Dairy products and brain structure in French older adults.

Among food groups with putative benefits for brain structures, dairy products (DP) have been poorly studied. The sample included participants without dementia from the ancillary brain imaging study of the Three-City cohort who were aged 65+ years, had their DP intake assessed with a FFQ at baseline and underwent an anatomical scan 3 years (n 343) or 9 years (n 195) after completing the dietary survey. The frequencies of consumption of total DP, milk and cheese were not associated with brain structure. Compared with the lowest frequency, the highest frequency of fresh DP (F-DP) consumption (< 0·5 v. > 1·5 times/d) was significantly associated with a lower medial temporal lobe volume (MTLV) (ß = -1·09 cm3, 95 % CI - 1·83, -0·36) 9 years later. In this population-based study of older adults, the consumption of F-DP more than 1·5 times/d was associated with a lower MTLV, which is considered an early biomarker of Alzheimer's disease, 9 years later. This original study should be replicated in different settings before conclusions are drawn.

Association between sleep slow-wave activity and in-vivo estimates of myelin in healthy young men.

Sleep has been suggested to contribute to myelinogenesis and associated structural changes in the brain. As a principal hallmark of sleep, slow-wave activity (SWA) is homeostatically regulated but also differs between individuals. Besides its homeostatic function, SWA topography is suggested to reflect processes of brain maturation. Here, we assessed whether interindividual differences in sleep SWA and its homeostatic response to sleep manipulations are associated with in-vivo myelin estimates in a sample of healthy young men. Two hundred twenty-six participants (18-31 y.) underwent an in-lab protocol in which SWA was assessed at baseline (BAS), after sleep deprivation (high homeostatic sleep pressure, HSP) and after sleep saturation (low homeostatic sleep pressure, LSP). Early-night frontal SWA, the frontal-occipital SWA ratio, as well as the overnight exponential SWA decay were computed over sleep conditions. Semi-quantitative magnetization transfer saturation maps (MTsat), providing markers for myelin content, were acquired during a separate laboratory visit. Early-night frontal SWA was negatively associated with regional myelin estimates in the temporal portion of the inferior longitudinal fasciculus. By contrast, neither the responsiveness of SWA to sleep saturation or deprivation, its overnight dynamics, nor the frontal/occipital SWA ratio were associated with brain structural indices. Our results indicate that frontal SWA generation tracks inter-individual differences in continued structural brain re-organization during early adulthood. This stage of life is not only characterized by ongoing region-specific changes in myelin content, but also by a sharp decrease and a shift towards frontal predominance in SWA generation.

pyActigraphy: Open-source python package for actigraphy data visualization and analysis.

Over the past 40 years, actigraphy has been used to study rest-activity patterns in circadian rhythm and sleep research. Furthermore, considering its simplicity of use, there is a growing interest in the analysis of large population-based samples, using actigraphy. Here, we introduce pyActigraphy, a comprehensive toolbox for data visualization and analysis including multiple sleep detection algorithms and rest-activity rhythm variables. This open-source python package implements methods to read multiple data formats, quantify various properties of rest-activity rhythms, visualize sleep agendas, automatically detect rest periods and perform more advanced signal processing analyses. The development of this package aims to pave the way towards the establishment of a comprehensive open-source software suite, supported by a community of both developers and researchers, that would provide all the necessary tools for in-depth and large scale actigraphy data analyses.

Daytime rest: Association with 24-h rest-activity cycles, circadian timing and cognition in older adults.

Growing epidemiological evidence points toward an association between fragmented 24-h rest-activity cycles and cognition in the aged. Alterations in the circadian timing system might at least partially account for these observations. Here, we tested whether daytime rest (DTR) is associated with changes in concomitant 24-h rest probability profiles, circadian timing and neurobehavioural outcomes in healthy older adults. Sixty-three individuals (59-82 years) underwent field actigraphy monitoring, in-lab dim light melatonin onset assessment and an extensive cognitive test battery. Actimetry recordings were used to measure DTR frequency, duration and timing and to extract 24-h rest probability profiles. As expected, increasing DTR frequency was associated not only with higher rest probabilities during the day, but also with lower rest probabilities during the night, suggesting more fragmented night-time rest. Higher DTR frequency was also associated with lower episodic memory performance. Moreover, later DTR timing went along with an advanced circadian phase as well as with an altered phase angle of entrainment between the rest-activity cycle and circadian phase. Our results suggest that different DTR characteristics, as reflective indices of wake fragmentation, are not only underlined by functional consequences on cognition, but also by circadian alteration in the aged.

ENIGMA-Sleep: Challenges, opportunities, and the road map.

Neuroimaging and genetics studies have advanced our understanding of the neurobiology of sleep and its disorders. However, individual studies usually have limitations to identifying consistent and reproducible effects, including modest sample sizes, heterogeneous clinical characteristics and varied methodologies. These issues call for a large-scale multi-centre effort in sleep research, in order to increase the number of samples, and harmonize the methods of data collection, preprocessing and analysis using pre-registered well-established protocols. The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) consortium provides a powerful collaborative framework for combining datasets across individual sites. Recently, we have launched the ENIGMA-Sleep working group with the collaboration of several institutes from 15 countries to perform large-scale worldwide neuroimaging and genetics studies for better understanding the neurobiology of impaired sleep quality in population-based healthy individuals, the neural consequences of sleep deprivation, pathophysiology of sleep disorders, as well as neural correlates of sleep disturbances across various neuropsychiatric disorders. In this introductory review, we describe the details of our currently available datasets and our ongoing projects in the ENIGMA-Sleep group, and discuss both the potential challenges and opportunities of a collaborative initiative in sleep medicine.

Relationship between brain AD biomarkers and episodic memory performance in healthy aging.

The presence of brain biomarkers can be observed decades before the first clinical symptoms of Alzheimer's disease (AD). We aimed to determine whether associations between biomarkers and episodic memory performance already exist in a healthy late middle-aged population or only in participants over 60 years old. Performance at the Free and Cued Selective Reminding Test [FCSRT], the Logical Memory test and the Mnemonic Similarity Task [MST] was determined in sixty healthy participants (50-70 y.) with a negative status for amyloid-beta (Aß) biomarker. We assessed Aß cortical level and tau/neuroinflammation burden using PET scanner, and hippocampal atrophy with MRI scanner. Generalized linear mixed models showed that MST scores (recognition and pattern separation) were positively associated with hippocampal volume in participants over 60 years. No association between memory performance and Aß and tau/neuroinflammation burden was found in the older or in the younger age group. This suggests that visual recognition memory and discrimination of lures may constitute early cognitive markers of memory decline in an older population.

Blood polyunsaturated omega-3 fatty acids, brain atrophy, cognitive decline, and dementia risk.

INTRODUCTION: We searched for consistent associations of an omega-3 index in plasma (sum of eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) with several dementia-related outcomes in a large cohort of older adults. METHODS: We included 1279 participants from the Three-City study, non-demented at the time of blood measurements at baseline, with face-to-face neuropsychological assessment and systematic detection of incident dementia over a 17-year follow-up. An ancillary study included 467 participants with up to three repeated brain imaging exams over 10 years. RESULTS: In multivariable models, higher levels of plasma EPA+DHA were consistently associated with a lower risk of dementia (hazard ratio for 1 standard deviation = 0.87 [95% confidence interval, 0.76-0.98]), and a lower decline in global cognition (P = .04 for change over time), memory (P = .06), and medial temporal lobe volume (P = .02). DISCUSSION: This prospective study provides compelling evidence for a relationship between long-chain omega-3 fatty acids levels and lower risks for dementia and related outcomes.

Activity/rest cycle and disturbances of structural backbone of cerebral networks in aging.

OBJECTIVE: Although aging is associated with alterations of both activity/rest cycle and brain structure, few studies have evaluated associations between these processes. The aim of this study was to examine relationship between activity/rest cycle quality and brain structural integrity in aging subjects by exploring both grey and white matter compartments. MATERIAL AND METHODS: Fifty-eight elderly subjects (76±0.5 years; 41% female) without dementia, sleep disorders and medications were included in the analysis. Actigraphy was used to measure parameters of activity/rest cycle (24-h amplitude, 24-h fragmentation and 24-h stability) and sleep (total sleep time and sleep fragmentation) over a minimal period of 5 days. Whole brain linear regression analyses were performed on grey matter volumes maps using voxel based morphometry and on white matter integrity using tract based statistics analyses. RESULTS: A lower 24-h amplitude and a higher sleep fragmentation were independently associated with a reduction of white matter integrity in models including age and gender as covariates. The association between 24-h amplitude and white matter integrity decreased but remained significant in a model accounted for sleep fragmentation, indicating a specific effect of 24-h cycle disturbances. No association with grey matter volumes was observed. CONCLUSION: In elderly, not only sleep but also 24-h cycle disturbances were associated with altered structural connectivity. This alteration of structural backbone networks related to activity/rest cycle disturbances in aging might constitute a cerebral frailty factor for the development of cognitive impairment.

Circadian rapid eye movement sleep expression is associated with brain microstructural integrity in older adults.

Rapid eye movement sleep (REMS) is increasingly suggested as a discriminant sleep state for subtle signs of age-related neurodegeneration. While REMS expression is under strong circadian control and circadian dysregulation increases with age, the association between brain aging and circadian REMS regulation has not yet been assessed. Here, we measure the circadian amplitude of REMS through a 40-h in-lab multiple nap protocol in controlled laboratory conditions, and brain microstructural integrity with quantitative multi-parameter mapping (MPM) imaging in 86 older individuals. We show that reduced circadian REMS amplitude is related to lower magnetization transfer saturation (MTsat), longitudinal relaxation rate (R1) and effective transverse relaxation rate (R2*) values in several white matter regions mostly located around the lateral ventricles, and with lower R1 values in grey matter clusters encompassing the hippocampus, parahippocampus, thalamus and hypothalamus. Our results further highlight the importance of considering circadian regulation for understanding the association between sleep and brain structure in older individuals.

Night-to-night variability in sleep and amyloid beta burden in normal aging.

INTRODUCTION: Alzheimer's disease is associated with sleep disturbances and accumulation of cerebral amyloid beta. The objective was to examine whether actigraphy-detected sleep parameters might be biomarkers for early amyloid burden. METHODS: Participants underwent a week of actigraphy and an amyloid positron emission tomography (PET) scan. Sleep duration and continuity disruption (sleep fragmentation and nocturnal awakenings) were extracted and compared between amyloid-positive and amyloid-negative participants. Then multiple linear regressions were used between mean or night-to-night intra-individual variability (standard deviation) of sleep parameters and brain amyloid burden in a voxel-wise analysis. RESULTS: Eighty-six subjects were included (80.3 ± 5.4 years; 48.8% of women). Amyloid-positive participants had a higher variability of sleep fragmentation compared to amyloid-negative participants. This parameter was associated with a higher amyloid burden in the frontal and parietal regions, and in the precuneus, in the whole sample. DISCUSSION: This study highlights the relevance of using variability in sleep continuity as a potential biomarker of early amyloid pathogenesis.

Association between circadian sleep regulation and cortical gyrification in young and older adults.

The circadian system orchestrates sleep timing and structure and is altered with increasing age. Sleep propensity, and particularly REM sleep is under strong circadian control and has been suggested to play an important role in brain plasticity. In this exploratory study, we assessed whether surface-based brain morphometry indices are associated with circadian sleep regulation and whether this link changes with age. Twenty-nine healthy older (55-82 years; 16 men) and 28 young participants (20-32 years; 13 men) underwent both structural magnetic resonance imaging and a 40-h multiple nap protocol to extract sleep parameters over day and night time. Cortical thickness and gyrification indices were estimated from T1-weighted images acquired during a classical waking day. We observed that REM sleep was significantly modulated over the 24-h cycle in both age groups, with older adults exhibiting an overall reduction in REM sleep modulation compared to young individuals. Interestingly, when taking into account the observed overall age-related reduction in REM sleep throughout the circadian cycle, higher day-night differences in REM sleep were associated with increased cortical gyrification in the right inferior frontal and paracentral regions in older adults. Our results suggest that a more distinctive allocation of REM sleep over the 24-h cycle is associated with regional cortical gyrification in aging, and thereby point towards a protective role of circadian REM sleep regulation for age-related changes in brain organization.

Napping and circadian sleep-wake regulation during healthy aging.

STUDY OBJECTIVES: Daytime napping is frequently reported among the older population and has attracted increasing attention due to its association with multiple health conditions. Here, we tested whether napping in the aged is associated with altered circadian regulation of sleep, sleepiness and vigilance performance. METHODS: Sixty healthy older individuals (mean age: 69y., 39 women) were recruited with respect to their napping habits (30 nappers, 30 non-nappers). All participants underwent an in-lab 40-h multiple nap protocol (10 cycles of 80 mins of sleep opportunity alternating with 160 mins of wakefulness), preceded and followed by a baseline and recovery sleep period. Saliva samples for melatonin assessment, sleepiness and vigilance performance were collected during wakefulness and electrophysiological data were recorded to derive sleep parameters during scheduled sleep opportunities. RESULTS: The circadian amplitude of melatonin secretion was reduced in nappers, compared to non-nappers. Furthermore, nappers were characterized by higher sleep efficiencies and REM sleep proportion during day- compared to night-time naps. The nap group also presented altered modulation in sleepiness and vigilance performance at specific circadian phases. DISCUSSION: Our data indicate that napping is associated with an altered circadian sleep-wake propensity rhythm and thereby contribute to the understanding of the biological correlates underlying napping and/or sleep-wake cycle fragmentation during healthy aging. Altered circadian sleep-wake promotion can lead to a less distinct allocation of sleep into night-time and/or a reduced wakefulness drive during the day, thereby potentially triggering the need to sleep at adverse circadian phase.

Herpes simplex virus, early neuroimaging markers and incidence of Alzheimer's disease.

While previous studies suggest the implication of herpes simplex virus (HSV) in the onset of Alzheimer's disease (AD), no study has investigated its association with early neuroimaging markers of AD. In the Three-City and the AMI cohorts, the associations between HSV infection and (i) hippocampal volume (n = 349), (ii) white matter alterations in the parahippocampal cingulum and fornix using diffusion tensor imaging (n = 260), and (iii) incidence of AD (n = 1599) were assessed according to APOE4 status. Regardless of APOE4 status, infected subjects presented (i) significantly more microstructural alterations of the parahippocampal cingulum and fornix, (ii) lower hippocampal volumes only when their anti-HSV IgG level was in the highest tercile-reflecting possibly more frequent reactivations of the virus (p = 0.03 for subjects with a high anti-HSV IgG level while there was no association for all infected subjects, p = 0.19), and (iii) had no increased risk of developing AD. Nevertheless, among APOE4 carriers, infected subjects presented lower hippocampal volumes, although not significant (p = 0.09), and a two or three times higher risk of developing AD (adjusted Hazard ratio (aHR) = 2.72 [1.07-6.91] p = 0.04 for infected subjects and aHR = 3.87 [1.45-10.28] p = 0.007 for infected subjects with an anti-HSV IgG level in the highest tercile) while no association was found among APOE4 noncarriers. Our findings support an association between HSV infection and AD and a potential interaction between HSV status and APOE4. This reinforces the need to further investigate the infectious hypothesis of AD, especially the associated susceptibility factors and the possibility of preventive treatments.

Plasma carotenoids and medial temporal lobe atrophy in older adults.

BACKGROUND & AIMS: Carotenoids are vegetable pigments with neuroprotective properties. Clinical studies found efficacy of specific carotenoids on improving brain perfusion and functioning with aging. However, evidence of an effect on neurodegeneration, which may require longer follow-up period to observe, is more limited. Leveraging biomarkers from a large population-based cohort study of older adults, we investigated whether blood carotenoids were associated with atrophy of the medial temporal lobe (a biomarker of neurodegeneration in aging) over 10 years. METHODS: This study included 461 dementia-free participants from the Three-City Bordeaux study (aged ≥65) who had plasma carotenoids measured at baseline and up to three repeated brain imaging exams in the subsequent 10 years. RESULTS: In adjusted linear mixed models, each increase of 1 SD in plasma level of total carotenoids and of ß-carotene was associated with 0.02 cm3 (95% CI, 0.001-0.04; P = 0.04) and 0.02 cm3 (95% CI, 0.01-0.04; P = 0.008) smaller medial temporal lobe volume loss per year, respectively. CONCLUSIONS: Our results based on a unique long-term prospective evaluation of a neuroimaging biomarker suggest a beneficial role of carotenoids for the prevention of age-related neurodegeneration.

Changes Over Time of Diffusion MRI in the White Matter of Aging Brain, a Good Predictor of Verbal Recall.

Objective: Extensive research using water-diffusion MRI reported age-related modifications of cerebral White Matter (WM). Moreover, water-diffusion parameter modifications have been frequently associated with cognitive performances in the elderly sample, reinforcing the idea of aging inducing microstructural disconnection of the brain which in turn impacts cognition. However, only few studies really assessed over-time modifications of these parameters and their relationship with episodic memory outcome of elderly. Materials and Methods: One-hundred and thirty elderly subjects without dementia (74.1 ± 4.1 years; 47% female) were included in this study. Diffusion tensor imaging (DTI) was performed at two-time points (3.49 ± 0.68 years apart), allowing the assessment of changes in water-diffusion parameters over time using a specific longitudinal pipeline. White matter hyperintensity (WMH) burden and gray matter (GM) atrophy were also measured on FLAIR and T1-weighted sequences collected during these two MRI sessions. Free and cued verbal recall scores assessed at the last follow-up of the cohort were used as episodic memory outcome. Changes in water-diffusion parameters over time were included in serial linear regression models to predict retrieval or storage ability of elderly. Results: GM atrophy and an increase in mean diffusivity (MD) and WMH load between the two-time points were observed. The increase in MD was significantly correlated with WMH load and the different memory scores. In models accounting for the baseline cognitive score, GM atrophy, or WMH load, MD changes still significantly predict free verbal recall, and not total verbal recall, suggesting the specific association with the retrieval deficit in healthy aging. Conclusion: In elderly, microstructural WM changes are good predictors of lower free verbal recall performances. Moreover, this contribution is not only driven by WMH load increase. This last observation is in line with studies reporting early water-diffusion modification in WM tissue during aging, resulting lately in the appearance of WMH on conventional MRI.

Mood Influences the Concordance of Subjective and Objective Measures of Sleep Duration in Older Adults.

OBJECTIVE/BACKGROUND: Sleep plays a central role in maintaining health and cognition. In most epidemiologic studies, sleep is evaluated by self-report questionnaires but several reports suggest that these evaluations might be less accurate than objective measures such as polysomnography or actigraphy. Determinants of the discrepancy between objective and subjective measures remain to be investigated. The aim of this pilot-study was to examine the role of mood states in determining the discrepancy observed between objective and subjective measures of sleep duration in older adults. PATIENTS/METHODS: Objective sleep quantity and quality were recorded by actigraphy in a sample of 45 elderly subjects over at least three consecutive nights. Subjective sleep duration and supplementary data, such as mood status and memory, were evaluated using ecological momentary assessment (EMA). RESULTS: A significant discrepancy was observed between EMA and actigraphic measures of sleep duration (p < 0.001). The magnitude of this difference was explained by the patient's mood status (p = 0.020). No association was found between the magnitude of this discrepancy and age, sex, sleep quality or memory performance. CONCLUSION: The discrepancy classically observed between objective and subjective measures of sleep duration can be explained by mood status at the time of awakening. These results have potential implications for epidemiologic and clinical studies examining sleep as a risk factor for morbidity or mortality.