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.

Association of Self-reflection With Cognition and Brain Health in Cognitively Unimpaired Older Adults.

BACKGROUND AND OBJECTIVES: Self-reflection (the active evaluation of ones thoughts, feelings, and behaviors) can confer protection against adverse health outcomes. Its effect on markers sensitive to Alzheimer disease (AD), however, is unknown. The primary objective of this cross-sectional study was to examine the association between self-reflection and AD-sensitive markers. METHODS: This study used baseline data from cognitively unimpaired older adults enrolled in the Age-Well clinical trial and older adults with subjective cognitive decline from the SCD-Well clinical trial. In both cohorts, self-reflection was measured via the reflective pondering subscale of the Rumination Response Scale, global cognition assessed via the Preclinical Alzheimer's Cognitive Composite 5, and a modified late-life Lifestyle-for-Brain-Health (LIBRA) index computed to assess health and lifestyle factors. In Age-Well, glucose metabolism and amyloid deposition were quantified in AD-sensitive gray matter regions via fluorodeoxyglucose- and AV45-PET scans, respectively. Associations between self-reflection and AD-sensitive markers (global cognition, glucose metabolism, and amyloid deposition) were assessed via unadjusted and adjusted regressions. Furthermore, we explored whether associations were independent of health and lifestyle factors. To control for multiple comparisons in Age-Well, false discovery rate-corrected p values (p FDR) are reported. RESULTS: A total of 134 (mean age 69.3 ± 3.8 years, 61.9% women) Age-Well and 125 (mean age 72.6 ± 6.9 years, 65.6% women) SCD-Well participants were included. Across unadjusted and adjusted analyses, self-reflection was associated with better global cognition in both cohorts (Age-Well: adjusted-ß = 0.22, 95% CI 0.05-0.40, p FDR = 0.041; SCD-Well: adjusted-ß = 0.18, 95% CI 0.03-0.33, p = 0.023) and with higher glucose metabolism in Age-Well after adjustment for all covariates (adjusted-ß = 0.29, 95% CI 0.03-0.55, p FDR = 0.041). Associations remained following additional adjustment for LIBRA but did not survive false discovery rate (FDR) correction. Self-reflection was not associated with amyloid deposition (adjusted-ß = 0.13, 95% CI -0.07 to 0.34, p FDR = 0.189). DISCUSSION: Self-reflection was associated with better global cognition in 2 independent cohorts and with higher glucose metabolism after adjustment for covariates. There was weak evidence that relationships were independent from health and lifestyle behaviors. Longitudinal and experimental studies are warranted to elucidate whether self-reflection helps preserve cognition and glucose metabolism or whether reduced capacity to self-reflect is a harbinger of cognitive decline and glucose hypometabolism. TRIAL REGISTRATION INFORMATION: Age-Well: NCT02977819; SCD-Well: NCT03005652.

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.

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.

Evaluation of the early-phase [18F]AV45 PET as an optimal surrogate of [18F]FDG PET in ageing and Alzheimer's clinical syndrome.

Dual-phase [18F]AV45 positron emission tomography (PET) is highly promising in the assessment of neurodegenerative diseases, allowing to obtain information on both neurodegeneration (early-phase; eAV45) and amyloid deposition (late-phase; lAV45) which are highly complementary; yet eAV45 needs further evaluation. This study aims at validating eAV45 as an optimal proxy of [18F]FDG PET in a large mixed-population of healthy ageing and Alzheimer's clinical syndrome participants (n = 191) who had [18F]FDG PET, eAV45 and lAV45 scans. We found early time frame 0-4 min to give maximal correlation with [18F]FDG PET and minimal correlation with lAV45. Moreover, maximal overlap of [18F]FDG PET versus eAV45 associations with clinical diagnosis and cognition was obtained with pons scaling. Across reference regions, classification performance between clinical subgroups was similar for both eAV45 and [18F]FDG PET. These findings highlight the optimal use of eAV45 to assess neurodegeneration as a validated proxy of [18F]FDG PET. On top of this purpose, this study showed that combined [18F]AV45 PET dual-biomarker even outperformed [18F]FDG PET or lAV45 alone.

Whole blood serotonin levels in healthy elderly are negatively associated with the functional activity of emotion-related brain regions.

Understanding the role of neuromodulators of socio-affective processing is important to ensure psychological wellbeing during older years. Here, we investigated the link between blood serotonin levels and brain and behavioral responses to emotional information in healthy elderly. A priori regions of interest (ROI) were selected due to their role in emotion processing and their dense serotonergic innervation. Correlation analyses were performed between ROI-specific responses to emotional stimuli and whole blood serotonin levels. We found significant negative associations between serotonin and functional activity for the bilateral insula, dorsal anterior cingulate cortex and subgenual gyrus. No association with behavioral measures survived correction for multiple testing. Our results mirror prior pharmacological and genetic work on the link between serotonin and emotional brain reactivity in younger adults. Given the involvement of serotonin in several age-related changes, our study encourages future research to characterize the role of this neuromodulator in emotion processing across the lifespan.

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.

White matter hyperintensities across the adult lifespan: relation to age, Aß load, and cognition.

BACKGROUND: White matter hyperintensities (WMH) are very frequent in older adults and associated with worse cognitive performance. Little is known about the links between WMH and vascular risk factors, cortical ß-amyloid (Aß) load, and cognition in cognitively unimpaired adults across the entire lifespan, especially in young and middle-aged adults. METHODS: One hundred and thirty-seven cognitively unimpaired adults from the community were enrolled (IMAP cohort). Participants underwent (i) a comprehensive neuropsychological assessment of episodic memory, processing speed, working memory, and executive functions; (ii) brain structural T1 and FLAIR MRI scans used for the automatic segmentation of total and regional (frontal, parietal, temporal, occipital, and corpus callosum) WMH; and (iii) a Florbetapir-PET scan to measure cortical Aß. The relationships of total and regional WMH to age, vascular risk factors, cortical Aß, and cognition were assessed within the whole sample, but also splitting the sample in two age groups (≤ or > 60 years old). RESULTS: WMH increased with age across the adult lifespan, i.e., even in young and middle-aged adults. Systolic blood pressure, diastolic blood pressure, and glycated hemoglobin were all associated with higher WMH before, but not after, adjusting for age and the other vascular risk factors. Higher frontal, temporal, and occipital WMH were associated with greater Aß, but this association was no longer significant when adjusting for age and vascular risk factors. Higher total and frontal WMH were associated with worse performance in executive functions, with no interactive effect of the age group. In contrast, there was a significant interaction of the age group on the link between WMH and working memory, which was significant within the subgroup of young/middle-aged adults only. Adding cortical Aß load in the models did not alter the results, and there was no interaction between WMH and Aß on cognition. CONCLUSION: WMH increased with age and were associated with worse executive functions across the adult lifespan and with worse working memory in young/middle-aged adults. Aß load was weakly associated with WMH and did not change the relationship found between WMH and executive functions. This study argues for the clinical relevance of WMH across the adult lifespan, even in young and middle-aged adults with low WMH.

Reduced age-associated brain changes in expert meditators: a multimodal neuroimaging pilot study.

Aging is associated with progressive cerebral volume and glucose metabolism decreases. Conditions such as stress and sleep difficulties exacerbate these changes and are risk factors for Alzheimer's disease. Meditation practice, aiming towards stress reduction and emotion regulation, can downregulate these adverse factors. In this pilot study, we explored the possibility that lifelong meditation practice might reduce age-related brain changes by comparing structural MRI and FDG-PET data in 6 elderly expert meditators versus 67 elderly controls. We found increased gray matter volume and/or FDG metabolism in elderly expert meditators compared to controls in the bilateral ventromedial prefrontal and anterior cingulate cortex, insula, temporo-parietal junction, and posterior cingulate cortex /precuneus. Most of these regions were also those exhibiting the strongest effects of age when assessed in a cohort of 186 controls aged 20 to 87 years. Moreover, complementary analyses showed that these changes were still observed when adjusting for lifestyle factors or using a smaller group of controls matched for education. Pending replication in a larger cohort of elderly expert meditators and longitudinal studies, these findings suggest that meditation practice could reduce age-associated structural and functional brain changes.

Expression of aromatase in human ejaculated spermatozoa: a putative marker of motility.

Cytochrome p450 aromatase (p450arom) is a key enzyme responsible for the irreversible transformation of androgens into estrogens. In the present study, we have analysed the ability of human ejaculated spermatozoa to produce estrogens and for that purpose we have looked for the expression of specific aromatase transcript and protein. We have confirmed the presence of p450arom transcript in all normospermic purified samples by nested PCR. The sequence of PCR products from purified spermatozoa shares 98% identity with published human p450arom sequence. Using a semi-quantitative approach, we have observed in immotile sperm a significant decrease (28%) of the aromatase/glyceraldehyde-3-phosphate dehydrogenase ratio compared with the motile sperm fraction. On Western blot with a monoclonal antibody directed against aromatase, we have detected two bands (53 and 49 kDa) in microsome preparations from purified spermatozoa. In total protein extracts of purified spermatozoa (with and without cytoplasmic droplets), we have only found the aromatase as a 49 kDa band with a stronger intensity when cytoplasmic droplets are present. Moreover, the band seems to be weaker in immotile spermatozoa (with and without cytoplasmic droplets). Our data demonstrate the expression of aromatase both in terms of mRNA and protein in each sample of human purified spermatozoa and in addition, our results suggest that aromatase could be concerned with the acquisition of sperm motility.