Different heart rate variability profile during sleep in mid-later life adults with remitted early-onset versus late-onset depression.

BACKGROUND: In mid-later life adults, early-onset and late-onset (i.e., onset ≥50 years) depression appear to be underpinned by different pathophysiology yet have not been examined in relation to autonomic function. Sleep provides an opportunity to examine the autonomic nervous system as the physiology changes across the night. Hence, we aimed to explore if autonomic profile is altered in mid-later life adults with remitted early-onset, late-onset and no history of lifetime depression. METHODS: Participants aged 50-90 years (n = 188) from a specialised clinic underwent a comprehensive clinical assessment and completed an overnight polysomnography study. General Linear Models were used to examine the heart rate variability differences among the three groups for four distinct sleep stages and the wake after sleep onset. All analyses controlled for potential confounders - age, sex, current depressive symptoms and antidepressant usage. RESULTS: For the wake after sleep onset, mid-later life adults with remitted early-onset depression had reduced standard deviation of Normal to Normal intervals (SDNN; p = .014, d = -0.64) and Shannon Entropy (p = .004, d = -0.46,) than those with no history of lifetime depression. Further, the late-onset group showed a reduction in high-frequency heart rate variability (HFn.u.) during non-rapid eye movement sleep stage 2 (N2; p = .005, d = -0.53) and non-rapid eye movement sleep stage 3 (N3; p = .009, d = -0.55) when compared to those with no lifetime history. LIMITATIONS: Causality between heart rate variability and depression cannot be derived in this cross-sectional study. Longitudinal studies are needed to examine the effects remitted depressive episodes on autonomic function. CONCLUSION: The findings suggest differential autonomic profile for remitted early-onset and late-onset mid-later life adults during sleep stages and wake periods. The differences could potentially serve as peripheral biomarkers in conjunction with more disease-specific markers of depression to improve diagnosis and prognosis.

The AUstralian multidomain Approach to Reduce dementia Risk by prOtecting brain health With lifestyle intervention study (AU-ARROW): A study protocol for a single-blind, multi-site, randomized controlled trial.

INTRODUCTION: The Finnish Geriatric Intervention Study (FINGER) led to the global dementia risk reduction initiative: World-Wide FINGERS (WW-FINGERS). As part of WW-FINGERS, the Australian AU-ARROW study mirrors aspects of FINGER, as well as US-POINTER. METHOD: AU-ARROW is a randomized, single-blind, multisite, 2-year clinical trial (n = 600; aged 55-79). The multimodal lifestyle intervention group will engage in aerobic exercise, resistance training and stretching, dietary advice to encourage MIND diet adherence, BrainHQ cognitive training, and medical monitoring and health education. The Health Education and Coaching group will receive occasional health education sessions. The primary outcome measure is the change in a global composite cognitive score. Extra value will emanate from blood biomarker analysis, positron emission tomography (PET) imaging, brain magnetic resonance imaging (MRI), and retinal biomarker tests. DISCUSSION: The finalized AU-ARROW protocol is expected to allow development of an evidence-based innovative treatment plan to reduce cognitive decline and dementia risk, and effective transfer of research outcomes into Australian health policy. Highlights: Study protocol for a single-blind, randomized controlled trial, the AU-ARROW Study.The AU-ARROW Study is a member of the World-Wide FINGERS (WW-FINGERS) initiative.AU-ARROW's primary outcome measure is change in a global composite cognitive score.Extra significance from amyloid PET imaging, brain MRI, and retinal biomarker tests.Leading to development of an innovative treatment plan to reduce cognitive decline.

A novel method for PET connectomics guided by fibre-tracking MRI: Application to Alzheimer's disease.

This study introduces a novel brain connectome matrix, track-weighted PET connectivity (twPC) matrix, which combines positron emission tomography (PET) and diffusion magnetic resonance imaging data to compute a PET-weighted connectome at the individual subject level. The new method is applied to characterise connectivity changes in the Alzheimer's disease (AD) continuum. The proposed twPC samples PET tracer uptake guided by the underlying white matter fibre-tracking streamline point-to-point connectivity calculated from diffusion MRI (dMRI). Using tau-PET, dMRI and T1-weighted MRI from the Alzheimer's Disease Neuroimaging Initiative database, structural connectivity (SC) and twPC matrices were computed and analysed using the network-based statistic (NBS) technique to examine topological alterations in early mild cognitive impairment (MCI), late MCI and AD participants. Correlation analysis was also performed to explore the coupling between SC and twPC. The NBS analysis revealed progressive topological alterations in both SC and twPC as cognitive decline progressed along the continuum. Compared to healthy controls, networks with decreased SC were identified in late MCI and AD, and networks with increased twPC were identified in early MCI, late MCI and AD. The altered network topologies were mostly different between twPC and SC, although with several common edges largely involving the bilateral hippocampus, fusiform gyrus and entorhinal cortex. Negative correlations were observed between twPC and SC across all subject groups, although displaying an overall reduction in the strength of anti-correlation with disease progression. twPC provides a new means for analysing subject-specific PET and MRI-derived information within a hybrid connectome using established network analysis methods, providing valuable insights into the relationship between structural connections and molecular distributions. PRACTITIONER POINTS: New method is proposed to compute patient-specific PET connectome guided by MRI fibre-tracking. Track-weighted PET connectivity (twPC) matrix allows to leverage PET and structural connectivity information. twPC was applied to dementia, to characterise the PET nework abnormalities in Alzheimer's disease and mild cognitive impairment.

EEG slowing during REM sleep in older adults with subjective cognitive impairment and mild cognitive impairment.

STUDY OBJECTIVES: In older adults with Alzheimer's disease, slowing of electroencephalographic (EEG) activity during REM sleep has been observed. Few studies have examined EEG slowing during REM in those with mild cognitive impairment (MCI) and none have examined its relationship with cognition in this at-risk population. METHODS: 210 older adults (mean age = 67.0, sd = 8.2 years) underwent comprehensive neuropsychological, medical, and psychiatric assessment and overnight polysomnography. Participants were classified as subjective cognitive impairment (SCI; n=75), non-amnestic MCI (naMCI, n=85), and amnestic MCI (aMCI, n=50). REM EEG slowing was defined as (delta + theta) / (alpha + sigma + beta) power and calculated for frontal, central, parietal, and occipital regions. Analysis of variance compared REM EEG slowing between groups. Correlations between REM EEG slowing and cognition, including learning and memory, visuospatial and executive functions, were examined within each subgroup. RESULTS: The aMCI group had significantly greater REM EEG slowing in the parietal and occipital regions compared to the naMCI and SCI groups (partial η2 = 0.06, p<0.05 and 0.06, p<0.05, respectively), and greater EEG slowing in the central region compared to SCI group (partial η2 = 0.03, p<0.05). Greater REM EEG slowing in parietal (r = -0.49) and occipital regions (r = -0.38 (O1/M2) and -0.33 (O2/M1) were associated with poorer visuospatial performance in naMCI. CONCLUSION: REM EEG slowing may differentiate older adults with memory impairment from those without. Longitudinal studies are now warranted to examine the prognostic utility of REM EEG slowing for cognitive and dementia trajectories.

Recent advances in understanding of sleep disorders and disturbances for dementia risk and prevention.

PURPOSE OF REVIEW: To synthesise the recent work examining the relationship between sleep disturbances and dementia, emphasising studies involving individuals with mild cognitive impairment (MCI) or Alzheimer's disease (AD) and/or those investigating AD biomarkers. Additionally, we provide an update on recent interventions targeting sleep-related issues in older adults with MCI or AD. RECENT FINDINGS: Various studies have examined obstructive sleep apnoea, sleep duration, and circadian alterations in relation to Alzheimer's pathology and dementia risk, with an emerging body of evidence suggesting that cardiovascular disease, hypertension, glymphatic function, and inflammation might serve as plausible pathophysiological mechanisms contributing to dementia during critical brain periods. Conversely, recent studies investigating insomnia have produced disparate results. Regarding intervention studies, the scarcity of prospective randomised control trials poses a challenge in establishing the benefits of addressing sleep disorders and disturbances. SUMMARY: Recent work examining the pathophysiological links between sleep and dementia is strongest for obstructive sleep apnoea and sleep duration, while findings in insomnia studies exhibit inconsistency, possibly due to varied associations with dementia among different insomnia subtypes. It is apparent that more longitudinal studies examining the underlying pathophysiological mechanisms are necessary, alongside more rigorous clinical trials. Although some trials are underway in this field, there is still scarcity in trials examining interventions for circadian disturbances.

Predicting neurodegeneration from sleep related biofluid changes.

Sleep-wake disturbances are common in neurodegenerative diseases and may occur years before the clinical diagnosis, potentially either representing an early stage of the disease itself or acting as a pathophysiological driver. Therefore, discovering biomarkers that identify individuals with sleep-wake disturbances who are at risk of developing neurodegenerative diseases will allow early diagnosis and intervention. Given the association between sleep and neurodegeneration, the most frequently analyzed fluid biomarkers in people with sleep-wake disturbances to date include those directly associated with neurodegeneration itself, such as neurofilament light chain, phosphorylated tau, amyloid-beta and alpha-synuclein. Abnormalities in these biomarkers in patients with sleep-wake disturbances are considered as evidence of an underlying neurodegenerative process. Levels of hormonal sleep-related biomarkers such as melatonin, cortisol and orexin are often abnormal in patients with clinical neurodegenerative diseases, but their relationships with the more standard neurodegenerative biomarkers remain unclear. Similarly, it is unclear whether other chronobiological/circadian biomarkers, such as disrupted clock gene expression, are causal factors or a consequence of neurodegeneration. Current data would suggest that a combination of fluid biomarkers may identify sleep-wake disturbances that are most predictive for the risk of developing neurodegenerative disease with more optimal sensitivity and specificity.

REducing Sleep Apnoea for the PrEvention of Dementia (REShAPED): Protocol for a multi-site feasibility randomised controlled trial.

There is accumulating evidence that has linked OSA with increased risk of cognitive decline and dementia. Here we present the protocol for an Australian, multi-site randomised controlled, parallel open-label trial which will evaluate the feasibility for a full-scale trial investigating the effects of treating OSA on cognitive decline in older adults at risk of dementia within memory clinic settings. We will randomise 180 older adults to either the treatment intervention group or control group for 2 years. Inclusion criteria include: 50-85 years; mild-severe OSA (defined average ODI ≥ 10 with 3% oxygen desaturation determined by wrist oximetry over two nights); and subjective cognitive complaints or mild cognitive impairment. The treatment intervention arm aims to achieve an optimal treatment response based on reducing hypoxic burden with either CPAP, mandibular advancement splint, positional therapy, or oxygen therapy. Furthermore, participants will receive up to 8 sessions which involve motivational interviewing, collaborative goal setting, and behavioural sleep management. The control arm will not receive OSA treatment as part of this trial, however there will be no OSA treatment restrictions, and any treatment will be documented. Primary outcomes are 1) acceptability based upon willingness of participants to be randomised; 2) alleviating hypoxic burden by reducing OSA severity; 3) tolerability of the trial burden based upon collection of outcomes over the 2-year follow-up. Secondary outcomes include safety and cognitive function. Outcomes will be collected at 0, 6 and 24-months. This feasibility study aims to will provide the basis for a larger longer-term trial of dementia prevention.

Assessing sleep architecture and cognition in older adults with depressive symptoms attending a memory clinic.

BACKGROUND: While depression is intrinsically and bidirectionally linked with both sleep disturbance and cognition, the inter-relationships between sleep, cognition, and brain integrity in older people with depression, especially those with late-onset depression are undefined. METHODS: One hundred and seventy-two older adults (mean age 64.3 ± 6.9 years, Depression: n = 66, Control: n = 106) attending a memory clinic underwent a neuropsychological battery of declarative memory, executive function tasks, cerebral magnetic resonance imaging and overnight polysomnography with quantitative electroencephalography. RESULTS: The time spent in slow-wave sleep (SWS) and rapid eye movement (REM) sleep, slow-wave activity, sleep spindles, hippocampal volume and prefrontal cortex thickness did not differ between depression and control and depression onset groups. However, sleep onset latency (p = 0.005) and REM onset latency (p = 0.02) were later in the Depression group compared to controls. Less SWS was associated with poorer memory (r = 0.31, p = 0.023) in the depression group, and less SWS was related to better memory in the control group (r = -0.20, p = 0.043; Fishers r-to-z = -3.19). LIMITATIONS: Longitudinal studies are needed to determine if changes in sleep in those with depressive symptoms predict cognitive decline and illness trajectory. CONCLUSION: Older participants with depressive symptoms had delayed sleep initiation, suggestive of delayed sleep phase. The association between SWS and memory suggests SWS may be a useful target for cognitive intervention in older adults with depression symptoms. Reduced hippocampal volumes did not mediate this relationship, indicating a broader distributed neural network may underpin these associations.

Sleep spindle architecture associated with distinct clinical phenotypes in older adults at risk for dementia.

Sleep spindles are a hallmark of non-REM sleep and play a fundamental role in memory consolidation. Alterations in these spindles are emerging as sensitive biomarkers for neurodegenerative diseases of ageing. Understanding the clinical presentations associated with spindle alterations may help to elucidate the functional role of these distinct electroencephalographic oscillations and the pathophysiology of sleep and neurodegenerative disorders. Here, we use a data-driven approach to examine the sleep, memory and default mode network connectivity phenotypes associated with sleep spindle architecture in older adults (mean age = 66 years). Participants were recruited from a specialist clinic for early diagnosis and intervention for cognitive decline, with a proportion showing mild cognitive deficits on neuropsychological testing. In a sample of 88 people who underwent memory assessment, overnight polysomnography and resting-state fMRI, a k-means cluster analysis was applied to spindle measures of interest: fast spindle density, spindle duration and spindle amplitude. This resulted in three clusters, characterised by preserved spindle architecture with higher fast spindle density and longer spindle duration (Cluster 1), and alterations in spindle architecture (Clusters 2 and 3). These clusters were further characterised by reduced memory (Clusters 2 and 3) and nocturnal hypoxemia, associated with sleep apnea (Cluster 3). Resting-state fMRI analysis confirmed that default mode connectivity was related to spindle architecture, although directionality of this relationship differed across the cluster groups. Together, these results confirm a diversity in spindle architecture in older adults, associated with clinically meaningful phenotypes, including memory function and sleep apnea. They suggest that resting-state default mode connectivity during the awake state can be associated with sleep spindle architecture; however, this is highly dependent on clinical phenotype. Establishing relationships between clinical and neuroimaging features and sleep spindle alterations will advance our understanding of the bidirectional relationships between sleep changes and neurodegenerative diseases of ageing.

Tackling Dementia Together via The Australian Dementia Network (ADNeT): A Summary of Initiatives, Progress and Plans.

In 2018, the Australian Dementia Network (ADNeT) was established to bring together Australia's leading dementia researchers, people with living experience and clinicians to transform research and clinical care in the field. To address dementia diagnosis, treatment, and care, ADNeT has established three core initiatives: the Clinical Quality Registry (CQR), Memory Clinics, and Screening for Trials. Collectively, the initiatives have developed an integrated clinical and research community, driving practice excellence in this field, leading to novel innovations in diagnostics, clinical care, professional development, quality and harmonization of healthcare, clinical trials, and translation of research into practice. Australia now has a national Registry for Mild Cognitive Impairment and dementia with 55 participating clinical sites, an extensive map of memory clinic services, national Memory and Cognition Clinic Guidelines and specialized screening for trials sites in five states. This paper provides an overview of ADNeT's achievements to date and future directions. With the increase in dementia cases expected over coming decades, and with recent advances in plasma biomarkers and amyloid lowering therapies, the nationally coordinated initiatives and partnerships ADNeT has established are critical for increased national prevention efforts, co-ordinated implementation of emerging treatments for Alzheimer's disease, innovation of early and accurate diagnosis, driving continuous improvements in clinical care and patient outcome and access to post-diagnostic support and clinical trials. For a heterogenous disorder such as dementia, which is now the second leading cause of death in Australia following cardiovascular disease, the case for adequate investment into research and development has grown even more compelling.

STAREE-Mind Imaging Study: a randomised placebo-controlled trial of atorvastatin for prevention of cerebrovascular decline and neurodegeneration in older individuals.

Introduction: Cerebrovascular disease and neurodegeneration are causes of cognitive decline and dementia, for which primary prevention options are currently lacking. Statins are well-tolerated and widely available medications that potentially have neuroprotective effects. The STAREE-Mind Imaging Study is a randomised, double-blind, placebo-controlled clinical trial that will investigate the impact of atorvastatin on markers of neurovascular health and brain atrophy in a healthy, older population using MRI. This is a nested substudy of the 'Statins for Reducing Events in the Elderly' (STAREE) primary prevention trial. Methods: Participants aged 70 years or older (n=340) will be randomised to atorvastatin or placebo. Comprehensive brain MRI assessment will be undertaken at baseline and up to 4 years follow-up, including structural, diffusion, perfusion and susceptibility imaging. The primary outcome measures will be change in brain free water fraction (a composite marker of vascular leakage, neuroinflammation and neurodegeneration) and white matter hyperintensity volume (small vessel disease). Secondary outcomes will include change in perivascular space volume (glymphatic drainage), cortical thickness, hippocampal volume, microbleeds and lacunae, prefrontal cerebral perfusion and white matter microstructure. Ethics and dissemination: Academic publications from this work will address the current uncertainty regarding the impact of statins on brain structure and vascular integrity. This study will inform the utility of repurposing these well-tolerated, inexpensive and widely available drugs for primary prevention of neurological outcomes in older individuals. Ethics approval was given by Monash University Human Research Ethics Committee, Protocol 12206. Trial registration number: ClinicalTrials.gov Identifier: NCT05586750.

Isolated rapid eye movement sleep behaviour disorder (iRBD) in the Island Study Linking Ageing and Neurodegenerative Disease (ISLAND) Sleep Study: protocol and baseline characteristics.

Isolated rapid eye movement (REM) sleep behaviour disorder (iRBD) is a sleep disorder that is characterised by dream enactment episodes during REM sleep. It is the strongest known predictor of α-synuclein-related neurodegenerative disease (αNDD), such that >80% of people with iRBD will eventually develop Parkinson's disease, dementia with Lewy bodies, or multiple system atrophy in later life. More research is needed to understand the trajectory of phenoconversion to each αNDD. Only five 'gold standard' prevalence studies of iRBD in older adults have been undertaken previously, with estimates ranging from 0.74% to 2.01%. The diagnostic recommendations for video-polysomnography (vPSG) to confirm iRBD makes prevalence studies challenging, as vPSG is often unavailable to large cohorts. In Australia, there have been no iRBD prevalence studies, and little is known about the cognitive and motor profiles of Australian people with iRBD. The Island Study Linking Ageing and Neurodegenerative Disease (ISLAND) Sleep Study will investigate the prevalence of iRBD in Tasmania, an island state of Australia, using validated questionnaires and home-based vPSG. It will also explore several cognitive, motor, olfactory, autonomic, visual, tactile, and sleep profiles in people with iRBD to better understand which characteristics influence the progression of iRBD to αNDD. This paper details the ISLAND Sleep Study protocol and presents preliminary baseline results.

Neuronal connected burst cascades bridge macroscale adaptive signatures across arousal states.

The human brain displays a rich repertoire of states that emerge from the microscopic interactions of cortical and subcortical neurons. Difficulties inherent within large-scale simultaneous neuronal recording limit our ability to link biophysical processes at the microscale to emergent macroscopic brain states. Here we introduce a microscale biophysical network model of layer-5 pyramidal neurons that display graded coarse-sampled dynamics matching those observed in macroscale electrophysiological recordings from macaques and humans. We invert our model to identify the neuronal spike and burst dynamics that differentiate unconscious, dreaming, and awake arousal states and provide insights into their functional signatures. We further show that neuromodulatory arousal can mediate different modes of neuronal dynamics around a low-dimensional energy landscape, which in turn changes the response of the model to external stimuli. Our results highlight the promise of multiscale modelling to bridge theories of consciousness across spatiotemporal scales.

Digital Application of Clinical Staging to Support Stratification in Youth Mental Health Services: Validity and Reliability Study.

BACKGROUND: As the demand for youth mental health care continues to rise, managing wait times and reducing treatment delays are key challenges to delivering timely and quality care. Clinical staging is a heuristic model for youth mental health that can stratify care allocation according to individuals' risk of illness progression. The application of staging has been traditionally limited to trained clinicians yet leveraging digital technologies to apply clinical staging could increase the scalability and usability of this model in services. OBJECTIVE: The aim of this study was to validate a digital algorithm to accurately differentiate young people at lower and higher risk of developing mental disorders. METHODS: We conducted a study with a cohort comprising 131 young people, aged between 16 and 25 years, who presented to youth mental health services in Australia between November 2018 and March 2021. Expert psychiatrists independently assigned clinical stages (either stage 1a or stage 1b+), which were then compared to the digital algorithm's allocation based on a multidimensional self-report questionnaire. RESULTS: Of the 131 participants, the mean age was 20.3 (SD 2.4) years, and 72% (94/131) of them were female. Ninety-one percent of clinical stage ratings were concordant between the digital algorithm and the experts' ratings, with a substantial interrater agreement (κ=0.67; P<.001). The algorithm demonstrated an accuracy of 91% (95% CI 86%-95%; P=.03), a sensitivity of 80%, a specificity of 93%, and an F1-score of 73%. Of the concordant ratings, 16 young people were allocated to stage 1a, while 103 were assigned to stage 1b+. Among the 12 discordant cases, the digital algorithm allocated a lower stage (stage 1a) to 8 participants compared to the experts. These individuals had significantly milder symptoms of depression (P<.001) and anxiety (P<.001) compared to those with concordant stage 1b+ ratings. CONCLUSIONS: This novel digital algorithm is sufficiently robust to be used as an adjunctive decision support tool to stratify care and assist with demand management in youth mental health services. This work could transform care pathways and expedite care allocation for those in the early stages of common anxiety and depressive disorders. Between 11% and 27% of young people seeking care may benefit from low-intensity, self-directed, or brief interventions. Findings from this study suggest the possibility of redirecting clinical capacity to focus on individuals in stage 1b+ for further assessment and intervention.

Region-specific changes in brain activity and memory after continuous positive airway pressure therapy in obstructive sleep apnea: a pilot high-density electroencephalography study.

STUDY OBJECTIVES: Limited channel electroencephalography (EEG) investigations in obstructive sleep apnea (OSA) have revealed deficits in slow wave activity (SWA) and spindles during sleep and increased EEG slowing during resting wakefulness. High-density EEG (Hd-EEG) has also detected local parietal deficits in SWA (delta power) during NREM. It is unclear whether effective continuous positive airway pressure (CPAP) treatment reverses regional SWA deficits, and other regional sleep and wake EEG abnormalities, and whether any recovery relates to improved overnight memory consolidation. METHODS: A clinical sample of men with moderate-severe OSA underwent sleep and resting wake recordings with 256-channel Hd-EEG before and after 3 months of CPAP. Declarative and procedural memory tasks were administered pre- and post-sleep. Topographical spectral power maps and differences between baseline and treatment were compared using t-tests and statistical nonparametric mapping (SnPM). RESULTS: In 11 compliant CPAP users (5.2 ±â€…1.1 hours/night), total sleep time did not differ after CPAP but N1 and N2 sleep were lower and N3 was higher. Centro-parietal gamma power during N3 increased and fronto-central slow spindle activity during N2 decreased (SnPM < 0.05). No other significant differences in EEG power were observed. When averaged specifically within the parietal region, N3 delta power increased after CPAP (p = 0.0029) and was correlated with the change in overnight procedural memory consolidation (rho = 0.79, p = 0.03). During resting wakefulness, there were trends for reduced delta and theta power. CONCLUSIONS: Effective CPAP treatment of OSA may correct regional EEG abnormalities, and regional recovery of SWA may relate to procedural memory improvements in the short term.

Pilot Randomized, Double-Blind, Placebo-Controlled Crossover Trial Evaluating the Feasibility of an Intranasal Oxytocin in Improving Social Cognition in Individuals Living with Alzheimer's Disease.

Background: Individuals living with Alzheimer's disease (AD) demonstrate extensive deficits in social cognition. To date, no studies have investigated the feasibility of an intranasal oxytocin (INOT) treatment to improve social cognition in individuals living with AD. Objective: We conducted a pilot trial to determine recruitment feasibility, enrolment acceptability, and adherence to an INOT treatment to inform on the subsequent design of a future randomized controlled trial (RCT). We also estimated the effect sizes of potential social cognitive function outcome measures related to participants and their caregivers. Methods: Four individuals with AD were enrolled in a single-center, randomized, double-blind, placebo-controlled crossover trial involving a one-week treatment period with both INOT (72 IU twice daily) and placebo. Results: All participants reported no treatment-causative or serious adverse events following repeated INOT administration. While enrolment acceptability (100%) and INOT adherence (placebo, 95%; INOT, 98%) were excellent, feasibility of recruitment was not acceptable (i.e., n = 4/58 individuals screened met inclusion criteria). However, positive/large effects were associated with secondary outcomes of self-reported health and wellbeing, caregiver 'burden', intimacy and interpersonal-bonding, following repeated INOT administration. No positive effects were associated with participant outcomes of social cognition. Conclusion: This pilot RCT provides first evidence that INOT administration in individuals living with AD is safe and well-tolerated. Despite limitations in sample size, moderate-to-large effect size improvements were identified in participant health outcomes as well as core social cognitive functions and 'burden' as reported by a caregiver. This suggests potential broad-ranging beneficial effects of INOT which should be assessed in future RCTs.

Knowledge, Attitudes, and Behaviours Concerning the Mediterranean Diet Among Older Adults in Australia.

Despite the growing body of evidence demonstrating the positive health effects of the Mediterranean diet, it is not routinely recommended in practice and adherence is low in the general population in Australia. The knowledge-attitude-behaviour model explains how health behaviours are supported through a process of acquiring knowledge, developing attitudes, and forming behaviours. Evidence has suggested that having a high level of nutrition-related knowledge is associated with more positive attitudes, which is directly linked to positive dietary behaviours. However, reports of knowledge and attitudes towards the Mediterranean diet, and how these directly relate to behaviours in older adults, are lacking. This study explored Mediterranean diet-related knowledge, attitudes, and behaviours among community-dwelling older adults in Australia. Participants were adults aged 55 years and older who completed an online survey that contained three parts: (a) knowledge - Mediterranean Diet Nutrition Knowledge Questionnaire (Med-NKQ); (b) nutrition-related attitudes and behaviours, and barriers and enablers to dietary change; (c) demographics. The sample included 61 adults who ranged in age from 55 to 89 years. The overall knowledge score was 30.5 out of a possible 40 points, with 60.7% classified as having a high level of knowledge. Knowledge was lowest for nutrient content and label reading. Attitudes and behaviours were generally positive and were not associated with level of knowledge. The most common barriers to dietary change were perceived cost and lack of knowledge, and motivational factors. There are a number of key gaps in knowledge that should be addressed through targeted educational programs. Strategies and tools to overcome perceived barriers and improve self-efficacy are needed to facilitate positive dietary behaviours.

Heart rate variability during slow wave sleep is linked to functional connectivity in the central autonomic network.

Reduced heart rate variability can be an early sign of autonomic dysfunction in neurodegenerative diseases and may be related to brain dysfunction in the central autonomic network. As yet, such autonomic dysfunction has not been examined during sleep-which is an ideal physiological state to study brain-heart interaction as both the central and peripheral nervous systems behave differently compared to during wakefulness. Therefore, the primary aim of the current study was to examine whether heart rate variability during nocturnal sleep, specifically slow wave (deep) sleep, is associated with central autonomic network functional connectivity in older adults 'at-risk' of dementia. Older adults (n = 78; age range = 50-88 years; 64% female) attending a memory clinic for cognitive concerns underwent resting-state functional magnetic resonance imaging and an overnight polysomnography. From these, central autonomic network functional connectivity strength and heart rate variability data during sleep were derived, respectively. High-frequency heart rate variability was extracted to index parasympathetic activity during distinct periods of sleep, including slow wave sleep as well as secondary outcomes of non-rapid eye movement sleep, wake after sleep onset, and rapid eye movement sleep. General linear models were used to examine associations between central autonomic network functional connectivity and high-frequency heart rate variability. Analyses revealed that increased high-frequency heart rate variability during slow wave sleep was associated with stronger functional connectivity (F = 3.98, P = 0.022) in two core brain regions within the central autonomic network, the right anterior insular and posterior midcingulate cortex, as well as stronger functional connectivity (F = 6.21, P = 0.005) between broader central autonomic network brain regions-the right amygdala with three sub-nuclei of the thalamus. There were no significant associations between high-frequency heart rate variability and central autonomic network connectivity during wake after sleep onset or rapid eye movement sleep. These findings show that in older adults 'at-risk' of dementia, parasympathetic regulation during slow wave sleep is uniquely linked to differential functional connectivity within both core and broader central autonomic network brain regions. It is possible that dysfunctional brain-heart interactions manifest primarily during this specific period of sleep known for its role in memory and metabolic clearance. Further studies elucidating the pathophysiology and directionality of this relationship should be conducted to determine if heart rate variability drives neurodegeneration, or if brain degeneration within the central autonomic network promotes aberrant heart rate variability.

Overnight declarative memory consolidation and non-rapid eye movement sleep electroencephalographic oscillations in older adults with obstructive sleep apnea.

STUDY OBJECTIVES: To compare overnight declarative memory consolidation and non-rapid eye movement (NREM) sleep electroencephalogram (EEG) oscillations in older adults with obstructive sleep apnea (OSA) to a control group and assess slow-wave activity (SWA) and sleep spindles as correlates of memory consolidation. METHODS: Forty-six older adults (24 without OSA and 22 with OSA) completed a word-pair associate's declarative memory task before and after polysomnography. Recall and recognition were expressed as a percentage of the morning relative to evening scores. Power spectral analysis was performed on EEG recorded at frontal (F3-M2, F4-M1) and central (C3-M2, C4-M1) sites. We calculated NREM absolute slow oscillation (0.25-1 Hz) and delta (0.5-4.5 Hz) EEG power, and slow (11-13 Hz) spindle density (number of events per minute of N2 sleep) and fast (13-16 Hz) spindle density. RESULTS: There were no significant differences in overnight recall and recognition between OSA (mean age 58.7 ± 7.1 years, apnea-hypopnea index (AHI) 41.9 ± 29.7 events/hour) and non-OSA (age 61.1 ± 10.3 years, AHI 6.6 ± 4.2 events/hour) groups. The OSA group had lower fast spindle density in the frontal region (p = 0.007). No between-group differences in SWA were observed. In the Control group, overnight recognition positively correlated with slow spindle density in frontal (rho = 0.555, p = 0.020) and central regions (rho = 0.490, p = 0.046). Overnight recall was not related to SWA or spindle measures in either group. CONCLUSIONS: Older adults with OSA had deficits in fast sleep spindles but showed preserved overnight declarative memory consolidation. It is possible that compensatory mechanisms are being recruited by OSA patients to preserve declarative memory consolidation despite the presence of sleep spindle deficits.

The relationship between midlife dyslipidemia and lifetime incidence of dementia: A systematic review and meta-analysis of cohort studies.

Introduction: We conducted a systematic review and meta-analysis to review the relationship between midlife dyslipidemia and lifetime incident dementia. Methods: The databases Medline, Embase, Scopus, Web of Science, and Cochrane were searched from inception to February 20, 2022. Longitudinal studies examining the relationship between midlife lipid levels on dementia, dementia subtypes, and/or cognitive impairment were pooled using inverse-variance weighted random-effects meta-analysis. Results: Seventeen studies (1.2 million participants) were included. Midlife hypercholesterolemia was associated with increased incidence of mild cognitive impairment (effect size [ES] = 2.01; 95% confidence interval [CI] 1.19 to 2.84; I2 = 0.0%) and all-cause dementia (ES = 1.14; 95% CI: 1.07 to 1.21; I2 = 0.0%). Each 1 mmol/L increase in low-density lipoprotein was associated with an 8% increase (ES = 1.08, 95% CI: 1.03 to 1.14; I2 = 0.3%) in incidence of all-cause dementia. Discussion: Midlife dyslipidemia is associated with an increased risk of cognitive impairment in later life.