The evolution of subjective cognition after meditation training in older people: a secondary analysis of the three-arm age-well randomized controlled trial.

Aging is associated with cognitive changes, even in the absence of brain pathology. This study aimed to determine if meditation training, by comparison to active and passive control groups, is linked to changes in the perception of cognitive functioning in older adults. One hundred thirty-four healthy older participants from the Age-Well Randomized Clinical Trial were included: 45 followed a meditation training, 45 a non-native language training and 44 had no intervention. Subjective cognition was assessed at baseline and following the 18-month intervention period. Perception of attentional efficiency was assessed using internal and external Attentional Style Questionnaire (ASQ) subscale scores. Perception of global cognitive capacities was measured via the total score of Cognitive Difficulties Scale (CDS). Deltas ([posttest minus pretest scores]/standard deviation at pretest) were calculated for the analyses. Generalized mixed effects models controlling for age, sex, education and baseline scores revealed that meditation training decreased the vulnerability score toward external distractors measured by the ASQ compared to non-native language training. However, no between-groups differences on ASQ internal or CDS total scores were observed. Results suggest a beneficial effect of meditation practice on perceived management of external distracting information in daily life. Meditation training may cultivate the ability to focus on specific information (e.g., breath) and ignore stimulation from other kinds of stimuli (e.g., noise).

Brain age as a biomarker for pathological versus healthy ageing - a REMEMBER study.

OBJECTIVES: This study aimed to evaluate the potential clinical value of a new brain age prediction model as a single interpretable variable representing the condition of our brain. Among many clinical use cases, brain age could be a novel outcome measure to assess the preventive effect of life-style interventions. METHODS: The REMEMBER study population (N = 742) consisted of cognitively healthy (HC,N = 91), subjective cognitive decline (SCD,N = 65), mild cognitive impairment (MCI,N = 319) and AD dementia (ADD,N = 267) subjects. Automated brain volumetry of global, cortical, and subcortical brain structures computed by the CE-labeled and FDA-cleared software icobrain dm (dementia) was retrospectively extracted from T1-weighted MRI sequences that were acquired during clinical routine at participating memory clinics from the Belgian Dementia Council. The volumetric features, along with sex, were combined into a weighted sum using a linear model, and were used to predict 'brain age' and 'brain predicted age difference' (BPAD = brain age-chronological age) for every subject. RESULTS: MCI and ADD patients showed an increased brain age compared to their chronological age. Overall, brain age outperformed BPAD and chronological age in terms of classification accuracy across the AD spectrum. There was a weak-to-moderate correlation between total MMSE score and both brain age (r = -0.38,p < .001) and BPAD (r = -0.26,p < .001). Noticeable trends, but no significant correlations, were found between BPAD and incidence of conversion from MCI to ADD, nor between BPAD and conversion time from MCI to ADD. BPAD was increased in heavy alcohol drinkers compared to non-/sporadic (p = .014) and moderate (p = .040) drinkers. CONCLUSIONS: Brain age and associated BPAD have the potential to serve as indicators for, and to evaluate the impact of lifestyle modifications or interventions on, brain health.

Awareness and cognitive rehabilitation in Alzheimer's disease and frontotemporal dementia.

INTRODUCTION: Awareness influences the evolution of neurodegenerative dementias. We gathered participants' and caregivers assessments of dependence in daily activities and we studied how each score would be related to next year participant autonomy, independently of other explicative variables. METHOD: We retrospectively analyzed data from mildly demented participants with a clinical diagnosis of Alzheimer's disease (AD, n = 186) and frontotemporal dementia (FTD, n = 29) and their relatives. A research tool was used to assess participant dependence in 98 daily activities and associated caregiver burden. A discrepancy score between the patient's and relative's judgment was calculated to evaluate awareness of dependence in activities at baseline. This dependence scores, as well as sex, age, education, and 1 year difference in Mini-Mental State Examination were taken as possible explicative variables for dependence in activities adapted by therapists during a 1-year cognitive rehabilitation program. RESULTS: Patients with FTD showed less awareness for daily dependence (discrepancy 20.9% vs. 11.8% in AD). Both groups benefited from cognitive rehabilitation (25% decrease in dependence) and subjective burden of relatives was decreased in both groups. In the AD group, there was a significant positive relationship between both caregiver (P < 0.001) and participant's (P < 0.02) evaluation of dependence in daily activities at inclusion and dependence of participants in adapted activities after 1 year. DISCUSSION: Awareness of impairment in daily activities is a clinical symptom that is more important at inclusion in FTD than in AD. However, in participants with AD who, as a group, significantly benefit from a cognitive rehabilitation program, not only caregiver's but also participant's assessment of dependence at baseline is correlated to subsequent, next year greater dependence in daily activities adapted by the therapists. Although discrepant, both caregiver and participant evaluations appear to be important variables to understand the evolution and the benefit of care in participants at early stages of dementia.

Neural correlates of impaired cognitive processes underlying self-unawareness in Alzheimer's disease.

Self-unawareness concerning current symptoms remains a clinical challenge in Alzheimer's disease. Reduced self-awareness likely depends on complex biopsychosocial mechanisms that comprise multiple cognitive processes, regulated by personal goals and values. We specifically reviewed the cognitive processes impaired in unaware participants with AD by emphasizing the related impaired brain activity observed during task-based fMRI. Unawareness can be explained by a failure in functioning of or in connection between brain regions that intervene in access, retrieval and updating of (present or extended) self-information (posterior midline, medial temporal, inferior parietal cortices), or in its monitoring, evaluation, or control (medial and lateral prefrontal cortices). Although one must be cautious when relating function to brain regions, impaired processes were tentatively related to the Cognitive Awareness Model. Although brain function depends on neural networks, impaired brain activity during cognitive processes was discussed according to previous studies reporting correlations between brain regions and scores of anosognosia. The review provides a framework to help clinicians considering processes that can explain unawareness in dementia. In patients at early stages of AD, different levels of awareness of cognitive or social clinical changes might be described as impairment in the interaction between specific cognitive processes and contents.

Prediction of cognitive decline in healthy aging based on neuropsychiatric symptoms and PET-biomarkers of Alzheimer's disease.

Neuropsychiatric symptoms (NPS) have been associated with a risk of accelerated cognitive decline or conversion to dementia of the Alzheimer's Disease (AD) type. Moreover, the NPS were also associated with higher AD biomarkers (brain tau and amyloid burden) even in non-demented patients. But the effect of the relationship between NPS and biomarkers on cognitive decline has not yet been studied. This work aims to assess the relationship between longitudinal cognitive changes and NPS, specifically depression and anxiety, in association with AD biomarkers in healthy middle-aged to older participants. The cohort consisted of 101 healthy participants aged 50-70 years, 66 of whom had neuropsychological assessments of memory, executive functions, and global cognition at a 2-year follow-up. At baseline, NPS were assessed using the Beck Depression and Anxiety Inventories while brain tau and amyloid loads were measured using positron emission topography. For tau burden, THK5351 uptake is used as a proxy of tau and neuroinflammation. Participants, declining or remaining stable at follow-up, were categorized into groups for each cognitive domain. Group classification was investigated using binary logistic regressions based on combined AD biomarkers and the two NPS. The results showed that an association between anxiety and prefrontal amyloid burden significantly classified episodic memory decline, while the classification of global cognitive decline involved temporal and occipital amyloid burden but not NPS. Moreover, depression together with prefrontal and hippocampal tau burden were associated with a decline in memory. The classification of participants based on executive decline was related to depression and mainly prefrontal tau burden. These findings suggest that the combination of NPS and brain biomarkers of AD predicts the occurrence of cognitive decline in aging.

How Periodontitis or Periodontal Bacteria Can Influence Alzheimer's Disease Features? A Systematic Review of Pre-Clinical Studies.

BACKGROUND: The negative effects of periodontitis on systemic diseases, including diabetes, cardiovascular diseases, and Alzheimer's disease (AD), have been widely described. OBJECTIVE: This systematic review aimed to gather the current understanding of the pathophysiological mechanisms linking periodontitis to AD. METHODS: An electronic systematic search of the PubMed/MEDLINE, Scopus, and Embase databases was performed using the following PECO question: How can periodontitis or periodontal bacteria influence Alzheimer's disease features?". Only preclinical studies exploring the biological links between periodontitis and AD pathology were included. This study was registered at the International Prospective Register of Systematic Reviews (PROSPERO), and the Syrcle and Camarades protocols were used to assess the risk of bias. RESULTS: After a systematic screening of titles and abstracts (n = 3,307), thirty-six titles were selected for abstract reading, of which 13 were excluded (k = 1), resulting in the inclusion of 23 articles. Oral or systemic exposure to periodontopathogens or their byproducts is responsible for both in situ brain manifestations and systemic effects. Significant elevated rates of cytokines and amyloid peptides (Aß) and derivate products were found in both serum and brain. Additionally, in infected animals, hyperphosphorylation of tau protein, hippocampal microgliosis, and neuronal death were observed. Exposure to periodontal infection negatively impairs cognitive behavior, leading to memory decline. CONCLUSIONS: Systemic inflammation and brain metastatic infections induced by periodontal pathogens contribute to neuroinflammation, amyloidosis, and tau phosphorylation, leading to brain damage and subsequent cognitive impairment.

In vivo marker of brainstem myelin is associated to quantitative sleep parameters in healthy young men.

The regional integrity of brain subcortical structures has been implicated in sleep-wake regulation, however, their associations with sleep parameters remain largely unexplored. Here, we assessed association between quantitative Magnetic Resonance Imaging (qMRI)-derived marker of the myelin content of the brainstem and the variability in the sleep electrophysiology in a large sample of 18-to-31 years healthy young men (N = 321; ~ 22 years). Separate Generalized Additive Model for Location, Scale and Shape (GAMLSS) revealed that sleep onset latency and slow wave energy were significantly associated with MTsat estimates in the brainstem (pcorrected ≤ 0.03), with overall higher MTsat value associated with values reflecting better sleep quality. The association changed with age, however (MTsat-by-age interaction-pcorrected ≤ 0.03), with higher MTsat value linked to better values in the two sleep metrics in the younger individuals of our sample aged ~ 18 to 20 years. Similar associations were detected across different parts of the brainstem (pcorrected ≤ 0.03), suggesting that the overall maturation and integrity of the brainstem was associated with both sleep metrics. Our results suggest that myelination of the brainstem nuclei essential to regulation of sleep is associated with inter-individual differences in sleep characteristics during early adulthood. They may have implications for sleep disorders or neurological diseases related to myelin.

Locus coeruleus activity while awake is associated with REM sleep quality in older individuals.

BACKGROUNDThe locus coeruleus (LC) is the primary source of norepinephrine in the brain and regulates arousal and sleep. Animal research shows that it plays important roles in the transition between sleep and wakefulness, and between slow wave sleep and rapid eye movement sleep (REMS). It is unclear, however, whether the activity of the LC predicts sleep variability in humans.METHODSWe used 7-Tesla functional MRI, sleep electroencephalography (EEG), and a sleep questionnaire to test whether the LC activity during wakefulness was associated with sleep quality in 33 healthy younger (~22 years old; 28 women, 5 men) and 19 older (~61 years old; 14 women, 5 men) individuals.RESULTSWe found that, in older but not in younger participants, higher LC activity, as probed during an auditory attentional task, was associated with worse subjective sleep quality and with lower power over the EEG theta band during REMS. The results remained robust even when accounting for the age-related changes in the integrity of the LC.CONCLUSIONThese findings suggest that LC activity correlates with the perception of the sleep quality and an essential oscillatory mode of REMS, and we found that the LC may be an important target in the treatment of sleep- and age-related diseases.FUNDINGThis work was supported by Fonds National de la Recherche Scientifique (FRS-FNRS, T.0242.19 & J. 0222.20), Action de Recherche Concertée - Fédération Wallonie-Bruxelles (ARC SLEEPDEM 17/27-09), Fondation Recherche Alzheimer (SAO-FRA 2019/0025), ULiège, and European Regional Development Fund (Radiomed & Biomed-Hub).

Multimodal imaging of microstructural cerebral alterations and loss of synaptic density in Alzheimer's disease.

Multiple neuropathological events are involved in Alzheimer's disease (AD). The current study investigated the concurrence of neurodegeneration, increased iron content, atrophy, and demyelination in AD. Quantitative multiparameter magnetic resonance imaging (MRI) maps providing neuroimaging biomarkers for myelination and iron content along with synaptic density measurements using [18F] UCB-H PET were acquired in 24 AD and 19 Healthy controls (19 males). The whole brain voxel-wise group comparison revealed demyelination in the right hippocampus, while no significant iron content difference was detected. Bilateral atrophy and synaptic density loss were observed in the hippocampus and amygdala. The multivariate GLM (mGLM) analysis shows a bilateral difference in the hippocampus and amygdala, right pallidum, left fusiform and temporal lobe suggesting that these regions are the most affected despite the diverse differences in brain tissue properties in AD. Demyelination was identified as the most affecting factor in the observed differences. Here, the mGLM is introduced as an alternative for multiple comparisons between different modalities, reducing the risk of false positives while informing about the co-occurrence of neuropathological processes in AD.

Effects of Meditation Training and Non-Native Language Training on Cognition in Older Adults: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Nonpharmacological interventions are a potential strategy to maintain or promote cognitive functioning in older adults. Objective: To investigate the effects of 18 months' meditation training and 18 months' non-native language training on cognition in older adults. Design, Setting, and Participants: This study was a secondary analysis of the Age-Well trial, an 18-month, observer-masked, randomized clinical trial with 3 parallel arms. Eligible participants were community-dwelling adults aged 65 years and older residing in Caen, France. Participants were enrolled from November 24, 2016, to March 5, 2018, and randomly assigned (1:1:1) to meditation training, non-native language (English) training, or no intervention arms. Final follow-up was completed on February 6, 2020. Data were analyzed between December 2021 and November 2022. Interventions: The 18-month meditation and non-native language training interventions were structurally equivalent and included 2-hour weekly group sessions, daily home practice of 20 minutes or longer, and 1 day of more intensive home practice. The no intervention group was instructed not to change their habits and to continue living as usual. Main Outcomes and Measures: Cognition (a prespecified secondary outcome of the Age-Well trial) was assessed preintervention and postintervention via the Preclinical Alzheimer Cognitive Composite 5 (PACC5), and composites assessing episodic memory, executive function, and attention. Results: Among 137 randomized participants, 2 were excluded for not meeting eligibility criteria, leaving 135 (mean [SD] age, 69.3 [3.8] years; 83 female [61%]) eligible for analysis. One participant among the remaining 135 did not complete the trial. In adjusted mixed effects models, no interaction effects were observed between visit and group for PACC5 (F2,131.39 = 2.58; P = .08), episodic memory (F2,131.60 = 2.34; P = .10), executive function (F2,131.26 = 0.89; P = .41), or attention (F2,131.20 = 0.34; P = .79). Results remained substantively unchanged across sensitivity and exploratory analyses. Conclusions and Relevance: In this secondary analysis of an 18-month randomized trial, meditation and non-native language training did not confer salutary cognitive effects. Although further analyses are needed to explore the effects of these interventions on other relevant outcomes related to aging and well-being, these findings did not support the use of these interventions for enhancing cognition in cognitively healthy older adults. Trial Registration: ClinicalTrials.gov Identifier: NCT02977819.

Perirhinal cortex is associated with fine-grained discrimination of conceptually confusable objects in Alzheimer's disease.

The perirhinal cortex (PrC) stands among the first brain areas to deteriorate in Alzheimer's disease (AD). This study tests to what extent the PrC is involved in representing and discriminating confusable objects based on the conjunction of their perceptual and conceptual features. To this aim, AD patients and control counterparts performed 3 tasks: a naming, a recognition memory, and a conceptual matching task, where we manipulated conceptual and perceptual confusability. A structural MRI of the antero-lateral parahippocampal subregions was obtained for each participant. We found that the sensitivity to conceptual confusability was associated with the left PrC volume in both AD patients and control participants for the recognition memory task, while it was specifically associated with the volume of the left PrC in AD patients for the conceptual matching task. This suggests that a decreased volume of the PrC is related to the ability to disambiguate conceptually confusable items. Therefore, testing recognition memory or conceptual matching of easily conceptually confusable items can provide a potential cognitive marker of PrC atrophy.

Hippocampal metabolic subregions and networks: Behavioral, molecular, and pathological aging profiles.

INTRODUCTION: Hippocampal local and network dysfunction is the hallmark of Alzheimer's disease (AD). METHODS: We characterized the spatial patterns of hippocampus differentiation based on brain co-metabolism in healthy elderly participants and demonstrated their relevance to study local metabolic changes and associated dysfunction in pathological aging. RESULTS: The hippocampus can be differentiated into anterior/posterior and dorsal cornu ammonis (CA)/ventral (subiculum) subregions. While anterior/posterior CA show co-metabolism with different regions of the subcortical limbic networks, the anterior/posterior subiculum are parts of cortical networks supporting object-centered memory and higher cognitive demands, respectively. Both networks show relationships with the spatial patterns of gene expression pertaining to cell energy metabolism and AD's process. Finally, while local metabolism is generally lower in posterior regions, the anterior-posterior imbalance is maximal in late mild cognitive impairment with the anterior subiculum being relatively preserved. DISCUSSION: Future studies should consider bidimensional hippocampal differentiation and in particular the posterior subicular region to better understand pathological aging.

In vivo Locus Coeruleus activity while awake is associated with REM sleep quality in healthy older individuals.

The locus coeruleus (LC) is the primary source of norepinephrine (NE) in the brain, and the LC-NE system is involved in regulating arousal and sleep. It plays key roles in the transition between sleep and wakefulness, and between slow wave sleep (SWS) and rapid eye movement sleep (REMS). However, it is not clear whether the LC activity during the day predicts sleep quality and sleep properties during the night, and how this varies as a function of age. Here, we used 7 Tesla functional Magnetic Resonance Imaging (7T fMRI), sleep electroencephalography (EEG) and a sleep questionnaire to test whether the LC activity during wakefulness was associated with sleep quality in 52 healthy younger (N=33; ~22y; 28 women) and older (N=19; ~61y; 14 women) individuals. We find that, in older, but not in younger participants, higher LC activity, as probed during an auditory mismatch negativity task, is associated with worse subjective sleep quality and with lower power over the EEG theta band during REMS (4-8Hz), which are two sleep parameters significantly correlated in our sample of older individuals. The results remain robust even when accounting for the age-related changes in the integrity of the LC. These findings suggest that the activity of the LC may contribute to the perception of the sleep quality and to an essential oscillatory mode of REMS, and that the LC may be an important target in the treatment of sleep disorders and age-related diseases.

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.

Effort during prolonged wakefulness is associated with performance to attentional and executive tasks but not with cortical excitability in late-middle-aged healthy individuals.

OBJECTIVE: Sleep loss negatively affects brain function with repercussion not only on objective measures of performance but also on many subjective dimensions, including effort perceived for the completion of cognitive processes. This may be particularly important in aging, which is accompanied by important changes in sleep and wakefulness regulation. We aimed to determine whether subjectively perceived effort covaried with cognitive performance in healthy late-middle-aged individuals. METHOD: We assessed effort and performance to cognitive tasks in 99 healthy adults (66 women; 50-70 years) during a 20-hr wake extension protocol, following 7 days of regular sleep and wake times and a baseline night of sleep in the laboratory. We further explored links with cortical excitability using transcranial magnetic stimulation coupled to electroencephalography. RESULTS: Perceived effort increased during wake extension and was highly correlated to subjective metrics of sleepiness, fatigue, and motivation, but not to variations in cortical excitability. Moreover, effort increase was associated with decreased performance to some cognitive tasks (psychomotor vigilance and two-back working memory task). Importantly, effort variations during wakefulness extension decreased from age 50 to 70 years, while more effort is associated with worse performance in older individuals. CONCLUSION: In healthy late-middle-aged individuals, more effort is perceived to perform cognitive tasks, but it is not sufficient to overcome the performance decline brought by lack of sleep. Entry in the seventh decade may stand as a turning point in the daily variations of perceived effort and its link with cognition. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Genetic risk for insomnia is associated with objective sleep measures in young and healthy good sleepers.

Insomnia disorder (ID) is the second most common neuropsychiatric disorder. Its socioeconomic burden is enormous while diagnosis and treatment are difficult. A novel approach that reveals associations between insomnia genetic propensity and sleep phenotypes in youth may help understand the core of the disease isolated from comorbidities and pave the way for new treatments. We obtained quantitative nocturnal sleep electroencephalogram (EEG) features in 456 participants (18-31y, 49 women). Sleep EEG was recorded during a baseline night following at least 7 days of regular sleep times. We then assessed daytime sleep onset latency in a subsample of N = 359 men exposed to manipulations affecting sleep pressure. We sampled saliva or blood for polygenic risk score (PRS) determination. The PRS for ID was computed based on genome-wide common single nucleotide polymorphism assessments. Participants also completed a battery of behavioral and cognitive tests. The analyses revealed that the PRS for ID was negatively associated with cumulated EEG power in the delta (0.5-4 Hz) and theta (4-8 Hz) bands across rapid eye movement (REM) and non-REM sleep (p ≤ .0026; ß ≥ -0.13) controlling for age, sex and BMI. The PRS for ID was also negatively associated with daytime likelihood of falling asleep (ß = -0.19, p = .0009). Other explorations for associations with non-baseline-nights, cognitive measures, and mood did not yield significant results. These results propose that the need or the ability to fall asleep and to generate slow brain activity during sleep may constitute the core sleep-related risk factors for developing ID.

Effects of a mindfulness-based versus a health self-management intervention on objective cognitive performance in older adults with subjective cognitive decline (SCD): a secondary analysis of the SCD-Well randomized controlled trial.

BACKGROUND: Older individuals with subjective cognitive decline (SCD) perceive that their cognition has declined but do not show objective impairment on neuropsychological tests. Individuals with SCD are at elevated risk of objective cognitive decline and incident dementia. Non-pharmacological interventions (including mindfulness-based and health self-management approaches) are a potential strategy to maintain or improve cognition in SCD, which may ultimately reduce dementia risk. METHODS: This study utilized data from the SCD-Well randomized controlled trial. One hundred forty-seven older adults with SCD (MAge = 72.7 years; 64% female) were recruited from memory clinics in four European countries and randomized to one of two group-based, 8-week interventions: a Caring Mindfulness-based Approach for Seniors (CMBAS) or a health self-management program (HSMP). Participants were assessed at baseline, post-intervention (week 8), and at 6-month follow-up (week 24) using a range of cognitive tests. From these tests, three composites were derived-an "abridged" Preclinical Alzheimer's Cognitive Composite 5 (PACC5Abridged), an attention composite, and an executive function composite. Both per-protocol and intention-to-treat analyses were performed. Linear mixed models evaluated the change in outcomes between and within arms and adjusted for covariates and cognitive retest effects. Sensitivity models repeated the per-protocol analyses for participants who attended ≥ 4 intervention sessions. RESULTS: Across all cognitive composites, there were no significant time-by-trial arm interactions and no measurable cognitive retest effects; sensitivity analyses supported these results. Improvements, however, were observed within both trial arms on the PACC5Abridged from baseline to follow-up (Δ [95% confidence interval]: CMBAS = 0.34 [0.19, 0.48]; HSMP = 0.30 [0.15, 0.44]). There was weaker evidence of an improvement in attention but no effects on executive function. CONCLUSIONS: Two non-pharmacological interventions conferred small, non-differing improvements to a global cognitive composite sensitive to amyloid-beta-related decline. There was weaker evidence of an effect on attention, and no evidence of an effect on executive function. Importantly, observed improvements were maintained beyond the end of the interventions. Improving cognition is an important step toward dementia prevention, and future research is needed to delineate the mechanisms of action of these interventions and to utilize clinical endpoints (i.e., progression to mild cognitive impairment or dementia). TRIAL REGISTRATION: ClinicalTrials.gov, NCT03005652.

Frontal grey matter microstructure is associated with sleep slow waves characteristics in late midlife.

STUDY OBJECTIVES: The ability to generate slow waves (SW) during non-rapid eye movement (NREM) sleep decreases as early as the 5th decade of life, predominantly over frontal regions. This decrease may concern prominently SW characterized by a fast switch from hyperpolarized to depolarized, or down-to-up, state. Yet, the relationship between these fast and slow switcher SW and cerebral microstructure in ageing is not established. METHODS: We recorded habitual sleep under EEG in 99 healthy late midlife individuals (mean age = 59.3 ± 5.3 years; 68 women) and extracted SW parameters (density, amplitude, frequency) for all SW as well as according to their switcher type (slow vs. fast). We further used neurite orientation dispersion and density imaging (NODDI) to assess microstructural integrity over a frontal grey matter region of interest (ROI). RESULTS: In statistical models adjusted for age, sex, and sleep duration, we found that a lower SW density, particularly for fast switcher SW, was associated with a reduced orientation dispersion of neurites in the frontal ROI (p = 0.018, R2ß* = 0.06). In addition, overall SW frequency was positively associated with neurite density (p = 0.03, R2ß* = 0.05). By contrast, we found no significant relationships between SW amplitude and NODDI metrics. CONCLUSIONS: Our findings suggest that the complexity of neurite organization contributes specifically to the rate of fast switcher SW occurrence in healthy middle-aged individuals, corroborating slow and fast switcher SW as distinct types of SW. They further suggest that the density of frontal neurites plays a key role for neural synchronization during sleep. TRIAL REGISTRATION NUMBER: EudraCT 2016-001436-35.

Timely coupling of sleep spindles and slow waves linked to early amyloid-ß burden and predicts memory decline.

Sleep alteration is a hallmark of ageing and emerges as a risk factor for Alzheimer's disease (AD). While the fine-tuned coalescence of sleep microstructure elements may influence age-related cognitive trajectories, its association with AD processes is not fully established. Here, we investigated whether the coupling of spindles and slow waves (SW) is associated with early amyloid-ß (Aß) brain burden, a hallmark of AD neuropathology, and cognitive change over 2 years in 100 healthy individuals in late-midlife (50-70 years; 68 women). We found that, in contrast to other sleep metrics, earlier occurrence of spindles on slow-depolarisation SW is associated with higher medial prefrontal cortex Aß burden (p=0.014, r²ß*=0.06) and is predictive of greater longitudinal memory decline in a large subsample (p=0.032, r²ß*=0.07, N=66). These findings unravel early links between sleep, AD-related processes, and cognition and suggest that altered coupling of sleep microstructure elements, key to its mnesic function, contributes to poorer brain and cognitive trajectories in ageing.