Rosemary Greenwood

Background: Sleep holds promise as a modifiable risk factor for neurodegenerative diseases and dementia. Clinical trials to modify sleep in people at risk of or in the early stages of dementia are needed. Monitoring natural sleep from home could support pragmatic and decentralized large-scale clinical trials. However, whether longitudinal sleep research can be successfully delivered remotely in this population has not been established yet. Objective: We investigated the feasibility of remote longitudinal research using wearable devices, web-based cognitive tasks, and a smartphone app to record sleep and cognition in older adults with mild cognitive impairment (MCI) or dementia. Methods: Older adults with MCI or dementia due to Alzheimer disease or Lewy body disease and cognitively healthy participants completed at-home sleep and circadian monitoring (digital sleep diaries, actigraphy, wearable sleep electroencephalography, and saliva samples) and digital cognitive assessments for 8 weeks. Feasibility outcomes included recruitment, retention, and data completeness. Results: In total, 41 participants consented (n=10, 24% participants with Alzheimer disease; n=11, 27% participants with Lewy body disease; and n=20, 49% controls). There were predominantly male and White British participants, with a mean age of 70.9 (SD 5.9) years. Retention was very high, with 40 (98%) participants completing 8 weeks of remote monitoring. Data completeness for sleep electroencephalography was 91% and ranged from 79% to 97% for all remote tasks and was overall high across all participant subgroups. In total, 30% (12/40) of participants reported receiving external support with completing study tasks. Conclusions: High rates of retention, data completeness, and data quality suggested that longitudinal multimodal sleep and cognitive profiling using novel and remote monitoring technology is feasible in older adults with MCI and dementia and healthy older adults, even without study partner support. Remote monitoring should be considered for mechanistic and interventional trials. Careful consideration should be given to how to ensure remote monitoring technologies reduce burden and enhance inclusivity, particularly in communities traditionally underserved by research and those with lower digital literacy. International Registered Report Identifier (IRRID): RR2-10.2196/52652

STRUCTURED INTRODUCTION: We investigated the feasibility of remote longitudinal research using wearable devices and smartphone applications to record sleep and cognition in older adults with mild cognitive impairment (MCI) or dementia. METHODS: Older adults with MCI or dementia due to Alzheimer’s disease (AD) or Lewy body disease (LBD) and cognitively healthy participants completed at-home sleep and circadian monitoring (digital sleep diaries, actigraphy, wearable sleep electroencephalography (EEG), saliva samples) and digital cognitive assessments for 8 weeks. Feasibility outcomes included recruitment, retention, and data completeness. RESULTS: 41 participants consented (10 AD, 11 LBD, and 20 controls) and 40 completed the 8-week study. Data completeness for sleep EEG was 91% and ranged from 79% to 97% for all remote tasks. 12/40 (30%) participants reported receiving external support with completing study tasks. DISCUSSION: Longitudinal multimodal sleep and cognitive profiling using novel technology is feasible in older adults with MCI and dementia and healthy older adults.

BACKGROUND Sleep holds promise as a modifiable risk factor for neurodegenerative diseases and dementia. Clinical trials to modify sleep in people at risk of or in the early stages of dementia are needed. Monitoring natural sleep from home could support pragmatic and decentralized large-scale clinical trials. However, whether longitudinal sleep research can be successfully delivered remotely in this population has not been established yet. OBJECTIVE We investigated the feasibility of remote longitudinal research using wearable devices, web-based cognitive tasks, and a smartphone app to record sleep and cognition in older adults with mild cognitive impairment (MCI) or dementia. METHODS Older adults with MCI or dementia due to Alzheimer disease or Lewy body disease and cognitively healthy participants completed at-home sleep and circadian monitoring (digital sleep diaries, actigraphy, wearable sleep electroencephalography, and saliva samples) and digital cognitive assessments for 8 weeks. Feasibility outcomes included recruitment, retention, and data completeness. RESULTS In total, 41 participants consented (n=10, 24% participants with Alzheimer disease; n=11, 27% participants with Lewy body disease; and n=20, 49% controls). There were predominantly male and White British participants, with a mean age of 70.9 (SD 5.9) years. Retention was very high, with 40 (98%) participants completing 8 weeks of remote monitoring. Data completeness for sleep electroencephalography was 91% and ranged from 79% to 97% for all remote tasks and was overall high across all participant subgroups. In total, 30% (12/40) of participants reported receiving external support with completing study tasks. CONCLUSIONS High rates of retention, data completeness, and data quality suggested that longitudinal multimodal sleep and cognitive profiling using novel and remote monitoring technology is feasible in older adults with MCI and dementia and healthy older adults, even without study partner support. Remote monitoring should be considered for mechanistic and interventional trials. Careful consideration should be given to how to ensure remote monitoring technologies reduce burden and enhance inclusivity, particularly in communities traditionally underserved by research and those with lower digital literacy. INTERNATIONAL REGISTERED REPORT RR2-10.2196/52652

Background: Sleep disturbances are a potentially modifiable risk factor for neurodegenerative dementia secondary to Alzheimer disease (AD) and Lewy body disease (LBD). Therefore, we need to identify the best methods to study sleep in this population. Objective: This study will assess the feasibility and acceptability of various wearable devices, smart devices, and remote study tasks in sleep and cognition research for people with AD and LBD. Methods: We will deliver a feasibility and acceptability study alongside a prospective observational cohort study assessing sleep and cognition longitudinally in the home environment. Adults aged older than 50 years who were diagnosed with mild to moderate dementia or mild cognitive impairment (MCI) due to probable AD or LBD and age-matched controls will be eligible. Exclusion criteria include lack of capacity to consent to research, other causes of MCI or dementia, and clinically significant sleep disorders. Participants will complete a cognitive assessment and questionnaires with a researcher and receive training and instructions for at-home study tasks across 8 weeks. At-home study tasks include remote sleep assessments using wearable devices (electroencephalography headband and actigraphy watch), app-based sleep diaries, online cognitive assessments, and saliva samples for melatonin- and cortisol-derived circadian markers. Feasibility outcomes will be assessed relating to recruitment and retention, data completeness, data quality, and support required. Feedback on acceptability and usability will be collected throughout the study period and end-of-study interviews will be analyzed using thematic analysis. Results: Recruitment started in February 2022. Data collection is ongoing, with final data expected in February 2024 and data analysis and publication of findings scheduled for the summer of 2024. Conclusions: This study will allow us to assess if remote testing using smart devices and wearable technology is a viable alternative to traditional sleep measurements, such as polysomnography and questionnaires, in older adults with and without MCI or dementia due to AD or LBD. Understanding participant experience and the barriers and facilitators to technology use for research purposes and remote research in this population will assist with the development of, recruitment to, and retention within future research projects studying sleep and cognition outside of the clinic or laboratory. International Registered Report Identifier (IRRID): DERR1-10.2196/52652

BACKGROUND Sleep disturbances are a potentially modifiable risk factor for neurodegenerative dementia secondary to Alzheimer disease (AD) and Lewy body disease (LBD). Therefore, we need to identify the best methods to study sleep in this population. OBJECTIVE This study will assess the feasibility and acceptability of various wearable devices, smart devices, and remote study tasks in sleep and cognition research for people with AD and LBD. METHODS We will deliver a feasibility and acceptability study alongside a prospective observational cohort study assessing sleep and cognition longitudinally in the home environment. Adults aged older than 50 years who were diagnosed with mild to moderate dementia or mild cognitive impairment (MCI) due to probable AD or LBD and age-matched controls will be eligible. Exclusion criteria include lack of capacity to consent to research, other causes of MCI or dementia, and clinically significant sleep disorders. Participants will complete a cognitive assessment and questionnaires with a researcher and receive training and instructions for at-home study tasks across 8 weeks. At-home study tasks include remote sleep assessments using wearable devices (electroencephalography headband and actigraphy watch), app-based sleep diaries, online cognitive assessments, and saliva samples for melatonin- and cortisol-derived circadian markers. Feasibility outcomes will be assessed relating to recruitment and retention, data completeness, data quality, and support required. Feedback on acceptability and usability will be collected throughout the study period and end-of-study interviews will be analyzed using thematic analysis. RESULTS Recruitment started in February 2022. Data collection is ongoing, with final data expected in February 2024 and data analysis and publication of findings scheduled for the summer of 2024. CONCLUSIONS This study will allow us to assess if remote testing using smart devices and wearable technology is a viable alternative to traditional sleep measurements, such as polysomnography and questionnaires, in older adults with and without MCI or dementia due to AD or LBD. Understanding participant experience and the barriers and facilitators to technology use for research purposes and remote research in this population will assist with the development of, recruitment to, and retention within future research projects studying sleep and cognition outside of the clinic or laboratory. INTERNATIONAL REGISTERED REPORT DERR1-10.2196/52652

GCA is systemic vasculitis manifesting as cranial, ocular or large vessel vasculitis. A prior qualitative study developed 40 candidate items to assess the impact of GCA on health-related quality of life (HRQoL). This study aimed to determine final scale structure and measurement properties of the GCA patient reported outcome (GCA-PRO) measure. Cross-sectional study included UK patients with clinician-confirmed GCA. They completed 40 candidate items for the GCA-PRO at times 1 and 2 (3 days apart), EQ-5D-5L, ICECAP-A, CAT-PROM5 and self-report of disease activity. Rasch and exploratory factor analyses informed item reduction and established structural validity, reliability and unidimensionality of the final GCA-PRO. Evidence of validity was also established with hypothesis testing (GCA-PRO vs other PRO scores, and between participants with ‘active disease’ vs those ‘in remission’) and test–retest reliability. The study population consisted of 428 patients: mean (s.d.) age 74.2 (7.2), 285 (67%) female; 327 (76%) cranial GCA, 114 (26.6%) large vessel vasculitis and 142 (33.2%) ocular involvement. Rasch analysis eliminated 10 candidate GCA items and informed restructuring of response categories into four-point Likert scales. Factor analysis confirmed four domains: acute symptoms (eight items), activities of daily living (seven items), psychological (seven items) and participation (eight items). The overall scale had adequate Rasch model fit (χ² = 25.219, degrees of freedom = 24, P = 0.394). Convergent validity with EQ5D-5L, ICECAP-A and Cat-PROM5 was confirmed through hypothesis testing. Internal consistency and test–retest reliability were excellent. The final GCA-PRO is a 30-item, four-domain scale with robust evidence of validity and reliability in measuring HRQoL in people with GCA.

Background: A multicentre feasibility trial (MIAMI), comparing outcomes and quality of life of women with multiple ipsilateral breast cancer randomised to therapeutic mammoplasty or mastectomy, was conducted from September 2018 to March 2020. The MIAMI surgical trial aimed to investigate recruitment of sufficient numbers of women. Multidisciplinary teams at 10 breast care centres in the UK identified 190 with MIBC diagnosis; 20 were eligible for trial participation but after being approached only four patients were recruited. A nested qualitative study sought to understand the reasons for this lack of recruitment. Methods: Interviews were conducted from November 2019 to September 2020 with 17 staff from eight hospital-based breast care centres that recruited and attempted to recruit to MIAMI; and seven patients from four centres, comprising all patients who were recruited to the trial and some who declined to take part. Interviews were audio-recorded, anonymised and analysed using thematic methods of building codes into themes and sub-themes using the process of constant comparison. Results: Overarching themes of (1) influences on equipoise and recruitment and (2) effects of a lack of equipoise were generated. Within these themes, health professional themes described the barriers to recruitment as ‘the treatment landscape has changed’, ‘staff preferences and beliefs’ which influenced equipoise and patient advice; and how different the treatments were for patients. Patient themes of ‘altruism and timing of trial approach’, ‘influences from consultants and others’ and ‘diagnostic journey doubts’ all played a part in whether patients agreed to take part in the trial. Conclusions: Barriers to recruiting to breast cancer surgical trials can be significant, especially where there are substantial differences between the treatments being offered and a lack of equipoise communicated by healthcare professionals to patients. Patients can become overwhelmed by numerous requests for participation in research trials and inappropriate timing of trial discussions. Alternative study designs to the gold standard randomised control trial for surgical interventions may be required to provide the high-quality evidence on which to base practice. Trial registration: ISRCTN (ISRCTN17987569) registered on April 20, 2018, and ClinicalTrials.gov (NCT03514654).

Background: Barth syndrome is a rare, life-threatening, X-linked recessive genetic disease that predominantly affects young males and is caused by abnormal mitochondrial lipid metabolism. Currently, there is no definitive treatment for Barth syndrome other than interventions to ameliorate acute symptoms, such as heart failure, cardiac arrhythmias, neutropenia, and severe muscle fatigue. Previous mechanistic studies have identified the lipid-lowering drug bezafibrate as a promising potential treatment; however, to date, no human trials have been performed in this population. Objective: The aim of this study is to determine whether bezafibrate (and resveratrol in vitro) will increase mitochondrial biogenesis and potentially modify the cellular ratio of monolysocardiolipin (MLCL) to tetralinoleoyl-cardiolipin (L4-CL), ameliorating the disease phenotype in those living with the disease. Methods: The CARDIOMAN (Cardiolipin Manipulation) study is a UK single-center, double-blinded, randomized, placebo-controlled crossover study investigating the efficacy of bezafibrate in participants with Barth syndrome. Treatment was administered in two 15-week phases with a minimum washout period of 1 month between the phases where no treatment was administered. The primary outcome is peak oxygen consumption (VO2 peak). Secondary outcomes include MLCL/L4-CL ratio and CL profile in blood cells, amino acid expression, phosphocreatine to adenosine triphosphate ratio in cardiac muscle and skeletal muscle oxidative function on phosphorus-31 magnetic resonance spectroscopy, quality of life using the Pediatric Quality of Life Inventory questionnaire, absolute neutrophil count, cardiac function and rhythm profiles at rest and during exercise, and mitochondrial organization and function assessments. Outcomes were assessed at baseline and during the final week of each treatment phase. Results: A total of 12 patients were scheduled to participate across three consecutive research clinics between March and April 2019. In total, 11 participants were recruited, and the follow-up was completed in January 2020. Data analysis is ongoing, with publication expected in 2021. Conclusions: This trial was approved by the United Kingdom National Research Ethics Service Committee and the Medicines and Healthcare products Regulatory Agency. The feasibility of the CARDIOMAN study will help to inform the future conduct of randomized controlled trials in rare disease populations as well as testing the efficacy of bezafibrate as a potential treatment for the disease and advancing the mechanistic understanding of Barth syndrome. Trial Registration: International Standard Randomized Controlled Trial Number (ISRCTN): 58006579; https://www.isrctn.com/ISRCTN58006579 International Registered Report Identifier (IRRID): DERR1-10.2196/22533

BACKGROUND Barth syndrome is a rare, life-threatening, X-linked recessive genetic disease that predominantly affects young males and is caused by abnormal mitochondrial lipid metabolism. Currently, there is no definitive treatment for Barth syndrome other than interventions to ameliorate acute symptoms, such as heart failure, cardiac arrhythmias, neutropenia, and severe muscle fatigue. Previous mechanistic studies have identified the lipid-lowering drug bezafibrate as a promising potential treatment; however, to date, no human trials have been performed in this population. OBJECTIVE The aim of this study is to determine whether bezafibrate (and resveratrol in vitro) will increase mitochondrial biogenesis and potentially modify the cellular ratio of monolysocardiolipin (MLCL) to tetralinoleoyl-cardiolipin (L4-CL), ameliorating the disease phenotype in those living with the disease. METHODS The CARDIOMAN (Cardiolipin Manipulation) study is a UK single-center, double-blinded, randomized, placebo-controlled crossover study investigating the efficacy of bezafibrate in participants with Barth syndrome. Treatment was administered in two 15-week phases with a minimum washout period of 1 month between the phases where no treatment was administered. The primary outcome is peak oxygen consumption (VO2 peak). Secondary outcomes include MLCL/L4-CL ratio and CL profile in blood cells, amino acid expression, phosphocreatine to adenosine triphosphate ratio in cardiac muscle and skeletal muscle oxidative function on phosphorus-31 magnetic resonance spectroscopy, quality of life using the Pediatric Quality of Life Inventory questionnaire, absolute neutrophil count, cardiac function and rhythm profiles at rest and during exercise, and mitochondrial organization and function assessments. Outcomes were assessed at baseline and during the final week of each treatment phase. RESULTS A total of 12 patients were scheduled to participate across three consecutive research clinics between March and April 2019. In total, 11 participants were recruited, and the follow-up was completed in January 2020. Data analysis is ongoing, with publication expected in 2021. CONCLUSIONS This trial was approved by the United Kingdom National Research Ethics Service Committee and the Medicines and Healthcare products Regulatory Agency. The feasibility of the CARDIOMAN study will help to inform the future conduct of randomized controlled trials in rare disease populations as well as testing the efficacy of bezafibrate as a potential treatment for the disease and advancing the mechanistic understanding of Barth syndrome. CLINICALTRIAL International Standard Randomized Controlled Trial Number (ISRCTN): 58006579; https://www.isrctn.com/ISRCTN58006579 INTERNATIONAL REGISTERED REPORT DERR1-10.2196/22533

Behavioural responses to COVID-19 lockdown will define the long-term impact of psychological stressors on sleep and brain health. Here we tease apart factors that help protect against sleep disturbance. We capitalise on the unique restrictions during COVID-19 to understand how time of day of daylight exposure and outside exercise interact with chronotype and sleep quality. 3474 people from the UK (median age 62, range 18-91) completed our online ‘SleepQuest’ Study between 29th April and 13th May 2020 – a set of validated questionnaires probing sleep quality, depression, anxiety and attitudes to sleep alongside bespoke questions on the effect of COVID-19 lockdown on sleep, time spent outside and exercising and self-help sleep measures. Significantly more people (n=1252) reported worsened than improved sleep (n=562) during lockdown (p<0.0001). Factors significantly associated with worsened sleep included low mood (p<0.001), anxiety (p<0.001) and suspected, proven or at risk of COVID-19 symptoms (all p<0.03). Sleep improvement was related to the increased length of time spent outside (P<0.01). Older people’s sleep quality was less affected than younger people by COVID lockdown (p<0.001). Better sleep quality was associated with going outside and exercising earlier, rather than later, in the day. However, the benefit of being outside early is driven by improved sleep in ‘owl’ (p=0.0002) and not ‘lark’ (p=0.27) chronotype, whereas, the benefit of early exercise (inside or outside) did not depend on chronotype. Defining the interaction between chronotype, mental health and behaviour will be critical for targeted lifestyle adaptations to protect brain health through current and future crises.