Blood-Based Transcriptomic Biomarkers Are Predictive of Neurodegeneration Rather Than Alzheimer's Disease.

Alzheimer's disease (AD) is a growing global health crisis affecting millions and incurring substantial economic costs. However, clinical diagnosis remains challenging, with misdiagnoses and underdiagnoses being prevalent. There is an increased focus on putative, blood-based biomarkers that may be useful for the diagnosis as well as early detection of AD. In the present study, we used an unbiased combination of machine learning and functional network analyses to identify blood gene biomarker candidates in AD. Using supervised machine learning, we also determined whether these candidates were indeed unique to AD or whether they were indicative of other neurodegenerative diseases, such as Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Our analyses showed that genes involved in spliceosome assembly, RNA binding, transcription, protein synthesis, mitoribosomes, and NADH dehydrogenase were the best-performing genes for identifying AD patients relative to cognitively healthy controls. This transcriptomic signature, however, was not unique to AD, and subsequent machine learning showed that this signature could also predict PD and ALS relative to controls without neurodegenerative disease. Combined, our results suggest that mRNA from whole blood can indeed be used to screen for patients with neurodegeneration but may be less effective in diagnosing the specific neurodegenerative disease.

Safety of higher doses of melatonin in adults: A systematic review and meta-analysis.

Melatonin is commonly used for sleep and jetlag at low doses. However, there is less documentation on the safety of higher doses, which are being increasingly used for a wide variety of conditions, including more recently COVID-19 prevention and treatment. The aim of this review was to investigate the safety of higher doses of melatonin in adults. Medline, Scopus, Embase and PsycINFO databases from inception until December 2019 with convenience searches until October 2020. Randomised controlled trials investigating high-dose melatonin (≥10 mg) in human adults over 30 years of age were included. Two investigators independently abstracted articles using PRISMA guidelines. Risk of bias was assessed by a committee of three investigators. 79 studies were identified with a total of 3861 participants. Studies included a large range of medical conditions. The meta-analysis was pooled data using a random effects model. The outcomes examined were the number of adverse events (AEs), serious adverse events (SAEs) and withdrawals due to AEs. A total of 29 studies (37%) made no mention of the presence or absence of AEs. Overall, only four studies met the pre-specified low risk of bias criteria for meta-analysis. In that small subset, melatonin did not cause a detectable increase in SAEs (Rate Ratio = 0.88 [0.52, 1.50], p = .64) or withdrawals due to AEs (0.93 [0.24, 3.56], p = .92), but did appear to increase the risk of AEs such as drowsiness, headache and dizziness (1.40 [1.15, 1.69], p < .001). Overall, there has been limited AE reporting from high-dose melatonin studies. Based on this limited evidence, melatonin appears to have a good safety profile. Better safety reporting in future long-term trials is needed to confirm this as our confidence limits were very wide due to the paucity of suitable data.

Obesity and Oxidative Stress in Older Adults At Risk for Dementia: A Magnetic Resonance Spectroscopy Study.

OBJECTIVE: This study aimed to investigate the relationship between obesity and oxidative stress in older adults at risk for dementia. It also aimed to explore the influence of physical activity on the relationship between obesity and oxidative stress in this at risk cohort. METHODS: Older adults at risk for dementia underwent comprehensive medical, neuropsychological, and psychiatric assessment. At risk was defined as participants with subjective or mild cognitive impairment. Glutathione was assessed by magnetic resonance spectroscopy in the left hippocampus and the anterior and posterior cingulate cortex. Body mass index (BMI) was calculated and classified as healthy (BMI <25 kg/m2) or overweight/obese (BMI ≥25 kg/m2). RESULTS: Sixty-five older adults (mean age=66.2 y) were included for analysis. The overweight/obese group had significantly greater glutathione in the hippocampus compared with the healthy weight group (t=-2.76, P=0.008). No significant difference in glutathione was observed between groups in the anterior or posterior cingulate. In the overweight/obese group, a higher BMI was associated with a diabetes diagnosis and lower total time engaging in physical activity (r=-0.36, P=0.025), however, glutathione did not correlate with activity levels across groups. CONCLUSION: This study demonstrates that changes in in vivo markers of oxidative stress are present in overweight/obese older adults at risk for dementia. Future research should explore the relationship with diabetes and the longitudinal relationship between BMI and oxidative stress, and response to therapeutic interventions.

Structural brain correlates of obstructive sleep apnoea in older adults at risk for dementia.

This study aimed to investigate associations between obstructive sleep apnoea (OSA) and cortical thickness in older adults with subjective and objective cognitive difficulties, who are considered "at-risk" for dementia.83 middle-aged to older adults (51-88 years) underwent neuropsychological testing, polysomnography assessment of OSA and a structural magnetic resonance imaging brain scan. A principal components analysis was performed on OSA measures. Cortical thickness and subcortical volumes were compared to extracted components of "oxygen desaturation" and "sleep disturbance".Oxygen desaturation was significantly related to reduced cortical thickness in the bilateral temporal lobes (left: r=-0.44, p<0.001; right: r=-0.39, p=0.003). Conversely, sleep disturbance was associated with increased thickness in the right postcentral gyrus (r=0.48, p<0.001), pericalcarine (r=0.50, p=0.005) and pars opercularis (r=0.46, p=0.009) and increased volume of the hippocampus and amygdala. Decreased thickness in the bilateral temporal regions was associated with reduced verbal encoding (r=0.28, p=0.010).Given the clinical significance of this sample in terms of dementia prevention, these changes in grey matter reveal how OSA might contribute to neurodegenerative processes in older adults.

In vivo imaging of oxidative stress and fronto-limbic white matter integrity in young adults with mood disorders.

Fronto-limbic connectivity is compromised in mood disorders, as reflected by impairments in white matter (WM) integrity revealed by diffusion tensor imaging. Although the underlying mechanisms remain unclear, disruption to normal myelination due to oxidative stress is thought to play a key role. We aimed to determine whether fronto-limbic WM integrity is compromised, and associated with in vivo antioxidant levels (indexed by glutathione; GSH), in young adults with unipolar depression (DEP) and bipolar (BD) disorders. Ninety-four patients with DEP, 76 with BD and 59 healthy controls (18-30 years) underwent diffusion tensor and proton magnetic resonance spectroscopy imaging. Fractional anisotropy (FA) was calculated from the cingulum bundle (cingulate, hippocampus), fornix, stria terminalis (ST) and uncinate fasciculus tracts. GSH concentration was measured in anterior cingulate cortex (ACC) and hippocampus (HIPP). Compared to controls, DEP showed significantly reduced FA in ST, whereas BD did not significantly differ in FA across the five tracts. There were significant positive correlations between ST-FA and HIPP-GSH across groups. Regression analysis revealed that having DEP or BD and reduced HIPP-GSH were significantly associated with reduced ST-FA. Similarly, decreased ST-FA was associated with poorer neuropsychological performance in conjunction with having DEP. Our findings suggest a structural disconnectivity specific to the limbic region of young adults with DEP. Decreased WM integrity was associated with depleted levels of hippocampal GSH suggesting that this particular disruption may be linked to oxidative stress at early stages of illness. Young adults with BD do not have the same degree of impairment.

Association between Sleep Disordered Breathing and Nighttime Driving Performance in Mild Cognitive Impairment.

OBJECTIVES: The effect of sleep disordered breathing (SDB) on driving performance in older adults has not been extensively investigated, especially in those with mild cognitive impairment (MCI). The aim of this study was to examine the relationship between severity measures of SDB and a simulated driving task in older adults with and without MCI. METHODS: Nineteen older adults (age ≥50) meeting criteria for MCI and 23 age-matched cognitively intact controls underwent neuropsychological assessment and a driving simulator task in the evening before a diagnostic sleep study. RESULTS: There were no differences in driving simulator performance or SDB severity between the two groups. In patients with MCI, a higher oxygen desaturation index (ODI) was associated with an increased number of crashes on the simulator task, as well as other driving parameters such as steering and speed deviation. Poorer driving performance was also associated with poorer executive functioning (set-shifting) but the relationship between ODI and crashes was independent of executive ability. CONCLUSIONS: While driving ability did not differ between older adults with and without MCI, oxygen saturation dips in MCI were related to worse driving performance. These results suggest that decreased brain integrity may render those with SDB particularly vulnerable to driving accidents. In older adults, both cognition and SDB need to be considered concurrently in relation to driving ability. (JINS, 2017, 23, 502-510).

Napping in older people 'at risk' of dementia: relationships with depression, cognition, medical burden and sleep quality.

Sleep disturbance is prevalent in older adults, particularly so in those at a greater risk of dementia. However, so far the clinical, medical and neuropsychological correlates of daytime sleep have not been examined. The aims of this study were to investigate the characteristics and effects of napping using actigraphy in older people, particularly in those 'at risk' of dementia. The study used actigraphy and sleep diaries to measure napping habits in 133 older adults 'at risk' of dementia (mean age = 65.5 years, SD = 8.4 years), who also underwent comprehensive medical, psychiatric and neuropsychological assessment. When defined by actigraphy, napping was present in 83.5% (111/133) of participants; however, duration and timing varied significantly among subjects. Nappers had significantly greater medical burden and body mass index, and higher rates of mild cognitive impairment. Longer and more frequent naps were associated with poorer cognitive functioning, as well as higher levels of depressive symptoms, while the timing of naps was associated with poorer nocturnal sleep quality (i.e. sleep latency and wake after sleep onset). This study highlights that in older adults 'at risk' of dementia, napping is associated with underlying neurobiological changes such as depression and cognition. Napping characteristics should be more routinely monitored in older individuals to elucidate their relationship with psychological and cognitive outcomes.

Mild Cognitive Impairment Subtypes in Older People With Depressive Symptoms: Relationship With Clinical Variables and Hippocampal Change.

AIMS: To examine the rates and clinical characteristics of mild cognitive impairment (MCI) in older people with depressive symptoms and to determine the relative contribution of hippocampal volume and MCI to memory change. METHOD: One hundred and fifty-two participants with lifetime Major Depression and remitted or mild symptoms and 28 healthy controls underwent psychiatric and neuropsychological assessments. Magnetic resonance imaging was also conducted in a subset of the patients (n = 81) and healthy controls (n = 18). RESULTS: MCI was diagnosed in 75.7% of the patients and was associated with increasing age, medical burden, vascular risk factors, later age of depression onset and smaller hippocampi. Multiple regression showed that both hippocampal volume and MCI diagnosis mediate memory performance in depression. CONCLUSIONS: MCI occurs in older adults with a history of depression and is not simply due to symptom severity. Memory change is linked to underlying hippocampal atrophy in this patient group.

Cognitive impairment with and without depression history: an analysis of white matter microstructure.

BACKGROUND: Mild cognitive impairment (MCI) and late-life depression are clinical syndromes that often co-occur and may represent an early manifestation of neurodegenerative disease. The present study examined white matter microstructure in patients with MCI with and without a history of major depression compared with healthy controls. METHODS: Older adults with MCI and no history of major depression (MCI), adults with MCI and euthymic major depression (MCI-MD) and healthy controls underwent comprehensive medical, psychiatric and neuropsychological assessments. Participants also underwent diffusion tensor imaging, which was analyzed using tract-based spatial statistics. White matter hyperintensity (WMH) burden and medical burden were also quantified. RESULTS: We enrolled 30 participants in the MCI group, 36 in the MCI-MD group and 22 in the control group. Compared with controls, participants in the MCI group had significantly reduced fractional anisotropy (FA) in the corpus callosum, superior longitudinal fasciculus (SLF), corona radiata and posterior thalamic radiation. Participants in the MCI-MD group had significantly reduced FA in the corpus callosum, internal capsule, external capsule, corona radiata, posterior thalamic radiation, sagittal striatum, fornix, SLF, uncinate fasciculus and right cingulum compared with controls. No significant differences in FA were observed between the MCI and MCI-MD groups. Participants in the MCI-MD group had greater medical burden (p = 0.020) and WMH burden than controls (p = 0.013). LIMITATIONS: Study limitations include the cross-sectional design and antidepressant medication use. CONCLUSION: To our knowledge, this study is the first to compare white matter microstructure in patients with MCI with and without a history of major depression and suggests that a common underlying structural white matter change may underpin cognitive impairment in both MCI groups. Further research is needed to delineate the pathophysiological mechanisms underlying these microstructural changes.

Delayed circadian phase is linked to glutamatergic functions in young people with affective disorders: a proton magnetic resonance spectroscopy study.

BACKGROUND: While the association between affective disorders and sleep and circadian disturbance is well established, little is known about the neurobiology underpinning these relationships. In this study, we sought to determine the relationship between a marker of circadian rhythm and neuronal integrity (N-Acetyl Aspartate, NAA), oxidative stress (glutathione, GSH) and neuronal-glial dysfunction (Glutamate + Glutamine, Glx). METHODS: Fifty-three young adults (age range 15-33 years, mean = 21.8, sd = 4.3) with emerging affective disorders were recruited from a specialized tertiary referral service. Participants underwent clinical assessment and actigraphy monitoring, from which sleep midpoint was calculated as a marker of circadian rhythm. Proton magnetic resonance spectroscopy was performed in the anterior cingulate cortex (ACC). The metabolites NAA, GSH and Glx were obtained, and expressed as a ratio to Creatine. RESULTS: Neither NAA or GSH were associated with sleep midpoint. However, higher levels of ACC Glx were associated with later sleep midpoints (rho = 0.35, p = 0.013). This relationship appeared to be independent of age and depression severity. CONCLUSIONS: This study is the first to demonstrate that delayed circadian phase is related to altered glutamatergic processes. It is aligned with animal research linking circadian rhythms with glutamatergic neurotransmission as well as clinical studies showing changes in glutamate with sleep interventions. Further studies may seek to examine the role of glutamate modulators for circadian misalignment.

Glutathione relates to neuropsychological functioning in mild cognitive impairment.

BACKGROUND: Mild cognitive impairment (MCI) represents an at-risk state for Alzheimer's disease in which underlying pathophysiological mechanisms could be delineated. Oxidative stress has been implicated in Alzheimer's disease and can be measured by levels of the antioxidant glutathione. This study aims to assess in vivo levels of glutathione via proton magnetic resonance spectroscopy in patients with MCI and to determine how glutathione relates to cognitive decline. METHODS: Fifty-four patients with MCI and 41 healthy control subjects underwent proton magnetic resonance spectroscopy in conjunction with medical, psychiatric, and neuropsychological assessments. The concentration of glutathione was measured in the anterior and posterior cingulate, and ratios of glutathione were calculated relative to creatine. Neuropsychological performance was assessed across the domains of processing speed, learning, memory, and executive functions. RESULTS: In comparison with control subjects, patients with MCI had significantly elevated ratios of glutathione in the anterior (t = -2.2, P = .03) and posterior (t = -2.9, P = .005) cingulate. Higher levels of anterior cingulate glutathione were related to neuropsychological decrements on tests of executive functions. Elevated posterior cingulate glutathione was associated with poorer memory consolidation. CONCLUSION: This study has shown for the first time that MCI is associated with increased glutathione in the cingulate, which in turn relates to neuropsychological performance. This finding may be indicative of an early compensatory or neuroprotective response, and the role of glial cells and glutathione enzymes requires delineation. Longitudinal studies examining the utility of glutathione as a marker for cognitive decline are now required.

Hippocampal Neuronal Integrity and Functional Connectivity Within the Default Mode Network in Mild Cognitive Impairment: A Multimodal Investigation.

Background: In older people with mild cognitive impairment (MCI), the relationship between early changes in functional connectivity and in vivo changes in key neurometabolites is not known. Two established correlates of MCI diagnosis are decreased N-acetylaspartate (NAA) in the hippocampus, indicative of decreased neuronal integrity, and changes in the default mode network (DMN) functional network. If and how these measures interrelate is yet to be established, and such understanding may provide insight into the processes underpinning observed cognitive decline. Objectives: To determine the relationship between NAA levels in the left hippocampus and functional connectivity within the DMN in an aging cohort. Methods: In a sample of 51 participants with MCI and 30 controls, hippocampal NAA was determined using magnetic resonance spectroscopy, and DMN connectivity was quantified using resting-state functional MRI. The association between hippocampal NAA and the DMN functional connectivity was tested within the MCI group and separately within the control group. Results: In the DMN, we showed a significant inverse association between functional connectivity and hippocampal NAA in 20 specific brain connections for patients with MCI. This was despite no evidence of any associations in the healthy control group or group differences in either of these measures alone. Conclusions: This study suggests that decreased neuronal integrity in the hippocampus is associated with functional change within the DMN for those with MCI, in contrast to healthy older adults. These results highlight the potential of multimodal investigations to better understand the processes associated with cognitive decline. Impact statement This study measured activity within the default mode network (DMN) and quantified N-acetylaspartate (NAA), a measure of neuronal integrity, within the hippocampus in participants with mild cognitive impairment (MCI) and healthy controls. In participants with MCI, NAA levels were inversely associated with connectivity between specific regions of the DMN, a relationship not evident in healthy controls. This association was present even in the absence of group differences in DMN connectivity or NAA levels. This research illustrates the possibility of using multiple magnetic resonance modalities for more sensitive measures of early cognitive decline to identify and intervene earlier.

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.

Brain oxidative stress and cognitive function in older adults with diabetes and pre-diabetes who are at risk for dementia.

AIMS: Diabetes is an established risk factor for dementia. This study aimed to examine the relationship between various cognitive domains, brain oxidative stress and markers of diabetes in older adults at risk for dementia. METHODS: Older adults at risk for dementia underwent comprehensive neuropsychological and medical assessment. At risk was defined as those with subjective and/or objective cognitive impairment. Pre-diabetes and type 2 diabetes were defined using American Diabetes Association definitions for fasting blood glucose and HbA1c. Brain oxidative stress as indicated by glutathione (GSH) was assessed via magnetic resonance spectroscopy in the anterior cingulate cortex. RESULTS: One-hundred and forty-seven older adults completed a neuropsychological assessment and fasting blood sample with 63 also undergoing magnetic resonance spectroscopy. Those with pre-diabetes/diabetes according to FBG had impaired memory retention, set-shifting and response inhibition, compared to those with normal blood glucose. In contrast, there were no significant differences in any cognitive outcome using the HbA1c definition. Increasing glucose and HbA1c levels were associated with reduced GSH concentration in the anterior cingulate. CONCLUSIONS: This study demonstrates that in older adults at risk for dementia, having pre-diabetes or diabetes is associated with impaired memory and executive dysfunction. It also highlights the potential role of oxidative stress as a pathophysiological mechanism that may underpin the link between diabetes and cognitive dysfunction.

Thalamic abnormalities in older adults with remitted early-onset depression using structural magnetic resonance imaging.

BACKGROUND: The thalamus is a key diencephalic structure involved in major depressive disorder (MDD). Studies have consistently revealed abnormalities in thalamic volumes in older adults with late-onset depression (LOD), however abnormalities in older adults with early-onset depression (EOD) have not yet been well-studied. METHODS: Fifty-nine euthymic participants with a history of EOD and fifty-nine matched comparison participants without a lifetime history of depression underwent neuroimaging, medical and neuropsychological assessments. Thalamic volumes were compared between groups. To investigate the previously-proposed right hemispheric (RH) dominance theory of MDD, we explored the bilateral, right and left hemispheric (LH) thalamic volumes. Multiple regression analyses were used to evaluate between-group and within-group effects. Correlational analyses examined associations between group and cognitive performance. RESULTS: Relative to the comparison group, those with EOD had significantly larger bilateral, LH and RH thalamic volumes. Those with EOD, those who were younger, and those who had fewer years of education demonstrated larger bilateral and LH thalamic volumes. For RH thalamic volumes, those with EOD and those who were younger demonstrated larger RH thalamic volumes. EOD within-group models were also run to assess associations between relevant depression variables. The results showed that only age was significant for bilateral and RH thalamic volumes. For the LH thalamic volumes, the model was not significant. No significant correlations were found between cognitive performance and EOD groups. CONCLUSION: Older adults with a history of EOD showed significantly larger bilateral, RH and LH thalamic volumes. Further research is needed to delineate potential underlying mechanisms of this change.

Rest-activity functioning is related to white matter microarchitecture and modifiable risk factors in older adults at-risk for dementia.

STUDY OBJECTIVES: Growing evidence demonstrates pronounced alterations in rest-activity functioning in older adults at-risk for dementia. White matter degeneration, poor cardiometabolic functioning, and depression have also been linked to a greater risk of decline; however, limited studies have examined the white matter in relation to rest-activity functioning in at-risk older adults. METHODS: We investigated associations between nonparametric actigraphy measures and white matter microarchitecture using whole-brain fixel-based analysis of diffusion-weighted imaging in older adults (aged 50 years or older) at-risk for cognitive decline and dementia. The fixel-based metrics assessed were fiber density, fiber cross-section, and combined fiber-density, and cross-section. Interactions between rest-activity functioning and known clinical risk factors, specifically body mass index (BMI), vascular risk factors, depressive symptoms and self-reported exercise, and their association with white matter properties were then investigated. RESULTS: Sixty-seven older adults were included (mean = 65.78 years, SD = 7.89). Lower relative amplitude, poorer 24-h synchronization and earlier onset of the least active 5-h period were associated with reductions in markers of white matter atrophy in widespread regions, including cortico-subcortical and cortical association pathways. Preliminary evidence was also found indicating more pronounced white matter alterations in those with lower amplitude and higher BMI (ß = 0.25, 95% CI [0.05, 0.46]), poorer 24-h synchronization and more vascular risk factors (ß = 0.17, 95% CI [-0.02, 0.36]) and earlier onset of inactivity and greater depressive symptoms (ß = 0.17, 95% CI [0.03, 0.30]). CONCLUSIONS: These findings highlight the complex interplay between rest-activity rhythms, white matter, and clinical risk factors in individuals at-risk for dementia that should be considered in future studies.

Poorer Theory of Mind in Amnestic Mild Cognitive Impairment Is Associated with Decreased Functional Connectivity in the Default Mode Network.

BACKGROUND: Older adults living with amnestic mild cognitive impairment (aMCI) not only demonstrate impairments in Theory of Mind (ToM), relative to adults with non-amnestic MCI (naMCI), but are also at a higher risk of developing dementia. OBJECTIVE: Our primary objective was to ascertain whether default mode network (DMN) functional connectivity was differentially associated with ToM abilities between MCI subgroups. METHODS: Using functional magnetic resonance imaging, we investigated alterations in resting-state functional connectivity within the brain's DMN in a sample of 43 older adults with aMCI (n = 19) and naMCI (n = 24), previously reported to demonstrate poorer ToM abilities. RESULTS: Compared to naMCI, the aMCI subgroup revealed a significant association between poorer ToM performance and reduced functional connectivity between the bilateral temporal pole (TempP) and the left lateral temporal cortex (LTC) (LTC_L-TempP_L: b = -0.06, t(33) = -3.53, p = 0.02; LTC_L-TempP_R: b = -0.07,t(33) = -3.20, p = 0.03); between the right TempP and the dorsal medial prefrontal cortex (dMPFC) (b = -0.04, t(33) = -3.02, p = 0.03) and between the left and right TempP (b = -0.05, t(33) = -3.26, p = 0.03). In the naMCI subgroup, the opposite relationship was present between the bilateral TempP and the left LTC (Combined correlation: r = -0.47, p = 0.02), however, not between the right TempP and the dMPFC (r = -0.14, p = 0.51) or the left and right TempP (r = -0.31, p = 0.14). CONCLUSION: Our findings suggest that alterations in functional connectivity within the DMN involving temporal and frontal lobe regions are associated with ToM deficits in aMCI.

Actigraphy-recorded sleep efficiency and hippocampal volume are related to visual and verbal rate of forgetting in older adults.

This study aimed to determine if older adults "at-risk" for dementia (those with MCI or SMC) exhibit accelerated long-term forgetting (ALF) and whether rate of forgetting (RoF) is associated with sleep efficiency, hippocampal volume and demographic/clinical features. Forty-nine "at-risk" participants and eighteen controls underwent examination. Memory was assessed using the Scene Memory Task (SMT) and WMS-III Logical Memory (LM) subtest. Tests were administered at baseline, 24 hours and 2 weeks. While our study did not find ALF in those "at-risk" for dementia, on the SMT, RoF over 24 hours and 2 weeks was negatively correlated with sleep efficiency. For LM, RoF at 2 weeks was moderately associated with left hippocampal volume. Neither visual or verbal RoF was correlated with demographic or clinical variables (age, MMSE, IQ, GDS-15). While ALF was not observed in this sample, our results suggest that visual and verbal forgetting have differential predictors.

Altered heart rate variability during sleep in mild cognitive impairment.

STUDY OBJECTIVES: Cardiovascular autonomic dysfunction, as measured by short-term diurnal heart rate variability (HRV), has been reported in older adults with mild cognitive impairment (MCI). However, it is unclear whether this impairment also exists during sleep in this group. We, therefore, compared overnight HRV during sleep in older adults with MCI and those with subjective cognitive impairment (SCI). METHODS: Older adults (n = 210) underwent overnight polysomnography. Eligible participants were characterized as multi-domain MCI or SCI. The multi-domain MCI group was comprised of amnestic and non-amnestic subtypes. Power spectral analysis of HRV was conducted on the overnight electrocardiogram during non-rapid eye movement (NREM), rapid eye movement (REM), N1, N2, N3 sleep stages, and wake periods. High-frequency HRV (HF-HRV) was employed as the primary measure to estimate parasympathetic function. RESULTS: The MCI group showed reduced HF-HRV during NREM sleep (p = 0.018), but not during wake or REM sleep (p > 0.05) compared to the SCI group. Participants with aMCI compared to SCI had the most pronounced reduction in HF-HRV across all NREM sleep stages-N1, N2, and N3, but not during wake or REM sleep. The naMCI sub-group did not show any significant differences in HF-HRV during any sleep stage compared to SCI. CONCLUSIONS: Our study showed that amnestic MCI participants had greater reductions in HF-HRV during NREM sleep, relative to those with SCI, suggesting potential vulnerability to sleep-related parasympathetic dysfunction. HF-HRV, especially during NREM sleep, may be an early biomarker for dementia detection.

Feasibility of 3-month melatonin supplementation for brain oxidative stress and sleep in mild cognitive impairment: protocol for a randomised, placebo-controlled study.

INTRODUCTION: Melatonin has multiple proposed therapeutic benefits including antioxidant properties, synchronisation of the circadian system and lowering of blood pressure. In this protocol, we outline a randomised controlled trial to assess the feasibility, acceptability and tolerability of higher dose (25 mg) melatonin to target brain oxidative stress and sleep disturbance in older adults with mild cognitive impairment (MCI). METHODS AND ANALYSIS: The study design is a randomised double-blind, placebo-controlled, parallel group trial. Forty individuals with MCI will be recruited from the Healthy Brain Ageing Clinic, University of Sydney and from the community, and randomised to receive either 25 mg oral melatonin or placebo nightly for 12 weeks. The primary outcomes are feasibility of recruitment, acceptability of intervention and adherence to trial medication at 12 weeks. Secondary outcomes will include the effect of melatonin on brain oxidative stress as measured by magnetic resonance spectroscopy, blood pressure, blood biomarkers, mood, cognition and sleep. Outcomes will be collected at 6 and 12 weeks. The results of this feasibility trial will inform a future conclusive randomised controlled trial to specifically test the efficacy of melatonin on modifiable risk factors of dementia, as well as cognition and brain function. This will be the first trial to investigate the effect of melatonin in the population with MCI in this way, with the future aim of using this approach to reduce progression to dementia. ETHICS AND DISSEMINATION: This protocol has been approved by the Sydney Local Health District Ethics Committee (X18-0077). This randomised controlled trial will be conducted in compliance with the protocol published in the registry, the International Conference for Harmonisation on Good Clinical Practice and all other applicable regulatory requirements. The findings of the trial will be disseminated via conferences, publications and media, as applicable. Participants will be informed of results of the study at the conclusion of the trial. Eligible authors will include investigators who are involved in the conception and design of the study, the conduct of the trial, the analysis of the results, and reporting and presentation of study findings. TRIAL REGISTRATION NUMBER: Australian and New Zealand Clinical Trials Registry (ANZCTRN 12619000876190). PROTOCOL VERSION: V.8 15 October 2020.