Temporal trends in population attributable fractions of modifiable risk factors for dementia: a time-series study of the English Longitudinal Study of Ageing (2004-2019).

BACKGROUND: Interest in modifiable risk factors (MRFs) for dementia is high, given the personal, social, and economic impact of the disorder, especially in ageing societies such as the United Kingdom. Exploring the population attributable fraction (PAF) of dementia attributable to MRFs and how this may have changed over time remains unclear. Unravelling the temporal dynamics of MRFs is crucial for informing the development of evidence-based and effective public health policies. This investigation examined the temporal trajectories of MRFs for dementia in England. METHODS: We used data from the English Longitudinal Study of Ageing, a panel study over eight waves collected between 2004 and 2019 (76,904 interviews in total). We calculated the PAFs for twelve MRFs (including six early- to mid-life factors and six late-life factors), as recommended by the Lancet Commission, and the individual weighted PAFs (IW-PAFs) for each risk factor. Temporal trends were analysed to understand the changes in the overall PAF and IW-PAF over the study period. Subgroup analyses were conducted by sex and socioeconomic status (SES). RESULTS: The overall PAF for dementia MRFs changed from 46.73% in 2004/2005 to 36.79% in 2018/2019, though this trend was not statistically significant. During 2004-2019, hypertension, with an average IW-PAF of 8.21%, was the primary modifiable determinant of dementia, followed by obesity (6.16%), social isolation (5.61%), hearing loss (4.81%), depression (4.72%), low education (4.63%), physical inactivity (3.26%), diabetes mellitus (2.49%), smoking (2.0%), excessive alcohol consumption (1.16%), air pollution (0.42%), and traumatic brain injury (TBI) (0.26%). During 2004-2019, only IW-PAFs of low education, social isolation, and smoking showed significant decreasing trends, while IW-PAFs of other factors either did not change significantly or increased (including TBI, diabetes mellitus, and air pollution). Upon sex-specific disaggregation, a higher overall PAF for MRFs was found among women, predominantly associated with later-life risk factors, most notably social isolation, depression, and physical inactivity. Additionally, hearing loss, classified as an early- to mid-life factor, played a supplementary role in the identified sex disparity. A comparable discrepancy was evident upon PAF evaluation by SES, with lower income groups experiencing a higher dementia risk, largely tied to later-life factors such as social isolation, physical inactivity, depression, and smoking. Early- to mid-life factors, in particular, low education and obesity, were also observed to contribute to the SES-associated divergence in dementia risk. Temporal PAF and IW-PAF trends, stratified by sex and SES, revealed that MRF PAF gaps across sex or SES categories have persisted or increased. CONCLUSIONS: In England, there was little change over time in the proportion of dementia attributable to known modifiable risk factors. The observed trends underscore the continuing relevance of these risk factors and the need for targeted public health strategies to address them.

Predicting patients with dementia most at risk of needing psychiatric in-patient or enhanced community care using routinely collected clinical data: retrospective multi-site cohort study.

BACKGROUND: Dementia is a common and progressive condition whose prevalence is growing worldwide. It is challenging for healthcare systems to provide continuity in clinical services for all patients from diagnosis to death. AIMS: To test whether individuals who are most likely to need enhanced care later in the disease course can be identified at the point of diagnosis, thus allowing the targeted intervention. METHOD: We used clinical information collected routinely in de-identified electronic patient records from two UK National Health Service (NHS) trusts to identify at diagnosis which individuals were at increased risk of needing enhanced care (psychiatric in-patient or intensive (crisis) community care). RESULTS: We examined the records of a total of 25 326 patients with dementia. A minority (16% in the Cambridgeshire trust and 2.4% in the London trust) needed enhanced care. Patients who needed enhanced care differed from those who did not in age, cognitive test scores and Health of the Nation Outcome Scale scores. Logistic regression discriminated risk, with an area under the receiver operating characteristic curve (AUROC) of up to 0.78 after 1 year and 0.74 after 4 years. We were able to confirm the validity of the approach in two trusts that differed widely in the populations they serve. CONCLUSIONS: It is possible to identify, at the time of diagnosis of dementia, individuals most likely to need enhanced care later in the disease course. This permits the development of targeted clinical interventions for this high-risk group.

Estimating demand for potential disease-modifying therapies for Alzheimer's disease in the UK.

BACKGROUND: Phase three trials of the monoclonal antibodies lecanemab and donanemab, which target brain amyloid, have reported statistically significant differences in clinical end-points in early Alzheimer's disease. These drugs are already in use in some countries and are going through the regulatory approval process for use in the UK. Concerns have been raised about the ability of healthcare systems, including those in the UK, to deliver these treatments, considering the resources required for their administration and monitoring. AIMS: To estimate the scale of real-world demand for monoclonal antibodies for Alzheimer's disease in the UK. METHOD: We used anonymised patient record databases from two National Health Service trusts for the year 2019 to collect clinical, demographic, cognitive and neuroimaging data for these cohorts. Eligibility for treatment was assessed using the inclusion criteria from the clinical trials of donanemab and lecanemab, with consideration given to diagnosis, cognitive performance, cerebrovascular disease and willingness to receive treatment. RESULTS: We examined the records of 82 386 people referred to services covering around 2.2 million people. After applying the trial criteria, we estimate that a maximum of 906 people per year would start treatment with monoclonal antibodies in the two services, equating to 30 200 people if extrapolated nationally. CONCLUSIONS: Monoclonal antibody treatments for Alzheimer's disease are likely to present a significant challenge for healthcare services to deliver in terms of the neuroimaging and treatment delivery. The data provided here allows health services to understand the potential demand and plan accordingly.

Characteristics, outcomes, facilitators and barriers for psychosocial interventions on inpatient mental health dementia wards: a systematic review.

BACKGROUND: The National Institute for Health and Care Excellence guidelines state that psychosocial interventions should be the first line of treatment for people with dementia who are experiencing distress behaviours, such as agitation and depression. However, little is known about the characteristics and outcomes of psychosocial interventions or the facilitators and barriers to implementation on inpatient mental health dementia wards which provide care for people with dementia who are often experiencing high levels of distress. METHODS: A systematic search was conducted on MEDLINE, CINAHL, PsycINFO, Psychology and Behavioural Sciences Collection, and Scopus in May 2023, following PRISMA guidelines. Reference and citation searches were conducted on included articles. Peer-reviewed literature of any study design, relating to psychosocial interventions in inpatient mental health dementia wards, was included. One author reviewed all articles, with a third of results reviewed independently by a second author. Data were extracted to a bespoke form and synthesised using a narrative review. The quality of included studies was appraised using the Mixed Methods Appraisal Tool. RESULTS: Sixteen studies were included in the synthesis, which together included a total of 538 people with dementia. Study methods and quality varied. Psychosocial interventions delivered on wards included music therapy (five studies), multisensory interventions (four studies), multicomponent interventions (two studies), technology-based interventions (two studies), massage interventions (two studies) and physical exercise (one study). Reduction in distress and improvement in wellbeing was demonstrated inconsistently across studies. Delivering interventions in a caring and individualised way responding to patient need facilitated implementation. Lack of staff time and understanding of interventions, as well as high levels of staff turnover, were barriers to implementation. CONCLUSION: This review highlights a striking lack of research and therefore evidence base for the use of psychosocial interventions to reduce distress in this vulnerable population, despite current healthcare guidelines. More research is needed to understand which psychosocial interventions can reduce distress and improve wellbeing on inpatient mental health dementia wards, and how interventions should be delivered, to establish clinical and cost effectiveness and minimise staff burden.

The Use of Immersive Virtual Reality in Sensory Sessions on a Specialist Dementia Unit: Service Evaluation of Feasibility and Acceptability.

This service evaluation reviewed inclusion of Immersive Virtual Reality (iVR) relaxation activities as part of routine occupational therapy sensory sessions on a specialist dementia unit. Twenty-five sessions were completed over 13 wk with 14 participants. Nine participants chose to engage in multiple sessions. Feasibility was assessed through participant engagement and tolerability. Modal first session length was in the range 30 s to 2 min. This increased to over 2 min on second sessions. There was a lack of significant adverse effects measured by direct questioning, neuropsychiatric assessment before vs. after sessions and adverse incident reporting. Acceptability was assessed via structured review of user and staff feedback which noted positive experiences such as relaxation, openness to discussion, reminiscence, wider engagement and interest in future use. Further work is required to explore efficacy and use in other settings.

Food insecurity and subjective cognitive complaints among adults aged ≥ 65 years from low- and middle-income countries.

PURPOSE: To date, no study has investigated the association between food insecurity and subjective cognitive complaints (SCC). Thus, the aims of the present study were to examine this association among older adults in low- and middle-income countries (LMICs), and to identify the potential mediators in this association, given the importance of SCC in dementia risk among older people, and the projected particularly large increase in dementia in this setting. METHODS: Cross-sectional, community-based, nationally representative data from the World Health Organization (WHO) Study on global AGEing and Adult Health (SAGE) collected between 2007 and 2010 were analyzed. Two questions on subjective memory and learning complaints in the past 30 days were used to create a SCC scale ranging from 0 (No SCC) to 100 (worse SCC). Past 12 month food insecurity was assessed with two questions on frequency of eating less and hunger due to lack of food. Multivariable linear regression and mediation (Karlson-Holm-Breen method) analyses were conducted to assess associations. RESULTS: Data on 14,585 individuals aged ≥ 65 years [mean (SD) age 72.6 (11.5) years; 55.0% females] were analyzed. Severe food insecurity (vs. no food insecurity) was associated with 9.16 (95% CI = 6.95-11.37) points higher mean SCC score. Sleep/energy (mediated% 37.9%; P < 0.001), perceived stress (37.2%; P = 0.001), and depression (13.7%; P = 0.008) partially explained the association between severe food insecurity and SCC. CONCLUSION: Food insecurity was associated with SCC among older adults in LMICs. Future studies should assess whether addressing food insecurity among older adults in LMICs can improve cognitive health.

Including older people in health and social care research: best practice recommendations based on the INCLUDE framework.

BACKGROUND: Older people are often explicitly or implicitly excluded from research, in particular clinical trials. This means that study findings may not be applicable to them, or that older people may not be offered treatments due to an absence of evidence. AIMS: The aim of this work was to develop recommendations to guide all research relevant to older people. METHODS: A diverse stakeholder group identified barriers and solutions to including older people in research. In parallel, a rapid literature review of published papers was undertaken to identify existing papers on the inclusion of older people in research. The findings were synthesised and mapped onto a socio-ecological model. From the synthesis we identified themes that were developed into initial recommendations that were iteratively refined with the stakeholder group. RESULTS: A range of individual, interpersonal, organisational, community and policy factors impact on the inclusion of older people in research. A total of 14 recommendations were developed such as removing upper age limits and comorbidity exclusions, involving older people, advocates and health and social care professionals with expertise in ageing in designing the research, and considering flexible or alternative approaches to data collection to maximise opportunities for participation. We also developed four questions that may guide those developing, reviewing and funding research that is inclusive of older people. CONCLUSION: Our recommendations provide up to date, practical advice on ways to improve the inclusion of older people in health and care research.

Pain and mild cognitive impairment among adults aged 50 years and above residing in low- and middle-income countries.

BACKGROUND: Previous studies on the association between pain and cognitive decline or impairment have yielded mixed results, while studies from low- and middle-income countries (LMICs) or specifically on mild cognitive impairment (MCI) are scarce. Thus, we investigated the association between pain and MCI in LMICs and quantified the extent to which perceived stress, sleep/energy problems, and mobility limitations explain the pain/MCI relationship. METHODS: Data analysis of cross-sectional data from six LMICs from the Study on Global Ageing and Adult Health (SAGE) were performed. MCI was based on the National Institute on Aging-Alzheimer's Association criteria. "Overall in the last 30 days, how much of bodily aches or pain did you have?" was the question utilized to assess pain. Associations were examined by multivariable logistic regression analysis and meta-analysis. RESULTS: Data on 32,715 individuals aged 50 years and over were analysed [mean (SD) age 62.1 (15.6) years; 51.7% females]. In the overall sample, compared to no pain, mild, moderate, and severe/extreme pain were dose-dependently associated with 1.36 (95% CI = 1.18-1.55), 2.15 (95% CI = 1.77-2.62), and 3.01 (95% CI = 2.36-3.85) times higher odds for MCI, respectively. Mediation analysis showed that perceived stress, sleep/energy problems, and mobility limitations explained 10.4%, 30.6%, and 51.5% of the association between severe/extreme pain and MCI. CONCLUSIONS: Among middle-aged to older adults from six LMICs, pain was associated with MCI dose-dependently, and sleep problems and mobility limitations were identified as potential mediators. These findings raise the possibility of pain as a modifiable risk factor for developing MCI.

Eating disorders and physical multimorbidity in the English general population.

PURPOSE: People with eating disorders may be at increased risk for physical health problems, but there are no data on the relationship between eating disorders and physical multimorbidity (i.e., ≥ 2 physical conditions) and its potential mediators. Thus, we investigated this association in a representative sample of adults from the UK, and quantified the extent to which this can be explained by various psychological and physical conditions, and lifestyle factors. METHODS: Cross-sectional data of the 2007 Adult Psychiatric Morbidity Survey were analyzed. Questions from the five-item SCOFF screening instrument were used to identify possible eating disorder. Respondents were asked about 20 physical health conditions. Multivariable logistic regression and mediation analysis were conducted. RESULTS: Data on 7403 individuals aged ≥ 16 years were analyzed [mean (SD) age 46.3 (18.6) years; 48.6% males]. After adjustment, possible eating disorder was associated with 2.11 (95%CI = 1.67-2.67) times higher odds for physical multimorbidity. Anxiety disorder explained the largest proportion this association (mediated percentage 26.3%), followed by insomnia (21.8%), perceived stress (13.4%), depression (13.1%), obesity (13.0%), and alcohol dependence (4.3%). CONCLUSION: Future longitudinal studies are warranted to understand potential causality and the underlying mechanisms in the association between eating disorder and multimorbidity, and whether addressing the identified potential mediators in people with eating disorders can reduce multimorbidity.

Association between lithium use and the incidence of dementia and its subtypes: A retrospective cohort study.

BACKGROUND: Dementia is the leading cause of death in elderly Western populations. Preventative interventions that could delay dementia onset even modestly would provide a major public health impact. There are no disease-modifying treatments currently available. Lithium has been proposed as a potential treatment. We assessed the association between lithium use and the incidence of dementia and its subtypes. METHODS AND FINDINGS: We conducted a retrospective cohort study comparing patients treated between January 1, 2005 and December 31, 2019, using data from electronic clinical records of secondary care mental health (MH) services in Cambridgeshire and Peterborough NHS Foundation Trust (CPFT), United Kingdom (catchment area population approximately 0.86 million). Eligible patients were those aged 50 years or over at baseline and who had at least 1 year follow-up, excluding patients with a diagnosis of mild cognitive impairment (MCI) or dementia before, or less than 1 year after, their start date. The intervention was the use of lithium. The main outcomes were dementia and its subtypes, diagnosed and classified according to the International Classification of Diseases-10th Revision (ICD-10). In this cohort, 29,618 patients (of whom 548 were exposed to lithium) were included. Their mean age was 73.9 years. A total of 40.2% were male, 33.3% were married or in a civil partnership, and 71.0% were of white ethnicity. Lithium-exposed patients were more likely to be married, cohabiting or in a civil partnership, to be a current/former smoker, to have used antipsychotics, and to have comorbid depression, mania/bipolar affective disorder (BPAD), hypertension, central vascular disease, diabetes mellitus, or hyperlipidemias. No significant difference between the 2 groups was observed for other characteristics, including age, sex, and alcohol-related disorders. In the exposed cohort, 53 (9.7%) patients were diagnosed with dementia, including 36 (6.8%) with Alzheimer disease (AD) and 13 (2.6%) with vascular dementia (VD). In the unexposed cohort, corresponding numbers were the following: dementia 3,244 (11.2%), AD 2,276 (8.1%), and VD 698 (2.6%). After controlling for sociodemographic factors, smoking status, other medications, other mental comorbidities, and physical comorbidities, lithium use was associated with a lower risk of dementia (hazard ratio [HR] 0.56, 95% confidence interval [CI] 0.40 to 0.78), including AD (HR 0.55, 95% CI 0.37 to 0.82) and VD (HR 0.36, 95% CI 0.19 to 0.69). Lithium appeared protective in short-term (≤1-year exposure) and long-term lithium users (>5-year exposure); a lack of difference for intermediate durations was likely due to lack of power, but there was some evidence for additional benefit with longer exposure durations. The main limitation was the handling of BPAD, the most common reason for lithium prescription but also a risk factor for dementia. This potential confounder would most likely cause an increase in dementia in the exposed group, whereas we found the opposite, and the sensitivity analysis confirmed the primary results. However, the specific nature of the group of patients exposed to lithium means that caution is needed in extending these findings to the general population. Another limitation is that our sample size of patients using lithium was small, reflected in the wide CIs for results relating to some durations of lithium exposure, although again sensitivity analyses remained consistent with our primary findings. CONCLUSIONS: We observed an association between lithium use and a decreased risk of developing dementia. This lends further support to the idea that lithium may be a disease-modifying treatment for dementia and that this is a promising treatment to take forwards to larger randomised controlled trials (RCTs) for this indication.

The epidemiology and clinical features of personality disorders in later life; a study of secondary care data.

OBJECTIVES: Personality disorders (PDs) are often conceptualised as impacting individuals throughout their life. However, there has been limited study of the disorders in those over the age of 65. We have used the psychiatric secondary care medical records of 21,971 individuals over the age of 65 from Cambridgeshire, UK, who received care between 2014 and 2021 to characterise older patients with a PD diagnosis. METHODS: The data from all patients >65 with a diagnosis of personality disorder (PD) was extracted (n = 217) along with two comparison groups (n = 2170); patients <65 with a diagnosis of PD and patients >65 with a psychiatric diagnosis other than PD or dementia. RESULTS: Compared to younger patients with PD, older patients were more likely to be male, married, suffering from a mixed PD and live in less deprived areas. Compared to patients >65 with diagnoses other than PD, older patients were more likely to be female, single or divorced and had a higher level of social deprivation. Our most striking finding was that older patients with PDs were more likely to experience polypharmacy. A mean of 18.48 different drugs had been prescribed over their lifetime, compared to 9.51 for patients >65 with other mental health diagnoses. CONCLUSION: Here we present the largest ever description of this group of patients and provide insights that could inform clinical practice and future research.

Trazodone and patient outcomes in dementia-Limitations of naturalistic cohort data.

The unfolded protein response has been increasingly implicated as an important pathological pathway and target for therapeutic intervention in neurodegeneration. The licensed antidepressant trazodone is one drug which has been proposed to act on this pathway and may therefore be a potential therapy. Previous examination of existing data for patients with dementia prescribed trazodone did not find a signal suggesting a disease modifying effect. Here we add to that literature by examining the electronic patient record of patients with dementia in Cambridgeshire UK. We found that trazodone is rarely prescribed and where it is used it is at a dose less than half that predicted to be disease modifying. We also found that patients prescribed trazodone had higher levels of neuropsychiatric symptoms and were relatively late in the disease course, likely beyond the optimal point for therapeutic intervention. We suggest it is therefore premature to discard potential therapies based on observational data alone, particularly when experimental medicine approaches to examine the effects of trazodone are feasible.

Targeting the Unfolded Protein Response as a Disease-Modifying Pathway in Dementia.

Dementia is a global medical and societal challenge; it has devastating personal, social and economic costs, which will increase rapidly as the world's population ages. Despite this, there are no disease-modifying treatments for dementia; current therapy modestly improves symptoms but does not change the outcome. Therefore, new treatments are urgently needed-particularly any that can slow down the disease's progression. Many of the neurodegenerative diseases that lead to dementia are characterised by common pathological responses to abnormal protein production and misfolding in brain cells, raising the possibility of the broad application of therapeutics that target these common processes. The unfolded protein response (UPR) is one such mechanism. The UPR is a highly conserved cellular stress response to abnormal protein folding and is widely dysregulated in neurodegenerative diseases. In this review, we describe the basic machinery of the UPR, as well as the evidence for its overactivation and pathogenicity in dementia, and for the marked neuroprotective effects of its therapeutic manipulation in murine models of these disorders. We discuss drugs identified as potential UPR-modifying therapeutic agents-in particular the licensed antidepressant trazodone-and we review epidemiological and trial data from their use in human populations. Finally, we explore future directions for investigating the potential benefit of using trazodone or similar UPR-modulating compounds for disease modification in patients with dementia.

The Characteristics and Outcomes of People with Dementia in Inpatient Mental Health Care: A Review.

OBJECTIVES: Inpatient mental health beds for people with dementia are a limited resource. Practitioners need an understanding of this population to provide high-quality care and design services. This review examines the characteristics, care, and outcomes of people with dementia admitted to inpatient mental health services. METHODS: Systematic searches of key databases were undertaken up to November 2021. Findings were grouped into categories and then synthesized into a narrative review. RESULTS: The review identified 36 international papers, the majority of which were retrospective audits. The literature describes significant psychiatric and medical comorbidity and significant risk of change in residence and death associated with admission. CONCLUSIONS: We found a limited literature describing the characteristics, care, and outcomes of people with dementia in inpatient mental health services. The lack of research is striking given the complexity and vulnerability of this client group. More research is needed to describe the needs of this group, current and best practice to optimize care. CLINICAL IMPLICATIONS: Professionals working in inpatient mental health services need to be aware of the evidence base available, consider how they evaluate patient outcomes, review their staffing and skills mix, and seek the views of patients and relatives in improving services.

Risk factors for excess deaths during lockdown among older users of secondary care mental health services without confirmed COVID-19: A retrospective cohort study.

OBJECTIVE: To investigate factors contributing to excess deaths of older patients during the initial 2020 lockdown beyond those attributable to confirmed COVID-19. METHODS: Retrospective cohort study comparing patients treated between 23 March 2020 and 14 June 2020, deemed exposed to the pandemic/lockdown, to patients treated between 18 December 2019 and 10 March 2020, deemed to be unexposed. Data came from electronic clinical records from secondary care mental health services in Cambridgeshire and Peterborough NHS Foundation Trust (CPFT), UK (catchment area population ∼0.86 million). Eligible patients were aged 65 years or over at baseline with at least 14 days' follow-up, excluding patients diagnosed with confirmed or suspected SARS-CoV-2 infection. The primary outcome was all-cause mortality. FINDINGS: In the two cohorts, 3,073 subjects were exposed to lockdown and 4,372 subjects were unexposed; the cohorts were followed up for an average of 74 and 78 days, respectively. After controlling for confounding by sociodemographic factors, smoking status, mental comorbidities, and physical comorbidities, patients with dementia suffered an additional 53% risk of death (HR = 1.53, 95% CI = 1.02-2.31), and patients with severe mental illness suffered an additional 123% risk of death (HR = 2.23, 95% CI = 1.42-3.49). No significant additional mortality risks were identified from physical comorbidities, potentially due to low statistical power in that respect. CONCLUSION: During lockdown people with dementia or severe mental illness had a higher risk of death without confirmed COVID-19. These data could inform future health service responses and policymaking to help prevent avoidable excess death during future outbreaks of this or a similar infectious disease.

Investigation of risk of dementia diagnosis and death in patients in older people's secondary care mental health services.

OBJECTIVES: Previous studies have shown increased rates of death and dementia in older people in specific serious mental illnesses (SMI) such as bipolar disorder or depression. We examined the rates of death and dementia in older people referred into a secondary care psychiatric service across a range of SMIs. METHODS: We used an anonymised dataset across 6 consecutive years with 28,340 patients aged 65 years and older from a single secondary care psychiatric trust in the United Kingdom. We identified deaths and incident dementia in patients with bipolar disorder/mania, schizophrenia, recurrent depression and anxiety disorders. We compared mortality and dementia rates between these diagnostic groups and in different treatment settings. We also examined mortality rates and dementia rates compared with general population rates. RESULTS: Patients with schizophrenia showed the highest hazard rate for death compared to other groups with SMIs (hazard ratio, 1.58; 95% confidence interval (CI), 1.18-2.1, with anxiety group the reference). Survival was reduced in patients referred to liaison psychiatry services. There were no significant differences between the SMI groups in terms of rates of dementia. However, risks of death and dementia were significantly increased compared to the general population (standardized mortality rates with 95% CI, 2.6(2.0-3.3), 3.5(2.6-4.5), 2.5(2.0-3.0) and 1.8 (1.4-2.2) and standardized dementia incidence rates with 95% CI, 2.7(1.5-4.1), 2.9(1.5-4.7), 3.8(2.6-5.2) and 4.3 (3.0-5.7) for bipolar disorder/mania, schizophrenia, recurrent depression and anxiety disorders respectively. CONCLUSIONS: Older adults referred into an old age psychiatry service show higher rates of dementia and death than those reported for the general population.

Mild cognitive impairment: the Manchester consensus.

Given considerable variation in diagnostic and therapeutic practice, there is a need for national guidance on the use of neuroimaging, fluid biomarkers, cognitive testing, follow-up and diagnostic terminology in mild cognitive impairment (MCI). MCI is a heterogenous clinical syndrome reflecting a change in cognitive function and deficits on neuropsychological testing but relatively intact activities of daily living. MCI is a risk state for further cognitive and functional decline with 5-15% of people developing dementia per year. However, ~50% remain stable at 5 years and in a minority, symptoms resolve over time. There is considerable debate about whether MCI is a useful clinical diagnosis, or whether the use of the term prevents proper inquiry (by history, examination and investigations) into underlying causes of cognitive symptoms, which can include prodromal neurodegenerative disease, other physical or psychiatric illness, or combinations thereof. Cognitive testing, neuroimaging and fluid biomarkers can improve the sensitivity and specificity of aetiological diagnosis, with growing evidence that these may also help guide prognosis. Diagnostic criteria allow for a diagnosis of Alzheimer's disease to be made where MCI is accompanied by appropriate biomarker changes, but in practice, such biomarkers are not available in routine clinical practice in the UK. This would change if disease-modifying therapies became available and required a definitive diagnosis but would present major challenges to the National Health Service and similar health systems. Significantly increased investment would be required in training, infrastructure and provision of fluid biomarkers and neuroimaging. Statistical techniques combining markers may provide greater sensitivity and specificity than any single disease marker but their practical usefulness will depend on large-scale studies to ensure ecological validity and that multiple measures, e.g. both cognitive tests and biomarkers, are widely available for clinical use. To perform such large studies, we must increase research participation amongst those with MCI.

Challenges and opportunities for conducting a vaccine trial during the COVID-19 pandemic in the United Kingdom.

The COVID-19 pandemic has resulted in unprecedented challenges for healthcare systems worldwide. It has also stimulated research in a wide range of areas including rapid diagnostics, novel therapeutics, use of technology to track patients and vaccine development. Here, we describe our experience of rapidly setting up and delivering a novel COVID-19 vaccine trial, using clinical and research staff and facilities in three National Health Service Trusts in Cambridgeshire, United Kingdom. We encountered and overcame a number of challenges including differences in organisational structures, research facilities available, staff experience and skills, information technology and communications infrastructure, and research training and assessment procedures. We overcame these by setting up a project team that included key members from all three organisations that met at least daily by teleconference. This group together worked to identify the best practices and procedures and to harmonise and cascade these to the wider trial team. This enabled us to set up the trial within 25 days and to recruit and vaccinate the participants within a further 23 days. The lessons learned from our experiences could be used to inform the conduct of clinical trials during a future infectious disease pandemic or public health emergency.

Complex inhibitory effects of nitric oxide on autophagy.

Autophagy, a major degradation process for long-lived and aggregate-prone proteins, affects various human processes, such as development, immunity, cancer, and neurodegeneration. Several autophagy regulators have been identified in recent years. Here we show that nitric oxide (NO), a potent cellular messenger, inhibits autophagosome synthesis via a number of mechanisms. NO impairs autophagy by inhibiting the activity of S-nitrosylation substrates, JNK1 and IKKß. Inhibition of JNK1 by NO reduces Bcl-2 phosphorylation and increases the Bcl-2-Beclin 1 interaction, thereby disrupting hVps34/Beclin 1 complex formation. Additionally, NO inhibits IKKß and reduces AMPK phosphorylation, leading to mTORC1 activation via TSC2. Overexpression of nNOS, iNOS, or eNOS impairs autophagosome formation primarily via the JNK1-Bcl-2 pathway. Conversely, NOS inhibition enhances the clearance of autophagic substrates and reduces neurodegeneration in models of Huntington's disease. Our data suggest that nitrosative stress-mediated protein aggregation in neurodegenerative diseases may be, in part, due to autophagy inhibition.