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.

Depressive symptoms in cognitively unimpaired older adults are associated with lower structural and functional integrity in a frontolimbic network.

Subclinical depressive symptoms are associated with increased risk of Alzheimer's disease (AD), but the brain mechanisms underlying this relationship are still unclear. We aimed to provide a comprehensive overview of the brain substrates of subclinical depressive symptoms in cognitively unimpaired older adults using complementary multimodal neuroimaging data. We included cognitively unimpaired older adults from the baseline data of the primary cohort Age-Well (n = 135), and from the replication cohort ADNI (n = 252). In both cohorts, subclinical depressive symptoms were assessed using the 15-item version of the Geriatric Depression Scale; based on this scale, participants were classified as having depressive symptoms (>0) or not (0). Voxel-wise between-group comparisons were performed to highlight differences in gray matter volume, glucose metabolism and amyloid deposition; as well as white matter integrity (only available in Age-Well). Age-Well participants with subclinical depressive symptoms had lower gray matter volume in the hippocampus and lower white matter integrity in the fornix and the posterior parts of the cingulum and corpus callosum, compared to participants without symptoms. Hippocampal atrophy was recovered in ADNI, where participants with subclinical depressive symptoms also showed glucose hypometabolism in the hippocampus, amygdala, precuneus/posterior cingulate cortex, medial and dorsolateral prefrontal cortex, insula, and temporoparietal cortex. Subclinical depressive symptoms were not associated with brain amyloid deposition in either cohort. Subclinical depressive symptoms in ageing are linked with neurodegeneration biomarkers in the frontolimbic network including brain areas particularly sensitive to AD. The relationship between depressive symptoms and AD may be partly underpinned by neurodegeneration in common brain regions.

Depressive Symptoms Have Distinct Relationships With Neuroimaging Biomarkers Across the Alzheimer's Clinical Continuum.

Background: Depressive and anxiety symptoms are frequent in Alzheimer's disease and associated with increased risk of developing Alzheimer's disease in older adults. We sought to examine their relationships to Alzheimer's disease biomarkers across the preclinical and clinical stages of the disease. Method: Fifty-six healthy controls, 35 patients with subjective cognitive decline and 56 amyloid-positive cognitively impaired patients on the Alzheimer's continuum completed depression and anxiety questionnaires, neuropsychological tests and neuroimaging assessments. We performed multiple regressions in each group separately to assess within group associations of depressive and anxiety symptoms with either cognition (global cognition and episodic memory) or neuroimaging data (gray matter volume, glucose metabolism and amyloid load). Results: Depressive symptoms, but not anxiety, were higher in patients with subjective cognitive decline and cognitively impaired patients on the Alzheimer's continuum compared to healthy controls. Greater depressive symptoms were associated with higher amyloid load in subjective cognitive decline patients, while they were related to higher cognition and glucose metabolism, and to better awareness of cognitive difficulties, in cognitively impaired patients on the Alzheimer's continuum. In contrast, anxiety symptoms were not associated with brain integrity in any group. Conclusion: These data show that more depressive symptoms are associated with greater Alzheimer's disease biomarkers in subjective cognitive decline patients, while they reflect better cognitive deficit awareness in cognitively impaired patients on the Alzheimer's continuum. Our findings highlight the relevance of assessing and treating depressive symptoms in the preclinical stages of Alzheimer's disease.

Sex-specificities in anxiety and depressive symptoms across the lifespan and their links with multimodal neuroimaging.

BACKGROUND: Anxiety and depressive symptoms are associated with impaired well-being, higher risk of developing psychoaffective disorders and are risk factors for Alzheimer's disease (AD). To further understand their relevance and the mechanisms underlying their link with AD, our aims were to assess how anxiety and depressive symptoms changed with age and related to AD neuroimaging biomarkers across the adult lifespan, while also exploring sex specificities. METHODS: 210 cognitively normal participants aged 19-86 years (101 men, 109 women) completed assessments of anxiety and depressive symptoms with the STAI-A and MADRS respectively, and neuroimaging measurements including structural MRI, FDG-PET and amyloid-PET. 167 of those were followed-up over 1.5-3 years. Multiple regressions were performed to assess the links between anxiety or depressive symptoms versus age, global cognition or each imaging modality, both cross-sectionally and longitudinally; and general linear models we used to test the interactive effect of sex on these associations. RESULTS: Depressive symptoms decreased with age, while anxiety symptoms increased only among women. Higher anxiety symptoms were associated with lower grey matter (GM) volume and glucose metabolism, with an interaction of sex, this relationship being significant only in women. Longitudinally, only low baseline GM volume predicted an increase in anxiety symptoms with time. LIMITATIONS: Only 43% of participants reported depressive symptoms. Despite additional analyses, the low variability in the measure might have prevented us from detecting subtle changes. CONCLUSIONS: This study emphasizes the need to consider anxiety symptoms in assessments for dementia risk, particularly in women.

The Effect of Mindfulness-based Programs on Cognitive Function in Adults: A Systematic Review and Meta-analysis.

Mindfulness-based programs (MBPs) are increasingly utilized to improve mental health. Interest in the putative effects of MBPs on cognitive function is also growing. This is the first meta-analysis of objective cognitive outcomes across multiple domains from randomized MBP studies of adults. Seven databases were systematically searched to January 2020. Fifty-six unique studies (n = 2,931) were included, of which 45 (n = 2,238) were synthesized using robust variance estimation meta-analysis. Meta-regression and subgroup analyses evaluated moderators. Pooling data across cognitive domains, the summary effect size for all studies favored MBPs over comparators and was small in magnitude (g = 0.15; [0.05, 0.24]). Across subgroup analyses of individual cognitive domains/subdomains, MBPs outperformed comparators for executive function (g = 0.15; [0.02, 0.27]) and working memory outcomes (g = 0.23; [0.11, 0.36]) only. Subgroup analyses identified significant effects for studies of non-clinical samples, as well as for adults aged over 60. Across all studies, MBPs outperformed inactive, but not active comparators. Limitations include the primarily unclear within-study risk of bias (only a minority of studies were considered low risk), and that statistical constraints rendered some p-values unreliable. Together, results partially corroborate the hypothesized link between mindfulness practices and cognitive performance. This review was registered with PROSPERO [CRD42018100904].

Association of quality of life with structural, functional and molecular brain imaging in community-dwelling older adults.

BACKGROUND: As the population ages, maintaining mental health and well-being of older adults is a public health priority. Beyond objective measures of health, self-perceived quality of life (QoL) is a good indicator of successful aging. In older adults, it has been shown that QoL is related to structural brain changes. However, QoL is a multi-faceted concept and little is known about the specific relationship of each QoL domain to brain structure, nor about the links with other aspects of brain integrity, including white matter microstructure, brain perfusion and amyloid deposition, which are particularly relevant in aging. Therefore, we aimed to better characterize the brain biomarkers associated with each QoL domain using a comprehensive multimodal neuroimaging approach in older adults. METHODS: One hundred and thirty-five cognitively unimpaired older adults (mean age ± SD: 69.4 ± 3.8 y) underwent structural and diffusion magnetic resonance imaging, together with early and late florbetapir positron emission tomography scans. QoL was assessed using the brief version of the World Health Organization's QoL instrument, which allows measuring four distinct domains of QoL: self-perceived physical health, psychological health, social relationships and environment. Multiple regression analyses were carried out to identify the independent global neuroimaging predictor(s) of each QoL domain, and voxel-wise analyses were then conducted with the significant predictor(s) to highlight the brain regions involved. Age, sex, education and the other QoL domains were entered as covariates in these analyses. Finally, forward stepwise multiple regressions were conducted to determine the specific items of the relevant QoL domain(s) that contributed the most to these brain associations. RESULTS: Only physical health QoL was associated with global neuroimaging values, specifically gray matter volume and white matter mean kurtosis, with higher physical health QoL being associated with greater brain integrity. These relationships were still significant after correction for objective physical health and physical activity measures. No association was found with global brain perfusion or global amyloid deposition. Voxel-wise analyses revealed that the relationships with physical health QoL concerned the anterior insula and ventrolateral prefrontal cortex, and the corpus callosum, corona radiata, inferior frontal white matter and cingulum. Self-perceived daily living activities and self-perceived pain and discomfort were the items that contributed the most to these associations with gray matter volume and white matter mean kurtosis, respectively. CONCLUSIONS: Better self-perceived physical health, encompassing daily living activities and pain and discomfort, was the only QoL domain related to brain structural integrity including higher global gray matter volume and global white matter microstructural integrity in cognitively unimpaired older adults. The relationships involved brain structures belonging to the salience network, the pain pathway and the empathy network. While previous studies showed a link between objective measures of physical health, our findings specifically highlight the relevance of monitoring and promoting self-perceived physical health in the older population. Longitudinal studies are needed to assess the direction and causality of the relationships between QoL and brain integrity.

Association of Sleep-Disordered Breathing With Alzheimer Disease Biomarkers in Community-Dwelling Older Adults: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Increasing evidence suggests that sleep-disordered breathing (SDB) increases the risk of developing Alzheimer clinical syndrome. However, the brain mechanisms underlying the link between SDB and Alzheimer disease are still unclear. Objective: To determine which brain changes are associated with the presence of SDB in older individuals who are cognitively unimpaired, including changes in amyloid deposition, gray matter volume, perfusion, and glucose metabolism. Design, Setting, and Participants: This cross-sectional study was conducted using data from the Age-Well randomized clinical trial of the Medit-Ageing European project, acquired between 2016 and 2018 at Cyceron Center in Caen, France. Community-dwelling older adults were assessed for eligibility and were enrolled in the Age-Well clinical trial if they did not meet medical or cognitive exclusion criteria and were willing to participate. Participants who completed a detailed neuropsychological assessment, polysomnography, a magnetic resonance imaging, and florbetapir and fluorodeoxyglucose positron emission tomography scans were included in the analyses. Main Outcomes and Measures: Based on an apnea-hypopnea index cutoff of 15 events per hour, participants were classified as having SDB or not. Voxelwise between-group comparisons were performed for each neuroimaging modality, and secondary analyses aimed at identifying which SDB parameter (sleep fragmentation, hypoxia severity, or frequency of respiratory disturbances) best explained the observed brain changes and assessing whether SDB severity and/or SDB-associated brain changes are associated with cognitive and behavioral changes. Results: Of 157 participants initially assessed, 137 were enrolled in the Age-Well clinical trial, and 127 were analyzed in this study. The mean (SD) age of the 127 participants was 69.1 (3.9) years, and 80 (63.0%) were women. Participants with SDB showed greater amyloid burden (t114 = 4.51; familywise error-corrected P = .04; Cohen d, 0.83), gray matter volume (t119 = 4.12; familywise error-corrected P = .04; Cohen d, 0.75), perfusion (t116 = 4.62; familywise error-corrected P = .001; Cohen d, 0.86), and metabolism (t79 = 4.63; familywise error-corrected P = .001; Cohen d, 1.04), overlapping mainly over the posterior cingulate cortex and precuneus. No association was found with cognition, self-reported cognitive and sleep difficulties, or excessive daytime sleepiness symptoms. Conclusions and Relevance: The SDB-associated brain changes in older adults who are cognitively unimpaired include greater amyloid deposition and neuronal activity in Alzheimer disease-sensitive brain regions, notably the posterior cingulate cortex and precuneus. These results support the need to screen and treat for SDB, especially in asymptomatic older populations, to reduce Alzheimer disease risk. Trial Registration: ClinicalTrials.gov Identifier: NCT02977819.

Cross-sectional and longitudinal characterization of SCD patients recruited from the community versus from a memory clinic: subjective cognitive decline, psychoaffective factors, cognitive performances, and atrophy progression over time.

BACKGROUND: Subjective cognitive decline (SCD) defines a heterogeneous population, part of which having Alzheimer's disease (AD). We aimed at characterizing SCD populations according to whether or not they referred to a memory clinic, by assessing the factors associated with increased AD risk. METHODS: Seventy-eight cognitively unimpaired older adults from the IMAP+ study (Caen) were included, amongst which 28 healthy controls (HC) and 50 SCD recruited from the community (SCD-community; n = 23) or from a memory clinic (SCD-clinic; n = 27). Participants underwent cognitive, psychoaffective, structural MRI, FDG-PET, and amyloid-PET assessments. They were followed up over a mean period of 2.4 ± 0.8 years. The groups were compared in terms of baseline and follow-up levels of SCD (self- and informant-reported), cognition, subclinical anxiety and depression, and atrophy progression over time. We also investigated SCD substrates within each SCD group through the correlations between self-reported SCD and other psychometric and brain measures. RESULTS: Compared to HC, both SCD groups showed similar cognitive performances but higher informant-reported SCD and anxiety. Compared to SCD-community, SCD-clinic showed higher informant-reported SCD, depression score, and atrophy progression over time but similar brain amyloid load. A significant increase over time was found for depression in the SCD-community and for self-reported praxis-domestic activities SCD factor in the SCD-clinic. Higher self-reported SCD correlated with (i) lower grey matter volume and higher anxiety in SCD-community, (ii) greater informant-reported SCD in SCD-clinic, and (iii) lower glucose metabolism in both SCD groups. CONCLUSIONS: Higher subclinical depression and informant-reported SCD specifically characterize the SCD group that refers to a memory clinic. The same group appears as a frailer population than SCD-community as they show greater atrophy progression over time. Yet, both the SCD groups were quite similar otherwise including for brain amyloid load and the SCD-community showed increased depression score over time. Altogether, our findings highlight the relevance of assessing psychoaffective factors and informant-reported SCD in SCD populations and point to both differences and similarities in SCD populations referring or not to a memory clinic.