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.

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.

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.

Rest-activity rhythms and tract specific white matter lesions in older adults at risk for cognitive decline.

White matter lesions (WMLs) are common in older adults and represent an important predictor of negative long-term outcomes. Rest-activity rhythm disturbance is also common, however, few studies have investigated associations between these factors. We employed a novel AI-based automatic WML segmentation tool and diffusion-weighted tractography to investigate associations between tract specific WML volumes and non-parametric actigraphy measures in older adults at risk for cognitive decline. The primary non-parametric measures of interest were inter-daily stability (IS), intra-daily variability and relative amplitude, with the anterior thalamic radiation (ATR), superior longitudinal fasciculus (SLF) and inferior longitudinal fasciculus (ILF) selected as tracts of interest. One hundred and eight participants at risk for cognitive decline (classified as experiencing subjective or objective cognitive decline) were included (mean age = 68.85 years, SD = 8.91). Of the primary non-parametric measures of interest, results showed that lower IS was associated with a greater likelihood of higher WML burden in the ATR (OR = 1.82, 95% CI [1.12,3.15]). Analysis of secondary non-parametric measures revealed later onset of the least active period to be associated with greater likelihood of high WML burden in the SLF (OR = 1.55, 95% CI [1.00,2.53]) and increased activity during the least active 5-h period to be associated with a greater likelihood of high whole-brain WML burden (OR = 1.83, 95% CI [1.06,3.47]). This study shows integrity of the ATR and SLF, and overall WML burden is linked to altered rest-activity rhythms in older adults at risk for cognitive decline, with those demonstrating altered rest-activity rhythms showing 50%-80% higher odds of having high WML burden.

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.

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.

Cognitive Function and the Relationship With Health Literacy and Secondary Prevention in Patients With Acute Coronary Syndrome at Early Discharge: A Prospective Observational Study.

BACKGROUND: Cognitive impairment (CI) may contribute to difficulties in understanding and implementing secondary prevention behavior change after acute coronary syndrome (ACS), but the association is poorly understood. OBJECTIVES: The aim of this study was to explore the prevalence of CI in patients 4 weeks post ACS and the association with health literacy and secondary prevention. METHODS: Patients with ACS who were free from visual deficits, auditory impairment, and dementia diagnoses were recruited and assessed 4 weeks post discharge for cognitive function (Montreal Cognitive Assessment and Hopkins Verbal Learning Test), health literacy (Newest Vital Sign), depression (Patient Health Questionnaire), physical activity (Fitbit Activity Tracker and Physical Activity Scale for the Elderly), and medication knowledge and adherence. RESULTS: Participants (n = 45) had an average age of 65 ± 11 years, 82% were male, 64% were married/partnered, and 82% had high school education or higher. Overall CI was identified in 28.9% (n = 13/45) of the patients 4 weeks after discharge, which was composed of patients detected on both the Montreal Cognitive Assessment and Hopkins Verbal Learning Test (n = 3), patients detected on Montreal Cognitive Assessment alone (n = 6), and patients detected on Hopkins Verbal Learning Test alone (n = 4). Fewer patients with CI had adequate health literacy (61.4%) than patients with normal cognition (90.3%, P = .024). Significant correlations were found between Hopkins Verbal Learning Test scores and medication knowledge (0.4, P = .008) and adherence (0.33, P = .029). CONCLUSIONS: In this exploratory study, 30% of patients with ACS demonstrated CI at 4 weeks post discharge. Two screening instruments were required to identify all cases. Cognitive impairment was significantly associated with health literacy and worth further investigation.

Age and Marital Status Predict Mild Cognitive Impairment During Acute Coronary Syndrome Admission: An Observational Study of Acute Coronary Syndrome Inpatients.

BACKGROUND: Mild cognitive impairment (MCI) has been reported after acute coronary syndrome (ACS), but it is uncertain who is at risk, particularly during inpatient admission. OBJECTIVE: In this study, we aimed to explore the prevalence and cognitive domains affected in MCI during ACS admission and determine factors that identify patients most at risk of MCI. METHODS: Inpatients with ACS were consecutively recruited from 2 tertiary hospital cardiac wards and screened with the Montreal Cognitive Assessment and the Hopkins Verbal Learning Test. Screening included health literacy (Newest Vital Sign), depressive symptoms (Patient Health Questionnaire-9), and physical activity (Physical Activity Scale for the Elderly). Factors associated with MCI were determined using logistic regression. RESULTS: Participants (n = 81) had a mean (SD) age of 63.5 (10.9) years, and 82.7% were male. In total, MCI was identified in 52.5%, 42.5% with 1 screen and 10% with both. Individually, the Montreal Cognitive Assessment identified MCI in 48.1%, and the Hopkins Verbal Learning Test identified MCI in 13.8%. In Montreal Cognitive Assessment screening, the cognitive domains in which participants most frequently did not achieve the maximum points available were delayed recall (81.5%), visuospatial executive function (48.1%), and attention (30.9%). Accounting for education, depression, physical activity, and ACS diagnosis, the likelihood of an MCI positive screen increased by 11% per year of age (odds ratio, 1.11; 95% confidence interval, 1.04-1.18) and by 3.6 times for those who are unmarried/unpartnered (odds ratio, 3.61; 95% confidence interval, 1.09-11.89). CONCLUSION: An estimated half of patients with ACS screen positive for MCI during admission, with single and older patients most at risk. Multiple areas of thinking were affected with potential impact on capacity for learning heart disease management.

Outcome measures for Alzheimer's disease: A global inter-societal Delphi consensus.

INTRODUCTION: We aim to provide guidance on outcomes and measures for use in patients with Alzheimer's clinical syndrome. METHODS: A consensus group of 20 voting members nominated by 10 professional societies, and a non-voting chair, used a Delphi approach and modified GRADE criteria. RESULTS: Consensus was reached on priority outcomes (n = 66), measures (n = 49) and statements (n = 37) across nine domains. A number of outcomes and measurement instruments were ranked for: Cognitive abilities; Functional abilities/dependency; Behavioural and neuropsychiatric symptoms; Patient quality of life (QoL); Caregiver QoL; Healthcare and treatment-related outcomes; Medical investigations; Disease-related life events; and Global outcomes. DISCUSSION: This work provides indications on the domains and ideal pertinent measurement instruments that clinicians may wish to use to follow patients with cognitive impairment. More work is needed to develop instruments that are more feasible in the context of the constraints of clinical routine.

Predicting the emergence of full-threshold bipolar I, bipolar II and psychotic disorders in young people presenting to early intervention mental health services.

BACKGROUND: Predictors of new-onset bipolar disorder (BD) or psychotic disorder (PD) have been proposed on the basis of retrospective or prospective studies of 'at-risk' cohorts. Few studies have compared concurrently or longitudinally factors associated with the onset of BD or PDs in youth presenting to early intervention services. We aimed to identify clinical predictors of the onset of full-threshold (FT) BD or PD in this population. METHOD: Multi-state Markov modelling was used to assess the relationships between baseline characteristics and the likelihood of the onset of FT BD or PD in youth (aged 12-30) presenting to mental health services. RESULTS: Of 2330 individuals assessed longitudinally, 4.3% (n = 100) met criteria for new-onset FT BD and 2.2% (n = 51) met criteria for a new-onset FT PD. The emergence of FT BD was associated with older age, lower social and occupational functioning, mania-like experiences (MLE), suicide attempts, reduced incidence of physical illness, childhood-onset depression, and childhood-onset anxiety. The emergence of a PD was associated with older age, male sex, psychosis-like experiences (PLE), suicide attempts, stimulant use, and childhood-onset depression. CONCLUSIONS: Identifying risk factors for the onset of either BD or PDs in young people presenting to early intervention services is assisted not only by the increased focus on MLE and PLE, but also by recognising the predictive significance of poorer social function, childhood-onset anxiety and mood disorders, and suicide attempts prior to the time of entry to services. Secondary prevention may be enhanced by greater attention to those risk factors that are modifiable or shared by both illness trajectories.

A randomized controlled trial of a web-based mindfulness programme for people with MS with and without a history of recurrent depression.

BACKGROUND: Evidence shows small positive effects associated with psychological treatments for people with multiple sclerosis (PwMS). In a recent meta-analysis, the treatment with the largest effect size was a mindfulness-based intervention (MBI). OBJECTIVES: We aimed to determine whether an Internet-delivered MBI was beneficial for PwMS. Furthermore, we aimed to investigate history of recurrent depression as a moderator of treatment outcome. METHODS: Participants (N = 132) were assessed based on whether they had a history of recurrent depression, then stratified and randomized to MBI or waitlist. Outcomes were assessed at baseline, post-intervention, and 3 and 6 months. RESULTS: The MBI group reported significantly improved depressive symptoms (primary outcome) compared with the waitlist (p = 0.046, Cohen's d = 0.39). Those with a history of recurrent depression benefitted significantly more than those without (p = 0.034, d = 0.66). There were benefits for health-related quality of life (HRQoL) in the MBI, irrespective of depression history (p = 0.009, d = 0.5). Pain interference was less overall in the MBI group (p < 0.001, d = 0.2), but change over time did not differ from waitlist. There were no treatment effects for anxiety, pain severity or fatigue. CONCLUSION: The Internet-delivered MBI significantly improved depressive symptoms and HRQoL in PwMS. For depression, the benefits were greater for those with a history of recurrent depression. TRIAL REGISTRATION: ACTRN12618001260213, available at: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=375598.

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.

The TAS Test project: a prospective longitudinal validation of new online motor-cognitive tests to detect preclinical Alzheimer's disease and estimate 5-year risks of cognitive decline and dementia.

BACKGROUND: The worldwide prevalence of dementia is rapidly rising. Alzheimer's disease (AD), accounts for 70% of cases and has a 10-20-year preclinical period, when brain pathology covertly progresses before cognitive symptoms appear. The 2020 Lancet Commission estimates that 40% of dementia cases could be prevented by modifying lifestyle/medical risk factors. To optimise dementia prevention effectiveness, there is urgent need to identify individuals with preclinical AD for targeted risk reduction. Current preclinical AD tests are too invasive, specialist or costly for population-level assessments. We have developed a new online test, TAS Test, that assesses a range of motor-cognitive functions and has capacity to be delivered at significant scale. TAS Test combines two innovations: using hand movement analysis to detect preclinical AD, and computer-human interface technologies to enable robust 'self-testing' data collection. The aims are to validate TAS Test to [1] identify preclinical AD, and [2] predict risk of cognitive decline and AD dementia. METHODS: Aim 1 will be addressed through a cross-sectional study of 500 cognitively healthy older adults, who will complete TAS Test items comprising measures of motor control, processing speed, attention, visuospatial ability, memory and language. TAS Test measures will be compared to a blood-based AD biomarker, phosphorylated tau 181 (p-tau181). Aim 2 will be addressed through a 5-year prospective cohort study of 10,000 older adults. Participants will complete TAS Test annually and subtests of the Cambridge Neuropsychological Test Battery (CANTAB) biennially. 300 participants will undergo in-person clinical assessments. We will use machine learning of motor-cognitive performance on TAS Test to develop an algorithm that classifies preclinical AD risk (p-tau181-defined) and determine the precision to prospectively estimate 5-year risks of cognitive decline and AD. DISCUSSION: This study will establish the precision of TAS Test to identify preclinical AD and estimate risk of cognitive decline and AD. If accurate, TAS Test will provide a low-cost, accessible enrichment strategy to pre-screen individuals for their likelihood of AD pathology prior to more expensive tests such as blood or imaging biomarkers. This would have wide applications in public health initiatives and clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05194787 , 18 January 2022. Retrospectively registered.

Sleep-Dependent Memory in Older People With and Without MCI: The Relevance of Sleep Microarchitecture, OSA, Hippocampal Subfields, and Episodic Memory.

This study aimed to determine if, relative to cognitively healthy controls, sleep-dependent memory consolidation (SDMC) is diminished in mild cognitive impairment (MCI), a group at high risk of conversion to dementia. We also sought to determine whether SDMC is associated with sleep characteristics, daytime episodic memory, and hippocampal integrity. Participants with MCI (n = 43) and controls (n = 20) underwent clinical and neuropsychological profiling. From polysomnography, apnea hypopnea index (AHI) and non-REM sleep spindle characteristics were derived. From magnetic resonance imaging, hippocampal subfield volumes were computed. Participants learned a novel 32-item word-pair prior to sleep; morning retention of the word-pairs was used to determine SDMC. Results showed that SDMC did not differ between MCI and controls, but there was a large effect size decrement in SDMC in those with multiple domain MCI (Hedge's g = 0.85). In MCI, poorer SDMC was correlated with CA1 and CA3 hippocampal atrophy, shorter spindle duration, and worse daytime episodic memory. In controls, poorer SDMC was associated with higher AHI. Impaired daytime memory consolidation, reduced hippocampal volumes, shorter sleep spindles, and greater sleep apnea severity are indicators of diminished SDMC in older adults and should be explored in future studies.

Characterising Australian memory clinics: current practice and service needs informing national service guidelines.

BACKGROUND: Memory clinics (MCs) play a key role in accurate and timely diagnoses and treatment of dementia and mild cognitive impairment. However, within Australia, there are little data available on current practices in MCs, which hinder international comparisons for best practice, harmonisation efforts and national coordination. Here, we aimed to characterise current service profiles of Australian MCs. METHODS: The 'Australian Dementia Network Survey of Expert Opinion on Best Practice and the Current Clinical Landscape' was conducted between August-September 2020 as part of a larger-scale Delphi process deployed to develop national MC guidelines. In this study, we report on the subset of questions pertaining to current practice including wait-times and post-diagnostic care. RESULTS: Responses were received from 100 health professionals representing 60 separate clinics (45 public, 11 private, and 4 university/research clinics). The majority of participants were from clinics in metropolitan areas (79%) and in general were from high socioeconomic areas. While wait-times varied, only 28.3% of clinics were able to offer an appointment within 1-2 weeks for urgent referrals, with significantly more private clinics (58.3%) compared to public clinics (19.5%) being able to do so. Wait-times were less than 8 weeks for 34.5% of non-urgent referrals. Only 20.0 and 30.9% of clinics provided cognitive interventions or post-diagnostic support respectively, with 7.3% offering home-based reablement programs, and only 12.7% offering access to group-based education. Metropolitan clinics utilised neuropsychological assessments for a broader range of cases and were more likely to offer clinical trials and access to research opportunities. CONCLUSIONS: In comparison to similar countries with comprehensive government-funded public healthcare systems (i.e., United Kingdom, Ireland and Canada), wait-times for Australian MCs are long, and post-diagnostic support or evidence-based strategies targeting cognition are not common practice. The timely and important results of this study highlight a need for Australian MCs to adopt a more holistic service of multidisciplinary assessment and post-diagnostic support, as well as the need for the number of Australian MCs to be increased to match the rising number of dementia cases.

Association between lifetime depression history, hippocampal volume and memory in non-amnestic mild cognitive impairment.

Hippocampal subfield volume loss in older adults with amnestic mild cognitive impairment (aMCI) and depression history are associated with amyloid beta and tau pathology, thereby increasing the risk for Alzheimer's disease (AD). However, no studies have exclusively examined distinct alterations in hippocampal subfields in non-amnestic MCI (naMCI) in relation to depression history. Here, we used both longitudinal and transverse hippocampal segmentation methods using the automated FreeSurfer software to examine whether a lifetime depression history is associated with differences in hippocampal head/body/tail (H/B/T) and key subfield volumes (CA1, subiculum, dentate gyrus) in older adults with naMCI. Further, we explored whether differences in hippocampal H/B/T and subfield volumes were associated with structured and unstructured verbal encoding and retention, comparing those with and without a depression history. The naMCI with a depression history group demonstrated larger or relatively preserved right CA1 volumes, which were associated with better unstructured verbal encoding and as well as structured verbal memory retention. This association between memory encoding and hippocampal CA1 and total head volume was significantly different to those with no depression history. The relationship between right CA1 volume and memory retention was also moderated by depression history status F (5,143) = 7.84, p < 0.001, R2  = 0.22. Those participants taking antidepressants had significantly larger hippocampal subiculum (p = 0.008), and right hippocampal body (p = 0.004) and better performance on structured encoding (p = 0.011) and unstructured memory retention (p = 0.009). These findings highlight the importance of lifetime depression history and antidepressant use on the hippocampus and encoding and memory retention in naMCI.

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.

Fatigue in Children With Moderate or Severe Traumatic Brain Injury Compared With Children With Orthopedic Injury: Characteristics and Associated Factors.

OBJECTIVE: To characterize fatigue in children with moderate or severe traumatic brain injury (TBI) and to identify associated factors. SETTING: Urban tertiary pediatric healthcare facility. PARTICIPANTS: Children aged 5 to 15 years with a moderate TBI (n = 21), severe TBI (n = 23), or an orthopedic injury (OI; n = 38). DESIGN: Case-control study. MAIN MEASURES: (i) Pediatric Quality of Life Inventory Multidimensional Fatigue Scale (PedsQL-MFS), completed by parents and children; (ii) Sleep Disturbance Scale for Children, completed by parents. Data on injury-specific factors and other factors of interest were also collected. RESULTS: The 2 TBI groups did not differ on any of the fatigue outcomes (child or parent ratings). Relative to the OI group, parents rated children in both TBI groups as experiencing greater fatigue. However, on self-ratings, only children with moderate TBI endorsed greater fatigue. Sleep was commonly associated with fatigue, with child sleep disturbance and child sleep hygiene associated with parent-rated and self-rated child fatigue, respectively. Individually, there were no cases of "normal" fatigue coinciding with severe sleep disturbance. However, there were several cases of severe fatigue coinciding with normal sleep. Additional factors associated with fatigue were older age at injury, longer time since injury, and/or greater internalizing difficulties. CONCLUSION: Children with moderate and severe TBI experience greater fatigue than OI controls. Parent and child ratings of fatigue appear to be associated with different factors, indicating that fatigue management may require a broad range of treatments.

Children who sustained traumatic brain injury take longer to fall asleep compared to children who sustained orthopedic injuries: actigraphy findings.

Objective:Primary: to examine objective sleep outcomes in children who sustained moderate to severe traumatic brain injury (TBI). Secondary: to examine the relation of objective sleep with subjective sleep, fatigue, and injury variables.Setting: A single tertiary brain injury unit.Participants: Children (5-15 years) with moderate to severe TBI (n = 23) or orthopedic injury (OI; n = 13).Design: Cohort study.Measures: Primary: objective sleep measure (actigraphy watch). Secondary: subjective sleep measure (questionnaire), fatigue questionnaire, and injury variables.Results: On actigraphy, children with TBI had longer sleep onset latency compared to children with OI. On the sleep questionnaire, children with TBI obtained higher scores for total sleep disturbance, initiating and maintaining sleep, and excessive somnolence. On the fatigue questionnaire, greater difficulties were found for total, sleep/rest, and cognitive fatigue for the TBI group. In the TBI group, actigraphy data did not correlate with sleep questionnaire, fatigue, or injury variables.Conclusion: Our study showed evidence of objective and subjective sleep disturbance in children with moderate to severe TBI, but these two types of sleep measures were not related. It is possible that distinct mechanisms underpin objective and subjective sleep disturbance, which may require different interventions.

Development of a Web-Based Mindfulness Program for People With Multiple Sclerosis: Qualitative Co-Design Study.

BACKGROUND: Mindfulness-based stress reduction is an efficacious treatment for people with chronic health problems; however, it is highly intensive and time-consuming, which is a barrier for service provision. OBJECTIVE: This study aims to develop an internet-delivered adapted version of mindfulness-based stress reduction for people with multiple sclerosis to make the intervention more accessible. METHODS: We co-designed a web-based mindfulness program with end users, that is, people with multiple sclerosis (N=19). Iterative feedback was also collected from a subsample of the initial group of end users (n=11), and the program was reviewed by experts (n=8). RESULTS: We identified three main themes common to people with multiple sclerosis: dealing with uncertainty and fears for the future, grief and loss, and social isolation. These themes were incorporated into narratives throughout the program. People with multiple sclerosis who reviewed the program gave feedback that the program was relatable, feasible, and acceptable. Experts agreed that the program appropriately represented the main tenets of mindfulness. Iterative feedback was used to further refine the program. CONCLUSIONS: The web-based mindfulness program that we developed was viewed positively by both experts and end users. The program reflects common concerns for people with multiple sclerosis and has the potential to meet important unmet psychological needs. A randomized controlled trial was planned to determine the efficacy of the program.