Conveying Risks of Harm in Alzheimer Disease by Amyloid Lowering.

This Viewpoint discusses how data gaps in published research impede clinicians' ability to clearly discuss the risks and benefits of amyloid-lowering drugs for treating Alzheimer disease.

Perspectives on the diagnosis and management of functional cognitive disorder: An international Delphi study.

BACKGROUND: Current proposed criteria for functional cognitive disorder (FCD) have not been externally validated. We sought to analyse the current perspectives of cognitive specialists in the diagnosis and management of FCD in comparison with neurodegenerative conditions. METHODS: International experts in cognitive disorders were invited to assess seven illustrative clinical vignettes containing history and bedside characteristics alone. Participants assigned a probable diagnosis and selected the appropriate investigation and treatment. Qualitative, quantitative and inter-rater agreement analyses were undertaken. RESULTS: Eighteen diagnostic terminologies were assigned by 45 cognitive experts from 12 countries with a median of 13 years of experience, across the seven scenarios. Accurate discrimination between FCD and neurodegeneration was observed, independently of background and years of experience: 100% of the neurodegenerative vignettes were correctly classified and 75%-88% of the FCD diagnoses were attributed to non-neurodegenerative causes. There was <50% agreement in the terminology used for FCD, in comparison with 87%-92% agreement for neurodegenerative syndromes. Blood tests and neuropsychological evaluation were the leading diagnostic modalities for FCD. Diagnostic communication, psychotherapy and psychiatry referral were the main suggested management strategies in FCD. CONCLUSIONS: Our study demonstrates the feasibility of distinguishing between FCD and neurodegeneration based on relevant patient characteristics and history details. These characteristics need further validation and operationalisation. Heterogeneous labelling and framing pose clinical and research challenges reflecting a lack of agreement in the field. Careful consideration of FCD diagnosis is advised, particularly in the presence of comorbidities. This study informs future research on diagnostic tools and evidence-based interventions.

Acceptance and Commitment Therapy plus usual care for improving quality of life in people with motor neuron disease (COMMEND): a multicentre, parallel, randomised controlled trial in the UK.

BACKGROUND: Motor neuron disease is a progressive, fatal neurodegenerative disease for which there is no cure. Acceptance and Commitment Therapy (ACT) is a psychological therapy incorporating acceptance, mindfulness, and behaviour change techniques. We aimed to evaluate the effectiveness of ACT plus usual care, compared with usual care alone, for improving quality of life in people with motor neuron disease. METHODS: We conducted a parallel, multicentre, two-arm randomised controlled trial in 16 UK motor neuron disease care centres or clinics. Eligible participants were aged 18 years or older with a diagnosis of definite or laboratory-supported probable, clinically probable, or possible familial or sporadic amyotrophic lateral sclerosis; progressive muscular atrophy; or primary lateral sclerosis; which met the World Federation of Neurology's El Escorial diagnostic criteria. Participants were randomly assigned (1:1) to receive up to eight sessions of ACT adapted for people with motor neuron disease plus usual care or usual care alone by a web-based system, stratified by site. Participants were followed up at 6 months and 9 months post-randomisation. Outcome assessors and trial statisticians were masked to treatment allocation. The primary outcome was quality of life using the McGill Quality of Life Questionnaire-Revised (MQOL-R) at 6 months post-randomisation. Primary analyses were multi-level modelling and modified intention to treat among participants with available data. This trial was pre-registered with the ISRCTN Registry (ISRCTN12655391). FINDINGS: Between Sept 18, 2019, and Aug 31, 2022, 435 people with motor neuron disease were approached for the study, of whom 206 (47%) were assessed for eligibility, and 191 were recruited. 97 (51%) participants were randomly assigned to ACT plus usual care and 94 (49%) were assigned to usual care alone. 80 (42%) of 191 participants were female and 111 (58%) were male, and the mean age was 63·1 years (SD 11·0). 155 (81%) participants had primary outcome data at 6 months post-randomisation. After controlling for baseline scores, age, sex, and therapist clustering, ACT plus usual care was superior to usual care alone for quality of life at 6 months (adjusted mean difference on the MQOL-R of 0·66 [95% CI 0·22-1·10]; d=0·46 [0·16-0·77]; p=0·0031). Moderate effect sizes were clinically meaningful. 75 adverse events were reported, 38 of which were serious, but no adverse events were deemed to be associated with the intervention. INTERPRETATION: ACT plus usual care is clinically effective for maintaining or improving quality of life in people with motor neuron disease. As further evidence emerges confirming these findings, health-care providers should consider how access to ACT, adapted for the specific needs of people with motor neuron disease, could be provided within motor neuron disease clinical services. FUNDING: National Institute for Health and Care Research Health Technology Assessment and Motor Neurone Disease Association.

Cost-effectiveness of acceptance and commitment therapy for people living with motor neuron disease, and their health-related quality of life.

BACKGROUND: Given the degenerative nature of the condition, people living with motor neuron disease (MND) experience high levels of psychological distress. The purpose of this research was to investigate the cost-effectiveness of acceptance and commitment therapy (ACT), adapted for the specific needs of this population, for improving quality of life. METHODS: A trial-based cost-utility analysis over a 9-month period was conducted comparing ACT plus usual care (n = 97) versus usual care alone (n = 94) from the perspective of the National Health Service. In the primary analysis, quality-adjusted life years (QALYs) were computed using health utilities generated from the EQ-5D-5L questionnaire. Sensitivity analyses and subgroup analyses were also carried out. RESULTS: Difference in costs was statistically significant between the two arms, driven mainly by the intervention costs. Effects measured by EQ-5D-5L were not statistically significantly different between the two arms. The incremental cost-effectiveness was above the £20,000 to £30,000 per QALY gained threshold used in the UK. However, the difference in effects was statistically significant when measured by the McGill Quality of Life-Revised (MQOL-R) questionnaire. The intervention was cost-effective in a subgroup experiencing medium deterioration in motor neuron symptoms. CONCLUSIONS: Despite the intervention being cost-ineffective in the primary analysis, the significant difference in the effects measured by MQOL-R, the low costs of the intervention, the results in the subgroup analysis, and the fact that ACT was shown to improve the quality of life for people living with MND, suggest that ACT could be incorporated into MND clinical services.

Adapted problem adaptation therapy for depression in mild to moderate Alzheimer's disease dementia: A randomized controlled trial.

INTRODUCTION: Trials of effectiveness of treatment options for depression in dementia are an important priority. METHODS: Randomized controlled trial to assess adapted Problem Adaptation Therapy (PATH) for depression in mild/moderate dementia caused by Alzheimer's disease. RESULTS: Three hundred thirty-six participants with mild or moderate dementia, >7 on Cornell Scale for Depression in Dementia (CSDD), randomized to adapted PATH or treatment as usual. Mean age 77.0 years, 39.0% males, mean Mini-Mental State Examination 21.6, mean CSDD 12.9. For primary outcome (CSDD at 6 months), no statistically significant benefit with adapted PATH on the CSDD (6 months: -0.58; 95% CI -1.71 to 0.54). The CSDD at 3 months showed a small benefit with adapted PATH (-1.38; 95% CI -2.54 to -0.21) as did the EQ-5D (-4.97; 95% CI -9.46 to -0.48). DISCUSSION: An eight-session course of adapted PATH plus two booster sessions administered within NHS dementia services was not effective treatment for depression in people with mild and moderate dementia. Future studies should examine the effect of more intensive and longer-term therapy.

Phosphodiesterase Type 5 Inhibitors in Men With Erectile Dysfunction and the Risk of Alzheimer Disease: A Cohort Study.

BACKGROUND AND OBJECTIVES: Repurposing phosphodiesterase type 5 inhibitors (PDE5Is) as drugs for Alzheimer disease (AD) risk reduction has shown promise based on animal studies. However, evidence in humans remains inconclusive. Therefore, we conducted a cohort study to evaluate the association between PDE5I initiation compared with nonuse and the risk of developing AD in men with erectile dysfunction (ED). METHODS: Using electronic health records from IQVIA Medical Research Data UK (formerly known as the THIN database), we identified men aged ≥40 years with a new diagnosis of ED between 2000 and 2017. Individuals with a previous diagnosis of dementia, cognitive impairment, confusion, or prescription for dementia symptoms were excluded. The occurrence of incident AD was identified using diagnostic read codes. To minimize immortal-time bias, PDE5I initiation was treated as a time-varying exposure variable. Potential confounders were adjusted using inverse probability of treatment weighting based on propensity scores. Cox proportional hazard models were used to estimate the adjusted hazard ratio (HR) with 95% CIs. A secondary analysis explored the association between AD and the cumulative number of PDE5I prescriptions. Sensitivity analyses included lag (delay) periods of 1 and 3 years after cohort entry to address the prodromal stage of AD. RESULTS: The study included 269,725 men, with 1,119 newly diagnosed with AD during a median follow-up of 5.1 (interquartile range 2.9-8.9) years. The adjusted HR in PDE5I initiators compared with nonuse was 0.82 (95% CI 0.72-0.93). The associated risk of AD decreased in individuals issued >20 prescriptions: HR 0.56 (95% CI 0.43-0.73) for 21-50 prescriptions and HR 0.65 (95% CI 0.49-0.87) for >50 prescriptions. Sensitivity analysis with a 1-year lag period supported the primary findings (HR 0.82, 95% CI 0.72-0.94), but the results differed with the inclusion of a 3-year lag period (HR 0.93, 95% CI 0.80-1.08). DISCUSSION: PDE5I initiation in men with ED was associated with a lower risk of AD, particularly in those most frequently issued prescriptions. The differences between primary and sensitivity analyses highlight the need to explore the optimal lag period. To enhance the generalizability of our findings, a randomized controlled trial including both sexes and exploring various PDE5I doses would be beneficial to confirm the association between PDE5I and AD.

A population pharmacokinetic model to guide clozapine dose selection, based on age, sex, ethnicity, body weight and smoking status.

AIMS: Guidance on clozapine dosing in treatment-resistant schizophrenia is based largely on data from White young adult males. This study aimed to investigate the pharmacokinetic profiles of clozapine and N-desmethylclozapine (norclozapine) across the age range, accounting for sex, ethnicity, smoking status and body weight. METHODS: A population pharmacokinetic model, implemented in Monolix, that linked plasma clozapine and norclozapine via a metabolic rate constant, was used to analyse data from a clozapine therapeutic drug monitoring service, 1993-2017. RESULTS: There were 17 787 measurements from 5960 patients (4315 male) aged 18-86 years. The estimated clozapine plasma clearance was reduced from 20.2 to 12.0 L h-1 between 20 and 80 years. Model-based dose predictions to attain a predose plasma clozapine concentration of 0.35 mg L-1 was 275 (90% prediction interval 125, 625) mg day-1 in nonsmoking, White males weighing 70 kg and aged 40 years. The corresponding predicted dose was increased by 30% in smokers, decreased by 18% in females, and was 10% higher and 14% lower in otherwise analogous Afro-Caribbean and Asian patients, respectively. Overall, the predicted dose decreased by 56% between 20 and 80 years. CONCLUSION: The large sample size and wide age range of the patients studied allowed precise estimation of dose requirements to attain predose clozapine concentration of 0.35 mg L-1 . The analysis was, however, limited by the absence of data on clinical outcome and future studies are required to determine optimal predose concentrations specifically in those aged over 65 years.

Online clinical tools to support the use of new plasma biomarker diagnostic technology in the assessment of Alzheimer's disease: a narrative review.

Recent advances in new diagnostic technologies for Alzheimer's disease have improved the speed and precision of diagnosis. However, accessing the potential benefits of this technology poses challenges for clinicians, such as deciding whether it is clinically appropriate to order a diagnostic test, which specific test or tests to order and how to interpret test results and communicate these to the patient and their caregiver. Tools to support decision-making could provide additional structure and information to the clinical assessment process. These tools could be accessed online, and such 'e-tools' can provide an interactive interface to support patients and clinicians in the use of new diagnostic technologies for Alzheimer's disease. We performed a narrative review of the literature to synthesize information available on this research topic. Relevant studies that provide an understanding of how these online tools could be used to optimize the clinical utility of diagnostic technology were identified. Based on these, we discuss the ways in which e-tools have been used to assist in the diagnosis of Alzheimer's disease and propose recommendations for future research to aid further development.

Heart rate variability and risk of agitation in Alzheimer's disease: the Atherosclerosis Risk in Communities Study.

Agitation in Alzheimer's disease is common and may be related to impaired emotion regulation capacity. Heart rate variability, a proposed index of autonomic and emotion regulation neural network integrity, could be associated with agitation propensity in Alzheimer's disease. We used the Atherosclerosis Risk in Communities Study cohort data, collected over seven visits spanning over two decades, to investigate whether heart rate variability (change) was associated with agitation risk in individuals clinically diagnosed with dementia due to Alzheimer's disease. Agitation (absence/presence) at Visit 5, the primary outcome, was based on the Neuropsychiatric Inventory agitation/aggression subscale, or a composite score comprising the total number of agitation/aggression, irritability, disinhibition and aberrant motor behaviour subscales present. Visit 1-5 heart rate variability measures were the log-transformed root mean square of successive differences in R-R intervals and standard deviation of normal-to-normal R-R intervals obtained from resting, supine, standard 12-lead ECGs. To aid interpretability, heart rate variability data were scaled such that model outputs were expressed for each 0.05 log-unit change in heart rate variability (which approximated to the observed difference in heart rate variability with every 5 years of age). Among 456 participants who had dementia, 120 were clinically classified to have dementia solely attributable to Alzheimer's disease. This group showed a positive relationship between heart rate variability and agitation risk in regression models, which was strongest for measures of (potentially vagally mediated) heart rate variability change over the preceding two decades. Here, a 0.05 log-unit of heart rate variability change was associated with an up to 10-fold increase in the odds of agitation and around a half-unit increase in the composite agitation score. Associations persisted after controlling for participants' cognitive status, heart rate (change), sociodemographic factors, co-morbidities and medications with autonomic effects. Further confirmatory studies, incorporating measures of emotion regulation, are needed to support heart rate variability indices as potential agitation propensity markers in Alzheimer's disease and to explore underlying mechanisms as targets for treatment development.

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.

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.

Evaluation of clinical benefits of treatments for Alzheimer's disease.

The need for regulatory approval of new therapies for the treatment of Alzheimer's disease-a progressive neurodegenerative condition-has made the assessment of treatment efficacy an urgent priority for discussion and investigation in the field. In the first part of this Personal View, we summarise current views on what constitutes a clinically meaningful benefit from treatment for Alzheimer's disease, including the concept of a minimum treatment effect against which to compare trial outcomes and its limitations. Considering existing and divergent definitions of clinically meaningful change, we define this concept in the second part of the Personal View by proposing a new approach that consecutively considers whether a treatment benefit for Alzheimer's disease is noticeable, valuable, and worthwhile in the context of costs and risks. This approach could be a useful foundation from which the field can move forwards on this issue and address existing gaps in understanding.

Navigating polycrisis: long-run socio-cultural factors shape response to changing climate.

Climate variability and natural hazards like floods and earthquakes can act as environmental shocks or socioecological stressors leading to instability and suffering throughout human history. Yet, societies experience a wide range of outcomes when facing such challenges: some suffer from social unrest, civil violence or complete collapse; others prove more resilient and maintain key social functions. We currently lack a clear, generally agreed-upon conceptual framework and evidentiary base to explore what causes these divergent outcomes. Here, we discuss efforts to develop such a framework through the Crisis Database (CrisisDB) programme. We illustrate that the impact of environmental stressors is mediated through extant cultural, political and economic structures that evolve over extended timescales (decades to centuries). These structures can generate high resilience to major shocks, facilitate positive adaptation, or, alternatively, undermine collective action and lead to unrest, violence and even societal collapse. By exposing the ways that different societies have reacted to crises over their lifetime, this framework can help identify the factors and complex social-ecological interactions that either bolster or undermine resilience to contemporary climate shocks. This article is part of the theme issue 'Climate change adaptation needs a science of culture'.

Trends in the incidence of dementia in people with hypertension in the UK 2000 to 2021.

INTRODUCTION: We investigated trends in the incidence of dementia in UK adults with hypertension. METHODS: Primary care electronic health records from IQVIA Medical Research Data UK, previously known as THIN, were used to identify 2,133,118 adults aged ≥40 years with hypertension over 2000 to 2021. The annual incidence rate and average annual percentage change in recorded dementia diagnoses were estimated and stratified by sex, 10-year age bands, Townsend deprivation quintiles and dementia subtype. RESULTS: The crude incidence rate of dementia in people with hypertension increased from 1.98 (95% confidence internal [CI] 1.89-2.07) per 1000 person-years at risk (PYAR) in 2000 to 5.29 per 1000 PYAR (95% CI 5.07-5.53) in 2021, corresponding to an average annual increase of 4.1% (95% CI 3.3-5.0). Those aged ≥80 years, the most economically deprived (Townsend = 5), and Alzheimer's disease subtype reported the highest incidence rate within their respective categories. DISCUSSION: The annual incidence rate of dementia in the hypertensive population has increased over the last 22 years. Highlights: New dementia diagnosis in the hypertensive population has increased over 22 years.The Alzheimer's disease subtype reported the highest incidence rate in people with hypertension.Difference in dementia incidence between hypertensive females and males has reduced.Difference in dementia incidence among deprivation categories has reduced in recent years.

Dissociable effects of dopaminergic medications on depression symptom dimensions in Parkinson's disease.

Background: Depression in Parkinson's disease (PD) is common, disabling and responds poorly to standard antidepressant medication. Motivational symptoms of depression, such as apathy and anhedonia, are particularly prevalent in depression in PD and predict poor response to antidepressant treatment. Loss of dopaminergic innervation of the striatum is associated with emergence of motivational symptoms in PD, and mood fluctuations correlate with dopamine availability. Accordingly, optimising dopaminergic treatment for PD can improve depressive symptoms, and dopamine agonists have shown promising effects in improving apathy. However, the differential effect of antiparkinsonian medication on symptom dimensions of depression is not known. Aims: We hypothesised that there would be dissociable effects of dopaminergic medications on different depression symptom dimensions. We predicted that dopaminergic medication would specifically improve motivational symptoms, but not other symptoms, of depression. We also hypothesised that antidepressant effects of dopaminergic medications with mechanisms of action reliant on pre-synaptic dopamine neuron integrity would attenuate as pre-synaptic dopaminergic neurodegeneration progresses. Methods: We analysed data from a longitudinal study of 412 newly diagnosed PD patients followed over five years in the Parkinson's Progression Markers Initiative cohort. Medication state for individual classes of Parkinson's medications was recorded annually. Previously validated "motivation" and "depression" dimensions were derived from the 15-item geriatric depression scale. Dopaminergic neurodegeneration was measured using repeated striatal dopamine transporter (DAT) imaging. Results: Linear mixed-effects modelling was performed across all simultaneously acquired data points. Dopamine agonist use was associated with relatively fewer motivation symptoms as time progressed (interaction: ß=-0.07, 95%CI [-0.13,-0.01], p=0.015) but had no effect on the depression symptom dimension (p=0.6). In contrast, monoamine oxidase-B (MAO-B) inhibitor use was associated with relatively fewer depression symptoms across all years (ß=-0.41, 95%CI [-0.81,-0.01], p=0.047). No associations were observed between either depression or motivation symptoms and levodopa or amantadine use. There was a significant interaction between striatal DAT binding and MAO-B inhibitor use on motivation symptoms: MAO-B inhibitor use was associated with lower motivation symptoms in patients with higher striatal DAT binding (interaction: ß=-0.24, 95%CI [-0.43, -0.05], p=0.012). No other medication effects were moderated by striatal DAT binding measures. Conclusions: We identified dissociable associations between dopaminergic medications and different dimensions of depression in PD. Dopamine agonists may be effective for treatment of motivational symptoms of depression. In contrast, MAO-B inhibitors may improve both depressive and motivation symptoms, albeit the latter effect appears to be attenuated in patients with more severe striatal dopaminergic neurodegeneration, which may be a consequence of dependence on pre-synaptic dopaminergic neuron integrity.

Has COVID-19 affected dementia diagnosis rates in England?

BACKGROUND: The COVID-19 pandemic impacted on the provision of care and routine activity of all National Health Service (NHS) services. While General Practitioner referrals to memory services in England have returned to pre-pandemic levels, the estimated dementia diagnosis rate (DDR) fell by 5.4% between March 2020 and February 2023. METHODS: In this paper we explore whether this reduction is accurate or is an artefact of the way the NHS collects data. RESULTS: We explore the processes that may have affected national dementia diagnosis rates during and following the COVID-19 pandemic. CONCLUSIONS: We discuss what action could be taken to improve the DDR in the future.

Acceptance and Commitment Therapy for people living with motor neuron disease: an uncontrolled feasibility study.

BACKGROUND: Motor neuron disease (MND) is a fatal, progressive neurodegenerative disease that causes progressive weakening and wasting of limb, bulbar, thoracic and abdominal muscles. Clear evidence-based guidance on how psychological distress should be managed in people living with MND (plwMND) is lacking. Acceptance and Commitment Therapy (ACT) is a form of psychological therapy that may be particularly suitable for this population. However, to the authors' knowledge, no study to date has evaluated ACT for plwMND. Consequently, the primary aim of this uncontrolled feasibility study was to examine the feasibility and acceptability of ACT for improving the psychological health of plwMND. METHODS: PlwMND aged ≥ 18 years were recruited from 10 UK MND Care Centres/Clinics. Participants received up to 8 one-to-one ACT sessions, developed specifically for plwMND, plus usual care. Co-primary feasibility and acceptability outcomes were uptake (≥ 80% of the target sample [N = 28] recruited) and initial engagement with the intervention (≥ 70% completing ≥ 2 sessions). Secondary outcomes included measures of quality of life, anxiety, depression, disease-related functioning, health status and psychological flexibility in plwMND and quality of life and burden in caregivers. Outcomes were assessed at baseline and 6 months. RESULTS: Both a priori indicators of success were met: 29 plwMND (104%) were recruited and 76% (22/29) attended ≥ 2 sessions. Attrition at 6-months was higher than anticipated (8/29, 28%), but only two dropouts were due to lack of acceptability of the intervention. Acceptability was further supported by good satisfaction with therapy and session attendance. Data were possibly suggestive of small improvements in anxiety and psychological quality of life from baseline to 6 months in plwMND, despite a small but expected deterioration in disease-related functioning and health status. CONCLUSIONS: There was good evidence of acceptability and feasibility. Limitations included the lack of a control group and small sample size, which complicate interpretation of findings. A fully powered RCT to evaluate the clinical and cost-effectiveness of ACT for plwMND is underway. TRIAL REGISTRATION: The study was pre-registered with the ISRCTN Registry (ISRCTN12655391).

Key questions for the evaluation of anti-amyloid immunotherapies for Alzheimer's disease.

The clinical benefit associated with anti-amyloid immunotherapies, a new class of drugs for the treatment of Alzheimer's disease, is predicated on their ability to modify disease course by lowering brain amyloid levels. At the time of writing, two amyloid-lowering antibodies, aducanumab and lecanemab, have obtained United States Food and Drug Administration accelerated approval, with further agents of this class in the Alzheimer's disease treatment pipeline. Based on limited published clinical trial data to date, regulators, payors and physicians will need to assess their efficacy, clinical effectiveness and safety, as well as cost and accessibility. We propose that attention to three important questions related to treatment efficacy, clinical effectiveness and safety should guide evidence-based consideration of this important class of drugs. These are: (1) Were trial statistical analyses appropriate and did they convincingly support claims of efficacy? (2) Do reported treatment effects outweigh safety concerns and are they generalizable to a representative clinical population of people with Alzheimer's disease? and (3) Do the data convincingly demonstrate disease course modification, suggesting that increasing clinical benefits beyond the duration of the trials are likely? We suggest specific approaches to interpreting trial results for these drugs and highlight important areas of uncertainty where additional data and a cautious interpretation of existing results is warranted. Safe, effective and accessible treatments for Alzheimer's disease are eagerly awaited by millions of patients and their caregivers worldwide. While amyloid-targeting immunotherapies may be promising disease-modifying Alzheimer's disease treatments, rigorous and unbiased assessment of clinical trial data is critical to regulatory decision-making and subsequently determining their provision and utility in routine clinical practice. Our recommendations provide a framework for evidence-based appraisal of these drugs by regulators, payors, physicians and patients.

Feasibility randomised controlled trial of online group Acceptance and Commitment Therapy for Functional Cognitive Disorder (ACT4FCD).

INTRODUCTION: Functional cognitive disorder (FCD) is seen increasingly in clinics commissioned to assess cognitive disorders. Patients report frequent cognitive, especially memory, failures. The diagnosis can be made clinically, and unnecessary investigations avoided. While there is some evidence that psychological treatments can be helpful, they are not routinely available. Therefore, we have developed a brief psychological intervention using the principles of acceptance and commitment therapy (ACT) that can be delivered in groups and online. We are conducting a feasibility study to assess whether the intervention can be delivered within a randomised controlled trial. We aim to study the feasibility of recruitment, willingness to be randomised to intervention or control condition, adherence to the intervention, completion of outcome measures and acceptability of treatment. METHODS AND ANALYSIS: We aim to recruit 48 participants randomised 50:50 to either the ACT intervention and treatment as usual (TAU), or TAU alone. ACT will be provided to participants in the treatment arm following completion of baseline outcome measures. Completion of these outcome measures will be repeated at 8, 16 and 26 weeks. The measures will assess several domains including psychological flexibility, subjective cognitive symptoms, mood and anxiety, health-related quality of life and functioning, healthcare utilisation, and satisfaction with care and participant-rated improvement. Fifteen participants will be selected for in-depth qualitative interviews about their experiences of living with FCD and of the ACT intervention. ETHICS AND DISSEMINATION: The study received a favourable opinion from the South East Scotland Research Ethics Committee 02 on 30 September 2022 (REC reference: 22/SS/0059). HRA approval was received on 1 November 2022 (IRAS 313730). The results will be published in full in an open-access journal. TRIAL REGISTRATION NUMBER: ISRCTN12939037.