Brigitte Landeau

INTRODUCTION: The locus coeruleus (LC), the first region to contain tau pathology in Alzheimer's disease (AD), releases norepinephrine, which has a neuroprotective role. We examined whether LC integrity relates to whole‐brain integrity and how AD biomarkers may moderate this relationship. METHODS: LC intensity and volume were estimated using automatic segmentation on neuromelanin‐sensitive magnetic resonance imaging acquired in n = 71 cognitively unimpaired elderly from the Age‐Well randomized controlled trial. We investigated the associations between LC integrity and whole‐brain gray matter volume (GMV) and glucose metabolism, as well as the interactions with amyloid positron emission tomography and plasma phosphorylated tau231, neurofilament light chain and glial fibrillary acidic protein. RESULTS: While only LC intensity was directly associated with GMV, both LC measures (intensity and volume) interacted positively with AD biomarkers to predict GMV and glucose metabolism. DISCUSSION: Our results support concomitant LC and gray matter alterations in the context of aging and elevated AD biomarker levels. CLINICAL TRIAL REGISTRATION: Age‐Well randomized clinical trial of the Medit‐Ageing European Project. Trial registration number: EudraCT:2016–002,441–36; IDRCB:2016‐A01767–44; ClinicalTrials.gov Identifier: NCT02977819.

Lifestyle behaviors, including engagement in complex mental activities, have been associated with dementia risk and neuroimaging markers of aging and Alzheimer disease. However, the life period(s) at which lifestyle factors have the greatest influence on brain health remains unclear. Our objective was to determine the relative influence of lifestyle (i.e., engagement in complex mental activities) at different life periods on older adults' brain health. This observational study included community-dwelling cognitively unimpaired seniors (older than 65 years) from the Age-Well randomized controlled trial (Caen, France). All participants completed at baseline the Lifetime of Experiences Questionnaire, assessing engagement in complex mental activities during young adulthood (13-30 years: LEQ-young), midlife (30-65 years: LEQ-midlife), and late-life (older than 65 years: LEQ-late). LEQ scores were divided into specific and non-specific activities. Multiple regressions were conducted including LEQ scores at the 3 life periods (same model) to predict gray matter volume (GMv; structural-MRI), glucose metabolism (fluorodeoxyglucose-PET), perfusion (early-Florbetapir-PET), or amyloid burden (late-Florbetapir-PET), both in AD-signature regions and voxel-wise (significance for voxel-wise analyses: p < 0.005_uncorrected, k > 100). Correlations between LEQ and neuroimaging outcomes were then compared between (1) life periods and (2) specific and non-specific activities. Analyses were controlled for age and sex. In 135 older adults (mean age = 69.3 years; women = 61.5%), no associations were found within AD-signature regions (all p > 0.25). Voxel-wise analyses revealed no association between LEQ-young and neuroimaging. LEQ-midlife showed stronger voxel-wise associations than the other periods with GMv, notably in the anterior cingulate cortex, and with amyloid burden in the precuneus. These correlations were stronger for the LEQ-midlife specific (i.e., occupation) than the non-specific subscore (GMv: z = 3.25, p < 0.001, 95% CI [0.1292-0.5135]; amyloid: z = -1.88, p < 0.05, 95% CI [-0.3810 to -0.0113]). LEQ-late showed stronger voxel-wise associations than the other periods with perfusion and glucose metabolism in medial frontal regions. The correlation of perfusion with LEQ-late was stronger for non-specific than specific subscore (z = 2.88, p < 0.01, 95% CI [0.0894-0.4606]). Lifestyle at different life periods may have complementary benefits on brain health in regions related to reserve/resilience in aging. While past (midlife) engagement could promote resistance against structural/pathologic alterations, current (late-life) engagement could enhance cognitive reserve. Future larger longitudinal studies should explore mechanisms by which lifestyle promotes reserve.

Background: Locus coeruleus (LC) imaging using neuromelanin-sensitive (NM) MRI sequences is a promising biomarker for detecting early Alzheimer’s Disease (AD) and Parkinson’s Disease (PD). Although semi or fully automatic approaches have been developed to estimate LC integrity by measuring its intensity, these techniques most often rely on a single template built in a standardized space and/or depend on a number of voxels to be accounted that is defined a priori. Thus, these algorithms make it impossible to perform direct volumetric analyses and do not properly account for inter-individual anatomical variability. To fill this gap, our aim was to develop a new multi-atlas fully automated segmentation method using the Automatic Segmentation of Hippocampal Subfields (ASHS) software. A second aim was to investigate the effects of age, sex and education on LC intensity and volume. Method: We used cross-sectional data from 101 cognitively unimpaired older adults (mean age: 73.8±6.6 years; mean education: 13.2±3.0 years; 58 women, 43 men) from the Age-Well randomized controlled trial for whom high-resolution NM-MRI (T1-w with magnetization transfer; 0.3×0.3×0.75mm ³ ) and standard T1-w MRI (1×1x1mm ³ ) were available. The LC were manually segmented in 30 randomly selected participants on NM-MRI, and the standard T1-w MRI, NM-MRI and bilateral segmentations were fed into the ASHS training pipeline to generate a new atlas (ASHS-LC). ASHS-LC was applied to the 71 remaining subjects to segment the LC and we assessed the effects of age, sex and education on both i) LC intensity (normalized by the intensity of the pons) and ii) LC volume (normalized by the total intracranial volume). Result: Five-fold cross-validation experiments revealed high accuracy of the automatic segmentation relative to manual segmentation (Dice coefficient 0,83±0,04). ICCs demonstrated excellent reliability for intensity (ICC = 0.99), whereas reliability for volume was lower (ICC = 0.43). LC intensity was significantly higher in women than in men (Cohen’s d = 0.94, p < 0.001) while no associations with age (β = -0.0002, p = 0.98) or education (β = 0.11, p = 0.37) were found. In contrast, LC volume was not different between men and women (Cohen’s d = 0.10, p= 0.55) but was significantly negatively associated with age (β = -0.25, p = 0.04) and education (β = -0.27, p = 0.04). Lastly, LC intensity and volume were not statistically correlated, neither using manual segmentation (atlas set: β = 0.05, p = 0.78) nor ASHS segmentation (atlas set: β = 0.11, p = 0.57; analysis set: β = -0.07, p = 0.55). Conclusion: Overall, this new method allows to automatically and accurately segment the LC and offers the opportunity to measure its integrity both in terms of intensity and volume. This is of importance since these two metrics may offer complementary insights into LC integrity, as evidenced by the differing influences of demographic factors on LC intensity and volume.

Episodic memory consolidation relies on the functional specialization of brain networks and sleep quality, both of which are affected by aging. Functional connectivity during wakefulness is crucial to support the integration of newly acquired information into memory networks. Additionally, the temporal dynamics of sleep spindles facilitates overnight memory consolidation by promoting hippocampal replay and integration of memories within neocortical structures. This study aimed at exploring how resting-state functional connectivity during wakefulness contributes to sleep-dependent memory consolidation in aging, and whether spindles clustered in trains modulates this relationship. Forty-two healthy older adults (68.82 ± 3.03 years), enrolled in the Age-Well clinical trial, were included. Sleep-dependent memory consolidation was assessed using a visuo-spatial memory task performed before and after a polysomnography night. Resting-state functional connectivity data were analyzed using graph theory applied to the whole brain, specific brain networks and the hippocampus. Lower limbic network integration and higher centrality of the anterior hippocampus were associated with better memory consolidation. Spindle trains modulated these effects, such that older participants with longer spindle trains exhibited a stronger negative association between limbic network integration and memory consolidation. These results indicate that lower functional specialization at rest is associated with weaker memory consolidation during sleep. This aligns with the dedifferentiation hypothesis, which posits that aging is associated with reduced brain specificity, leading to less efficient cognitive functioning. These findings reveal a novel mechanism linking daytime brain network organization and sleep-dependent memory consolidation, and suggest that targeting spindle dynamics could help preserve cognitive functioning in aging.

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.

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 (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.