Background Dementia represents a major public health challenge worldwide. Interventions are required to maintain functional ability and prevent crises. Exercise-based therapy may improve activities of daily living and prevent falls. Objective We aimed to systematically develop an intervention, called Promoting Activity, Independence and Stability in Early Dementia and mild cognitive impairment (PrAISED), and evaluate its clinical and cost-effectiveness. Design A mixed-methods study. Literature review, co-design, patient and public involvement and practical experience were used to develop and refine a therapy intervention. We applied principles of behaviour change to promote engagement and motivation. Three-arm feasibility randomised controlled trial to test research procedures, the practicality of intervention, and establish the need for prolonged supervision. Two-arm, multicentre randomised controlled trial, comparing intervention with control, with 15 months’ follow-up. Process and realist evaluations, including quantitative data, interviews and thematic analyses. Health economic evaluations, including a cost-effectiveness analysis using Markov modelling and social return on investment. Implementation study. Setting Therapy and research were undertaken in participants’ homes and local communities across 5 sites in England. Participants People with diagnosed mild dementia or mild cognitive impairment, Montreal Cognitive Assessment score 13–25, living at home and a family member or carer. In the main trial, there were five sites in England, participants were 98% White ethnicity and 20% had mild cognitive impairment. Interventions A specially designed, dementia-specific, rehabilitation programme focusing on strength, balance, physical activity and performance of activities of daily living, which was tailored, progressive and addressed risk, providing up to 50 therapy sessions over 12 months. The control group received usual care plus a falls risk assessment. Main outcome measures The primary trial outcome was the informant-reported Disability Assessment for Dementia 12 months after randomisation. Secondary outcomes were: self-reported activities of daily living, physical activity, quality of life, frailty, balance, functional mobility, cognition, fear of falling, mood, carer strain and service use (at 12 months) and falls (between months 4 and 15). Results Three hundred and sixty-five people were randomised in the multicentre trial, 183 to intervention and 182 to control. Median age of participants was 80 years (range 65–95), median Montreal Cognitive Assessment score was 20/30 (range 13–26) and 58% were men. Participants received a median of 31 (interquartile range = 22–40) therapy sessions out of a possible maximum of 50. Participants reported completing a mean 121 minutes/week of PrAISED activity. Primary outcome data were available for 149 (intervention) and 141 (control) participants. There was no difference in Disability Assessment for Dementia scores between groups: adjusted mean difference −1.3/100, 95% confidence interval (−5.2 to 2.6); Cohen’s d effect size −0.06 (−0.26 to 0.15); p = 0.5. Upper 95% confidence intervals excluded small to moderate effects on any secondary outcome measures. Between months 4 and 15, there were 79 falls in the intervention group and 200 falls in the control group, and adjusted incidence rate ratio was 0.78 (0.5 to 1.3); p = 0.3. Participants and therapists liked the intervention and thought that it produced health benefits. Tailoring, perceiving benefits, professional supervision and family or carer support were important facilitators. Cognitive and physical impairment, risk aversion and tapering the level of support were barriers. Therapeutic relationship between participant and therapist was important. The cost per quality-adjusted life-year gained was £130,000 over a lifetime horizon. Social return on investment was positive before the onset of the COVID-19 pandemic but was negative after the first pandemic lockdown, largely due to unavailability of access to community facilities. Limitations The multicentre randomised controlled trial was disrupted by the COVID-19 pandemic. The first lockdown occurred when 301 participants had been randomised and 64 participants had completed the trial. Recruitment was suspended, and some therapy and data collection were undertaken remotely. The intervention was diminished compared with in-person delivery, but reported fidelity remained reasonable. Our participant population lacked socioeconomic and ethnic diversity – over 30% lived in the least deprived decile of postcodes. The intervention was very popular with participants and therapists, and it is possible that our predominantly biomedical and functionally orientated outcome variables failed to capture intervention benefits. Conclusions The intensive PrAISED programme of exercise and functional activity training did not improve activities of daily living, physical activity, quality of life, reduce falls or improve any other secondary health status outcomes. Due to the pandemic, the population recruited, and the outcomes chosen, some uncertainty remains about the effectiveness of the intervention. Future work Consider: (1) repeating the trial outside of a pandemic; (2) more psychosocial outcomes, such as social participation, affirming personhood and valuing therapeutic relationships; (3) alternative approaches to risk reduction and ability maintenance in dementia; (4) other models of support to manage problems associated with inevitable progression and decline; (5) that conventional randomised controlled trials may not be the best way to evaluate complex intervention for complex and degenerative conditions; interpretative and realist methods should supplement evaluation; and (6) work to include a wider range of ethnicities and socioeconomic circumstances. Study registration This study is registered as ISRCTN10550694, 15320670. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research programme (NIHR award ref: RP-PG-0614-20007) and is published in full in Programme Grants for Applied Research; Vol. 14, No. 1. See the NIHR Funding and Awards website for further award information. Plain language summary Dementia causes deterioration in memory and thinking abilities. The Promoting Activity, Independence and Stability in Early Dementia (PrAISED) programme aimed to develop and test a physical exercise and activity intervention to improve the ability to do daily activities among older people in the early stages of dementia. We developed a therapy programme specifically designed for people with dementia. We paid particular attention to encouraging participation. Therapy was tailored to participants’ goals, preferences and abilities. We confirmed that we could deliver the intervention and do the research to test it in a small-scale feasibility study. We tested PrAISED by recruiting 365 people with dementia and a family member from five English counties. We randomly assigned them to receive PrAISED therapy or to a control group, who were given advice on falls prevention. The PrAISED group received up to 50 therapy sessions, delivered by trained therapists, and were also encouraged to do exercises on their own. At the start and after 12 months, we measured ability to do everyday activities and other aspects of health, including falls, quality of life, activity and National Health Service and social care use. We did interviews and observations to explain the findings. Those receiving PrAISED therapy did no better on any of our measurements than those in the control group. The therapy programme was popular, and participants described benefits to their lives. Professional supervision and family support were important. However, memory and physical health problems often prevented full participation. The study was disrupted by the COVID-19 pandemic. An economic study showed that PrAISED was not cost-effective. A method which values social outcomes suggested that PrAISED gave a good return before the pandemic but not during it. We conclude that it might be more appropriate to help people manage problems associated with the inevitable decline seen in dementia rather than to try to change the course of the disease. Scientific summary Background The prevalence of dementia is increasing with the ageing population and is expected to double in the next 30 years. About 950,000 people live with dementia in the UK. Dementia causes progressive deterioration in a person’s cognitive and functional abilities. People with dementia are often dependent on other people. Dementia results in high levels of demand on health and social care as well as family and other informal carers. We need therapeutic interventions to reduce the decline in functional abilities so people with dementia can remain independent for longer. Exercise-based activities and functional rehabilitation may improve people with dementia’s activities of daily living (ADL). Objectives The Promoting Activity, Independence and Stability in Early Dementia and mild cognitive impairment (PrAISED) programme aimed to develop and evaluate an exercise and activity intervention to increase independence in ADL for older people living with dementia or mild cognitive impairment (MCI). The programme comprised seven work packages (WPs): WP1 – intervention development: develop, manualise and support the delivery of an evidence-based multicomponent therapy intervention. WP2 – adherence and motivation: develop strategies to support engagement with the intervention and achieve long-term adherence. WP3 – feasibility study: test the feasibility and practicality of delivering the intervention and conducting a randomised controlled trial (RCT). WP4 – process evaluation: conduct process and realist evaluations of the trials. WP5 – multicentre RCT: establish the clinical effectiveness of the PrAISED intervention in a multicentre RCT. WP6 – health economics: establish the cost-effectiveness of the intervention and social return on investment (SROI). WP7 – implementation: understand factors that would affect implementation of the intervention in practice. Methods Work package 1 – intervention development The PrAISED intervention was developed by a team of clinical academics, practitioners and patient and public involvement and engagement representatives using evidence and theory from systematic reviews, interviews, focus groups, empirical studies and expert opinion. This followed work in an Alzheimer’s Society PhD fellowship (Dr Vicky Booth) and a National Institute for Health and Care Research (NIHR) Programme Development Grant. We used theory about how to motivate people with dementia to do exercises. The intervention was described in a manual. We developed practitioner training courses. These were refined following experience in the feasibility study and described using the Template for Intervention Description and Replication (TIDieR) checklist. Work package 2 – adherence and motivation We initially used self-determination theory (SDT) to inform intervention development but later developed a new dementia-specific behaviour change model (PHYT-in-dementia), derived from literature reviews, synthesis and empirical evidence from the feasibility study. It was validated using interview data collected during the RCT process evaluation. PHYT-in-dementia identified factors that mediate behaviour change and maintenance in people living with dementia. These were: characteristics of the person with dementia, support, expectations, goals, carer characteristics, progress, social opportunity, self-efficacy, capability, intervention characteristics, autonomy, control, physical infrastructure, personal history, information, knowledge, characteristics of therapists and personal beliefs. Work package 3 – feasibility study We conducted a three-arm randomised feasibility trial to establish that we could recruit and randomise participants at a sufficient rate, deliver the intervention in participants’ homes across two sites, retain and follow up participants; that the intervention was practical and safe; that we could collect trial data and that our sample size assumptions were reasonable. We explored the level of supervision participants would need to undertake 3 hours of PrAISED exercises and activities a week and sustain this over the duration of the trial. We compared the PrAISED intervention with supervision over 12 months to a shorter intervention comprising nine therapy visits and three telephone calls delivered over 12 weeks and a control group who received a falls prevention assessment and advice. Data were collected at baseline and 12-month follow-up, during face-to-face interviews with two researchers. Health status measures comprised disability in ADL [Disability Assessment for Dementia scale (DAD)], habitual physical activity, quality of life (QoL), frailty, cognition, other intermediate outcomes and carer outcomes. Monthly calendars were completed for falls and activity ascertainment. Work package 4 – process evaluation We investigated implementation of the PrAISED intervention during the trials, the mechanisms of impact and context. We adopted a mixed-methods approach investigating fidelity, adaptations, dose and reach, including quantitative data, interviews and thematic analyses. Mechanisms of impact and context were identified through semistructured qualitative interview with a sample of therapists, participants and carers. Interviews were conducted 6 and 12 months into involvement in PrAISED. Interviews were conducted remotely during the COVID-19 lockdown between May 2020 and September 2020. Work package 5 – multicentre randomised controlled trial Participants were recruited from five sites in England via secondary care memory assessment clinics, general practice registers, dementia support groups and the NIHR Join Dementia Research register. Participants were recruited as patient–carer dyads. The RCT was conducted between September 2018 and June 2022. This included the COVID-19 pandemic period, which impacted recruitment, intervention delivery and data collection. Between March 2020 and September 2020, research and intervention contacts were delivered remotely. We included participants aged over 65 years, with a diagnosis of dementia or MCI, a Montreal Cognitive Assessment (MoCA) score of 13–25 (out of 30), a family member or unpaid carer who knew the participant well and who was willing to participate. Participants had to have mental capacity to consent and be willing to take part in an exercise intervention. Separate consent was taken for the carer. Active intervention comprised a specially designed, dementia-specific, rehabilitation programme focusing on strength, balance, physical activity and performance of ADL, which was tailored, progressive and addressed risk, providing up to 50 therapy sessions over 12 months. The control group received usual care plus a falls risk assessment. The primary outcome was ADL, measured at 12 months by the informant-completed DAD scale. Secondary outcomes included self-assessed ADL (Nottingham Extended ADL scale); cognition (MoCA, animal-naming verbal fluency; Cambridge Neuropsychological Test Automated Battery), balance (Berg Balance Scale); mobility and ability in divided attention [Timed Up and Go (TUG), dual-task (TUG)]; hand grip strength; health and social care resource use for patient and carer Client Service Receipt Inventory; fear of falling; frailty, mood; carer strain, carer and self-assessed health-related quality of life (EQ5D DemQoL scales), physical activity; step count by accelerometer; and apathy. Participants were followed up after 12 months. Between months 1 and 15, self-completed calendars were used to record falls and PrAISED exercise undertaken. A brief postal follow-up questionnaire was completed by the patient’s carer/informant after 6 months. A sample of 368 participants (184 per group), with 23% attrition, had 80% statistical power to detect a change in disability outcome (DAD), with a moderate effect size of 0.5. A secure internet-based system based in a Clinical Trials Unit was used to randomise individuals, 1 : 1, stratified by site, presence of a co-resident and history of previous falls. Blinding of participants and therapists was not possible due to the nature of the intervention. Analysis was conducted blind. An analysis of covariance was conducted for the primary outcome (DAD) at the 12-month follow-up, using group, stratification variables and baseline DAD score as covariates. The analysis was conducted on an intention-to-treat basis. Scaled secondary outcome measures were analysed similarly. Adjusted mean differences, Cohen’s d standardised effect size, 95% confidence intervals (CIs) and p-values were reported. Work package 6 – health economics Cost–utility analysis using a Markov-modelled projection over a 15-year time frame, and a SROI analysis. Work package 7 – implementation We undertook four small-scale implementation studies, using the Consolidated Framework for Implementation Research. We investigated adaptation and adoption of a pilot service in routine practice at one site. We interviewed therapists who delivered the PrAISED intervention, commissioners and service leaders. We explored lack of participation by ethnic minority populations through discussions with community groups and leaders. We developed advice on compiling a business case for commissioning the intervention. Results We developed and refined the PrAISED intervention. This comprised a 12-month, home-based, individually tailored rehabilitation programme, focusing on strength, balance, physical activity and performance of ADL. Tailoring took account of individual history, personality and abilities, problems, interests, family and other resources. Fourteen core principles were defined to guide intervention delivery. A logic model was developed. Delivery was by physiotherapists, occupational therapists and rehabilitation support workers. Participants were encouraged to undertake a total of at least 180 minutes of exercise per week. The programme was progressed by therapists following periodic reassessments. Supervised sessions were tapered over the 12 months (twice-weekly visits in the first 3 months, reducing to monthly in the final 3 months) and community activities were signposted. An intervention manual was published. Therapists were supported throughout the intervention delivery period with training and regular clinical support sessions. We reviewed behaviour change frameworks for older people and people living with dementia. We adapted SDT to support the intervention, which posits the importance of autonomy, relatedness and competence, and 12 practical support approaches. Further reviews led to the development of a new behaviour change framework, PHYT-in-dementia, which was adapted, validated and applied to the intervention for the multicentre RCT. We undertook a two-site, three-arm feasibility RCT. We successfully recruited 60 participants, of whom 45 completed the intervention and provided outcome data. There were no serious, related adverse events (AEs). Missing data rates were satisfactory, apart from some scales that were investigating SDT. We made some other minor adjustments to eligibility criteria and outcome scales. We found that participants were unable to adhere to the programme in the absence of supervision and carried forward higher-intensity supervision but developed an algorithm to plan and gradually reduce intensity, considering ability to undertake activities independently. Analysis of outcomes supported the superiority of the higher-intensity programme and suggested moderate to large benefits in balance, gait speed and disability. We undertook a five-site, two-arm RCT, powered to detect a moderate effect size on the DAD scale. We recruited 365 participants, median age 80 years, 42% female, median MoCA score 20/30, predominantly from less-deprived localities. There were no significant differences in characteristics between groups at baseline. A median of 31 therapy sessions were delivered, interquartile range 22–40, 68% face to face. Fidelity judged from (pre pandemic) video-recorded therapy sessions was good. Intervention group participants reported undertaking an additional mean of 121 minutes of exercise per week. Two hundred and ninety (79%) were followed up. There were no significant differences on the primary outcome, the DAD: adjusted mean difference −1.3 (95% CI −5.2 to 2.6); standardised effect size (d) −0.06, 95% CI −0.26 to 0.15; p = 0.5; or on physical activity, balance, QoL, cognition or a range of other measures. There was a statistically significant small difference in favour of the control group, on the dual-task TUG test and on the self-report DemQoL scale. Upper 95% CIs excluded even small benefits on other scales. Rate of falling was reduced by 22%, but this was not statistically significant. Results did not change in a range of sensitivity analyses. Both service delivery and research were disrupted by the COVID-19 pandemic. Recruitment was delayed, some follow-up was undertaken remotely and some intervention sessions were delivered by telephone or video call, which were consequently much less ambitious than intended. Community facilities and activities became unavailable to vulnerable people. Results were no different for those completing the intervention before the COVID-19 pandemic. One hundred and sixty-seven AEs were recorded: 59 in control and 108 in the intervention groups, involving 68 participants. There were 91 serious adverse events: 29 in control and 62 in intervention, involving 60 participants. None was serious and related to intervention. There was no statistically significant difference between the intervention and control groups for AEs. The process evaluation studied implementation of the intervention, mechanisms of impact and context. Eighty-eight interviews were undertaken with participants, carers and staff. The PrAISED intervention was well received among participants and clinicians. Many gave examples of benefits gained as a result of taking part in PrAISED. However, cognitive impairment, physical comorbidity and fear of falls or getting lost prevented independent engagement. Tapered support was ineffective and acted as a barrier to continued engagement. Family members played a major role in supporting participation. A realist evaluation considered mechanisms behind the social benefits and concluded that participants improved social interactions when therapy activities were tailored to their preferences, when therapy support was maintained and when participants perceived improvements as a result of the intervention. The cost-effectiveness study showed a cost/quality-adjusted life-year of £130,000. SROI suggested benefits, but only in the feasibility and pre-COVID phases of the study. Participants completing the trial after the start of the pandemic had a negative social return, predominantly due to lack of availability of community facilities. We introduced PrAISED into routine practice in a socioeconomically deprived part of Nottingham. Eleven participants were referred and completed a shorter version of PrAISED, less than half what was anticipated or provided for. The intervention was well received by those who participated. We investigated reasons behind poor recruitment of participants from ethnic minority groups, finding feelings of mistrust towards health services and research, and stigma against dementia. We interviewed commissioners to provide guidelines on constructing a business case for implementing exercise and post-diagnostic support programmes. Conclusions We delivered an ambitious programme of research to address whether we can intervene to maintain safe activity and independence after a diagnosis of dementia. We systematically designed a new dementia-specific intervention, and used multiple methods to evaluate it, centred around a multicentre RCT. The intervention was about as intensive as it would be possible to deliver in the UK health and cultural context. Despite positive reception and perceived benefits by participants, we measured no benefits from the programme. Our RCT was significantly disrupted by the COVID-19 pandemic. This, a lack of diversity in the participant population and the fact that the outcome measures used might not have captured the impact of the intervention, leave persisting uncertainties about whether a PrAISED-like intervention might be beneficial. However, our findings suggest that a more ‘supportive’ approach to health care after a diagnosis of dementia may be appropriate, helping to manage problems associated with inevitable functional decline, rather than trying to change the course of disease or to maintain abilities. This would involve developing therapeutic relationships, providing support to live with limitations, minimising intervention burden, maintaining personhood, inclusion and occupation, providing psychological and emotional support and support to family and other carers. Study registration This study is registered as ISRCTN10550694, 15320670. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research programme (NIHR award ref: RP-PG-0612-20004) and is published in full in Programme Grants for Applied Research; Vol. 14, No. 1. See the NIHR Funding and Awards website for further award information.

Alzheimer’s disease is a devastating neurodegenerative disorder with a complex pathogenesis. One main pathological feature utilised in diagnosis is neurodegeneration or neuronal injury, which is reflected in reductions in cerebral glucose metabolism measured by [18F]Fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET). Here we evaluated the involvement of glial reactivity measured with magnetic resonance spectroscopy (MRS) and cerebral blood flow measured with arterial spin labelling (ASL) on [18F]FDG PET as a measure of cerebral glucose metabolism. 123 people living with early Alzheimer’s disease who completed baseline evaluations on the evaluating liraglutide in Alzheimer’s disease trial were enrolled. Participants completed [18F]FDG PET scans with arterial input, T1 weighted MRI, single-voxel 1 HMRS, and pulsed ASL scans at Imperial College London Clinical Imaging Facility. The Totally Automatic Robust Quantitation in NMR (TARQUIN) package was used to process MRS scans and identify the concentration of myo-inositol within the posterior cingulate cortex (PCC), a marker of glial activation. Oxford-ASL was utilised to process ASL and quantify cerebral blood flow in the PCC. Finally, spectral analysis was performed on the [18F]FDG PET scans to assess the cerebral metabolic rate of glucose in the PCC. Pearson’s correlations were performed between the cerebral metabolic rate of glucose, cerebral blood flow and glial activity measured by the level of myo-inositol in the PCC. Increased cerebral glucose metabolism was correlated with higher myo-inositol in this sample of Alzheimer’s disease participants. In contrast, cerebral blood flow was not associated with cerebral glucose metabolism. Here we demonstrate that increased glial reactivity contributes to [18F]FDG PET signal in the early stages of Alzheimer’s disease. In response to early neuronal injury, astrocytes and microglia may become activated and enhance regional rates of glucose consumption. Hence, the contribution from these cells in addition to neurons should be considered in interpreting [18F]FDG PET as a measure of cerebral glucose metabolism. Interestingly, cerebral blood flow did not influence glucose metabolism. Microglia and astrocyte reactivity may contribute to an increase the cerebral glucose metabolism while neuronal loss and synaptic function may contribute to lower glucose metabolism measured by [18F]FDG in the early stages of Alzheimer's disease.

Liraglutide, a glucagon-like peptide 1 (GLP-1) agonist and antidiabetic drug, has shown neuroprotective effects in animal models. In this study, we aimed to evaluate the safety and efficacy of liraglutide in mild to moderate Alzheimer's disease syndrome. 'Evaluating liraglutide in Alzheimer's disease' (ELAD) is a multicenter, randomized, double-blind, placebo-controlled phase 2b trial in 204 participants with mild to moderate Alzheimer's disease syndrome with no diabetes. Participants received daily injections of liraglutide or placebo for 52 weeks. They underwent fluorodeoxyglucose positron emission tomography, magnetic resonance imaging and detailed neuropsychometric evaluations. The primary outcome was a change in cerebral glucose metabolic rate. Secondary outcomes were safety and tolerability and cognitive changes. The primary outcome showed no significant differences in cerebral glucose metabolism (difference = -0.17; 95% confidence interval: -0.39 to 0.06; P = 0.14) between the two groups. The secondary outcome-score on the Alzheimer's Disease Assessment Scale-Executive domain (ADAS-Exec)-performed better in liraglutide-treated patients compared to placebo (0.15; 95% confidence interval: 0.03-0.28; unadjusted P = 0.01). No significant differences were observed in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) (-0.58; 95% confidence interval: -3.13 to 1.97; unadjusted P = 0.65) or Clinical Dementia Rating-Sum of Boxes (CDR-SoB) (-0.06; 95% confidence interval: -0.57 to 0.44; unadjusted P = 0.81) scores. Liraglutide was generally safe and well tolerated in non-diabetic patients with Alzheimer's disease. ClinicalTrials.gov identifier: NCT01843075 .

Magnetic resonance spectroscopy (MRS) is a non-invasive method of evaluating metabolite levels in the cerebral cortex. Measurable metabolites can provide markers of neuronal damage, glial activation and, neurotransmission, pathological features of Alzheimer’s disease. Here we sought to establish the effectiveness of several metabolites as biomarkers for Alzheimer’s disease. 198 participants with a single-voxel 1 H MRS scan were enrolled (n = 170 participants living with Alzheimer’s disease, n = 28 healthy controls). All participants underwent 3-tesla magnetic resonance imaging and cognitive assessment with the Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-cog). An experienced radiographer placed an 8cm 3 voxel within the posterior cingulate cortex for single-voxel 1 H MRS acquisition. Scans were then processed to evaluate levels of N-acetylaspartate, myo-inositol, choline, and glutamate. Creatine peak was additionally evaluated as a reference. N-acetylaspartate/creatine, myo-inositol /creatine, choline/creatine ratios and glutamate were compared between Alzheimer’s participants and controls to calculate the effect size. Correlations were then performed between metabolite ratios and ADAS-cog scores. N-acetylaspartate/creatine effectively distinguished between Alzheimer’s patients and healthy controls (Cohens D = 0.83) with a lowered ratio in Alzheimer’s participants. Elevated glutamate signal and myo-inositol/creatine ratios were also displayed in Alzheimer’s patients (Cohens D = 0.62 and 0.69, respectively). Choline/creatine ratio displayed no significant difference between groups (Cohens D = 0.26). Lower N-acetylaspartate /creatine and glutamate correlated with higher ADAS-cog scores (r = -0.29, p < 0.001, CIs: -0.42 to -0.14 and r = -0.30, p < 0.001, CIs: -0.44 to -0.16, respectively). Myo-inositol and choline failed to correlate with cognitive impairment. N-acetylaspartate, a signature of neuronal damage, is an effective biomarker of Alzheimer’s disease and associated cognitive decline. Enhanced glial activity, measured with myo-inositol, was shown in Alzheimer’s disease, suggesting that glial-reactivity markers deserve consideration in the diagnosis of Alzheimer’s disease. Glutamate demonstrated the strongest association with cognitive impairment, despite showing a smaller effect size than N-acetylaspartate and myo-inositol in distinguishing between Alzheimer’s patients and controls. Together we establish MRS is a useful, non-invasive biomarker of several pathological processes involved in the development of Alzheimer’s. Evaluation of N-acetylaspartate, glutamate, and myo-inositol may aid in the diagnosis of neurodegenerative disease, detecting markers undetectable by conventional MRI methodology.

Abstract Objective To determine the effectiveness of an exercise and functional activity therapy intervention in adults with early dementia or mild cognitive impairment compared with usual care. Design Randomised controlled trial. Setting Participants’ homes and communities at five sites in the United Kingdom. Participants 365 adults with early dementia or mild cognitive impairment who were living at home, and family members or carers. Intervention The intervention, Promoting activity, Independence, and Stability in Early Dementia and mild cognitive impairment (PrAISED), was a specially designed, dementia specific, rehabilitation programme focusing on strength, balance, physical activity, and performance of activities of daily living, which was tailored and progressive and addressed risk and the psychological needs of people with dementia. Up to 50 therapy sessions were provided over 12 months. The control group received usual care plus a falls risk assessment. Procedures were adapted during the covid-19 pandemic. Main outcome measures The primary outcome was score on the carer (informant) reported disability assessment for dementia scale 12 months after randomisation. Secondary outcomes were self-reported activities of daily living, physical activity, quality of life, balance, functional mobility, fear of falling, frailty, cognition, mood, carer strain, service use at 12 months, and falls between months 4 and 15. Results 365 patient participants were randomised, 183 to intervention and 182 to control. The median age of participants was 80 years (range 65-95), median Montreal cognitive assessment score was 20 out of 30 (range 13-26), and 58% (n=210) were men. Intervention participants received a median of 31 therapy sessions (interquartile range 22-40) and reported completing a mean 121 minutes of PrAISED exercise each week. Primary outcome data were available for 149 intervention and 141 control participants. Scores on the disability assessment for dementia scale did not differ between groups: adjusted mean difference −1.3, 95% confidence interval −5.2 to 2.6; Cohen’s d effect size −0.06, 95% confidence interval −0.26 to 0.15; P=0.51). Upper 95% confidence intervals excluded small to moderate effects on any of the range of outcome measures. Between months 4 and 15 the intervention group experienced 79 falls and the control group 200 falls (adjusted incidence rate ratio 0.78, 95% confidence interval 0.5 to 1.3; P=0.3). Conclusion The intensive PrAISED programme of exercise and functional activity training did not improve activities of daily living, physical activity, or quality of life; reduce falls; or improve any other secondary health status outcomes, despite good uptake. Future research should consider alternative approaches to maintaining ability and wellbeing in people with dementia. Trial registration ISRCTN Registry ISRCTN15320670 .

Preclinical evidence in transgenic models of Alzheimer’s disease (AD) suggests that liraglutide, a GLP1 analogue, exerts neuroprotective effects by reducing amyloid oligomers, normalising synaptic plasticity and reducing insulin resistance, and increasing the proliferation of neuronal progenitor cells. ELAD is a 12-month, multi-centre, randomised, double-blind, placebo-controlled, phase IIb trial of liraglutide in participants with mild to moderate AD conducted at 24 centres in the UK. As a part of this study, a total of 204 Alzheimer’s participants were randomised to receive either liraglutide or placebo as a daily subcutaneous injection for 12 months. All subjects underwent volumetric MRI scans at baseline and during follow up. Volumetric changes from baseline to follow up in MRI scans were evaluated using both regional volume analysis and voxel based morphometric analysis MRI analysis demonstrated that temporal lobe volume, total grey matter volume and frontoparietal volume change was lower in liraglutide treated patients compared to the placebo group. Voxel based morphometry (VBM) analysis demonstrated that liraglutide-treated participants showed a slower reduction in whole cortical grey matter, frontal, temporal and parietal lobe volume in participants treated with liraglutide compared to placebo. In the ELAD study, participants with mild to moderate AD who received liraglutide had slower reduction in MRI volume and cognition compared to the placebo demonstrating a potential benefit of liraglutide in the treatment of Alzheimer’s disease. These findings highlight the potential of GLP-1 analogues in the treatment of Alzheimer’s disease

Glucose is the primary energy source required for the homeostatic function of the brain. Glucose transporter 1 (GLUT1) present at the blood-brain barrier is a key regulator of glucose transport into the brain. Reduced GLUT1 expression is shown to exacerbate Alzheimer’s pathology in rodent models. Here we aimed to establish whether there are regional differences in ineffective glucose transport amongst people living with Alzheimer’s disease. 125 participants diagnosed with Alzheimer’s dementia, with an [ 18 F]FDG scan with atrial input were enrolled. All participants underwent 3-tesla magnetic resonance imaging and [18F]FDG scan with continuous and discrete arterial sampling. Spectral analysis was performed to create 1-minute input-response function parametric maps. To produce glucose transfer maps we applied the following equation; K1 ⁎ Ca / τ (K1 = 1-minute IRF map, Ca = Plasma glucose concentration, τ = 1.48 a lumped constant). Glucose transfer maps were then coregistered to the participants’ structural MRI and normalised to MNI space. Regional mean glucose transfer was then calculated for the anterior cingulate cortex, frontal lobe, hippocampus, parahippocampus, occipital lobe, parietal lobe, posterior cingulate cortex, striatum, temporal lobe, and thalamus. A within-subject ANOVA was then performed to evaluate the regional differences in cerebral glucose transport. The parahippocampus exhibited the lowest rate of glucose transfer in comparison to all other regions (p < 0.001), followed by the hippocampus. The striatum and occipital lobe demonstrated the regions of the highest mean glucose transportation from blood to the brain. In terms of brain lobes, the temporal lobe showed the lowest rates of glucose transfer, followed by the parietal lobe, then frontal and occipital (p < 0.001). We demonstrate dysfunctional BBB glucose transport in Alzheimer’s disease, with prominent glucose transport abnormalities localised in the parahippocampus. Impaired glucose transport was most apparent within temporal lobe structures. Targeting glucose transfer may be an effective way of treating Alzheimer’s disease.

Background Dementia is associated with frailty leading to increased risks of falls and hospitalisations. Interventions are required to maintain functional ability, strength and balance. Design Multi-centre parallel group randomised controlled trial, with embedded process evaluation. Procedures were adapted during the COVID-19 pandemic. Participants People with mild dementia or mild cognitive impairment (MCI), living at home, and a family member or carer. Objectives To determine the effectiveness of an exercise and functional activity therapy intervention compared to usual care. Intervention A specially-designed dementia-specific rehabilitation programme focussing on strength, balance, physical activity and performance of ADL, which was tailored, progressive, addressed risk and the psychological and learning needs of people with dementia, providing up to 50 therapy sessions over 12 months. The control group received usual care plus a falls risk assessment. Main outcome measure The primary outcome was the informant-reported Disability Assessment for Dementia (DAD) 12 months after randomisation. Secondary outcomes were: self-reported ADL, cognition, physical activity, quality of life, frailty, balance, functional mobility, fear of falling, mood, carer strain and service use (at 12 months) and falls (between months 4 and 15). Results 365 people were randomised, 183 to intervention and 182 to control. Median age of participants was 80 years (range 65-95), median Montreal Cognitive Assessment score 20/30 (range 13-26), 58% were men. Participants received a median of 31 (IQR = 22-40) therapy sessions out of a possible maximum of 50. Participants reported completing a mean 121 minutes/week of PrAISED activity outside of supervised sessions. Primary outcome data were available for 149 (intervention) and 141 (control) participants. There was no difference in DAD scores between groups: adjusted mean difference -1.3/100, 95% Confidence Interval (−5.2 to +2.6); Cohen’s d effect size -0.06 (−0.26 to +0.15); p=0.5. Upper 95% confidence intervals excluded small to moderate effects on any of the range of secondary outcome measures. Between months 4 and 15 there were 79 falls in the intervention group and 200 falls in the control group, adjusted incidence rate ratio 0.78 (0.5 to 1.3); p= 0.3. Conclusion The intensive PrAISED programme of exercise and functional activity training did not improve ADLs, physical activity, quality of life, reduce falls or improve any other secondary health status outcomes even though uptake was good. Future research should consider alternative approaches to risk reduction and ability maintenance. Trial registration ISRCTN15320670. Funding National Institute for Health and Care Research What is already known What this study tells us ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial ISRCTN15320670 ### Clinical Protocols ### Funding Statement This study was funded by the NIHR Programme Grants for Applied Health Research, award number RP-PG-0614-20007. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was approved by the Bradford-Leeds Research Ethics Committee (REC number 18/YH/0059, IRAS project identification 236099) and research governance departments in each participating organisation. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors

Liraglutide is a glucagon‐like peptide‐1 (GLP‐1) analogue licensed for the treatment of type 2 diabetes. 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.

BACKGROUND:Type 2 diabetes is a risk factor for Alzheimer's disease (AD), and AD brain shows impaired insulin signalling. The role of peripheral insulin resistance on AD aetiopathogenesis in non-diabetic patients is still debated. Here we evaluated the influence of insulin resistance on brain glucose metabolism, grey matter volume and white matter lesions (WMLs) in non-diabetic AD subjects.METHODS:In total, 130 non-diabetic AD subjects underwent MRI and [18F]FDG PET scans with arterial cannula insertion for radioactivity measurement. T1 Volumetric and FLAIR sequences were acquired on a 3-T MRI scanner. These subjects also had measurement of glucose and insulin levels after a 4-h fast on the same day of the scan. Insulin resistance was calculated by the updated homeostatic model assessment (HOMA2). For [18F]FDG analysis, cerebral glucose metabolic rate (rCMRGlc) parametric images were generated using spectral analysis with arterial plasma input function.RESULTS:In this non-diabetic AD population, HOMA2 was negatively associated with hippocampal rCMRGlc, along with total grey matter volumes. No significant correlation was observed between HOMA2, hippocampal volume and WMLs.CONCLUSIONS:In non-diabetic AD, peripheral insulin resistance is independently associated with reduced hippocampal glucose metabolism and with lower grey matter volume, suggesting that peripheral insulin resistance might influence AD pathology by its action on cerebral glucose metabolism and on neurodegeneration.

AbstractBackgroundCerebral metabolic rate of glucose (CMRglc) can be measured with fluorodeoxyglucose (FDG) positron emission tomography (PET) using arterial blood sampling. However, blood sampling is an invasive methodology for subjects. Standard uptake value (SUV) is a non‐invasive method to assess the cerebral glucose metabolism. Here we evaluate the relationship between semi‐quantitative measurements such as SUV and Pons ratio with a quantitative measurement such as Spectral analysis (SA) in order to assess their surrogate use in clinical trials.MethodsTo assess cerebral glucose metabolism by a non‐invasive and simplified method, the standardized uptake value (SUV) and used the Pons RATIO (where target region was divided by pons as a reference region, which requires no arterial input function or blood sampling. The SA was performed using blood sampling to create the input function. The study participants included 63 subjects (mean ± SD age, 71 ± 8 years) from the Evaluating Liraglutide in Alzheimer’s Disease (ELAD) trial. Regional CMRglucose (CMRglc) and regional SUV were measured using FDG PET, and the correlation between CMRglc and SUV together with CMRglc and Pons ratio were estimated for the temporal lobe, medial temporal lobe and hippocampusResultsIn this AD population, the SA and SUV in the temporal lobe (r=0.635, p= >0.001), medial temporal lobe (0.533, p= >0.001) and hippocampus (r=0.539, p= >0.001) had a positive correlation and were statistically significant. The correlation coefficient between SA and Pons ratio for the temporal lobe (r=0.166, p= 0.194), medial temporal lobe (r=0.146, p=0.146) and the hippocampus (r=0.193, p=0.129) was positive but not statistically significant.ConclusionThe SUV correlated better with cerebral glucose metabolic rate using SA than Pons RATIO in AD subjects, while Pons RATIO did not perform well. Therefore, SUV analysis maybe more reliable analysis method compared to Pons RATIO for FDG PET in clinical trials in AD subjects.

AbstractBackground18F‐fluorodeoxyglucose‐positron emission tomography (FDG‐PET) measures regional cerebral glucose metabolism –which is a biomarker of neuronal function in Alzheimer’s disease (AD) Neuropsychological measures such as the Alzheimer’s Disease Assessment Scale – Cognitive Subscale (ADAS‐Cog) – a measure of memory, language and praxis has been used as an outcome measure in AD clinical trials. ADAS‐Cog‐12 attempts to overcome such limitations, by including an additional delayed word recall measure. The objective of this study was to compare baseline ADAS‐Cog‐12 scores with cerebral glucose metabolic rate measured with FDG‐PET with arterial input in subjects who have undergone baseline scans for the Evaluation of Liraglutide in treatment of Alzheimer’s disease (ELAD) study.Method107 subjects diagnosed with AD underwent baseline FDG‐PET scans with continuous online blood sampling along with discrete sampling for radioactivity and plasma glucose. They also underwent detailed neurological and neuropsychological testing including ADAS‐Cog. FDG PET was analysed using spectral analysis with arterial input and following regions were sampled : hippocampus, medial temporal lobe, temporal, anterior cingulate, posterior cingulate, frontal, parietal and occipital cortices. ADAS‐Cog scores were calculated for all the subjects.ResultPearson’s product‐moment correlation showed that ADAS‐Cog scores (at 0.01 level) negatively correlated with all FDG‐PET ROIs derived from spectral analysis (‐0.36≤|r|≤‐0.54). Greatest correlations occurred between ADAS‐Cog and the temporal cortex (‐0.54), parietal cortex (‐0.51) and frontal lobe (‐0.51).ConclusionIn this study, ADAS‐Cog‐12 scores correlated well with the cerebral glucose metabolism, suggesting cerebral glucose metabolism could be used as a surrogate marker for cognitive function in Alzheimer’s disease intervention studies, and is a sensitive maker for neuronal function.

Behavioral and psychological symptoms of dementia (BPSD) are highly prevalent in Alzheimer’s disease (AD) and associated with adverse outcomes. There is increasing interest in identifying the risk factors for developing BPSD among AD patients. However, the pathophysiological mechanisms underlying BPSD remain poorly understood. Here we evaluated whether BPSD are associated with WMLs volume, brain atrophy and brain metabolism in AD subjects.

Brain atrophy can be reliably measured through volumetric analysis of structural MRI and is a valid biomarker of neurodegeneration in Alzheimer’s disease (AD) pathology1. The Alzheimer’s Disease Assessment Scale‐Cognitive subscale (ADAS‐Cog12) is a neuropsychological test designed to assess the level of cognitive dysfunction in AD within cognitive domains such as memory2. This study aimed to assess the relationship between brain atrophy and ADAS‐Cog12 score in patients with AD.

An amendment to this paper has been published and can be accessed via the original article.