risk.

Metabolic Syndrome and Short-Term and Long-Term Heart Rate Variability in Elderly Free of Clinical Cardiovascular Disease: The PROOF Study

OBJECTIVE Autonomic nervous system (ANS) activity decrease has been associated with a higher risk of sudden cardiovascular and cerebrovascular disease. Thus, we explored the relationship between ANS control of the cardiovascular system and metabolic syndrome. METHODS We analyzed the relationship with both short-term and long-term heart rate variability (HRV) and metabolic syndrome in the cross-sectional PROgnostic indicator OF cardiovascular and cerebrovascular events (PROOF) cohort study of 1,011 elderly subjects recruited amongst the inhabitants of the city of Saint Etienne, France, aged 65.6 ± 0.8 years at the inclusion date. Physical examination included measurements of height, weight, systolic and diastolic blood pressure, waist circumference, and biological parameters. HRV variables were measured over 5-min, nighttime, and 24-h periods using Holter monitoring. RESULTS After adjustment for current type 2 diabetes, depression, and smoking, we found that metabolic syndrome status, high-density lipoprotein cholesterol (HDL-C), and waist circumference were significantly (p < 0.05) associated with total power, very-low frequency, low-frequency/high-frequency (LF/HF) ratio, and normalized LF. HDL-C and metabolic syndrome status were significantly associated with decreased long-term HRV variables. Both nighttime and 24-h HRV showed closer associations with metabolic syndrome than did short-term HRV (5-min). Metabolic syndrome severity was associated with a decrease in both the long-term and short-term HRV variables. CONCLUSIONS ANS control alteration of the cardiovascular system was more pronounced when evaluated by long-term than short-term HRV recordings, particularly in women.

Analysis of the interbeat interval increment to detect obstructive sleep apnoea/hypopnoea

The prevalence of obstructive sleep apnoea/hypopnoea syndrome (OSAHS) is underestimated and its diagnosis is costly and restricted to specialised sleep laboratories. The frequency component of interbeat interval increment (III) has been proposed as a simple and inexpensive diagnostic tool in OSAHS. In a set of 150 patients with clinically suspected sleep-related breathing disorder, the actual predictive accuracy of the power spectral density of the III of the very low frequencies (%VLFI) was analysed by comparing with the apnoea/hypopnoea index (AHI), as assessed by synchronised polysomnography. OSAHS was defined in 100 patients according to an AHI ≥15 events·h−1. Receiver operator characteristic curves built for %VLFI confirmed that this variable was able to separate OSAHS positive from OSAHS negative with statistical significance. Using an appropriate threshold (>4%), %VLFI demonstrated a positive predictive value of 80%. Misclassification of false-positive subjects occurred when the patient presented significant sleep discontinuity and sleep fragmentation (sleep fragmentation index ≥50 events·h−1) related to insomnia or periodic limb movements. A power spectral density of the interbeat interval increment of very low frequencies >4% allowed correct classification of obstructive sleep apnoea/hypopnoea syndrome when the clinical history suggested sleep-related breathing disorders and when moderate-to-severe cases are considered. Higher power spectral density of the interbeat interval increment of very low frequencies may also indicate disrupted sleep in the absence of clear clinical symptoms of sleep apnoea/hypopnoea syndrome.

Undiagnosed sleep-related breathing disorders are associated with focal brainstem atrophy in the elderly.

Background: Sleep‐related breathing disorders (SRBDs) affect as many as 40% of elderly people. The association of SRBDs with structural brain abnormalities remains unclear. In this observational study, we evaluated gray matter changes in the brain associated with sleep abnormalities in volunteers and their relationship with the severity of SRBDs. Methods: One hundred fifty two healthy subjects aged 66.0 ± 0.6 years‐old underwent tridimensional brain MRI and nocturnal polygraphic recording during which apnea/hypopnea index (AHI) and the oxyhemoglobin desaturation index (ODI) were measured. Using voxel‐based morphometry, we investigated the presence of gray matter abnormalities in association with AHI and ODI. Findings: Seventy‐six subjects (50%) had SRBDs defined by an AHI ≥ to 15 and 25 subjects (16%) SRBDs defined by an ODI ≥ 15, in the absence of systematic excessive daytime sleepiness. A significant symmetrical loss of gray matter in the intermediate reticular zone of the bulbopontine area was found to correlate with both AHI and ODI (P < 0.05 corrected for multiple comparisons for cluster significance). Interpretation: This gray matter volume decrease in brain regions involved in breathing/autonomic functions, as well as their correlation with the severity of the disorder, suggests a pathophysiological link between structural changes and SRBDs. Hum Brain Mapp, 2009.

Relation of central fat mass to obstructive sleep apnea in the elderly.

STUDY OBJECTIVES Obesity is a recognized risk factor for obstructive sleep apnea syndrome (OSAS). We evaluated whether total trunk and central fat mass (CFM) is associated with OSAS in elderly subjects. DESIGN Cross-sectional. SETTING Body composition assessment by dual-energy X-ray absorbsiometry (DEXA). PARTICIPANTS 749 volunteers aged 67.2 ± 0.8 years (59.4% women). INTERVENTION All participants underwent evaluation of their body composition by DEXA in parallel with clinical and polygraphic assessments. The presence of OSAS was defined by an apnea plus hypopnea index (AHI) ≥ 15. MEASUREMENTS AND RESULTS A total of 44.8% of the population had an AHI < 15, and 55.2% presented OSAS. OSAS subjects were more frequently overweight and had a higher total trunk fat mass and central fat mass (CFM). Correlation analyses revealed that body mass index (r = 0.27, P < 0.001), neck circumference (r = 0.35, P < 0.001), and CFM (r = 0.23, P < 0.001) were significantly related to AHI. Logistic regression analysis indicated that in mild OSAS cases (> 15AHI < 30), BMI (OR: 1.10; 95% CI: 1.03-1.18; P = 0.008), and male gender (OR: 1.49; 95% CI: 1.05-2.12, P = 0.03) were key factors explaining an AHI between 15 and 30. In severe cases (AHI > 30), male gender (OR: 3.65; 95% CI: 2.40-5.55; P < 0.001) and CFM (OR: 1.10; 95% CI: 1.03-1.19; P = 0.009) were significant independent predictors of OSAS. CLINICAL TRIAL REGISTRATION NCT 00759304 and NCT 00766584. CONCLUSIONS Although central fat mass plays a role in the occurrence of severe OSAS in men older than 65 years of age, its low discriminative sensitivity in mild OSAS cases does not warrant systematic use of DEXA for the diagnosis of OSAS.

Association between C-reactive protein and unrecognised sleep-disordered breathing in the elderly

Elevated levels of C-reactive protein (CRP) have been reported in patients with sleep-disordered breathing (SDB) and may represent an inflammatory marker of cardiovascular risk. However, the association of CRP with SBD in presumed healthy elderly subjects is unknown. In total, 851 (58.5% females) 68-yr-old subjects, who were free of any known cardiac or sleep disorders, were prospectively examined. Subjects underwent unattended polygraphy, and the apnoea/hypopnoea index (AHI) and oxyhaemoglobin desaturation index (ODI) were assessed. Elevated levels of CRP were found on the morning after the sleep study in patients with more severe SDB. A significant correlation was found between CRP levels, time spent at night with arterial oxygen saturation <90% and ODI. No association was found between CRP levels and AHI. After adjustments for body mass index, smoking status, hypertension, diabetes and dyslipidaemia, a significant association remained between CRP levels and ODI >10 events·h−1. CRP levels were frequently increased in a large sample of elderly subjects free of major cardiovascular disease. CRP levels were not correlated with the AHI and the indices of sleep fragmentation; the ODI >10 events·h−1 was the strongest predictor of raised CRP level. The present results suggest that, in the elderly, intermittent hypoxaemia may underlie inflammatory processes leading to cardiovascular morbidity.

Desperately seeking grey matter volume changes in sleep apnea: A methodological review of magnetic resonance brain voxel-based morphometry studies

Cognitive impairment related to obstructive sleep apnea might be explained by subtle changes in brain anatomy. This has been mainly investigated using magnetic resonance brain scans coupled with a voxel-based morphometry analysis. However, this approach is prone to several methodological pitfalls that may explain the large discrepancy in the results reported in the literature. We critically reviewed twelve papers addressing grey matter volume modifications in association with obstructive sleep apnea. Finally, based on strict methodological criteria, only three studies reported robust, but conflicting, results. No clear evidence has emerged and exploring brain alteration due to obstructive sleep apnea should thus be considered as an open field. We provide recommendations for designing additional robust voxel-based morphometry studies, notably the use of larger cohorts, which is the only way to solve the underpowered issue and the underestimated role of confounders in neuroimaging studies.