Assessing and disclosing test results for 'mild cognitive impairment': the perspective of old age psychiatrists in Scotland.

BACKGROUND: Mild cognitive impairment (MCI) is a condition that exists between normal healthy ageing and dementia with an uncertain aetiology and prognosis. This uncertainty creates a complex dynamic between the clinicians' conception of MCI, what is communicated to the individual about their condition, and how the individual responds to the information conveyed to them. The aim of this study was to explore clinicians' views around the assessment and communication of MCI in memory clinics. METHOD: As part of a larger longitudinal study looking at patients' adjustment to MCI disclosure, we interviewed Old Age Psychiatrists at the five participating sites across Scotland. The study obtained ethics approvals and the interviews (carried out between Nov 2020-Jan 2021) followed a semi-structured schedule focusing on [1] how likely clinicians are to use the term MCI with patients; [2] what tests clinicians rely on and how much utility they see in them; and [3] how clinicians communicate risk of progression to dementia. The interviews were voice recorded and were analysed using reflective thematic analysis. RESULTS: Initial results show that most clinicians interviewed (Total N = 19) considered MCI to have significant limitations as a diagnostic term. Nevertheless, most clinicians reported using the term MCI (n = 15/19). Clinical history was commonly described as the primary aid in the diagnostic process and also to rule out functional impairment (which was sometimes corroborated by Occupational Therapy assessment). All clinicians reported using the Addenbrooke's Cognitive Examination-III as a primary assessment tool. Neuroimaging was frequently found to have minimal usefulness due to the neuroradiological reports being non-specific. CONCLUSION: Our study revealed a mixture of approaches to assessing and disclosing test results for MCI. Some clinicians consider the condition as a separate entity among neurodegenerative disorders whereas others find the term unhelpful due to its uncertain prognosis. Clinicians report a lack of specific and sensitive assessment methods for identifying the aetiology of MCI in clinical practice. Our study demonstrates a broad range of views and therefore variability in MCI risk disclosure in memory assessment services which may impact the management of individuals with MCI.

What matters to people with memory problems, healthy volunteers and health and social care professionals in the context of developing treatment to prevent Alzheimer's dementia? A qualitative study.

BACKGROUND: Alzheimer's disease (AD) is recognized as one of the greatest global public health challenges. There is increasing consensus that optimal disease modification using pharmaceuticals may best be achieved earlier in the disease continuum before symptoms occur. However, more needs to be understood about what outcomes are meaningful to potential participants in clinical trials within this preventative paradigm and how people make trade-offs between risks and benefits. The Electronic Person-Specific Outcome Measure (ePSOM) programme is developing an app to capture person-specific outcomes and preferences in clinical trials. OBJECTIVE: As one phase in the ePSOM programme, this study explored what matters when developing new treatments to prevent AD and how trade-offs are made between risks and benefits, from three perspectives. DESIGN: Focus groups were conducted with people living with memory problems (n = 21) and healthy volunteers (n = 10), and telephone interviews with health and social care professionals (n = 10). Differences and overlap between the three groups were explored. RESULTS: Outcomes that matter lie in five key domains in relation to what matters in everyday life: Everyday Functioning; Relationships and Social Connections; Enjoying Life; Sense of Identity; and Alleviating  Symptoms. Insights were gained into the significance of reducing the risk of developing dementia with drugs and the processes of weighing up risks versus benefits. DISCUSSION AND CONCLUSIONS: The key domains identified are being used to inform the next stage of the ePSOM programme which is to develop a survey to be distributed nationally in the UK to explore these issues further.

Evolution and future directions for the concept of mild cognitive impairment.

The term mild cognitive impairment has been associated with a varying degree of clinical utility and controversy. The concept has been introduced to try and define a pre-dementia period associated with underlying neurodegenerative pathology and a higher likelihood of the person developing a dementia syndrome. As scientific understanding improves then the definition of MCI rightly adapts, meaning that the MCI concept is prone quite rightly to frequent evolution. We consider that we are a long way away from the concept having evolved to a point where it can be embedded with confidence in clinical practice as a diagnosis but should remain as a term primarily for use in research.

Longitudinal observational cohort study: Speech for Intelligent cognition change tracking and DEtection of Alzheimer's Disease (SIDE-AD).

INTRODUCTION: There is emerging evidence that speech may be a potential indicator and manifestation of early Alzheimer's disease (AD) pathology. Therefore, the University of Edinburgh and Sony Research have partnered to create the Speech for Intelligent cognition change tracking and DEtection of Alzheimer's Disease (SIDE-AD) study, which aims to develop digital speech-based biomarkers for use in neurodegenerative disease. METHODS AND ANALYSIS: SIDE-AD is an observational longitudinal study, collecting samples of spontaneous speech. Participants are recruited from existing cohort studies as well as from the National Health Service (NHS)memory clinics in Scotland. Using an online platform, participants record a voice sample talking about their brain health and rate their mood, anxiety and apathy. The speech biomarkers will be analysed longitudinally, and we will use machine learning and natural language processing technology to automate the assessment of the respondents' speech patterns. ETHICS AND DISSEMINATION: The SIDE-AD study has been approved by the NHS Research Ethics Committee (REC reference: 23/WM/0153, protocol number AC23046, IRAS Project ID 323311) and received NHS management approvals from Lothian, Fife and Forth Valley NHS boards. Our main ethical considerations pertain to the remote administration of the study, such as taking remote consent. To address this, we implemented a consent process, whereby the first step of the consent is done entirely remotely but a member of the research team contacts the participant over the phone to consent participants to the optional, most sensitive, elements of the study. Results will be presented at conferences, published in peer-reviewed journals and communicated to study participants.

Towards a lifelong personalized brain health program: empowering individuals to define, pursue, and monitor meaningful outcomes.

Incorporating person-centered outcomes into clinical trials for neurodegenerative diseases has been challenging due to a deficiency in quantitative measures. Meanwhile, the integration of personally meaningful treatment targets in clinical practice remains qualitative, failing to truly inform evaluations, therapeutic interventions and longitudinal monitoring and support. We discuss the current advances and future directions in capturing individualized brain health outcomes and present an approach to integrate person-centered outcome in a scalable manner. Our approach stems from the evidence-based electronic Person-Specific Outcome Measure (ePSOM) program which prompts an individual to define personally meaningful treatment priorities and report level of confidence in managing items that matter to the individual the most (e.g., "Do I feel confident in my ability to contribute to a conversation?"). Deployed either as a single version (person only) or a dyad version (person and care partner), our proposed tool could be used as an endpoint in clinical trials, offering proof of meaningful intervention benefits and in clinical practice, by establishing an anchor for the therapeutic objectives sought by the individual.

Science disconnected: the translational gap between basic science, clinical trials, and patient care in Alzheimer's disease.

Both research and clinical practice have traditionally centred on the dementia syndrome of Alzheimer's disease rather than its preclinical and prodromal stages. However, there is a strong scientific and ethical impetus to shift focus to earlier disease stages to improve brain health outcomes and help to keep affected individuals symptom-free (dementia-free) for as long as possible. We provide an overview of recent advancements in early detection, drug development, and trial methodology that should be utilised in the development of new therapies for use in brain health clinics. We propose a triad approach to Alzheimer's disease clinical trials, encompassing (1) experimental medicine studies to gather greater knowledge of disease mechanisms, (2) a more comprehensive platform of phase 2 learning trials to inform phase 3 confirmatory trials, and (3) precision medicine involving smaller subgroups of patients with shared characteristics. This triad would ensure that treatment targets are identified accurately, trial methodology focuses on at-risk populations, and sensitive outcome measures capture potential treatment effects. Clinical services around the world must embrace the brain health clinic model so that neurodegenerative diseases can be detected in their earliest phase to quicken drug development pipelines and potentially improve prognosis.

The European Prevention of Alzheimer's Dementia Programme: An Innovative Medicines Initiative-funded partnership to facilitate secondary prevention of Alzheimer's disease dementia.

Introduction: Tens of millions of people worldwide will develop Alzheimer's disease (AD), and only by intervening early in the preclinical disease can we make a fundamental difference to the rates of late-stage disease where clinical symptoms and societal burden manifest. However, collectively utilizing data, samples, and knowledge amassed by large-scale projects such as the Innovative Medicines Initiative (IMI)-funded European Prevention of Alzheimer's Dementia (EPAD) program will enable the research community to learn, adapt, and implement change. Method: In the current article, we define and discuss the substantial assets of the EPAD project for the scientific community, patient population, and industry, describe the EPAD structure with a focus on how the public and private sector interacted and collaborated within the project, reflect how IMI specifically supported the achievements of the above, and conclude with a view for future. Results: The EPAD project was a €64-million investment to facilitate secondary prevention of AD dementia research. The project recruited over 2,000 research participants into the EPAD longitudinal cohort study (LCS) and included over 400 researchers from 39 partners. The EPAD LCS data and biobank are freely available and easily accessible via the Alzheimer's Disease Data Initiative's (ADDI) AD Workbench platform and the University of Edinburgh's Sample Access Committee. The trial delivery network established within the EPAD program is being incorporated into the truly global offering from the Global Alzheimer's Platform (GAP) for trial delivery, and the almost 100 early-career researchers who were part of the EPAD Academy will take forward their experience and learning from EPAD to the next stage of their careers. Discussion: Through GAP, IMI-Neuronet, and follow-on funding from the Alzheimer's Association for the data and sample access systems, the EPAD assets will be maintained and, as and when sponsors seek a new platform trial to be established, the learnings from EPAD will ensure that this can be developed to be even more successful than this first pan-European attempt.

Predictors of Mild Cognitive Impairment Stability, Progression, or Reversion in the Lothian Birth Cohort 1936.

BACKGROUND: Mild cognitive impairment (MCI) describes a borderland between healthy cognition and dementia. Progression to and reversion from MCI is relatively common but more research is required to understand the factors affecting this fluidity and improve clinical care interventions. OBJECTIVE: We explore these transitions in MCI status and their predictive factors over a six-year period in a highly-phenotyped longitudinal study, the Lothian Birth Cohort 1936. METHODS: MCI status was derived in the LBC1936 at ages 76 (n = 567) and 82 years (n = 341) using NIA-AA diagnostic guidelines. Progressions and reversions between healthy cognition and MCI over the follow-up period were assessed. Multinomial logistic regression assessed the effect of various predictors on the likelihood of progressing, reverting, or maintaining cognitive status. RESULTS: Of the 292 participants who completed both time points, 41 (14%) participants had MCI at T1 and 56 (19%) at T2. Over the follow-up period, 74%remained cognitively healthy, 12%transitioned to MCI, 7%reverted to healthy cognition, and 7%maintained their baseline MCI status. Findings indicated that membership of these transition groups was affected by age, cardiovascular disease, and number of depressive symptoms. CONCLUSION: Findings that higher baseline depressive symptoms increase the likelihood of reverting from MCI to healthy cognition indicate that there may be an important role for the treatment of depression for those with MCI. However, further research is required to identify prevention strategies for those at high risk of MCI and inform effective interventions that increase the likelihood of reversion to, and maintenance of healthy cognition.

Participant outcomes and preferences in Alzheimer's disease clinical trials: The electronic Person-Specific Outcome Measure (ePSOM) development program.

INTRODUCTION: Current pharmacological interventions for Alzheimer's dementia delay symptom progression for about a year. Although the outcomes in earlier disease states may include changes in biomarkers, the clinical effectiveness of any intervention can ultimately only be assessed by a patient's self-reported well-being. A better understanding of earlier manifestations of Alzheimer's disease and the drive for relevant outcome measures, allied to technological advances in artificial intelligence, have mediated the electronic Person-Specific Outcome Measure (ePSOM) development program. METHODS: There are 4 sequential stages in the ePSOM development program-(1) literature review, (2) focus group study, (3) national survey, and (4) development of an app for capturing person-specific outcomes. Here, we report the overall approach to the program incorporating our literature review on patient-reported outcome measures and patient preferences in the Alzheimer's disease population. RESULTS: Alzheimer's disease trials do not use any patient-reported outcome measures. Quality of life measures are often used as proxies for this, but they do not capture individual needs. Therefore, trials currently fail to reflect the participant's aspirations for effect but rather default to clinicostatistical measure of cognition and function. There is no implementation of patient preferences despite evidence that understanding preferences may influence adherence to treatment. DISCUSSION: It is important to consider preferences for an intervention and use PROMs for the measure of effectiveness given that both risk and benefit are judged by the recipient of the treatment. The ePSOM development program will deliver the methodology for incorporating meaningful outcomes in clinical trials to expand upon current biological and clinical measurements of effectiveness.

Research participants as collaborators: Background, experience and policies from the PREVENT Dementia and EPAD programmes.

AIM: Despite the growing importance of public and patient involvement in biomedical research, comparatively little attention has been paid to the important role of research participants themselves. Our aim in this paper is to explore the impact research participant involvement has within the PREVENT and the European Prevention of Alzheimer's Dementia (EPAD) projects. METHOD: In this paper, we report the experiences of involving research participants as collaborators in prospective cohort studies exploring early changes in the brain as pathways towards and risks for dementia. We use minutes and feedback from members of the panel and steering committee to understand the experience and impact on the study. RESULTS: We describe the aims and structure of the participant panel established within the PREVENT Dementia study and highlight its contributions to the organisation, conduct and future of the study. Key areas of contribution identified include recruitment, inclusion of additional sub-studies, understanding the participant experience and contributing to the future of the study. DISCUSSION: We then describe how the PREVENT Dementia panel forms the basis for participant involvement within EPAD project.