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.

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.

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.

Complexity and compositionality in fluid intelligence.

Compositionality, or the ability to build complex cognitive structures from simple parts, is fundamental to the power of the human mind. Here we relate this principle to the psychometric concept of fluid intelligence, traditionally measured with tests of complex reasoning. Following the principle of compositionality, we propose that the critical function in fluid intelligence is splitting a complex whole into simple, separately attended parts. To test this proposal, we modify traditional matrix reasoning problems to minimize requirements on information integration, working memory, and processing speed, creating problems that are trivial once effectively divided into parts. Performance remains poor in participants with low fluid intelligence, but is radically improved by problem layout that aids cognitive segmentation. In line with the principle of compositionality, we suggest that effective cognitive segmentation is important in all organized behavior, explaining the broad role of fluid intelligence in successful cognition.

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.

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).

Using quantitative magnetic resonance imaging to track cerebral alterations in multiple sclerosis brain: A longitudinal study.

INTRODUCTION: Quantitative MRI quantifies tissue microstructural properties and supports the characterization of cerebral tissue damages. With an MPM protocol, 4 parameter maps are constructed: MTsat, PD, R1 and R2*, reflecting tissue physical properties associated with iron and myelin contents. Thus, qMRI is a good candidate for in vivo monitoring of cerebral damage and repair mechanisms related to MS. Here, we used qMRI to investigate the longitudinal microstructural changes in MS brain. METHODS: Seventeen MS patients (age 25-65, 11 RRMS) were scanned on a 3T MRI, in two sessions separated with a median of 30 months, and the parameters evolution was evaluated within several tissue classes: NAWM, NACGM and NADGM, as well as focal WM lesions. An individual annual rate of change for each qMRI parameter was computed, and its correlation to clinical status was evaluated. For WM plaques, three areas were defined, and a GLMM tested the effect of area, time points, and their interaction on each median qMRI parameter value. RESULTS: Patients with a better clinical evolution, that is, clinically stable or improving state, showed positive annual rate of change in MTsat and R2* within NAWM and NACGM, suggesting repair mechanisms in terms of increased myelin content and/or axonal density as well as edema/inflammation resorption. When examining WM lesions, qMRI parameters within surrounding NAWM showed microstructural modifications, even before any focal lesion is visible on conventional FLAIR MRI. CONCLUSION: The results illustrate the benefit of multiple qMRI data in monitoring subtle changes within normal appearing brain tissues and plaque dynamics in relation with tissue repair or disease progression.

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).

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.

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.

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.

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.

Increased cortical excitability but stable effective connectivity index during attentional lapses.

Modern lifestyle curtails sleep and increases nighttime work and leisure activities. This has a deleterious impact on vigilance and attention, exacerbating chances of committing attentional lapses, with potential dramatic outcomes. Here, we investigated the brain signature of attentional lapses and assessed whether cortical excitability and brain response propagation were modified during lapses and whether these modifications changed with aging. We compared electroencephalogram (EEG) responses to transcranial magnetic stimulation (TMS) during lapse and no-lapse periods while performing a continuous attentional/vigilance task at night, after usual bedtime. Data were collected in healthy younger (N = 12; 18-30 years) and older individuals (N = 12; 50-70 years) of both sexes. The amplitude and slope of the first component of the TMS-evoked potential were larger during lapses. In contrast, TMS response scattering over the cortical surface, as well as EEG response complexity, did not significantly vary between lapse and no-lapse periods. Importantly, despite qualitative differences, age did not significantly affect any of the TMS-EEG measures. These results demonstrate that attentional lapses are associated with a transient increase of cortical excitability. This initial change is not associated with detectable changes in subsequent effective connectivity-as indexed by response propagation-and are not markedly different between younger and older adults. These findings could contribute to develop models aimed to predicting and preventing lapses in real-life situations.

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.

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.

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).

Early brainstem [18F]THK5351 uptake is linked to cortical hyperexcitability in healthy aging.

BACKGROUNDNeuronal hyperexcitability characterizes the early stages of Alzheimer's disease (AD). In animals, early misfolded tau and amyloid-ß (Aß) protein accumulation - both central to AD neuropathology - promote cortical excitability and neuronal network dysfunction. In healthy humans, misfolded tau and Aß aggregates are first detected, respectively, in the brainstem and frontomedial and temporobasal cortices, decades prior to the onset of AD cognitive symptoms. Whether cortical excitability is related to early brainstem tau - and its associated neuroinflammation - and cortical Aß aggregations remains unknown.METHODSWe probed frontal cortex excitability, using transcranial magnetic stimulation combined with electroencephalography, in a sample of 64 healthy late-middle-aged individuals (50-69 years; 45 women and 19 men). We assessed whole-brain [18F]THK5351 PET uptake as a proxy measure of tau/neuroinflammation, and we assessed whole-brain Aß burden with [18F]Flutemetamol or [18F]Florbetapir radiotracers.RESULTSWe found that higher [18F]THK5351 uptake in a brainstem monoaminergic compartment was associated with increased cortical excitability (r = 0.29, P = 0.02). By contrast, [18F]THK5351 PET signal in the hippocampal formation, although strongly correlated with brainstem signal in whole-brain voxel-based quantification analyses (P value corrected for family-wise error [PFWE-corrected] < 0.001), was not significantly associated with cortical excitability (r = 0.14, P = 0.25). Importantly, no significant association was found between early Aß cortical deposits and cortical excitability (r = -0.20, P = 0.11).CONCLUSIONThese findings reveal potential brain substrates for increased cortical excitability in preclinical AD and may constitute functional in vivo correlates of early brainstem tau accumulation and neuroinflammation in humans.TRIAL REGISTRATIONEudraCT 2016-001436-35.FUNDINGF.R.S.-FNRS Belgium, Wallonie-Bruxelles International, ULiège, Fondation Simone et Pierre Clerdent, European Regional Development Fund.

Alzheimer's disease genetic risk and sleep phenotypes in healthy young men: association with more slow waves and daytime sleepiness.

STUDY OBJECTIVES: Sleep disturbances and genetic variants have been identified as risk factors for Alzheimer's disease (AD). Our goal was to assess whether genome-wide polygenic risk scores (PRS) for AD associate with sleep phenotypes in young adults, decades before typical AD symptom onset. METHODS: We computed whole-genome PRS for AD and extensively phenotyped sleep under different sleep conditions, including baseline sleep, recovery sleep following sleep deprivation, and extended sleep opportunity, in a carefully selected homogenous sample of 363 healthy young men (22.1 years ± 2.7) devoid of sleep and cognitive disorders. RESULTS: AD PRS was associated with more slow-wave energy, that is, the cumulated power in the 0.5-4 Hz EEG band, a marker of sleep need, during habitual sleep and following sleep loss, and potentially with larger slow-wave sleep rebound following sleep deprivation. Furthermore, higher AD PRS was correlated with higher habitual daytime sleepiness. CONCLUSIONS: These results imply that sleep features may be associated with AD liability in young adults, when current AD biomarkers are typically negative, and support the notion that quantifying sleep alterations may be useful in assessing the risk for developing AD.

Validation of an Automatic Arousal Detection Algorithm for Whole-Night Sleep EEG Recordings.

Arousals during sleep are transient accelerations of the EEG signal, considered to reflect sleep perturbations associated with poorer sleep quality. They are typically detected by visual inspection, which is time consuming, subjective, and prevents good comparability across scorers, studies and research centres. We developed a fully automatic algorithm which aims at detecting artefact and arousal events in whole-night EEG recordings, based on time-frequency analysis with adapted thresholds derived from individual data. We ran an automated detection of arousals over 35 sleep EEG recordings in healthy young and older individuals and compared it against human visual detection from two research centres with the aim to evaluate the algorithm performance. Comparison across human scorers revealed a high variability in the number of detected arousals, which was always lower than the number detected automatically. Despite indexing more events, automatic detection showed high agreement with human detection as reflected by its correlation with human raters and very good Cohen's kappa values. Finally, the sex of participants and sleep stage did not influence performance, while age may impact automatic detection, depending on the human rater considered as gold standard. We propose our freely available algorithm as a reliable and time-sparing alternative to visual detection of arousals.