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.

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.

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).

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.

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.

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.

Imagetic and affective measures of memory reverberation diverge at sleep onset in association with theta rhythm.

The 'day residue' - the presence of waking memories into dreams - is a century-old concept that remains controversial in neuroscience. Even at the psychological level, it remains unclear how waking imagery cedes into dreams. Are visual and affective residues enhanced, modified, or erased at sleep onset? Are they linked, or dissociated? What are the neural correlates of these transformations? To address these questions we combined quantitative semantics, sleep EEG markers, visual stimulation, and multiple awakenings to investigate visual and affect residues in hypnagogic imagery at sleep onset. Healthy adults were repeatedly stimulated with an affective image, allowed to sleep and awoken seconds to minutes later, during waking (WK), N1 or N2 sleep stages. 'Image Residue' was objectively defined as the formal semantic similarity between oral reports describing the last image visualized before closing the eyes ('ground image'), and oral reports of subsequent visual imagery ('hypnagogic imagery). Similarly, 'Affect Residue' measured the proximity of affective valences between 'ground image' and 'hypnagogic imagery'. We then compared these grounded measures of two distinct aspects of the 'day residue', calculated within participants, to randomly generated values calculated across participants. The results show that Image Residue persisted throughout the transition to sleep, increasing during N1 in proportion to the time spent in this stage. In contrast, the Affect Residue was gradually neutralized as sleep progressed, decreasing in proportion to the time spent in N1 and reaching a minimum during N2. EEG power in the theta band (4.5-6.5 Hz) was inversely correlated with the Image Residue during N1. The results show that the visual and affective aspects of the 'day residue' in hypnagogic imagery diverge at sleep onset, possibly decoupling visual contents from strong negative emotions, in association with increased theta rhythm.

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.

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.

Variability of sleep stage scoring in late midlife and early old age.

Sleep stage scoring can lead to important inter-expert variability. Although likely, whether this issue is amplified in older populations, which show alterations of sleep electrophysiology, has not been thoroughly assessed. Algorithms for automatic sleep stage scoring may appear ideal to eliminate inter-expert variability. Yet, variability between human experts and algorithm sleep stage scoring in healthy older individuals has not been investigated. Here, we aimed to compare stage scoring of older individuals and hypothesized that variability, whether between experts or considering the algorithm, would be higher than usually reported in the literature. Twenty cognitively normal and healthy late midlife individuals' (61 ± 5 years; 10 women) night-time sleep recordings were scored by two experts from different research centres and one algorithm. We computed agreements for the entire night (percentage and Cohen's κ) and each sleep stage. Whole-night pairwise agreements were relatively low and ranged from 67% to 78% (κ, 0.54-0.67). Sensitivity across pairs of scorers proved lowest for stages N1 (8.2%-63.4%) and N3 (44.8%-99.3%). Significant differences between experts and/or algorithm were found for total sleep time, sleep efficiency, time spent in N1/N2/N3 and wake after sleep onset (p ≤ 0.005), but not for sleep onset latency, rapid eye movement (REM) and slow-wave sleep (SWS) duration (N2 + N3). Our results confirm high inter-expert variability in healthy aging. Consensus appears good for REM and SWS, considered as a whole. It seems more difficult for N3, potentially because human raters adapt their interpretation according to overall changes in sleep characteristics. Although the algorithm does not substantially reduce variability, it would favour time-efficient standardization.

Heterogeneity in the links between sleep arousals, amyloid-ß, and cognition.

BACKGROUNDTight relationships between sleep quality, cognition, and amyloid-ß (Aß) accumulation, a hallmark of Alzheimer's disease (AD) neuropathology, have been shown. Sleep arousals become more prevalent with aging and are considered to reflect poorer sleep quality. However, heterogeneity in arousals has been suggested while their associations with Aß and cognition are not established.METHODSWe recorded undisturbed night-time sleep with EEG in 101 healthy individuals aged 50-70 years, devoid of cognitive and sleep disorders. We classified spontaneous arousals according to their association with muscular tone increase (M+/M-) and sleep stage transition (T+/T-). We assessed cortical Aß burden over earliest affected regions via PET imaging and assessed cognition via neuropsychological testing.RESULTSArousal types differed in their oscillatory composition in θ (4-8 Hz) and ß (16-30 Hz) EEG bands. Furthermore, T+M- arousals, interrupting sleep continuity, were positively linked to Aß burden (P = 0.0053, R²ß* = 0.08). By contrast, more prevalent T-M+ arousals, upholding sleep continuity, were associated with lower Aß burden (P = 0.0003, R²ß* = 0.13), and better cognition, particularly over the attentional domain (P < 0.05, R²ß* ≥ 0.04).CONCLUSIONContrasting with what is commonly accepted, we provide empirical evidence that arousals are diverse and differently associated with early AD-related neuropathology and cognition. This suggests that sleep arousals, and their coalescence with other brain oscillations during sleep, may actively contribute to the beneficial functions of sleep and constitute markers of favorable brain and cognitive health trajectories.TRIAL REGISTRATIONEudraCT 2016-001436-35.FUNDINGFRS-FNRS Belgium (FRSM 3.4516.11), Actions de Recherche Concertées Fédération Wallonie-Bruxelles (SLEEPDEM 17/27-09), ULiège, and European Regional Development Fund (Radiomed Project).

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.

Associations Between Cognitive Complaints, Memory Performance, Mood, and Amyloid-ß Accumulation in Healthy Amyloid Negative Late-Midlife Individuals.

BACKGROUND: Cognitive complaints are gaining more attention as they may represent an early marker of increased risk for AD in individuals without objective decline at standard neuropsychological examination. OBJECTIVE: Our aim was to assess whether cognitive complaints in late middle-aged individuals not seeking medical help are related to objective cognitive outcomes known as early markers for AD risk, concomitant affective state, and amyloid-ß (Aß) burden. METHODS: Eighty-seven community-based cognitively normal individuals aged 50-69 years underwent neuropsychological assessment for global cognition, using Preclinical Alzheimer's Cognitive Composite 5 (PACC5) score, and a more specific episodic memory measure. Affective state was based on self-assessment questionnaires for depression and anxiety. Aß PET burden was assessed via [18F]Flutemetamol (N = 84) and [18F]Florbetapir (N = 3) uptake. Cognitive complaints were evaluated using Cognitive Difficulties Scale. RESULTS: Higher cognitive complaints were significantly associated with lower episodic memory performance and worse affective state. Moreover, higher level of cognitive complaints was related to higher (but still sub-clinical) global Aß accumulation (at uncorrected significance level). Importantly, all three aspects remained significant when taken together in the same statistical model, indicating that they explained distinct parts of variance. CONCLUSION: In healthy Aß negative late middle-aged individuals, a higher degree of cognitive complaints is associated with lower episodic memory efficiency, more anxiety and depression, as well as, potentially, with higher Aß burden, suggesting that complaints might signal subtle decline. Future studies should untangle how cognitive complaints in healthy aging populations are related to longitudinal changes in objective cognition and AD biomarker correlates.

Positive Effect of Cognitive Reserve on Episodic Memory, Executive and Attentional Functions Taking Into Account Amyloid-Beta, Tau, and Apolipoprotein E Status.

Studies exploring the simultaneous influence of several physiological and environmental factors on domain-specific cognition in late middle-age remain scarce. Therefore, our objective was to determine the respective contribution of modifiable risk/protective factors (cognitive reserve and allostatic load) on specific cognitive domains (episodic memory, executive functions, and attention), taking into account non-modifiable factors [sex, age, and genetic risk for Alzheimer's disease (AD)] and AD-related biomarker amount (amyloid-beta and tau/neuroinflammation) in a healthy late-middle-aged population. One hundred and one healthy participants (59.4 ± 5 years; 68 women) were evaluated for episodic memory, executive and attentional functioning via neuropsychological test battery. Cognitive reserve was determined by the National Adult Reading Test. The allostatic load consisted of measures of lipid metabolism and sympathetic nervous system functioning. The amyloid-beta level was assessed using positron emission tomography in all participants, whereas tau/neuroinflammation positron emission tomography scans and apolipoprotein E genotype were available for 58 participants. Higher cognitive reserve was the main correlate of better cognitive performance across all domains. Moreover, age was negatively associated with attentional functioning, whereas sex was a significant predictor for episodic memory, with women having better performance than men. Finally, our results did not show clear significant associations between performance over any cognitive domain and apolipoprotein E genotype and AD biomarkers. This suggests that domain-specific cognition in late healthy midlife is mainly determined by a combination of modifiable (cognitive reserve) and non-modifiable factors (sex and age) rather than by AD biomarkers and genetic risk for AD.