Effect of cognitive reserve on the association between slow wave sleep and cognition in community-dwelling older adults

Sleep, especially slow wave sleep (SWS), is essential for cognitive functioning and is reduced in aging. The impact of sleep quality on cognition is variable, especially in aging. Cognitive reserve (CR) may be an important modulator of these effects. We aimed at investigating this question to better identify individuals in whom sleep disturbances might have greater behavioral consequences. Polysomnography and neuropsychological assessments were performed in 135 cognitively intact older adults (mean age ± SD: 69.4 ± 3.8y) from the Age-Well randomized controlled trial (baseline data). Two measures of cognitive engagement throughout life were used as CR proxies. Linear regression analyses were performed between the proportion of SWS, and executive function and episodic memory composite scores. Then, interaction analyses between SWS and CR proxies on cognition were conducted to assess the possible impact of CR on these links. SWS was positively associated with episodic memory, but not with executive function. CR proxies modulated the associations between SWS and both executive and episodic memory performance. Specifically, individuals with higher CR were able to maintain cognitive performance despite low amounts of SWS. This study provides the first evidence that CR may protect against the deleterious effects of age-related sleep changes on cognition

Effect of an 18-Month Meditation Training on Regional Brain Volume and Perfusion in Older Adults: The Age-Well Randomized Clinical Trial.

peer reviewedImportance: No lifestyle-based randomized clinical trial directly targets psychoaffective risk factors of dementia. Meditation practices recently emerged as a promising mental training exercise to foster brain health and reduce dementia risk. Objective: To investigate the effects of meditation training on brain integrity in older adults. Design, Setting, and Participants: Age-Well was a randomized, controlled superiority trial with blinded end point assessment. Community-dwelling cognitively unimpaired adults 65 years and older were enrolled between November 24, 2016, and March 5, 2018, in France. Participants were randomly assigned (1:1:1) to (1) an 18-month meditation-based training, (2) a structurally matched non-native language (English) training, or (3) no intervention arm. Analysis took place between December 2020 and October 2021. Interventions: Meditation and non-native language training included 2-hour weekly group sessions, practice of 20 minutes or longer daily at home, and 1-day intensive practices. Main Outcomes and Measures: Primary outcomes included volume and perfusion of anterior cingulate cortex (ACC) and insula. Main secondary outcomes included a global composite score capturing metacognitive, prosocial, and self-regulatory capacities and constituent subscores. Results: Among 137 participants (mean [SD] age, 69.4 [3.8] years; 83 [60.6%] female; 54 [39.4%] male) assigned to the meditation (n = 45), non-native language training (n = 46), or no intervention (n = 46) groups, all but 1 completed the trial. There were no differences in volume changes of ACC (0.01 [98.75% CI, -0.02 to 0.05]; P = .36) or insula (0.01 [98.75% CI, -0.02 to 0.03]; P = .58) between meditation and no intervention or non-native language training groups, respectively. Differences in perfusion changes did not reach statistical significance for meditation compared with no intervention in ACC (0.02 [98.75% CI, -0.01 to 0.05]; P = .06) or compared with non-native language training in insula (0.02 [98.75% CI, -0.01 to 0.05]; P = .09). Meditation was superior to non-native language training on 18-month changes in a global composite score capturing attention regulation, socioemotional, and self-knowledge capacities (Cohen d, 0.52 [95% CI, 0.19-0.85]; P = .002). Conclusions and Relevance: The study findings confirm the feasibility of meditation and non-native language training in elderly individuals, with high adherence and very low attrition. Findings also show positive behavioral effects of meditation that were not reflected on volume, and not significantly on perfusion, of target brain areas. Trial Registration: ClinicalTrials.gov Identifier: NCT02977819

Vers une meilleure compréhension des biomarqueurs en tant que facteurs de risque dans le vieillissement normal et la maladie d’Alzheimer : liens avec la cognition et la neuroimagerie multimodale

Vascular risk factors (i.e. high but subclinical glycemia and platelet activity) or related to the impact of stress throughout life (i.e., allostatic load) are thought to be associated with cognitive decline and an increased risk of developing Alzheimer's disease (AD). However, the brain mechanisms underlying these associations are still unclear and few studies focused on in cognitively unimpaired older adults. The objective of this thesis was to contribute to characterize the links between these risk factors and brain, cognitive and emotional alterations in ageing and the AD continuum. We also assessed the potential moderating effect of lifestyle factors on the associations between allostatic load and dementia risk. Our results show that high allostatic load and high but subclinical glycemia levels are associated with lower brain integrity (i.e. gray matter volume, white matter, and glucose metabolism) in regions particularly sensitive to ageing or AD in cognitively unimpaired older adults. Moreover, in individuals with low physical activity, this increase in allostatic load is associated with elevated levels of plasma biomarkers related to pathophysiological processes of AD, reflecting a poorer brain integrity, and an increased risk of developing AD. Finally, high but subclinical platelet activity levels are associated with poorer brain integrity (i.e. gray matter volume) in temporal regions, which are particularly sensitive to AD. These results highlight the need to screen these modifiable risk factors in order to reduce the risk of developing AD and to implement preventive and/or interventional strategies to reduce these factors and limit their consequences in the older adults.Les facteurs de risque vasculaire (i.e. niveau de glycémie et d’activité plaquettaire élevés mais subcliniques) ou liés à l’impact du stress tout au long de la vie (i.e. charge allostatique) seraient associés au déclin cognitif et à un risque accru de développer une maladie d’Alzheimer (MA). Cependant, les mécanismes cérébraux sous-tendant ces associations restent mal compris et peu étudiés chez des sujets âgés cognitivement sains. L’objectif général de cette thèse était de contribuer à caractériser les liens entre ces facteurs de risque et les altérations cérébrales, cognitives et émotionnelles dans le vieillissement et le continuum de la MA. Nous avons également évalué le potentiel effet modérateur des facteurs liés au style de vie sur les liens entre la charge allostatique et le risque de démence. Nos résultats montrent qu’une charge allostatique élevée ainsi qu’une glycémie élevée mais subclinique sont associées à une plus faible intégrité cérébrale (i.e. volume de substance grise, substance blanche et métabolisme du glucose) dans des régions particulièrement sensibles au vieillissement ou à la MA chez des sujets âgés cognitivement sains. De plus, chez les individus pratiquant peu d’activité physique, cette augmentation de la charge allostatique est associée à des niveaux élevés de biomarqueurs sanguins liés à différents processus physiopathologiques de la maladie, et reflétant une moins bonne intégrité cérébrale ainsi qu’un risque accru de développer la MA. Enfin, des niveaux élevés mais subcliniques d’activité plaquettaire sont associés à une moins bonne intégrité cérébrale (i.e. volume de substance grise) dans des régions temporales, particulièrement sensibles à la MA. Ces résultats soulignent la nécessité de surveiller ces facteurs de risque modifiables afin de réduire les risques de développer la MA et de mettre en place des stratégies préventives et/ou interventionnelles visant à réduire ces facteurs et d’en limiter les conséquences chez le sujet âgé

Vers une meilleure compréhension des biomarqueurs en tant que facteurs de risque dans le vieillissement normal et la maladie d’Alzheimer : liens avec la cognition et la neuroimagerie multimodale

Vascular risk factors (i.e. high but subclinical glycemia and platelet activity) or related to the impact of stress throughout life (i.e., allostatic load) are thought to be associated with cognitive decline and an increased risk of developing Alzheimer's disease (AD). However, the brain mechanisms underlying these associations are still unclear and few studies focused on in cognitively unimpaired older adults. The objective of this thesis was to contribute to characterize the links between these risk factors and brain, cognitive and emotional alterations in ageing and the AD continuum. We also assessed the potential moderating effect of lifestyle factors on the associations between allostatic load and dementia risk. Our results show that high allostatic load and high but subclinical glycemia levels are associated with lower brain integrity (i.e. gray matter volume, white matter, and glucose metabolism) in regions particularly sensitive to ageing or AD in cognitively unimpaired older adults. Moreover, in individuals with low physical activity, this increase in allostatic load is associated with elevated levels of plasma biomarkers related to pathophysiological processes of AD, reflecting a poorer brain integrity, and an increased risk of developing AD. Finally, high but subclinical platelet activity levels are associated with poorer brain integrity (i.e. gray matter volume) in temporal regions, which are particularly sensitive to AD. These results highlight the need to screen these modifiable risk factors in order to reduce the risk of developing AD and to implement preventive and/or interventional strategies to reduce these factors and limit their consequences in the older adults.Les facteurs de risque vasculaire (i.e. niveau de glycémie et d’activité plaquettaire élevés mais subcliniques) ou liés à l’impact du stress tout au long de la vie (i.e. charge allostatique) seraient associés au déclin cognitif et à un risque accru de développer une maladie d’Alzheimer (MA). Cependant, les mécanismes cérébraux sous-tendant ces associations restent mal compris et peu étudiés chez des sujets âgés cognitivement sains. L’objectif général de cette thèse était de contribuer à caractériser les liens entre ces facteurs de risque et les altérations cérébrales, cognitives et émotionnelles dans le vieillissement et le continuum de la MA. Nous avons également évalué le potentiel effet modérateur des facteurs liés au style de vie sur les liens entre la charge allostatique et le risque de démence. Nos résultats montrent qu’une charge allostatique élevée ainsi qu’une glycémie élevée mais subclinique sont associées à une plus faible intégrité cérébrale (i.e. volume de substance grise, substance blanche et métabolisme du glucose) dans des régions particulièrement sensibles au vieillissement ou à la MA chez des sujets âgés cognitivement sains. De plus, chez les individus pratiquant peu d’activité physique, cette augmentation de la charge allostatique est associée à des niveaux élevés de biomarqueurs sanguins liés à différents processus physiopathologiques de la maladie, et reflétant une moins bonne intégrité cérébrale ainsi qu’un risque accru de développer la MA. Enfin, des niveaux élevés mais subcliniques d’activité plaquettaire sont associés à une moins bonne intégrité cérébrale (i.e. volume de substance grise) dans des régions temporales, particulièrement sensibles à la MA. Ces résultats soulignent la nécessité de surveiller ces facteurs de risque modifiables afin de réduire les risques de développer la MA et de mettre en place des stratégies préventives et/ou interventionnelles visant à réduire ces facteurs et d’en limiter les conséquences chez le sujet âgé

Toward a better understanding of biomarkers as risk factors in normal aging and Alzheimer's disease : links to cognition and neuroimaging

Les facteurs de risque vasculaire (i.e. niveau de glycémie et d’activité plaquettaire élevés mais subcliniques) ou liés à l’impact du stress tout au long de la vie (i.e. charge allostatique) seraient associés au déclin cognitif et à un risque accru de développer une maladie d’Alzheimer (MA). Cependant, les mécanismes cérébraux sous-tendant ces associations restent mal compris et peu étudiés chez des sujets âgés cognitivement sains. L’objectif général de cette thèse était de contribuer à caractériser les liens entre ces facteurs de risque et les altérations cérébrales, cognitives et émotionnelles dans le vieillissement et le continuum de la MA. Nous avons également évalué le potentiel effet modérateur des facteurs liés au style de vie sur les liens entre la charge allostatique et le risque de démence. Nos résultats montrent qu’une charge allostatique élevée ainsi qu’une glycémie élevée mais subclinique sont associées à une plus faible intégrité cérébrale (i.e. volume de substance grise, substance blanche et métabolisme du glucose) dans des régions particulièrement sensibles au vieillissement ou à la MA chez des sujets âgés cognitivement sains. De plus, chez les individus pratiquant peu d’activité physique, cette augmentation de la charge allostatique est associée à des niveaux élevés de biomarqueurs sanguins liés à différents processus physiopathologiques de la maladie, et reflétant une moins bonne intégrité cérébrale ainsi qu’un risque accru de développer la MA. Enfin, des niveaux élevés mais subcliniques d’activité plaquettaire sont associés à une moins bonne intégrité cérébrale (i.e. volume de substance grise) dans des régions temporales, particulièrement sensibles à la MA. Ces résultats soulignent la nécessité de surveiller ces facteurs de risque modifiables afin de réduire les risques de développer la MA et de mettre en place des stratégies préventives et/ou interventionnelles visant à réduire ces facteurs et d’en limiter les conséquences chez le sujet âgé.Vascular risk factors (i.e. high but subclinical glycemia and platelet activity) or related to the impact of stress throughout life (i.e., allostatic load) are thought to be associated with cognitive decline and an increased risk of developing Alzheimer's disease (AD). However, the brain mechanisms underlying these associations are still unclear and few studies focused on in cognitively unimpaired older adults. The objective of this thesis was to contribute to characterize the links between these risk factors and brain, cognitive and emotional alterations in ageing and the AD continuum. We also assessed the potential moderating effect of lifestyle factors on the associations between allostatic load and dementia risk. Our results show that high allostatic load and high but subclinical glycemia levels are associated with lower brain integrity (i.e. gray matter volume, white matter, and glucose metabolism) in regions particularly sensitive to ageing or AD in cognitively unimpaired older adults. Moreover, in individuals with low physical activity, this increase in allostatic load is associated with elevated levels of plasma biomarkers related to pathophysiological processes of AD, reflecting a poorer brain integrity, and an increased risk of developing AD. Finally, high but subclinical platelet activity levels are associated with poorer brain integrity (i.e. gray matter volume) in temporal regions, which are particularly sensitive to AD. These results highlight the need to screen these modifiable risk factors in order to reduce the risk of developing AD and to implement preventive and/or interventional strategies to reduce these factors and limit their consequences in the older adults

Medial Temporal Lobe Subregional Atrophy in Aging and Alzheimer's Disease: A Longitudinal Study

International audienceMedial temporal lobe (MTL) atrophy is a key feature of Alzheimer's disease (AD), however, it also occurs in typical aging. To enhance the clinical utility of this biomarker, we need to better understand the differential effects of age and AD by encompassing the full AD-continuum from cognitively unimpaired (CU) to dementia, including all MTL subregions with up-to-date approaches and using longitudinal designs to assess atrophy more sensitively. Age-related trajectories were estimated using the best-fitted polynomials in 209 CU adults (aged 19–85). Changes related to AD were investigated among amyloid-negative (Aβ−) ( n = 46) and amyloid-positive (Aβ+) ( n = 14) CU, Aβ+ patients with mild cognitive impairment (MCI) ( n = 33) and AD ( n = 31). Nineteen MCI-to-AD converters were also compared with 34 non-converters. Relationships with cognitive functioning were evaluated in 63 Aβ+ MCI and AD patients. All participants were followed up to 47 months. MTL subregions, namely, the anterior and posterior hippocampus (aHPC/pHPC), entorhinal cortex (ERC), Brodmann areas (BA) 35 and 36 [as perirhinal cortex (PRC) substructures], and parahippocampal cortex (PHC), were segmented from a T1-weighted MRI using a new longitudinal pipeline (LASHiS). Statistical analyses were performed using mixed models. Adult lifespan models highlighted both linear (PRC, BA35, BA36, PHC) and nonlinear (HPC, aHPC, pHPC, ERC) trajectories. Group comparisons showed reduced baseline volumes and steeper volume declines over time for most of the MTL subregions in Aβ+ MCI and AD patients compared to Aβ− CU, but no differences between Aβ− and Aβ+ CU or between Aβ+ MCI and AD patients (except in ERC). Over time, MCI-to-AD converters exhibited a greater volume decline than non-converters in HPC, aHPC, and pHPC. Most of the MTL subregions were related to episodic memory performances but not to executive functioning or speed processing. Overall, these results emphasize the benefits of studying MTL subregions to distinguish age-related changes from AD. Interestingly, MTL subregions are unequally vulnerable to aging, and those displaying non-linear age-trajectories, while not damaged in preclinical AD (Aβ+ CU), were particularly affected from the prodromal stage (Aβ+ MCI). This volume decline in hippocampal substructures might also provide information regarding the conversion from MCI to AD-dementia. All together, these findings provide new insights into MTL alterations, which are crucial for AD-biomarkers definition

Relationships between diabetes-related vascular risk factors and neurodegeneration biomarkers in healthy aging and Alzheimer's disease

International audienceVascular risk factors such as hyperglycemia and platelet hyperactivation play a significant role in type 2 diabetes (T2D), a risk factor for AD. We investigated the relationships between glycemia levels, platelet indices (platelet count; mean platelet volume (MPV)) and AD neuroimaging markers in 105 cognitively unimpaired adults, including 21 amyloid-negative older adults (Aβ-neg controls), and 45 amyloid-positive patients with mild cognitive impairment or dementia (Aβ-pos patients). We assessed between-group differences on the two T2D-related vascular risk factors, then the association between blood parameters and multimodal neuroimaging (structural MRI, 18F-fluorodeoxyglucose, and 18F-florbetapir-PET) in cognitively unimpaired adults and Aβ-pos patients using multiple regressions. Compared to Aβ-neg controls, Aβ-pos patients showed lower platelet count and higher MPV. In cognitively unimpaired adults, increased glycemia levels were associated with atrophy and hypometabolism in AD-sensitive regions. In Aβ-pos patients, increased MPV was associated with entorhinal and perirhinal cortex atrophy. Subclinical but high glycemia levels in healthy individuals and MPV in AD patients are associated with neurodegeneration in AD-sensitive brain regions but not with amyloid deposition

Role of Cardiovascular Risk Factors on the Association Between Physical Activity and Brain Integrity Markers in Older Adults

International audienceBackground and Objectives Physical activity has been associated with a decreased risk for dementia, but the mechanisms underlying this association remain to be determined. Our objective was to assess whether cardiovascular risk factors mediate the association between physical activity and brain integrity markers in older adults. Methods At baseline, participants from the Age-Well study completed a physical activity questionnaire and underwent cardiovascular risk factors collection (systolic blood pressure, body mass index [BMI], current smoker status, and high-density lipoprotein cholesterol, total cholesterol, and insulin levels) and multimodal neuroimaging (structural MRI, diffusion MRI, FDG-PET, and florbetapir PET). Multiple regressions were conducted to assess the association among physical activity, cardiovascular risk factors, and neuroimaging. Mediation analyses were performed to test whether cardiovascular risk factors mediated the associations between physical activity and neuroimaging. Results A total of 134 cognitively unimpaired older adults (≥65 years) were included. Higher physical activity was associated with higher gray matter (GM) volume (β = 0.174, p = 0.030) and cerebral glucose metabolism (β = 0.247, p = 0.019) but not with amyloid deposition or white matter integrity. Higher physical activity was associated with lower insulin level and BMI but not with the other cardiovascular risk factors. Lower insulin level and BMI were related to higher GM volume but not to cerebral glucose metabolism. When controlling for insulin level and BMI, the association between physical activity and cerebral glucose metabolism remained unchanged, while the association with GM volume was lost. When insulin level and BMI were entered in the same model, only BMI remained a significant predictor of GM volume. Mediation analyses confirmed that insulin level and BMI mediated the association between physical activity and GM volume. Analyses were replicated within Alzheimer disease–sensitive regions and results remained overall similar. Discussion The association between physical activity and GM volume is mediated by changes in insulin level and BMI. In contrast, the association with cerebral glucose metabolism seems to be independent from cardiovascular risk factors. Older adults engaging in physical activity experience cardiovascular benefits through the maintenance of a lower BMI and insulin level, resulting in greater structural brain integrity. This study has implications for understanding how physical activity affects brain health and may help in developing strategies to prevent or delay age-related decline. Trial Registration Information EudraCT: 2016-002,441-36; IDRCB: 2016-A01767-44; ClinicalTrials.gov Identifier: NCT02977819

Association of Sleep-Disordered Breathing and Medial Temporal Lobe Atrophy in Cognitively Unimpaired Amyloid-Positive Older Adults

International audienceBackground and Objectives Sleep disordered breathing (SDB) has been related to amyloid deposition and an increased dementia risk. However, how SDB relates to medial temporal lobe neurodegeneration and subsequent episodic memory impairment is unclear. Our objective was to investigate the impact of amyloid positivity on the associations between SDB severity, medial temporal lobe subregions, and episodic memory performance in cognitively unimpaired older adults. Methods Data were acquired between 2016 and 2020 in the context of the Age-Well randomized controlled trial of the Medit-Aging European project. Participants older than 65 years who were free of neurologic, psychiatric, or chronic medical diseases were recruited from the community. They completed a neuropsychological evaluation, in-home polysomnography, a Florbetapir PET, and an MRI, including a specific high-resolution assessment of the medial temporal lobe and hippocampal subfields. Multiple linear regressions were conducted to test interactions between amyloid status and SDB severity on the volume of MTL subregions, controlling for age, sex, education, and the ApoE4 status. Secondary analyses aimed at investigating the links between SDB, MTL subregional atrophy, and episodic memory performance at baseline and at a mean follow-up of 20.66 months in the whole cohort and in subgroups stratified according to amyloid status. Results We included 122 cognitively intact community-dwelling older adults (mean age ± SD: 69.40 ± 3.85 years, 77 women, 26 Aβ+ individuals) in baseline analyses and 111 at follow-up. The apnea-hypopnea index interacted with entorhinal (β = −0.81, p < 0.001, pη 2 = 0.19), whole hippocampal (β = −0.61, p < 0.001, pη 2 = 0.10), subiculum (β = −0.56, p = 0.002, pη 2 = 0.08), CA1 (β = −0.55, p = 0.002, pη 2 = 0.08), and DG (β = −0.53, p = 0.003, pη 2 = 0.08) volumes such that a higher sleep apnea severity was related to lower MTL subregion volumes in amyloid-positive individuals, but not in those who were amyloid negative. In the whole cohort, lower whole hippocampal ( r = 0.27, p = 0.005) and CA1 ( r = 0.28, p = 0.003) volumes at baseline were associated with worse episodic memory performance at follow-up. Discussion Overall, we showed that SDB was associated with MTL atrophy in cognitively asymptomatic older adults engaged in the Alzheimer continuum, which may increase the risk of developing memory impairment over time

Interaction between APOE4 and lifestyle on neuroimaging biomarkers and cognition in cognitively unimpaired older adults

peer reviewedBackground: APOE4 is the main genetic risk factor for Alzheimer’s disease (AD). Recent findings suggest that lifestyle factors could modulate the association between APOE4 and cognitive impairment and/or dementia risk. However, a comprehensive assessment of the interactions between lifestyle and APOE4 status on neuroimaging and cognitive markers of aging and AD is still missing. Our objective is to assess this question in cognitively normal elderly. Method: Baseline data of 134 cognitively unimpaired older adults (mean age: 69) from the Age-Well study were analysed. They underwent lifestyle questionnaires (physical and cognitive activity, and diet), neuropsychological assessment (global cognition, memory, attention and executive functions) and multimodal neuroimaging (structural MRI, FDG- and Florbetapir-PET). Interactions between lifestyle and APOE4 status on neuroimaging and cognition were assessed for each lifestyle factor separately. Result: There was an interaction between APOE4 status and cognitive activity on neuroimaging measures (p-values<.04), such that higher cognitive engagement was associated with lower grey matter volume in the parahippocampal cortex and lower brain perfusion in the entorhinal and perirhinal cortices in APOE4 carriers only (Figure 1A). However, greater cognitive engagement was associated with increased cognitive performance (global cognition, executive function and attention, all p-values<.005), and this irrespective of APOE4 status (i.e., no cognitive activity x APOE4 status interaction; Figure 1B). For diet, interactions were evidenced (p-values <.04) such that higher adherence to the Mediterranean diet was associated with i) higher brain glucose metabolism in the medial temporal lobe (Figure 2A) and ii) higher performance on attention tests (Figure 2B) in APOE4 carriers only. No interactions were found for physical activity. Conclusion: Our results indicate that APOE4 carriers with higher cognitive activity had lower brain outcomes but preserved cognition, suggesting that enriched cognitive engagement promotes cognitive resilience in this population. On the other hand, APOE4 carriers with higher adherence to the Mediterranean diet had greater cerebral metabolism and greater attention capacities. Overall, this suggests that distinct lifestyle factors differentially help APOE4 carriers to resist or cope with brain alteration and postpone cognitive decline