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

BACKGROUND 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 Aß+ individuals) in baseline analyses and 111 at follow-up. The apnea-hypopnea index interacted with entorhinal (ß = -0.81, p < 0.001, pη2 = 0.19), whole hippocampal (ß = -0.61, p < 0.001, pη2 = 0.10), subiculum (ß = -0.56, p = 0.002, pη2 = 0.08), CA1 (ß = -0.55, p = 0.002, pη2 = 0.08), and DG (ß = -0.53, p = 0.003, pη2 = 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. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT02977819.

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.

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

BACKGROUND 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 (ß = 0.174, p = 0.030) and cerebral glucose metabolism (ß = 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.

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

Vascular 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 (Aß-neg controls), and 45 amyloid-positive patients with mild cognitive impairment or dementia (Aß-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 Aß-pos patients using multiple regressions. Compared to Aß-neg controls, Aß-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 Aß-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.

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

Importance: 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.

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

Medial 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 (Aß-) (n = 46) and amyloid-positive (Aß+) (n = 14) CU, Aß+ 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 Aß+ 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 Aß+ MCI and AD patients compared to Aß- CU, but no differences between Aß- and Aß+ CU or between Aß+ 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 (Aß+ CU), were particularly affected from the prodromal stage (Aß+ 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.