INTRODUCTION:The medial prefrontal cortex (mPFC) is critical for executive function, behavioral inhibition, and memory. Its high vulnerability to dementia, compared to other prefrontal regions, remains unclear. METHODS:We analyzed post mortem brain tissue from 118 older subjects, including post-stroke survivors, Alzheimer's disease; vascular, mixed, and frontotemporal dementia (FTD); and cognitively unimpaired controls. Three-dimensional stereology was used to assess pyramidal neuron densities and volumes in mPFC layers III and V. Immunohistochemistry evaluated metabolic dysfunction via cytochrome c oxidase subunit 1 (COX1), cytochrome c oxidase subunit 4 (COX4), and 78 kDa glucose-regulated protein expression. RESULTS:Pyramidal neuron densities were lowered by ≈ 45% and volumes by ≈ 37% within all dementia groups relative to controls, except for FTD densities. COX1 and COX4 mitochondrial markers were consistently reduced across dementias. Neuronal densities declined with age, especially in the sixth decade of life. Other prefrontal areas were less affected. DISCUSSION:The mPFC shows high neuronal vulnerability in dementia, while suggesting a vascular-metabolic mechanism, with implications for targeted therapeutic strategies. HIGHLIGHTS:Severe pyramidal neuron loss and atrophy arose in the medial prefrontal cortex. Neuronal morphometric changes correlated with cognitive status or aging effects. Metabolic changes decreased by the greatest extent in vascular-associated dementias. Metabolic neuronal markers correlated with aging and frontal vascular pathology.

Abstract Background People living with dementia (PLWD) and mild cognitive impairment (MCI), and their family carers, often experience sleep disturbance which can impair daily living and care. There are limited options for effective long-term pharmacological management of sleep disturbance, yet recent advances in non-pharmacological approaches offer promising alternatives. TIMES is a novel, complex intervention, which aims to improve wellbeing for PLWD/MCI and their carers in primary care, by developing whole-person, tailored care plans that optimise management of sleep disturbance in context. Methods Two-arm cluster-randomised (1:1), single-blinded, feasibility trial in 10 general practice sites in England, recruiting 64 patient–carer dyad participants (32 intervention + 32 treatment as usual). Co-primary objectives are to assess the feasibility and acceptability of conducting a subsequent definitive cluster-randomised controlled trial (cRCT) of the TIMES intervention. Secondary objectives include assessing the ability to collect data to address putative primary and secondary outcomes of a definitive cRCT. We will collect participant demographics at screening, and the following outcome measures at baseline, 9 and 15 week follow-ups: Sleep Disorders Inventory (SDI); Epworth Sleepiness Scale (ESS); Activities of Daily Living assessed with the Disability Assessment for Dementia (ADL DAD); Dementia Quality of Life Measure (DEMQOL); EQ-5D 5 level (EQ-5D-5L); ICEpop Capability measure for older people aged ≥ 65 (ICECAP-O); Neuropsychiatric Inventory Questionnaire (NPI-Q); Client Service Receipt Inventory (CSRI); Telephone Montreal Cognitive Assessment (T-MoCA); patient medical records review; patient serious adverse events (SAEs). We will conduct Process Evaluation interviews and Discrete Choice Experiments to inform refinement of the intervention content and delivery. Discussion Our findings will inform the refinement and delivery of a subsequent definitive cRCT that tests the clinical and cost-effectiveness of the TIMES intervention compared with usual care. Trial registration This study received approval from the Health Research Authority (HRA) and London–Harrow Research Ethics Committee (Reference: 24/LO/0123), and is sponsored by the University of Exeter (Reference: 2021–22-38). Trial registration: ISRCTN, ISRCTN54051676, registered 20 March 2024, https://www.isrctn.com/ISRCTN54051676 .

Abstract Objective A mixed-methods process evaluation was conducted alongside a multi-site feasibility trial of RecoverED, a multicomponent delirium rehabilitation intervention for older people in post-acute settings. A modified Conceptual Model for Implementation Fidelity was used. Findings on implementation and acceptability are presented. Design and methods Older adults with delirium, their carers, and trained healthcare professionals (HCPs) from six UK NHS hospitals participated. Adherence to content, dose, and coverage, alongside moderating factors such as recruitment, context, and delivery quality, were examined. Findings from in-depth interviews, focus groups, trial documentation, and training logs were triangulated. Results Nineteen participant-carer pairs were recruited to the study. Post-intervention, five older adults, nine carers, and eight HCPs participated in interviews, while seven HCPs took part in focus groups. Adherence to content was challenging to assess due to the intervention’s personalised nature. Psychosocial support was delivered more frequently than planned. Participant-led goals were highly valued, with strong engagement and perceived benefit. Implementation was largely as intended. Most withdrawals (N = 10) were attributed to complex needs. No participants from minority ethnic backgrounds were recruited. Conclusions The RecoverED intervention was acceptable, though recruitment and retention challenges necessitate caution when interpreting acceptability and fidelity to dose and coverage. Implementation fidelity was high and well-received.

Introduction Introduction: Ageing is associated with the pathological accumulation of damaged proteins (termed proteinopathies) that affect the cardiovascular system and the brain. Spontaneous chemical reactions such as deamidation lead to degenerative protein modifications (DPMs), including the formation of isoAsp-Gly-Arg (isoDGR) motifs. These DPMs can cause toxic gain-of-function effects, promote inflammation, and can contribute to chronic conditions such as vascular cognitive impairment and dementia. The burden of isoDGR in relation to neurofibrillary pathology however is not known across the dementias. Methods Methods: We systematically assessed isoDGR and phosphorylated-Tau (pTau) immunoreactivites in terms of densities and co-localisation frequencies across a range of dementia disorders including: post-stroke dementia, vascular dementia (VaD) and Alzheimer’s disease (AD), Mixed dementia as well as in post-stroke survivors without dementia and normal ageing control subjects (n=60; age range 73-99; male 52%). Results Results: We found that isoDGR and pTau immunoreactivities were similar across all assessed hippocampal regions including CA1, CA2/CA3 and entorhinal cortex (p=0.71), but isoDGR burden differed across disorder groups in all regions (CA1: p=0.008; CA2/3: p<0.001; entorhinal cortex: p=0.05). VaD had higher isoDGR concentrations in all hippocampal regions and was the only group with strong positive correlations between isoDGR and pTau levels (r=.86, p<0.01). AD subjects showed significantly higher levels of pTau and co-localisations in all regions. However, isoDGR exceeded pTau quantity in all hippocampal regions. Conclusions Conclusions: We noted isoDGR to be significantly high in VaD in the general absence of pTau or neurofibrillary pathology. While isoDGR may be used as a potential biomarker for this subtype of dementia, greater concentrations of isoDGR compared to pTau suggests it may precede and promote neurofibrillary pathology. This also highlights anti-isoDGR as a potential therapeutic target in dementia.

ObjectiveEvidence suggests that patient-level characteristics such as socio-economic status or ethnicity affect the likelihood of receiving guideline recommended anti-dementia medications. Existing studies often included all-cause dementia, not just the specific subtypes in which medication is indicated. Patterns of prescribing of Acetyl Cholinesterase Inhibitors (AChEIs) and memantine require further exploration, with little evidence about rates of co-prescribing in English primary care. We examined variations in anti-dementia medication prescribing with patient-level characteristics, and over time.Design and settingRetrospective cohort study, using the Clinical Practice Research Datalink Aurum. Data from 1,489 practices, in England between 2006-2024, were included and linked to patient level Index of Multiple Deprivation data (2019). Cox-regression modelling, clustered at practice level, assessed association between patient-level characteristics and receiving AChEIs, and/or memantine. Time-series analyses examined co-prescribing of memantine and AChEIs.Participants242,007 patients, aged >=18 years, with Alzheimer's or Lewy-Body Dementia, or mixed dementia including one of these subtypes, were included.ResultsAmong the 242,007 patients, 63.1% were prescribed an anti-dementia medication; co-prescribing of memantine and AChEIs peaked at 4.2%. Those in the most deprived quintile were less likely to be prescribed AChEIs (Hazard Ratio (HR) 0.82,0.78-0.86) compared to the most affluent quintile. People with Asian (HR 0.89,0.84-96), or Black (HR 0.79, 0.73-0.86) ethnicities were less likely to be prescribed memantine compared to white people. Those with learning disabilities were substantially less likely to be prescribed AChEIs (HR 0.46,0.42-0.50) or memantine (HR 0.58, 0.50-0.67) compared to those without.ConclusionOverall rates of prescribing of anti-dementia medications were lower than expected. Rates of co-prescription of AChEIs and memantine were low, despite guideline recommendations. We found inequity in anti-dementia medication prescribing, relating to multiple patient-level characteristics highlighting the need for more equitable access to evidence-based treatments.

BackgroundDelirium in older adults is associated with persistent cognitive and functional decline, increased institutionalisation, and higher mortality. Evidence-based strategies to support recovery after hospitalisation remain limited. This paper outlines the development and refinement of the programme theory underpinning RecoverED, a novel, home-based, multicomponent rehabilitation intervention designed to support post-delirium recovery.MethodsWe applied a realist-informed, multi-stage process to develop the RecoverED programme theory. This included a rapid realist review, qualitative interviews with older adults, carers, and healthcare professionals, an expert panel workshop, iterative programme theory meetings, and a process evaluation embedded within a single-arm feasibility trial. Data were synthesised into a logic model linking intervention components to hypothesised mechanisms and outcomes.ResultsThe programme theory outlines how cognitive and physical rehabilitation, psychosocial support, health monitoring, lifestyle guidance, and delirium education are expected to promote recovery. Cognitive activities aim to rebuild executive function and daily independence; physical rehabilitation maintains mobility; psychosocial support reduces anxiety and promotes confidence; health monitoring and lifestyle guidance address comorbidities; and delirium education supports sense-making. Key mechanisms include personalised goal-setting, continuity of professional support, and integration with community services. The process evaluation within the feasibility trial confirmed the relevance and acceptability of these pathways, while suggesting refinements to training, psychosocial strategies, and education delivery.ConclusionThis paper provides an empirically grounded framework detailing the development and refinement of a programme theory for post-delirium rehabilitation, illustrating the value of flexible, theory-driven approaches to guiding recovery.

BACKGROUND:Digital multidomain interventions hold promise for dementia risk reduction; however, populations at higher dementia risk, including those experiencing socioeconomic and educational disadvantage, remain underrepresented in trials, and engagement with digital interventions often declines over time. Coproduction and blended models that combine digital tools with human support may improve reach, acceptability, usability, and sustained engagement. Designing interventions that are usable and acceptable for individuals facing structural, educational, or digital barriers (underserved groups) is therefore likely to produce solutions that are both accessible and scalable for the wider midlife and older adult population. OBJECTIVE:This study aims to describe the coproduction process used to develop ENHANCE (Tailored Intervention for Brain Health and Cognitive Enrichment)-a coach-supported digital intervention targeting 10 modifiable dementia risk factors in older adults from underserved groups-and report key outputs and lessons learned for equitable digital prevention design. METHODS:We coproduced ENHANCE between July 2023 and February 2025 using a multistage development process guided by the Medical Research Council framework for complex interventions and the Double Diamond design model. The person-based approach informed user-centered guiding principles (key design objectives), while behavior change content was operationalized using behavioral change theories. Coproduction followed 4 phases. The Discovery phase explored barriers to engagement with existing digital materials and identified candidate components for each dementia risk-factor module. The Define phase translated these insights into guiding principles and blueprints of each risk-factor module integrated with behavioral change components. The Design phase involved iterative co-production and usability testing of prototypes. The Delivery phase evaluated a high-fidelity prototype through a 1-week usability study with coaching support. Contributors included 162 research participants recruited from underserved community settings, 33 patient and public involvement contributors, and 4 human-computer interaction experts. Throughout development, coproduction focused on reducing literacy, digital confidence, and cultural barriers to maximize usability across diverse adult populations. RESULTS:Coproduction produced (1) evidence-informed module strategies for targeted dementia risk factors; (2) a set of guiding principles to ensure low-literacy, culturally relevant, and accessible content, supporting both equity of access and wider population usability; (3) a meadow-themed app integrating tailored check-ins, educational videos, cognitive training games, and in-app messaging; and (4) a structured coaching model, including onboarding, brief follow-up, and accompanying coaching manuals. Iterative testing and refinement improved navigation, simplified language, reduced text burden, and ensured the use of familiar and accessible game formats, resulting in a feasibility-ready prototype. CONCLUSIONS:ENHANCE is a coproduced, coach-supported digital intervention designed to be accessible for underserved midlife and older adults at increased dementia risk, with design features to support accessibility, engagement, and scalability across the wider aging population. The development process illustrates how integrating coproduction with behavioral science and usability methods can support principled intervention design for equitable digital dementia prevention.

Detection and characterisation of dementia and Mild Cognitive Impairment (MCI) is essential for diagnosis and to support recruitment of patients into trials of disease-targeted therapies. Computerised systems offer a means of improving detection in community and primary care settings in a scalable way. This study presents further validation of the self-test PROTECT Cognitive Test System of eight assessments of memory, attention and executive function in 36,941 participants (35,822 healthy, 1046 MCI, 73 dementia). PROTECT shows robust separation of dementia and non-dementia participants ( p < 0.001), and good discriminative ability for dementia (Area Under the Curve = 0.966) with 90.90% sensitivity and 87.80% specificity. An optimised detection algorithm robustly identified MCI (P<0.001) and predicted 24-month decline across cognitive domains in both amnestic MCI and non-amnestic MCI phenotypes compared with healthy controls. PROTECT cognitive data also correlated strongly with the plasma biomarkers p-tau217 and Neurofilament Light ( n = 46). The system provides a means of improving dementia and MCI detection using self-testing, offering a scalable triage and monitoring tool for clinical pathways and trials.

Background Delirium is a common neurocognitive disorder in older adults and is associated with poor outcomes. Cognitive, mood and functional deficits can persist for months following an episode, impacting long-term well-being. While previous research has focused on delirium prevention and guidelines exist for short-term management, there remains a critical gap in understanding and supporting longer-term recovery. Objectives Objectives were to: (1) develop an intervention to improve recovery after delirium; (2) conduct a feasibility study of the intervention in people who have had delirium; and (3) conduct a definitive randomised controlled trial and cost-effectiveness analysis of the intervention in people who have had delirium compared with usual care, with parallel process evaluation and an embedded implementation study. Design The study consisted of four work packages. In work package 1, we designed a complex, theory-based rehabilitation intervention informed by a realist review, qualitative research and expert panel input. Work package 2, using a single-arm study, assessed the feasibility of the intervention and of undertaking a definitive randomised controlled trial and cost-effectiveness analysis with an embedded process evaluation, while the aim of work package 3 was to test its effectiveness in a definitive randomised controlled trial, and the aim of work package 4 was to focus on implementation in real-world settings. Setting Acute admissions wards and community follow-up after discharge at six National Health Service hospital sites. Participants Patients aged ≥ 65 years experiencing delirium during acute hospital admission. Intervention Home-based rehabilitation programme designed to support recovery after hospital discharge, addressing cognitive, physical, physiological and psychosocial needs. Delivered by a trained team of occupational therapists, physiotherapists and rehabilitation support workers, the intervention included a comprehensive home assessment, collaborative goal setting, up to 10 personalised therapy sessions over 12 weeks, the use of a recovery record to guide progress, education and psychosocial support. Main outcome measures The main objective of work package 1 was the development of a theory-based and person-centred rehabilitation intervention for individuals recovering from delirium. It included structured components targeting physical, cognitive and emotional recovery, along with an intervention manual and training materials for healthcare professionals. In work package 2, we assessed feasibility, including eligibility, recruitment, data collection, attrition, acceptability of the rehabilitation intervention and the cost-effectiveness framework for a subsequent definitive trial. Patient and carer participants and professional delivering the intervention were interviewed in a process evaluation. Results The intervention was developed using insights from a realist review, stakeholder interviews and expert panel discussions, identifying key recovery domains: physical, cognitive and emotional. Key facilitators included carer involvement, tailoring to individual needs, fostering interpersonal connections and promoting positive self-expression. The feasibility study identified 435 patients with delirium across 6 hospitals, of whom 36 (8%) met eligibility criteria, with 19 (53%) of these consenting to participate. Among those enrolled, 13 (68%) started the intervention, and 10 (53%) completed the final follow-up. Participants had a mean (standard deviation) baseline disability assessment for dementia score of 43.7 (27.1), reflecting the functional status of the recruited population. The mean cost of delivering the intervention was £1249 per participant. The process evaluation highlighted the intervention’s flexibility, acceptability and strong continuity of care, although challenges in recruitment and retention were noted. Limitations In work package 2, the study was limited by a lack of ethnic diversity, reliance on clinical teams for delirium diagnosis and potential selection bias due to staff capacity constraints, which may have impacted recruitment and generalisability. Recruitment was insufficient to progress to the definitive randomised controlled trial, preventing further evaluation and the final implementation study. Following a funding review, the programme was discontinued after work package 2. Patient and public involvement and engagement A patient and public involvement and engagement group of people who had experienced delirium and carers was involved throughout the programme. They assisted with participant materials, design of the intervention, interpretation of the results and recruitment strategies. Conclusions A multidisciplinary rehabilitation intervention for delirium recovery was successfully developed and implemented, with high engagement from participants who remained in the study. However, challenges in recruitment and retention to an evaluation study must be addressed. Future work Future research should focus on understanding hospital processes, the natural history of delirium recovery, community pathways and available services. Refining inclusion criteria will be essential to ensure the feasibility of conducting a randomised controlled trial or other evaluation of the intervention. Study registration This study is registered as ISRCTN15676570, registered 13 December 2022. https://doi.org/10.1186/ISRCTN15676570 Funding This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research Programme (NIHR award ref: NIHR202338) and is published in full in Programme Grants for Applied Research; Vol. 14, No. 7. See the NIHR Funding and Awards website for further award information. Plain language summary Delirium is a serious condition that often affects older people, especially those with dementia. It causes confusion, difficulty focusing and problems with memory and thinking. People with delirium in hospital often need more help on returning home due to problems with mobility and thinking. While most research has focused on preventing delirium, not enough attention has been given to helping people recover from it once back at home. The RecoverED programme was designed to help older adults recover from delirium by supporting their physical, mental and emotional well-being. The programme included exercises to help with physical recovery, activities to improve memory and thinking, and support to help people feel emotionally better. The first part of the study focused on creating the best possible recovery plan by talking to experts, patients and carers. In the second part, the programme was tested with older adults who had delirium in hospital, once they were back at home. We found 435 patients with delirium across 6 hospitals. Thirty-six (8%) were suitable for the trial and 19 took part. Ten people (53%) completed the final follow-up. The results showed that people found the programme to be helpful and felt better after taking part. However, if we had been able to recruit more people, we may have found more changes that needed to be made. The study also faced difficulty in finding enough participants, community rehabilitation staff to deliver it and making sure the programme reached people from all backgrounds. We planned to go on to a full randomised controlled trial of the programme and a study of how to make it work in the National Health Service. However, we were unable to do this because of the difficulties in finding participants in the second part of the study. The study showed that we need to improve how we recruit people, make it clearer who the programme is best suited to and find better ways to support those with complex health needs. Future studies will need to address the challenges we found in recruitment. They should focus on involving people from different backgrounds and finding ways to make the programme available to more people who need it. Scientific summary Background Delirium is a common and serious neurocognitive disorder affecting older adults, particularly those with pre-existing dementia. It is characterised by acute disturbances in attention, awareness and cognition, and it is associated with prolonged hospital stays, functional decline and increased mortality. Beyond the immediate episode, delirium has lasting consequences, with many individuals experiencing persistent cognitive and functional impairments and an increased likelihood of institutionalisation. The condition also places significant emotional and practical burdens on carers while contributing to healthcare costs. Despite its widespread impact, research on delirium has largely focused on prevention and short-term management, leaving a critical gap in understanding and supporting long-term recovery. Emerging evidence suggests that rehabilitation could aid recovery following delirium, yet older adults with cognitive impairment are often incorrectly perceived as having limited rehabilitation potential. Current guidelines highlight the need for effective, non-pharmacological interventions to support long-term recovery after an episode of delirium, particularly for individuals with delirium superimposed on dementia. However, there remains a lack of structured rehabilitation strategies tailored to this population. Addressing this gap requires a deeper understanding of the factors influencing recovery and the development of targeted interventions that promote cognitive and functional improvements, enhance patient and caregiver well-being and reduce healthcare burdens. Aims, objectives and summary of approach The aim of the RecoverED research programme was to develop an intervention to improve recovery following delirium and to evaluate its effectiveness, cost-effectiveness and feasibility for implementation in clinical practice. The intervention targeted the cognitive, functional and emotional aspects of recovery, providing a comprehensive approach to supporting individuals who have experienced delirium. Work package 1: intervention design Work package (WP) 1 aimed to develop a comprehensive programme theory to understand what improves recovery after delirium, for whom and in what context. This programme theory provided the foundation for co-designing a complex rehabilitation intervention for older adults (aged ≥ 65 years) recovering from delirium following acute hospital admission. Work package 2: feasibility and acceptability Work package 2 was a single-arm feasibility single-arm study aimed at assessing the feasibility and acceptability of a home-based rehabilitation intervention designed for older adults who have experienced delirium during acute hospitalisation. The primary objective was to evaluate trial feasibility, whether the intervention was acceptable to both participants and their carers. Secondary objectives included examining the intervention’s acceptability among diverse populations, testing the feasibility of collecting outcome data for a definitive randomised controlled trial (RCT), testing the framework for a future cost-effectiveness analysis (CEA) alongside a definitive trial and engaging in iterative refinements of the intervention. Stop-go criteria determined whether to go on to a full trial. The programme was coproduced with our patient and public involvement and engagement (PPIE) group. Work package 3 was planned to be a definitive RCT of the intervention in 12 sites across the UK. WP4 was planned to be an implementation study of the intervention in two sites, with clinical teams identifying participants rather than research teams. However, following a funding review, the programme was discontinued after WP2 due to significant challenges in identifying and recruiting participants. Despite efforts to refine recruitment strategies, the feasibility study faced persistent difficulties, which limited the number of participants who could take part. These challenges raised concerns about the viability of progressing to a full-scale RCT. As a result, plans for a definitive RCT, CEA and implementation study were halted. Methods and results Work package 1: methods Work package 1 of the RecoverED programme followed Medical Research Council guidelines for complex interventions, using a realist approach to develop a programme theory on improving delirium recovery. This involved five key stages: (1) a rapid realist review to synthesise mechanisms for improving recovery from delirium; (2) qualitative realist interviews with 8 older people who had experienced delirium, 14 carers and 24 healthcare professionals (HCPs) to understand rehabilitation needs; (3) an expert panel workshop to refine the theory and review findings; (4) a series of programme theory development meetings with the core team to revise and produce a logic model and (5) an evaluation of the intervention’s implementation, assessing fidelity and acceptability. A multidisciplinary approach was used in the intervention design, integrating expertise from physiotherapy, occupational therapy, psychology, geriatric medicine and other specialists, informed by the International Classification of Functioning, Disability and Health framework. Continued engagement with our PPIE group ensured that the intervention remained practical, patient-centred and culturally relevant. Work package 1: results The realist review identified three recovery domains: physical recovery through exercise, cognitive recovery with reality orientation and stimulation and emotional recovery through conversations with skilled professionals. Four key facilitators were identified: carer involvement, tailoring the intervention to individual needs, fostering interpersonal connections and promoting positive self-expression. Stakeholder interviews further emphasised the importance of rehabilitation, emotional support, delirium education and addressing health conditions. Expert panel discussions refined the programme theory, emphasising a person-centred approach, integration of rehabilitation into daily life, carer engagement and continuity of relationships with professional carers. This theory guided the development of the RecoverED intervention, ensuring that it addressed the complex needs of delirium recovery. Work package 2: methods Work package 2 employed a multicentre, single-arm feasibility study design with an embedded process evaluation. Participants were recruited from six NHS hospitals in the UK, focusing on individuals aged ≥ 65 years who had been diagnosed with delirium and were expected to return home. The RecoverED intervention, aimed at supporting recovery, began within 2 weeks of discharge and consisted of a structured rehabilitation programme, including assessments by physiotherapists (PTs) and occupational therapists (OTs) and up to 10 sessions delivered by a rehabilitation support worker (RSW) over 12 weeks. Feasibility outcomes were assessed through recruitment and retention rates, with mixed methods used to evaluate implementation fidelity and acceptability. The resources required to deliver the RecoverED intervention and their associated costs, health-related quality of life and well-being outcomes measured using instruments suitable for generating quality-adjusted life-years (QALYs) and well-being-adjusted life-years (WALYs), and participants’ use of health, social care and wider societal resources and their associated costs were also assessed to inform a potential future CEA. Work package 2: results Out of 435 patients identified with delirium across 6 hospitals, 36 (8.2%) met the eligibility criteria, and 19 (53%) of patient–carer pairs consented to participate. Of these, 13 participants (68%) started the intervention, and 10 (53%) completed the final follow-up. The mean participant age was 83.8 years, with 60% being men and 26% having dementia as a comorbidity. Participants had a mean [standard deviation (SD)] baseline disability assessment for dementia scores of 43.7 (SD: 27.1), reflecting the functional status of the recruited population. Intervention adherence was 53%, with 10 participants completed at least 6 or more intervention sessions. At baseline, 79% of participants showed delirium markers, but none did at follow-up. The mean cost per participant for delivering the RecoverED intervention was £1249, although challenges arose in gathering data for non-contact activities. Mean (SD) QALY gains for patients and carers, based on self-reported EuroQol-5 Dimensions, five-level version responses over the 6-month follow-up period, were 0.273 (0.168) and 0.403 (0.092), respectively. Mean (SD) WALY gains were 0.368 (0.075) for patients (based on ICEpop CAPability measure for older people) and 0.427 (0.056) for carers (ICEpop CAPability measure for adults), indicating positive effects on health-related quality of life and well-being in both groups. Analysis of total participant resource use and costs was limited due to missing data. Challenges in recruitment and retention were identified, with health-related withdrawals and inconsistent delirium screening contributing to lower recruitment than anticipated. The process evaluation showed that the intervention was well received and delivered with good fidelity. It was flexible and tailored to individual needs, with strong continuity of care provided by the same HCP team. While some mobility tasks were underdelivered due to health issues or poor weather, the intervention was largely seen as acceptable and beneficial. Discussion The RecoverED programme has several notable strengths, including its comprehensive, theory-driven design developed through an iterative co-design process. This process integrated expertise from geriatricians, PTs, OTs and clinical psychologists, ensuring the intervention’s clinical relevance and theoretical foundation. The involvement of a PPIE group ensured that the intervention was practical and patient-centred. Moreover, the development of a structured manual and training programme for RSWs was a significant achievement, enhancing their preparedness and ability to implement the intervention effectively. The intervention was well received by participants, with positive feedback regarding its perceived value and benefits. High consent rates among eligible participants and strong engagement from those who remained in the study further underscore the potential of the intervention. Despite these strengths, the study encountered several limitations. Recruitment was a significant challenge, with only a small percentage of screened patients meeting the eligibility criteria. This was partly due to staff capacity constraints, inconsistent routine delirium screening practices and the predominance of clinical teams diagnosing delirium rather than research staff. Since clinical teams were responsible for diagnosing delirium as part of routine care, there was variability in how and when delirium was identified, leading to potential inconsistencies in patient eligibility for the study. By contrast, if research staff had been directly involved in the screening and diagnosis process using standardised criteria, it may have improved consistency and ensured a more reliable identification of eligible participants. Additionally, missing data on intervention costs and participant resource use limited the ability to conduct a full economic evaluation. Future studies should implement more robust data collection strategies to ensure a more comprehensive assessment of cost-effectiveness. The process evaluation was limited due to the small number of participants and the withdrawal of more impaired participants from the trial. A more extensive evaluation may have revealed more weaknesses in the intervention and a need for further refinement. Another limitation was the homogeneity of the study sample, as all participants were White, which limits the understanding of how the intervention may be received by different ethnic and cultural groups. Furthermore, the reliance on clinical teams for diagnosis rather than standardised research staff-based approaches revealed weaknesses in the screening process, leading to missed recruitment opportunities. Finally, the absence of participants from minority ethnic, racial or linguistic groups and the challenges in retaining participants due to health deterioration or relocation suggest the need for improved inclusion strategies and a more inclusive approach to recruitment in future studies. Conclusion The RecoverED programme successfully developed a theory-driven, multidisciplinary intervention aimed at supporting recovery following delirium. Despite recruitment challenges and limitations in participant diversity, the qualitative data from the feasibility study demonstrated some evidence that the intervention could be delivered in clinical practice, was well received and participants reported perceived benefits. The process evaluation provided some insights into how the intervention was implemented and how it could be refined for future studies, but more participants were needed for a comprehensive evaluation. The findings from this study underline the importance of addressing key challenges in recruiting and retaining a diverse sample, including individuals from minority ethnic groups and those transitioning to care homes. Further research is needed to explore how the intervention can be adapted and optimised to support these groups. Given the pressing need for effective delirium recovery interventions, future studies should consider novel trial designs and alternative funding models to enable the continued development and evaluation of this important area of health care. Study registration This study is registered as ISRCTN15676570, registered 13 December 2022. https://doi.org/10.1186/ISRCTN15676570 Funding This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research Programme (NIHR award ref: NIHR202338) and is published in full in Programme Grants for Applied Research; Vol. 14, No. 7. See the NIHR Funding and Awards website for further award information.

OBJECTIVES:To test a theory-informed, person-centred rehabilitation intervention for older adults following a hospital admission complicated by delirium, developed in line with the Medical Research Council framework for complex interventions, to determine whether: (a) the intervention is acceptable to individuals with delirium and (b) a definitive trial and parallel economic evaluation of the intervention are feasible. DESIGN:Multicentre, single-arm feasibility study. PARTICIPANTS:19 patient (aged >65 years old) and carer pairs were recruited from six National Health Service acute hospitals across the UK. INTERVENTION:Home-based rehabilitation programme designed to support recovery after hospital discharge, addressing cognitive, physical, physiological and psychosocial needs. Delivered by a trained team of occupational therapists, physiotherapists and rehabilitation support workers, the intervention included a comprehensive home assessment, collaborative goal setting, up to 10 personalised sessions over 12 weeks and the use of a recovery record to guide progress, education and psychosocial support. OUTCOME MEASURES:Examined aspects of feasibility including eligibility, recruitment, data collection, attrition, acceptability of the rehabilitation intervention and potential to calculate cost-effectiveness. RESULTS:In total, 419 patients were identified as having delirium and 36 met the full eligibility. 19 patient and carer pairs agreed to participate in the study (consent rate 53%; 95% CI 35% to 70%) with 13 participants going on to start the intervention (68%; 95% CI 43% to 87%) and 10 participants completing final follow-up (53%; 95% CI 29% to 76%). Baseline assessments were conducted either during hospitalisation or postdischarge, with initial assessments occurring a mean of 18 days (SD=13.0) postdischarge, and 77% completed within 14 days. Participants completed a mean of eight sessions (SD=2.9). 19 participants completed the primary outcome at baseline, while 10 participants completed it at 6-month follow-up. The economic evaluation indicated a total cost of £1249.29 per participant, covering assessments, intervention sessions and training costs. CONCLUSIONS:The intervention showed feasibility among older adults recovering from delirium, as evidenced by the trial processes for participants who entered the study. However, recruitment challenges indicate a need for better strategies and further research through a definitive randomised controlled trial to demonstrate the effectiveness and cost-effectiveness of the intervention. TRIAL REGISTRATION NUMBER:ISRCTN15676570.

Carotid artery disease (CAD) is a recognised cause of stroke. However, the relationships between CAD, cerebral small vessel disease (SVD) and dementia remain unclear. We hypothesised that CAD in older individuals contributes to cerebral SVD pathology by altering cerebral perfusion. We performed a clinicopathological study in patients from the Cognitive Function After Stroke (CogFAST) study and prospectively recruited patients with various dementia diagnoses and evidence of cerebral SVD. In addition to brain tissues, we collected postmortem samples of the internal carotid arteries (ICA) from these cohorts in the Newcastle Brain Tissue Resource. Standard neuropathological examination was performed for diagnosis and assignment of the cases per current diagnostic criteria for vascular and neurodegenerative dementias, which were assessed for the presence of vascular pathology including the degree of stenosis and sclerosis in vascular tissues. We evaluated a total of 159 ICA samples and brain tissues from all cases with evidence of SVD. Severity of ICA stenosis and sclerotic index correlated strongly with both clinical stroke and brain infarction (P < 0.001). More than 90% of the subjects had one subtype of ICA lesion in the order: intimal thickening > fibrocalcific > fibrous cap (thick) > fibrous cap (thin) > thrombus group with a strong inflammatory reaction in fibrocalcific atheromas. Regression analyses showed that ICA stenosis was positively correlated to both SVD pathology scores (P < 0.034) and the total number of vascular lesions (P < 0.001). ICA stenosis was also related to dementia caused by cerebrovascular disease (P < 0.001) and by mixed pathologies characterised by Alzheimer's disease and SVD (P = 0.025). Severity of stenosis was related to subcortical and white matter (WM) vascular lesions within the anterior circulation. ICA stenosis and sclerosis were moreover correlated with the total intracranial artery pathology scores (P < 0.001). In the CogFAST group analysis, we observed that MMSE and CAMCOG scores were lower in subjects with moderate to severe stenosis scores compared to the mild stenosis group (P < 0.05). In these CogFAST cases, by far the majority of lesions in the WM were small in size (< 5 mm, range 72-91%) but not in the cortex or basal ganglia and thalamus. Linear regression analysis further indicated that there were greater numbers of these small lesions in the WM with increasing severity of ICA stenosis (P < 0.05). Our observations suggest carotid atherosclerosis promotes cerebral SVD types of change within the intracerebral arteries. It is conceivable that extracranial ICA pathology may influence perfusion and integrity of subcortical structures including the deep WM.

Objectives To evaluate the feasibility of conducting a full-scale randomised controlled trial to assess the clinical and cost-effectiveness of the MAINTAIN intervention, designed to support recovery and independence following a fall among people living with dementia.Design Pilot cluster randomised controlled trial (c-RCT).Setting Community-based healthcare services across six UK sites representing primary and secondary care settings.Participants 31 participant-carer dyads were recruited. Eligibility criteria included a diagnosis of dementia and a recent fall. Exclusion criteria included severe comorbidity precluding participation. The consent rate was 84%, and retention at follow-up was 81%.Interventions The MAINTAIN intervention comprised tailored, home-based therapy sessions delivered by trained professionals, focusing on functional recovery, confidence and re-engagement in daily activities, compared with usual care. The intervention was delivered over 12 weeks with booster sessions up to week 24, with the full trial period lasting 28 weeks.Primary and secondary outcome measures Feasibility outcomes included recruitment and retention rates, intervention adherence and data completeness for outcome and economic measures. Exploratory outcomes assessed functional performance and quality of life. Feasibility outcomes were assessed at baseline, 12 weeks and 28 weeks.Results Recruitment occurred over an 8-month period (September 2023-April 2024) across six UK sites. Most intervention participants (89%) attended at least 60% of planned sessions. Completion rates for outcome and economic data were high, indicating strong acceptability and feasibility of both the intervention and trial procedures.Conclusions The pilot c-RCT demonstrated that recruitment, retention and intervention delivery were feasible and well accepted. Findings support progression to a definitive trial to evaluate the effectiveness and cost-effectiveness of the MAINTAIN intervention.Trial registration number ISRCTN16413728 (International Standard Randomised Controlled Trial Number registry).

Background Computerised cognitive testing offers potential for large-scale cognitive assessment and may support the identification and monitoring of early cognitive impairment, while reducing clinical burden on healthcare staff and improving efficiency.Methods Three focus groups, comprising members of the public, clinicians, commissioners, business leaders, and academics, were conducted using a semi-structured interview guide addressing acceptability, engagement, benefits, risks, and adoption. Data were analysed using thematic analysis.Results Participants identified that the successful implementation of an interactive cognitive monitoring app would depend on its acceptability, perceived usefulness, sustained engagement, accuracy and appropriate interpretation of information, robust data security, and potential efficiency gains within the health and care systems. Perceived benefits for individuals include reassurance, reduced stress, early access to assessment and support, as well as the potential to maintain quality of life. For clinicians and the health system, perceived benefits include improved efficiency through reduced consultation times and shorter waiting lists.Conclusions The findings align with existing literature on earlier identification of cognitive decline and digital cognitive assessments, highlighting the potential relevance of such technologies for supporting service delivery and enhancing efficiency within cognitive health care.Trial Registration Not applicable.

Aim To understand general practitioners’ (GPs’) experience of existing care pathways for people with moderate-severe Alzheimer’s Disease (AD) and explore their attitudes towards potential modifications to these pathways.Design Secondary thematic analysis of qualitative interviews, originally conducted with GPs to explore prescribing of memantine in general practice. The theoretical domains framework was used to structure the data.Setting The study participants were recruited via an online survey completed by GPs across England.Participants Semi-structured, qualitative interviews were conducted with thirteen male and ten female GPs from a range of general practices in England.Primary outcome Insights into GPs’ views and experiences regarding existing and possible care pathways for individuals with moderate to severe AD.Results Gaps in GPs’ current levels of knowledge and skill in respect of caring for patients with moderate-to-severe AD affect their confidence and ability to identify opportunities for additional treatments. While GPs emphasise their role as providers of holistic care, features of the current healthcare context, including a lack of additional funding, inhibit their willingness to assume additional responsibilities as part of a revised pathway.Conclusion A considerable knowledge, skills and confidence gap must be addressed to support the implementation of new care pathways that include revised responsibilities for GPs. GPs need appropriate support and resources to manage their patients’ changing needs and to provide the best possible pharmacological management as the disease develops.

BACKGROUND:Acetylcholinesterase inhibitors (AChEIs) are routinely prescribed for mild-to-moderate Alzheimer's disease (AD). National guidance advises GPs to initiate memantine for patients already taking an AChEI, as it offers small benefits for moderate-to-severe AD, with good tolerability. But this is not routinely done, potentially depriving patients of a beneficial treatment. AIM:To assess prescribing for AD in general practice, to explore factors influencing prescribing, and to identify additional education needs. DESIGN & SETTING:Mixed-methods study involving GPs in England. METHOD:An online survey and semi-structured interviews were conducted. Survey responses were analysed in StataNow (version 18.5). Interview transcriptions were coded in NVivo (version 14) by two researchers, who agreed themes. Quantitative and qualitative analyses were integrated and mapped to the Theoretical Domains Framework (TDF) and behaviour change wheel (BCW). RESULTS:Survey responders (n = 104) mostly continued rather than initiated memantine. Less than half were confident in identifying AD stages and developing care plans for moderate-to-severe AD. Overall, 46% of responders were unaware of current national guidance concerning memantine. Interviews (n = 23) mostly concurred with survey findings. Direction from local formularies conflicts with current national guidance. Mapping to TDF and BCW identified barriers to, facilitators, and interventions for changing practice. CONCLUSION:Limited time, patchy support, and Quality and Outcomes Framework downgrading contribute to a perception that dementia is not prioritised in general practice. Local systems for diagnosis and treatment reinforce GPs' feelings of inadequacy. GPs assess the impact of AD on patients and families but may not map assessments to a disease stage for memantine initiation. Interventions to change practice should boost knowledge and confidence; local pathways should clearly reflect national guidance.

BACKGROUND:Mild cognitive impairment with Lewy bodies (MCI-LB) may be identified prospectively based on the presence of cognitive impairment and several core clinical features (visual hallucinations, cognitive fluctuations, parkinsonism, and REM sleep behavior disorder). MCI-LB may vary in its presenting features, which may reflect differences in underlying pathological pattern, severity, or comorbidity.We aimed to assess how clinical features of MCI-LB accumulate over time, and whether this is associated with the rate of cognitive decline. METHODS:In this cohort study, 74 individuals seen with MCI-LB prospectively underwent repeated annual cognitive and clinical assessment up to nine years. Relationships between clinical features (number of core features present and specific features present) and cognitive change on the Addenbrooke's Cognitive Examination-Revised (ACE-R) were examined with time-varying mixed models. The accumulation of core clinical features over time was examined with a multi-state Markov model. RESULTS:When an individual with MCI-LB endorsed more clinical features, they typically experienced a faster cognitive decline (ACE-R Score Difference β = -1.1 [-1.7 to -0.5]), specifically when experiencing visual hallucinations (β = -2.1 [-3.5 to -0.8]) or cognitive fluctuations (β = -3.4 [-4.8 to -2.1]).Individuals with MCI-LB typically acquired more clinical features with the passage of time (25.5% [20.0-32.0%] one-year probability), limiting the prognostic utility of baseline-only features. CONCLUSIONS:The clinical presentation of MCI-LB may evolve over time. The accumulation of more clinical features of Lewy body disease, in particular visual hallucinations and cognitive fluctuations, may be associated with a worse prognosis in clinical settings.

BACKGROUND:Multimorbidity, the presence of two or more conditions in one person, is common but studies are often limited to observational data and single datasets. We address this gap by integrating large-scale primary-care and genetic data from multiple studies to interrogate multimorbidity patterns and producing digital resources to support future research. METHODS:We defined chronic, common, and heritable conditions in individuals aged ≥65 years, using two large primary-care databases [CPRD (UK) N = 2,425,014 and SIDIAP (Spain) N = 1,053,640], and estimated heritability using the same definitions in UK Biobank (N = 451,197). We used logistic regression to estimate the co-occurrence of pairs of conditions in the primary care data. Linkage disequilibrium score regression was used to estimate genetic similarity between pairs of conditions. Meta-analyses were conducted across databases, and up to three sources of genetic data, for each pair of conditions. We classified pairs of conditions as across or within-domain based on the international classification of disease. FINDINGS:We identified 72 chronic conditions, with 43.6% of 2546 pairs showing higher co-occurrence than chance in primary care and evidence of shared genetics. Many across-domain pairs exhibited substantial shared genetics (e.g., iron deficiency anaemia and peripheral arterial disease: genetic correlation Rg = 0.45 [95% Confidence Intervals 0.27:0.64]). 33 pairs displayed negative genetic correlations, such as skin cancer and rheumatoid arthritis (Rg = -0.14 [-0.21:-0.06]), due to potential adverse drug effects. Discordance between genetic and primary care data was also observed, e.g., abdominal aortic aneurysm and bladder cancer co-occurred in primary care but were not genetically correlated (Odds-Ratio = 2.23 [2.09:2.37], Rg = 0.04 [-0.20:0.28]) and schizophrenia and fibromyalgia were less likely to co-occur together in primary care but were positively genetically correlated (OR = 0.84 [0.75:0.94], Rg = 0.20 [0.11:0.29]). INTERPRETATION:Most pairs of chronic conditions show evidence of shared genetics, and co-occurrence in primary care, suggesting shared mechanisms. The identified patterns of shared genetics, negative correlations and discordance between genetic and observational data provide a foundation for future multimorbidity research. FUNDING:UK Medical Research Council [MR/W014548/1].

IntroductionAlthough stroke is recognized as a chronic condition, estimates of different long-term outcomes after stroke are lacking in Africa. This study aimed to explore the profile, trajectory and determinants of long-term outcomes up to 4 years in a cohort of African stroke survivors.MethodThe data analyzed were collected in a longitudinal study of stroke survivors who were prospectively recruited into the CogFAST-Nigeria Study from two specialist hospitals in Nigeria. Subjects with subarachnoid hemorrhage, co-morbid psychiatric or neurologic illness, or any systemic disease that could impair cognition were excluded from the study. Cognition was assessed using the Vascular Neuropsychological Battery, depression with the Geriatric Depression Scale—short form, and functional performance with the Barthel Index. Weibull survival model, generalized estimating equation and linear mixed models were used to identify the predictors of mortality, cognitive impairment, functional performance, and caregiver burden respectively.ResultOf the 253 stroke survivors that were recruited into the study, 157 (59.7%) were males while the overall mean age was 60.2 ± 9.8 years.The proportions of those with cognitive impairment were 126/251 (50.2%) at 3 months after stroke, 69/160 (43.1%), and 12/36 (33.3%) at 1st and 4th year respectively, while the proportion of those with depression was 39.3% at 3 months post-stroke, 35.2%, and 36.1% at year 1 and 4 respectively. Cumulative Mortality increased from 13.8% (95% CI = 10.08–18.63) at 9 months post-stroke to 45.3% (95% CI = 39.42–51.6) at 4 years follow-up. The only factor associated with mortality after adjusting for ethnicity was working as an artisan (aHR = 2.22; 95% CI = 1.77–4.02). History of previous stroke increased the likelihood of functional dependency (OR = 2.17; 95% CI = 1.19–3.95). Meanwhile, higher education (OR = 0.05; 95% CI = 0.02–0.16) protected against cognitive impairment while previous stroke (OR = 2.17; 95% CI = 1.19–3.95;) and higher caregiver burden (OR = 1.02; 95% CI = 1.01–1.02) were associated with increased risk.ConclusionImproving stroke treatment and rehabilitation is crucial, especially for those with prior stroke, as it strongly predicts poor functional and cognitive outcomes.

INTRODUCTION:Dementia is a complex medical condition that poses significant challenges to healthcare systems and support services. People living with dementia (PLWD) often face complex needs, exacerbated by social isolation and difficulty accessing support. Social prescribing (SP) has been increasingly integrated into the United Kingdom's National Health Service (NHS) as a means to connect individuals with non-clinical services to address these challenges. However, current research provides limited detail on specific SP interventions tailored to dementia care, leaving gaps in understanding the targeted needs, participation drivers, effectiveness and potential benefits for PLWD. METHODS:A complex intervention systematic review of SP in dementia care was performed in the United Kingdom using an iterative logic model approach. Six databases and grey literature were searched, supplemented by hand searching for reference lists of included studies. Results were screened in a two-step process, followed by data extraction. Risk of bias was assessed using Gough's Evidence of Framework. Reporting was informed by the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA-CI) extension statement and checklist. RESULTS:Forty-nine studies, reporting on PLWD, met the inclusion criteria. Findings indicate that SP for PLWD in the United Kingdom is varied and lacks focus, reflecting the diverse demographics involved. Interventions encompass cognitive, educational, psychosocial, physical, community and complementary therapies, of inconsistent classification, with some being umbrella interventions and others standalone services. Provided by the NHS, charities and integrated services, SP involves a range of referrers and connectors. Finally, individual outcomes show benefits such as increased independence and improved mood, but challenges pertaining to suitability and logistical issues, whereas systemic outcomes include cost savings and better service delivery, despite high implementation costs. CONCLUSION:SP pathways for PLWD are varied, with success relying heavily on adequately resourced and trained connectors. While benefits extend beyond health improvements, further research is needed to assess long-term impacts, refine mechanisms and standardise evaluation metrics for SP effectiveness in dementia care. PATIENT AND PUBLIC CONTRIBUTIONS:A PPI advisory group, consisting of a person living with dementia and a caregiver, was actively involved throughout the review process, providing insights into the review questions, the logic model, emerging findings and interpretation of results.

BACKGROUND:Respiratory-related illness including asthma is a leading cause of avoidable higher mortality in those with intellectual disabilities. International guidelines stress the importance of good self-management in avoiding asthma-related deaths but give no guidance on how this is achieved with this vulnerable population. METHOD:A scoping review of published research to identify barriers and facilitators to promoting asthma self-management in people with intellectual disabilities. RESULTS:Only six studies published from 2015 to 2022 met study inclusion criteria. Studies commonly reported that the education of patients and caregivers was critical, with a lack of education being a barrier to good asthma control. Three studies also highlighted the importance of caregivers and support workers in helping those with intellectual disabilities to self-manage their asthma. CONCLUSIONS:This review highlights the paucity of research in this area. Further research is urgently needed to improve asthma self-management in those with intellectual disabilities thereby reducing asthma-related deaths.