What is the relationship between people with dementia and their caregiver’s illness perceptions post diagnosis and the impact on help seeking behaviour?:A systematic review

Background: As the number of people with dementia increases, more families will be affected by the daily challenges of providing effective support, given its current incurable status. Once individuals are diagnosed with dementia, the earlier they access support the more effective the outcome. However once people receive a diagnosis, how they make sense of their dementia can impact on their help seeking intentions. Exploring the illness beliefs of people with dementia and their caregivers and this relationship to help seeking may identify how best to facilitate early support. Aims: To systematically obtain and critically review relevant studies on the relationship between illness perceptions and help seeking of people with dementia and their caregivers. Method: A systematic search was conducted and included both quantitative and qualitative studies. The Initial search was conducted in October 2018, with an adjacent search conducted in April 2020. Findings: A total of 14 articles met the inclusion criteria. Conceptually the studies examined the association of illness perceptions and help seeking post diagnosis and revealed that people living with dementia and their caregivers sought help when symptoms became severe. Components of Illness perceptions revealed that lack of knowledge, cultural beliefs, complexity of the health care system, threat to independence and acceptance were identified as major factors for delaying help seeking. Conclusion: Although research interest in the area of illness perceptions and their impact on help seeking for dementia is increasing, further work is needed to understand this area, particularly regarding the influence of the relationship between the person with dementia and their caregiver

A Markov Chain Model for Identifying Changes in Daily Activity Patterns of People Living with Dementia

Malnutrition and dehydration are strongly associated with increased cognitive and functional decline in people living with dementia (PLWD), as well as an increased rate of hospitalisations in comparison to their healthy counterparts. Extreme changes in eating and drinking behaviours can often lead to malnutrition and dehydration, accelerating the progression of cognitive and functional decline and resulting in a marked reduction in quality of life. Unfortunately, there are currently no established methods by which to objectively detect such changes. Here, we present the findings of an extensive quantitative analysis conducted on in-home monitoring data collected from 73 households of PLWD using Internet of Things technologies. The Coronavirus 2019 (COVID-19) pandemic has previously been shown to have dramatically altered the behavioural habits, particularly the eating and drinking habits, of PLWD. Using the COVID-19 pandemic as a natural experiment, we conducted linear mixed-effects modelling to examine changes in mean kitchen activity within a subset of 21 households of PLWD that were continuously monitored for 499 days. We report an observable increase in day-time kitchen activity and a significant decrease in night-time kitchen activity (t(147) = -2.90, p < 0.001). We further propose a novel analytical approach to detecting changes in behaviours of PLWD using Markov modelling applied to remote monitoring data as a proxy for behaviours that cannot be directly measured. Together, these results pave the way to introduce improvements into the monitoring of PLWD in naturalistic settings and for shifting from reactive to proactive care.Comment: 12 pages, 7 figures, journa

Machine learning methods for detecting urinary tract infection and analysing daily living activities in people with dementia

Dementia is a neurological and cognitive condition that affects millions of people around the world. At any given time in the United Kingdom, 1 in 4 hospital beds are occupied by a person with dementia, while about 22% of these hospital admissions are due to preventable causes. In this paper we discuss using Internet of Things (IoT) technologies and in-home sensory devices in combination with machine learning techniques to monitor health and well-being of people with dementia. This will allow us to provide more effective and preventative care and reduce preventable hospital admissions. One of the unique aspects of this work is combining environmental data with physiological data collected via low cost in-home sensory devices to extract actionable information regarding the health and well-being of people with dementia in their own home environment. We have worked with clinicians to design our machine learning algorithms where we focused on developing solutions for real-world settings. In our solutions, we avoid generating too many alerts/alarms to prevent increasing the monitoring and support workload. We have designed an algorithm to detect Urinary Tract Infections (UTI) which is one of the top five reasons of hospital admissions for people with dementia (around 9% of hospital admissions for people with dementia in the UK). To develop the UTI detection algorithm, we have used a Non-negative Matrix Factorisation (NMF) technique to extract latent factors from raw observation and use them for clustering and identifying the possible UTI cases. In addition, we have designed an algorithm for detecting changes in activity patterns to identify early symptoms of cognitive decline or health decline in order to provide personalised and preventative care services. For this purpose, we have used an Isolation Forest (iForest) technique to create a holistic view of the daily activity patterns. This paper describes the algorithms and discusses the evaluation of the work using a large set of real-world data collected from a trial with people with dementia and their caregivers

Minocycline 200 mg or 400 mg versus placebo for mild Alzheimer's disease: the MADE Phase II, three-arm RCT

Background: Minocycline is an anti-inflammatory drug and protects against the toxic effects of β-amyloid in vitro and in animal models of Alzheimer’s disease. To the best of our knowledge, no randomised placebo-controlled clinical trials in patients with Alzheimer’s disease looking at the efficacy and tolerability of minocycline have been carried out. Objectives: The trial investigated whether or not minocycline was superior to placebo in slowing down the rate of decline in cognitive and functional ability over 2 years. The safety and tolerability of minocycline were also assessed. Design: A Phase II, three-arm, randomised, double-blind, multicentre trial with a semifactorial design. Participants continued on trial treatment for up to 24 months. Setting: Patients were identified from memory services, both within the 32 participating NHS trusts and within the network of memory services supported by the Dementias and Neurodegenerative Diseases Research Network (also known as DeNDRoN). Participants: Patients with standardised Mini Mental State Examination scores of > 23 points and with Alzheimer’s disease assessed by the National Institute on Aging–Alzheimer’s Association’s criteria were identified from memory services. Intervention: Patients with mild Alzheimer’s disease were randomly allocated 1 : 1 : 1 to receive one of three treatments: arm 1 – 400 mg per day of minocycline; arm 2 – 200 mg per day of minocycline; or arm 3 – placebo. Patients continued treatment for 24 months. Participants, investigators and outcome assessors were blind to treatment allocation. Main outcome measures: Primary outcome measures were decline in standardised Mini Mental State Examination and Bristol Activities of Daily Living Scale scores of combined minocycline treatment arms versus placebo, as analysed by intention-to-treat repeated measures regression. Results: Between 23 May 2014 and 14 April 2016, 554 participants were randomised. Of the 544 eligible participants, the mean age was 74.3 years and the average standardised Mini Mental State Examination score was 26.4 points. A total of 252 serious adverse events were reported, with the most common categories being neuropsychiatric and cardiocirculatory. Significantly fewer participants completed treatment with 400 mg of minocycline [29% (53/184)] than 200 mg [62% (112/181)] or placebo [64% (114/179)] (p < 0.0001), mainly because of gastrointestinal symptoms (p = 0.0008), dermatological side effects (p = 0.02) and dizziness (p = 0.01). Assessment rates were also lower in the 400-mg treatment arm: 68% (119 of 174 expected) for standardised Mini Mental State Examination scores at 24 months, compared with 82% (144/176) for the 200-mg treatment arm and 84% (140/167) for the placebo arm. Decline in standardised Mini Mental State Examination scores over the 24-month study period in the combined minocycline arms was similar to that in the placebo arm (4.1- vs. 4.3-point reduction; p = 0.9), as was the decline in the 400- and 200-mg treatment arms (3.3 vs. 4.7 points; p = 0.08). Likewise, worsening of Bristol Activities of Daily Living Scale scores over 24 months was similar in all trial arms (5.7, 6.6 and 6.2 points in the 400-mg treatment arm, 200-mg treatment arm and placebo arm, respectively; a p-value of 0.57 for minocycline vs. placebo and a p-value of 0.77 for 400 vs. 200 mg of minocycline). Results were similar in different patient subgroups and in sensitivity analyses adjusting for missing data. Limitations: Potential limitations of the study include that biomarkers were not used to confirm the diagnosis of Alzheimer’s disease, as these and apolipoprotein E (APOE) genotyping are not routinely available within the NHS. Compliance was also worse than expected and differential follow-up rates were observed, with fewer assessments obtained for the 400-mg treatment arm than for the 200-mg treatment and placebo arms. Conclusions: Minocycline does not delay the progress of cognitive or functional impairment in people with mild Alzheimer’s disease over a 2-year period. Minocycline at a dose of 400 mg is poorly tolerated in this population. Future work: The Minocycline in mild Alzheimer’s DiseasE (MADE) study provides a framework for a streamlined trial design that can be usefully applied to test other disease-modifying therapies

A comparative study of the effect of the Time for Dementia programme on medical students

Background Traditional healthcare education typically focuses on short block clinical placements based on acute care, investigations, and technical aspects of diagnosis and treatment. It may therefore fail to build the understanding, compassion, and person‐centred empathy needed to help those with long‐term conditions, like dementia. Time for Dementia was developed to address this. Method Parallel group comparison of two cohorts of UK medical students from universities, one participating in Time for Dementia (intervention group) and one not (control group). In Time for Dementia students visit a person with dementia and their family in pairs for two hours three times a year for two years, the control group received their normal curriculum. Results In an adjusted multilevel model of data (intervention group n=274, control n=112), there was strong evidence supporting improvements for Time for Dementia participants in: total Approaches to Dementia Questionnaire score (coefficient 2.19, p=0.003), and its person‐centredness subscale (1.32, p=0.006), and weaker evidence in its hopefulness subscale (0.78, p=0.070); Dementia Knowledge Questionnaire score (1.63, p<0.001); and Dementia Attitudes Scale (total score 6.55, p<0.001; social comfort subscale 4.15, p<0.001; dementia knowledge subscale 3.38, p=0.001) scores. No differences were observed on the Alzheimer's Disease Knowledge Scale, the Medical Condition Regard Scale, or the Jefferson Scale of Empathy. Discussion Time for Dementia may help improve the attitudes of medical students towards dementia promoting a person‐centred approach and increasing social comfort. Such patient‐focused programmes may be a useful complement to traditional medical education

A pragmatic, multicentre, double-blind, placebo-controlled randomised trial to assess the safety, clinical and cost-effectiveness of mirtazapine and carbamazepine in people with Alzheimer’s disease and agitated behaviours: the HTA-SYMBAD trial

Background Agitation is common and impacts negatively on people with dementia and carers. Non-drug patient-centred care is first-line treatment, but we need other treatment when this fails. Current evidence is sparse on safer and effective alternatives to antipsychotics. Objectives To assess clinical and cost-effectiveness and safety of mirtazapine and carbamazepine in treating agitation in dementia. Design Pragmatic, phase III, multicentre, double-blind, superiority, randomised, placebo-controlled trial of the clinical effectiveness of mirtazapine over 12 weeks (carbamazepine arm discontinued). Setting Twenty-six UK secondary care centres. Participants Eligibility: probable or possible Alzheimer’s disease, agitation unresponsive to non-drug treatment, Cohen-Mansfield Agitation Inventory score ≥ 45. Interventions Mirtazapine (target 45 mg), carbamazepine (target 300 mg) and placebo. Outcome measures Primary: Cohen-Mansfield Agitation Inventory score 12 weeks post randomisation. Main economic outcome evaluation: incremental cost per six-point difference in Cohen-Mansfield Agitation Inventory score at 12 weeks, from health and social care system perspective. Data from participants and informants at baseline, 6 and 12 weeks. Long-term follow-up Cohen-Mansfield Agitation Inventory data collected by telephone from informants at 6 and 12 months. Randomisation and blinding Participants allocated 1 : 1 : 1 ratio (to discontinuation of the carbamazepine arm, 1 : 1 thereafter) to receive placebo or carbamazepine or mirtazapine, with treatment as usual. Random allocation was block stratified by centre and residence type with random block lengths of three or six (after discontinuation of carbamazepine, two or four). Double-blind, with drug and placebo identically encapsulated. Referring clinicians, participants, trial management team and research workers who did assessments were masked to group allocation. Results Two hundred and forty-four participants recruited and randomised (102 mirtazapine, 102 placebo, 40 carbamazepine). The carbamazepine arm was discontinued due to slow overall recruitment; carbamazepine/placebo analyses are therefore statistically underpowered and not detailed in the abstract. Mean difference placebo-mirtazapine (−1.74, 95% confidence interval −7.17 to 3.69; p = 0.53). Harms: The number of controls with adverse events (65/102, 64%) was similar to the mirtazapine group (67/102, 66%). However, there were more deaths in the mirtazapine group (n = 7) by week 16 than in the control group (n = 1). Post hoc analysis suggests this was of marginal statistical significance (p = 0.065); this difference did not persist at 6- and 12-month assessments. At 12 weeks, the costs of unpaid care by the dyadic carer were significantly higher in the mirtazapine than placebo group [difference: £1120 (95% confidence interval £56 to £2184)]. In the cost-effectiveness analyses, mean raw and adjusted outcome scores and costs of the complete cases samples showed no differences between groups. Limitations Our study has four important potential limitations: (1) we dropped the proposed carbamazepine group; (2) the trial was not powered to investigate a mortality difference between the groups; (3) recruitment beyond February 2020, was constrained by the COVID-19 pandemic; and (4) generalisability is limited by recruitment of participants from old-age psychiatry services and care homes. Conclusions The data suggest mirtazapine is not clinically or cost-effective (compared to placebo) for agitation in dementia. There is little reason to recommend mirtazapine for people with dementia with agitation. Future work Effective and cost-effective management strategies for agitation in dementia are needed where non-pharmacological approaches are unsuccessful. Study registration This trial is registered as ISRCTN17411897/NCT03031184. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 23. See the NIHR Journals Library website for further project information. Plain language summary It is common for people with Alzheimer’s disease to experience agitation, for example feeling restless or unsettled. If left untreated, agitation can lead to poorer quality of life and increased hospitalisation and strain for family carers. Often these symptoms are treated with medications that are usually used to manage psychosis (antipsychotic drugs), but such medication has limited effectiveness and can cause serious adverse effects to patients, including risk of increased death. Two medications that are already commonly prescribed for other health issues, mirtazapine (an antidepressant) and carbamazepine (a drug used to treat epilepsy), had been identified as a possible alternative way of treating agitation in Alzheimer’s disease that might not have the harms associated with antipsychotic medication. In this study, we compared the effects of giving mirtazapine or carbamazepine with a dummy drug (placebo) in people with Alzheimer’s disease who were experiencing agitation. The results of the study showed that neither medication was any more effective than the placebo in reducing agitation over 12 weeks in terms of improving symptoms, or in economic terms. Mirtazapine may lead to additional carer costs as compared to placebo. The study findings are stronger for mirtazapine than carbamazepine because the carbamazepine arm was stopped when it had recruited less than half the numbers needed. That was done because the study was not recruiting quickly enough to support both the mirtazapine and the carbamazepine arms. The findings from this study show that mirtazapine should not be recommended to treat agitation in Alzheimer’s disease. More work is needed to formulate effective ways and to test new drug and non-drug treatments for agitation in dementia. Scientific summary Background Agitation is common in people with dementia and impacts negatively on the quality of life of both people with dementia and carers. Non-drug patient-centred care is the first-line treatment, but there is a need for other treatment when this fails. Current evidence is sparse on safer and effective alternatives to antipsychotics. We assessed efficacy and safety of mirtazapine (an antidepressant) and carbamazepine (an anticonvulsant) prescribed for agitation in dementia. Aim To assess the safety, clinical and cost-effectiveness of mirtazapine and carbamazepine in the treatment of agitation in dementia. Primary objectives To determine if mirtazapine is more clinically effective in reducing agitated behaviours in dementia than placebo, measured by Cohen-Mansfield Agitation Inventory (CMAI) score 12 weeks post randomisation. To determine if carbamazepine is more clinically effective in reducing agitated behaviours in dementia than placebo measured by CMAI score 12 weeks post randomisation. Methods Design Pragmatic, phase III, multicentre, double-blind, superiority, randomised, placebo-controlled trial of the clinical effectiveness of mirtazapine and carbamazepine over 12 weeks. Intervention (1) Mirtazapine, (2) carbamazepine and (3) placebo. Target dose: 45 mg of mirtazapine or 300 mg of carbamazepine. Inclusion and exclusion criteria Patients were eligible if the following criteria were met: a clinical diagnosis of probable or possible Alzheimer’s disease a diagnosis of co-existing agitated behaviours evidence that the agitated behaviours have not responded to management an assessment of CMAI (Long Form) score of 45 or greater written informed consent to enter and be randomised into the trial availability of a suitable informant. Exclusion criteria included: current treatment with antidepressants [including Monoamine Oxidase Inhibitors (MAOIs)], anticonvulsants or antipsychotics contraindications to the administration of mirtazapine or carbamazepine patients with second-degree atrioventricular block patients with a history of bone marrow depression or history of hepatic porphyrias cases too critical for randomisation (i.e. where there is a suicide risk or where the patient presents a risk of harm to others) female subjects under the age of 55 years of childbearing potential. Setting Participants were drawn from existing patients and new patient referrals to old age psychiatric services, memory clinics, specific Participant Identification Centres, primary care centres and those in care homes in 26 UK sites. Consent Capacity to consent was assessed before proceeding with the consent process and included consideration of the provision of assent by the patient and consent on their behalf by their legal representative. If the patient had capacity to consent, the carer consented to the provision of information on data for measures on the patient (e.g. CMAI) and also on themselves in terms of impact. Randomisation and blinding Participants were allocated in a 1 : 1 : 1 ratio (up to the discontinuation of the carbamazepine arm and 1 : 1 thereafter) to receive placebo or carbamazepine or mirtazapine, together with treatment as usual. Random allocation was block stratified by centre and type of residence (care home vs. own household) with random block lengths of three or six up to the discontinuation of the carbamazepine arm and thereafter of two or four. The trial was double-blind, with drug and placebo identically encapsulated. Referring clinicians, participants, the trial management team and the research workers who did baseline and follow-up assessments were masked to group allocation. Outcomes Primary outcome CMAI score (Long Form) at 12 weeks. Secondary outcomes Costs derived from Client Service Receipt Inventory, and quality-adjusted life-years from cost data alongside supplemented information from Dementia-Specific Quality of Life and EuroQol-5 Dimensions, five-level version interviews 12 weeks post randomisation. CMAI score and cost at 6 weeks post randomisation. Patient and carer quality of life, and carer outcomes at 6 and 12 weeks post randomisation. Adverse events from week 0 to week 16 and adherence at 6 and 12 weeks post randomisation. CMAI score, adverse events and adherence at 6 and 12 weeks, conditional on evidence of effectiveness of Investigational Medicinal Product over placebo. Longer-term follow-up: CMAI score, institutionalisation, death and clinical management at 26 and 52 weeks post randomisation. Sample size and statistical analysis An initial calculated sample size of 400 (randomised 1 : 1 : 1) provided 90% power using two-sided 5% significance tests to detect a drug versus placebo mean difference in CMAI score at 12 weeks of 6 points. This equated to an effect size of d = 0.4 (assuming a common standard deviation of 15) or a clinically significant 30% decrease in CMAI from placebo to active drug. With a realistic 15% attrition, a sample of 471 (157 per arm) was aimed for. Mid-trial, with the discontinuation of the carbamazepine arm, the sample size calculation was revisited with emerging data and it was adjusted so that the aim (excluding those randomised to carbamazepine) was for an overall sample of 222 (randomised 1 : 1) to provide 80% power using two-sided 5% significance tests to detect a mirtazapine versus placebo mean difference in CMAI score at 12 weeks of six points, assuming attrition of no more than 10%. Analyses were based on intention-to-treat (all participants were analysed according to the group to which they were randomised, irrespective of the treatment or dose received). The primary outcome (CMAI at 12 weeks) was analysed using a general linear regression model including baseline CMAI score as a covariate. General linear regression models were created for secondary outcomes. Economic evaluation The primary outcome for the economic evaluation was the incremental cost per six-point difference in CMAI score at 12 weeks, from a health and social care system perspective. Patient and public involvement Ensuring the involvement of people living with dementia and their family carers was integral to the Study of Mirtazapine for Agitated Behaviours in Dementia (SYMBAD) trial from the application for funding and trial design stage through to its conduct, analysis and communication. SN was a co-applicant and led on public/carer involvement in the trial throughout, and she was supported by a Lived Experience Advisory Panel (LEAP) group hosted by Sussex Partnership Foundation Trust (SPFT) co-ordinated by JF and the NIHR DeNDRoN (Dementias and Neurodegenerative Diseases Research Network) group. Protocol change Due to slower than expected recruitment the carbamazepine arm was discontinued in August 2018 when 40 people had been randomised to it. This summary therefore focusses on the mirtazapine versus placebo comparisons. Results Between January 2017 and February 2020, 204 participants were recruited and randomised to either the mirtazapine (n = 102) or placebo arm (n = 102). Mean CMAI scores at 12 weeks were not significantly different between participants allocated to receive mirtazapine and placebo [adjusted mean difference −1.74, 95% confidence interval (CI) −7.17 to 3.69; p = 0.53, direction of change in favour of mirtazapine but not statistically significant]. The number of controls with adverse events [65/102 (64%)] was similar to that in the mirtazapine group [67/102 (66%)]. There were more deaths in the mirtazapine group (n = 7) by week 16 than in the control group (n = 1), with post hoc analysis suggesting this was of marginal statistical significance (p = 0.065), but this difference did not persist at 6- and 12-month follow-ups. The cost-effectiveness analyses similarly showed no evidence of benefit of mirtazapine over placebo, and no difference in costs between groups at 12 weeks. The carbamazepine arm closed in August 2018 when there had been 40 randomisations to that group, we therefore do not have statistical power for comparisons with placebo. However, exploratory analyses using the same modelling as for mirtazapine versus placebo showed there was also little evidence of any benefits compared to placebo (adjusted mean difference 2.46, 95% CI −5.01 to 9.93; p = 0.52), with similar levels of adverse events reported [27/40 (68%)]. Conclusions This is a trial with negative findings but important clinical implications. The data suggest that mirtazapine is not clinically effective or cost-effective (compared to placebo) for clinically significant agitation in dementia. Our findings suggest that there is little reason to recommend the use of mirtazapine for people with dementia who experience agitation. Effective and cost-effective management strategies for agitation in dementia are needed, particularly where non-pharmacological approaches have been unsuccessful, and for people with dementia and their carers living in community settings. Trial registration This trial is registered as ISRCTN17411897 and ClinicalTrials.gov as NCT03031184. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment, Vol. 27, No. 23. See the NIHR Journals Library website for further project information

Evaluating the effects of the novel GLP-1 analogue liraglutide in Alzheimer's disease:Study protocol for a randomised controlled trial (ELAD study)

Background: Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue currently approved for type 2 diabetes and obesity. Preclinical evidence in transgenic models of Alzheimer's disease suggests that liraglutide exerts neuroprotective effects by reducing amyloid oligomers, normalising synaptic plasticity and cerebral glucose uptake, and increasing the proliferation of neuronal progenitor cells. The primary objective of the study is to evaluate the change in cerebral glucose metabolic rate after 12 months of treatment with liraglutide in participants with Alzheimer's disease compared to those who are receiving placebo. Methods/design: ELAD is a 12-month, multi-centre, randomised, double-blind, placebo-controlled, phase IIb trial of liraglutide in participants with mild Alzheimer's dementia. A total of 206 participants will be randomised to receive either liraglutide or placebo as a daily injection for a year. The primary outcome will be the change in cerebral glucose metabolic rate in the cortical regions (hippocampus, medial temporal lobe, and posterior cingulate) from baseline to follow-up in the treatment group compared with the placebo group. The key secondary outcomes are the change from baseline to 12 months in z scores for clinical and cognitive measures (Alzheimer's Disease Assessment Scale - Cognitive Subscale and Executive domain scores of the Neuropsychological Test Battery, Clinical Dementia Rating Sum of Boxes, and Alzheimer's Disease Cooperative Study - Activities of Daily Living) and the incidence and severity of treatment-emergent adverse events or clinically important changes in safety assessments. Other secondary outcomes are 12-month change in magnetic resonance imaging volume, diffusion tensor imaging parameters, reduction in microglial activation in a subgroup of participants, reduction in tau formation and change in amyloid levels in a subgroup of participants measured by tau and amyloid imaging, and changes in composite scores using support machine vector analysis in the treatment group compared with the placebo group. Discussion: Alzheimer's disease is a leading cause of morbidity worldwide. As available treatments are only symptomatic, the search for disease-modifying therapies is a priority. If the ELAD trial is successful, liraglutide and GLP-1 analogues will represent an important class of compounds to be further evaluated in clinical trials for Alzheimer's treatment. Trial registration: ClinicalTrials.gov, NCT01843075. Registration 30 April 2013