Robert Howard’s research while affiliated with National Institute of Neurology and Neurosurgery and other places

Background Functional cognitive disorder is an increasingly recognised subtype of functional neurological disorder for which treatment options are currently limited. We have developed a brief online group acceptance and commitment therapy (ACT)-based intervention. Aims To assess the feasibility of conducting a randomised controlled trial of this intervention versus treatment as usual (TAU). Method The study was a parallel-group, single-blind randomised controlled trial, with participants recruited from cognitive neurology, neuropsychiatry and memory clinics in London. Participants were randomised into two groups: ACT + TAU or TAU alone. Feasibility was assessed on the basis of recruitment and retention rates, the acceptability of the intervention, and signal of efficacy on the primary outcome measure (Acceptance and Action Questionnaire II (AAQ-II)) score, although the study was not powered to demonstrate this statistically. Outcome measures were collected at baseline and at 2, 4 and 6 months post-intervention, including assessments of quality of life, memory, anxiety, depression and healthcare use. Results We randomised 44 participants, with a participation rate of 51.1% (95% CI 40.8–61.5%); 36% of referred participants declined involvement, but retention was high, with 81.8% of ACT participants attending at least four sessions, and 64.3% of ACT participants reported being ‘satisfied’ or ‘very satisfied’ compared with 0% in the TAU group. Psychological flexibility as measured using the AAQ-II showed a trend towards modest improvement in the ACT group at 6 months. Other measures (quality of life, mood, memory satisfaction) also demonstrated small to modest positive trends. Conclusions It has proven feasible to conduct a randomised controlled trial of ACT versus TAU.

Plasma biomarkers for Alzheimer's disease (AD), such as plasma phosphorylated (p)‐tau217, offer a more accessible means of testing for the presence of AD pathology compared to cerebrospinal fluid (CSF) or positron emission tomography (PET) methods. They can support diagnostic assessment and determine patient eligibility for treatment with amyloid beta–lowering drugs in community settings where access to CSF examination and amyloid‐PET are limited. However, there are important challenges associated with interpreting and integrating plasma biomarker results in clinical practice. This article explores different approaches to interpreting plasma biomarker results in secondary care, important potential sources of uncertainty, and considerations for their clinical application. Highlights Plasma biomarkers such as phosphorylated tau‐217 (p‐tau217) offer a promising, accessible alternative to cerebrospinal fluid (CSF) and positron emission tomography (PET) for detecting Alzheimer's disease pathology, especially in settings with limited diagnostic resources. Clinical integration of plasma biomarker testing presents challenges, particularly in interpreting results. This includes uncertainties around intermediate results and their role in patient management. Clear frameworks and guidelines are essential to optimize the use of plasma biomarkers, supported by further research and education to ensure effective application in clinical practice.

Background Hallucinations are common and distressing symptoms in Parkinson’s disease (PD). Treatment response in clinical trials is measured using validated questionnaires, including the Scale for Assessment of Positive Symptoms-Hallucinations (SAPS-H) and University of Miami PD Hallucinations Questionnaire (UM-PDHQ). The minimum clinically important difference (MCID) has not been determined for either scale. This study aimed to estimate a range of MCIDs for SAPS-H and UM-PDHQ using both consensus-based and statistical approaches. Methods A Delphi survey was used to seek opinions of researchers, clinicians, and people with lived experience. We defined consensus as agreement ≥75%. Statistical approaches used blinded data from the first 100 PD participants in the Trial for Ondansetron as Parkinson’s Hallucinations Treatment (TOP HAT, NCT04167813). The distribution-based approach defined the MCID as 0.5 of the standard deviation of change in scores from baseline at 12 weeks. The anchor-based approach defined the MCID as the average change in scores corresponding to a 1-point improvement in clinical global impression-severity scale (CGI-S). Results Fifty-one researchers and clinicians contributed to three rounds of the Delphi survey and reached consensus that the MCID was 2 points on both scales. Sixteen experts with lived experience reached the same consensus. Distribution-defined MCIDs were 2.6 points for SAPS-H and 1.3 points for UM-PDHQ, whereas anchor-based MCIDs were 2.1 and 1.3 points, respectively. Conclusions We used triangulation from multiple methodologies to derive the range of MCID estimates for the two rating scales, which was between 2 and 2.7 points for SAPS-H and 1.3 and 2 points for UM-PDHQ.

Willingness to exert effort for a given goal is dependent on the magnitude of the potential rewards and effort costs of an action. Such effort-based decision making is an essential component of motivation, in which the dopaminergic system plays a key role. Depression in Parkinson’s disease (PD) is common, disabling and has poor outcomes. Motivational symptoms such as apathy and anhedonia, are prominent in PD depression and related to dopaminergic loss. We hypothesised that dopamine-dependent disruption in effort-based decision-making contributes to depression in PD. In the present study, an effort-based decision-making task was administered to 62 patients with PD, with and without depression, ON and OFF their dopaminergic medication across two sessions, as well as to 34 patients with depression and 29 matched controls on a single occasion. During the task, on each trial, participants decided whether to accept or reject offers of different levels of monetary reward in return for exerting varying levels of physical effort via grip force, measured using individually calibrated dynamometers. The primary outcome variable was choice (accept/decline offer), analysed using both logistic mixed-effects modelling and a computational model which dissected the individual contributions of reward and effort on depression and dopamine state in PD. We found PD depression was characterised by lower acceptance of offers, driven by markedly lower incentivisation by reward (reward sensitivity), compared to all other groups. Within-subjects analysis of the effect of dopamine medication revealed that, although dopamine treatment improves reward sensitivity in non-depressed PD patients, this therapeutic effect is not present in PD patients with depression. These findings suggest that disrupted effort-based decision-making, unresponsive to dopamine, contributes to PD depression. This highlights reward sensitivity as a key mechanism and treatment target for PD depression that potentially requires non-dopaminergic therapies.

Background Functional cognitive disorder (FCD) poses a diagnostic challenge due to its resemblance to other neurocognitive disorders and limited biomarker accuracy. We aimed to develop a new diagnostic checklist to identify FCD versus other neurocognitive disorders. Methods The clinical checklist was developed through mixed methods: (1) a literature review, (2) a three-round Delphi study with 45 clinicians from 12 countries and (3) a pilot discriminative accuracy study in consecutive patients attending seven memory services across the UK. Items gathering consensus were incorporated into a pilot checklist. Item redundancy was evaluated with phi coefficients. A briefer checklist was produced by removing items with >10% missing data. Internal validity was tested using Cronbach’s alpha. Optimal cut-off scores were determined using receiver operating characteristic curve analysis. Results A full 11-item checklist and a 7-item briefer checklist were produced. Overall, 239 patients (143 FCD, 96 non-FCD diagnoses) were included. The checklist scores were significantly different across subgroups (FCD and other neurocognitive disorders) (F(2, 236)=313.3, p<0.001). The area under the curve was excellent for both the full checklist (0.97, 95% CI 0.95 to 0.99) and its brief version (0.96, 95% CI 0.93 to 0.98). Optimal cut-off scores corresponded to a specificity of 97% and positive predictive value of 91% for identifying FCD. Both versions showed good internal validity (>0.80). Conclusions This pilot study shows that a brief clinical checklist may serve as a quick complementary tool to differentiate patients with neurodegeneration from those with FCD. Prospective blind large-scale validation in diverse populations is warranted.

Purpose: Functional cognitive disorder (FCD) is an increasingly recognised condition which causes significant disability and distress. While it is known to be associated with depression, anxiety and reduced functioning, like other functional neurological disorders it may be marred by stigma. To date, little is known about the lived experience of those with FCD. Materials & methods: As part of a randomised controlled feasibility trial of online group Acceptance and Commitment Therapy (ACT) for FCD we conducted in-depth qualitative interviews and utilised a thematic analysis approach to explore the challenges of living with FCD; how individuals cope with the symptoms; and their experiences of healthcare services. Results: We recruited six women and three men, with a median age of 54. They described living with FCD which included experiences of loss of identity, altered role, feelings of confusion, frustration and low self-esteem, stigma, social isolation, and dismissal by healthcare services. Nevertheless, suffers strove to find strategies to ameliorate their symptoms. Conclusions: FCD is a common and disabling condition which like other functional neurological symptoms leads to altered sense of self and unsatisfactory interactions with others, including healthcare professionals. The diagnosis should be made on positive grounds, clearly explained, and potential therapies investigated.

Recent regulatory approvals of three amyloid‐lowering monoclonal antibody therapies for the treatment of Alzheimer's disease (AD) have triggered a polarizing debate in the field on the clinical meaningfulness of their reported effects. The question of how to define clinical meaningfulness for any treatment that has a modest effect size is important and will likely be subject to influence from interested stakeholders. We warn of claims of evaluating meaningful within‐individual change from randomized parallel‐group trials of AD treatments, sometimes purportedly assessed by a commonly recognized “responder” analysis approach, and explain why it is likely to mislead and should simply be avoided. The average between‐group difference in score change is where the debate and research efforts should be focused to contextualize and evaluate the clinical meaningfulness of the true treatment effect. The statistical and communication principles we consider and would recommend are applicable to the evaluation of most interventions in medicine. Highlights Dichotomized outcome analysis approaches purporting to evaluate within‐individual meaningful change are highly likely to mislead. In our view, the most valid statistical approach to understanding the true treatment effect is to analyze the average between‐group difference in outcome scores. The average between‐group difference in score change is where the debate and research efforts should be focused to contextualize and evaluate the clinical meaningfulness of the true treatment effect.

Background Data from high‐income countries (HICs) suggest a decline in age‐specific incidence rates of dementia. However, this has happened primarily in HICs, with low‐ and middle‐ income countries (LMICs) facing two main challenges: a higher burden of risk factors and, in general, a faster ageing population. Most people with dementia live in LMICs, and this is set to increase, thus requiring urgent and robust action to prevent, treat and support people with dementia and their families. Methods We, in the Lancet Commission, reviewed the most recent literature, and conducted a new metanalysis on worldwide dementia risk. We have calculated worldwide figures, although there may be variation in different ethnic and socioeconomic groups. Results Dementia studies are overwhelmingly from HICs, and there is a tendency to recruit people of European origin with higher education and socioeconomic status, with few people from ethnic minority groups. The same applies in respect of worldwide clinical trials, including multicomponent interventions to reduce risk, biomarker research and pharmacological/non‐pharmacological interventions. Although most interventions are developed in HICs, culturally adapted interventions seem to be as effective in LMICs as in their original context, as long as the interventions’ core components are not compromised in the adaptation process. Conclusion Policy interventions can improve dementia prevention, particularly in LMICs and in minority and lower level socio‐economic groups ‐ precisely the people who have the greatest burden of modifiable risk and are more likely to develop dementia. Dementia prevention efforts should be tailored to the needs of the different countries and different groups within countries. Trials and research databases should aim for sociodemographic diversity to reflect real life populations. Although evidence‐based interventions developed in HICs can be effective in LMICs, there is often a lack of healthcare infrastructure and resources to deliver them. Moreover, cultural differences can make them inappropriate or less effective. Interventions should be developed in partnership with local communities to ensure their appropriateness in respect of the culture, beliefs and practises which vary within and between countries.