Remote data collection speech analysis and prediction of the identification of Alzheimer's disease biomarkers in people at risk for Alzheimer's disease dementia: the Speech on the Phone Assessment (SPeAk) prospective observational study protocol.

INTRODUCTION: Identifying cost-effective, non-invasive biomarkers of Alzheimer's disease (AD) is a clinical and research priority. Speech data are easy to collect, and studies suggest it can identify those with AD. We do not know if speech features can predict AD biomarkers in a preclinical population. METHODS AND ANALYSIS: The Speech on the Phone Assessment (SPeAk) study is a prospective observational study. SPeAk recruits participants aged 50 years and over who have previously completed studies with AD biomarker collection. Participants complete a baseline telephone assessment, including spontaneous speech and cognitive tests. A 3-month visit will repeat the cognitive tests with a conversational artificial intelligence bot. Participants complete acceptability questionnaires after each visit. Participants are randomised to receive their cognitive test results either after each visit or only after they have completed the study. We will combine SPeAK data with AD biomarker data collected in a previous study and analyse for correlations between extracted speech features and AD biomarkers. The outcome of this analysis will inform the development of an algorithm for prediction of AD risk based on speech features. ETHICS AND DISSEMINATION: This study has been approved by the Edinburgh Medical School Research Ethics Committee (REC reference 20-EMREC-007). All participants will provide informed consent before completing any study-related procedures, participants must have capacity to consent to participate in this study. Participants may find the tests, or receiving their scores, causes anxiety or stress. Previous exposure to similar tests may make this more familiar and reduce this anxiety. The study information will include signposting in case of distress. Study results will be disseminated to study participants, presented at conferences and published in a peer reviewed journal. No study participants will be identifiable in the study results.

Epigenetic measures of ageing predict the prevalence and incidence of leading causes of death and disease burden.

BACKGROUND: Individuals of the same chronological age display different rates of biological ageing. A number of measures of biological age have been proposed which harness age-related changes in DNA methylation profiles. These measures include five 'epigenetic clocks' which provide an index of how much an individual's biological age differs from their chronological age at the time of measurement. The five clocks encompass methylation-based predictors of chronological age (HorvathAge, HannumAge), all-cause mortality (DNAm PhenoAge, DNAm GrimAge) and telomere length (DNAm Telomere Length). A sixth epigenetic measure of ageing differs from these clocks in that it acts as a speedometer providing a single time-point measurement of the pace of an individual's biological ageing. This measure of ageing is termed DunedinPoAm. In this study, we test the association between these six epigenetic measures of ageing and the prevalence and incidence of the leading causes of disease burden and mortality in high-income countries (n ≤ 9537, Generation Scotland: Scottish Family Health Study). RESULTS: DNAm GrimAge predicted incidence of clinically diagnosed chronic obstructive pulmonary disease (COPD), type 2 diabetes and ischemic heart disease after 13 years of follow-up (hazard ratios = 2.22, 1.52 and 1.41, respectively). DunedinPoAm predicted the incidence of COPD and lung cancer (hazard ratios = 2.02 and 1.45, respectively). DNAm PhenoAge predicted incidence of type 2 diabetes (hazard ratio = 1.54). DNAm Telomere Length associated with the incidence of ischemic heart disease (hazard ratio = 0.80). DNAm GrimAge associated with all-cause mortality, the prevalence of COPD and spirometry measures at the study baseline. These associations were present after adjusting for possible confounding risk factors including alcohol consumption, body mass index, deprivation, education and tobacco smoking and surpassed stringent Bonferroni-corrected significance thresholds. CONCLUSIONS: Our data suggest that epigenetic measures of ageing may have utility in clinical settings to complement gold-standard methods for disease assessment and management.

Measuring multimorbidity beyond counting diseases: systematic review of community and population studies and guide to index choice.

OBJECTIVES: To identify and summarise existing indices for measuring multimorbidity beyond disease counts, to establish which indices include mental health comorbidities or outcomes, and to develop recommendations based on applicability, performance, and usage. DESIGN: Systematic review. DATA SOURCES: Seven medical research databases (Medline, Web of Science Core Collection, Cochrane Library, Embase, PsycINFO, Scopus, and CINAHL Plus) from inception to October 2018 and bibliographies and citations of relevant papers. Searches were limited to English language publications. ELIGIBILITY CRITERIA FOR STUDY SELECTION: Original articles describing a new multimorbidity index including more information than disease counts and not focusing on comorbidity associated with one specific disease. Studies were of adults based in the community or at population level. RESULTS: Among 7128 search results, 5560 unique titles were identified. After screening against eligibility criteria the review finally included 35 papers. As index components, 25 indices used conditions (weighted or in combination with other parameters), five used diagnostic categories, four used drug use, and one used physiological measures. Predicted outcomes included mortality (18 indices), healthcare use or costs (13), hospital admission (13), and health related quality of life (7). 29 indices considered some aspect of mental health, with most including it as a comorbidity. 12 indices are recommended for use. CONCLUSIONS: 35 multimorbidity indices are available, with differing components and outcomes. Researchers and clinicians should examine existing indices for suitability before creating new ones. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017074211.

Non-professional caregiver burden is associated with the severity of patients' cognitive impairment.

BACKGROUND/OBJECTIVES: To analyse the relationship between caregiver burden and severity of patients' cognitive impairment. DESIGN: Data were drawn from the cross-sectional 2015/2016 Adelphi Real World Dementia Disease-Specific Programme. SETTING: This research was multi-national and studied physicians and their consulting patients with cognitive impairment. PARTICIPANTS: 1,201 caregivers completed self-assessment forms. MEASUREMENTS: Validated instruments of caregiver wellbeing and burden (EQ-5D-3L questionnaire, EQ-VAS, Zarit Burden Interview, and Work Productivity and Activity Impairment questionnaire) and number of caregiver hours were analysed by severity of patients' cognitive impairment, categorised according to the Mini-Mental State Examination. Data were analysed using Spearman's rank correlation coefficients and ordinary least squares regression models, to compare outcomes between caregivers of patients with prodromal, mild, moderate, and severe dementia. RESULTS: The majority of caregivers were female (69.1%), lived with the patient they cared for (75.8%), and only approximately one third (28.3%) were in part- or full-time employment. There were statistically significant (p<0.001) increases in caregiver time (36.9 versus 108.6 hours per week for prodromal versus severe dementia, respectively) and measures of caregiver burden and health status (EQ-5D-3L, EQ-VAS, and Zarit Burden Interview) and increases in measures of work productivity and activity impairment with increasing severity of patients' disease. CONCLUSION: This study of real-world data confirmed an association between increased caregiver burden and severity of patients' cognitive impairment by analysis of a wide range of validated measures of caregiver burden. These findings suggest that maintaining patients in the earliest stages of their disease for as long as possible may potentially help to protect caregiver wellbeing, although further research is required to confirm this hypothesis.

Real-World, Multinational, Retrospective Observational Survey of the ADAS-Cog and Associations with Healthcare Resource Utilization in Patients with Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is one of the most costly conditions, both economically and regarding patient disability and dependency. The huge costs coupled with the predicted increase in prevalence worldwide are likely to challenge healthcare systems in the future. The classic version of the Alzheimer's Disease Assessment Scale-Cognition subscale (ADAS-Cog) is generally seen as the current gold standard primary outcome measure of cognitive symptom progression in dementia clinical trials. OBJECTIVE: This study evaluated the relationship between ADAS-Cog scores as a measure of clinical progression and the healthcare resource utilization (HCRU)-measured burden of cognitive impairment in patients with mild cognitive impairment, AD, or suspected AD in the real world. METHODS: A retrospective observational survey of physicians and their consulting patients with multiple ADAS-Cog scores. Regression models were constructed for HCRU variables (e.g., consultations, hospitalizations, caregiving requirements) with ADAS-Cog rate of change, baseline ADAS-Cog, and their interaction included as exposure variables. RESULTS: 651 patient records were completed by 154 physicians. Approximately 70% of patients had mild to moderate dementia. In 56.7% of patients, clinical progression was maintained/stable from baseline. Mean change in ADAS-Cog (adjusted to 12 months) was 2.8 points and change scores increased with increasing dementia severity. Most HCRU variables increased significantly (p < 0.05; joint test) with increasing ADAS-Cog scores (indexing clinical deterioration). CONCLUSION: The results suggest that further understanding the relationship between HCRU and ADAS-Cog changes in real-world clinical practice could potentially provide a baseline upon which the success of disease-modifying, as well as newer symptomatic, dementia therapies can be judged.

Memory assessment services and health-related quality of life: 1-year follow-up.

OBJECTIVES: Our group has already demonstrated that patients' health-related quality of life (HRQL) improves in the first 6 months after their first appointment at memory assessment services (MASs), but the sustainability of such gains is unknown. We aimed to describe changes in patients' HRQL at 12 months after their first MAS appointment and to examine associations with patient and MAS characteristics. METHODS: We collected data from 702 patients and 452 lay caregivers at the first appointment and 12 months later. Multivariable linear regression was used to examine the relationships of change in HRQL (self-reported and proxy-reported) with patients' characteristics and use of post-diagnostic interventions, and multilevel models were used to analyse the relationships of HRQL with MAS characteristics. RESULTS: In the whole group, self-reported HRQL improved over 12 months (+3.5 points, 95% CI 2.7 to 4.2). Among people diagnosed with dementia, improvement in HRQL was more than double that among those with mild cognitive impairment or no diagnosis. Proxy-reported HRQL improved only in those diagnosed with dementia (+1.2 points, 95% CI 0.2 to 2.2). Changes in HRQL were not associated with any patient characteristics. The only feature of MASs associated with larger improvements in HRQL was the presence of advisory and support staff. CONCLUSIONS: Improvements in HRQL observed at 6 months are maintained up to 1 year after the first MAS appointment, more so among those who receive a diagnosis of dementia. Continued follow-up will determine if the improvement is even longer lasting.

Is the effectiveness of memory assessment services associated with their structural and process characteristics?

OBJECTIVES: The aim of this study was to investigate whether structural and process characteristics of memory assessment services (MASs) are associated with outcomes (changes in patients' health-related quality of life (HRQL), carers' HRQL and carers' burden) over the first 6 months following the first appointment. METHODS: Data from 785 patients referred to 69 MASs and 511 of their lay carers, collected at the first appointment and 6 months later. Data on MAS characteristics were collected using a questionnaire at baseline. We used multilevel linear regression models to explore the associations of patients' HRQL and carers' outcomes with structural and process characteristics of MASs. Analyses were conducted on the full sample of patients and carers, and separately on those patients diagnosed with dementia. RESULTS: None of the structural (skill mix, workload, volume, provision of clinical assessments and provision of psychosocial support) or process (waiting time, length and number of appointments, anti-dementia drug use and psychosocial interventions use) characteristics included in the analyses were associated with patients' or carers' outcomes at 6 months, apart from the presence of allied health professionals (AHPs), which was associated with a DEMQOL score 2.7 points higher. When only those with a diagnosis of dementia were considered, the association with presence of AHPs was no longer observed. CONCLUSIONS: Apart from involving AHPs, alterations to the way MASs are structured or function appear unlikely to improve their effectiveness in improving patients' and carers' HRQL. It is possible that the characteristics of MASs may influence patients' and carers' experience, but this was not studied. Copyright © 2017 John Wiley & Sons, Ltd.

The Edinburgh Consensus: preparing for the advent of disease-modifying therapies for Alzheimer's disease.

CONTEXT: This commentary discusses the implications of disease-modifying treatments for Alzheimer's disease which seem likely to appear in the next few years and results from a meeting of British experts in neurodegenerative diseases in Edinburgh. The availability of such treatments would help change public and professional attitudes and accelerate engagement with the prodromal and preclinical populations who might benefit from them. However, this would require an updated understanding of Alzheimer's disease, namely the important distinction between Alzheimer's disease and Alzheimer's dementia. CONSENSUS: Since treatments are likely to be most effective in the early stages, identification of clinically relevant brain changes (for example, amyloid burden using imaging or cerebrospinal fluid biomarkers) will be crucial. While current biomarkers could be useful in identifying eligibility for new therapies, trial data are not available to aid decisions about stopping or continuing treatment in clinical practice. Therefore, effective monitoring of safety and effectiveness when these treatments are introduced into clinical practice will be necessary to inform wide-scale use. Equity of access is key but there is a tension between universal access for everyone with a diagnosis of Alzheimer's disease and specifying an eligible population most likely to respond. We propose the resources necessary for an optimal care pathway as well as the necessary education and training for primary and secondary care. CONCLUSION: The majority of current services in the UK and elsewhere would not be able to accommodate the specialist investigations required to select patients and prescribe these therapies. Therefore, a stepped approach would be necessary: from innovating sentinel clinical-academic centres that already have capacity to deliver the necessary phase IV trials, through early adoption in a hub and spoke model, to nationwide adoption for true equity of access. The optimism generated by recent and anticipated developments in the understanding and treatment of Alzheimer's disease presents a great opportunity to innovate and adapt our services to incorporate the next exciting development in the field of dementia.

Change in Health-related Quality of Life After Referral to Memory Assessment Services.

Despite strong support for the provision of memory assessment services (MASs) in England and other countries, their effectiveness in improving patient outcomes is uncertain. We aimed to describe change in patients' health-related quality of life (HRQL) 6 months after referral to MASs and to examine associations with patient characteristics and use of postdiagnostic interventions. Data from 883 patients referred to 69 MASs and their informal caregivers (n=569) were collected at referral and 6 months later. Multivariable linear regression was used to examine associations of change in HRQL (DEMQOL, DEMQOL-Proxy) with patient characteristics (age, sex, ethnicity, socioeconomic deprivation, and comorbidity) and use of postdiagnostic interventions (antidementia medications and nonpharmacological therapies). Mean HRQL improved, irrespective of diagnosis: self-reported HRQL increased 3.4 points (95% CI, 2.7-4.1) and proxy-reported HRQL 1.3 points (95% CI, 0.5-2.1). HRQL change was not associated with any of the patient characteristics studied. Patients with dementia (54%) receiving antidementia drugs reported greater improvement in their HRQL but those using nonpharmacological therapies reported less improvement compared with those note receiving therapy. HRQL improved in the first 6 months after referral to MASs. Research is needed to determine longer term sustainability of the benefits and the cost-effectiveness of MASs.

Health state values for use in the economic evaluation of treatments for Alzheimer's disease.

Alzheimer's disease (AD) is a chronic, progressive, neurodegenerative disease that places a heavy burden on people with the condition, their families and carers, health care systems and society in general. Health-related quality of life (HR-QOL) in patients deteriorates as the cognitive, behavioural and functional symptoms of AD develop. The human and financial cost of AD is forecast to grow rapidly as populations age, and those responsible for planning and financing health care face the challenge of allocating increasingly scarce resources against current and future interventions targeted towards AD. These include calls for early detection and diagnosis, preventative strategies, new medications, residential care, supportive care, and meeting the needs of carers as well as patients. Health care funders in many health systems now require a demonstration of the value of new interventions through a comparison of benefits in terms of improvements in HR-QOL and costs relative to those of competing or existing practices. Changes in HR-QOL provide the basis for the calculation of the quality-adjusted life-year (QALY), a key outcome used in economic evaluations to compare treatments within and between different disease conditions. The objective of this systematic review was to provide a summary of the published health state values (utilities) for AD patients and their carers that are currently available to estimate QALYs for use in health economic evaluations of interventions in AD. The health care literature was searched for articles published in English between 2000 and 2011, using keywords and variants including 'quality-adjusted life years', 'health state indicators', 'health utilities' and the specific names of generic measures of HR-QOL and health state valuation techniques. Databases searched included MEDLINE, EMBASE, NHS EED, PsycINFO and ISI Web of Science. This review identified 12 studies that reported utility values associated with health states in AD. Values for AD health states categorized according to cognitive impairment (where 1 = perfect health and 0 = dead) ranged from mild AD (0.52-0.73) to moderate AD (0.30-0.53) to severe AD (0.12-0.49). Utility values were almost all based on two generic measures of HR-QOL: the EQ-5D and Health Utility Index mark 2/3 (HUI2/3). There were no health state values estimated from condition- or disease-specific measures of HR-QOL. The review also identified 18 published cost-utility analyses (CUAs) of treatments for AD. The CUAs incorporated results from only three of the identified health state valuation studies. Twelve CUAs relied on the same study for health state values. We conclude that the literature on health state values in AD is limited and overly reliant on a single symptom (cognition) to describe disease progression. Other approaches to characterizing disease progression in AD based on multiple outcomes or dependency may be better predictors of costs and utilities in economic evaluations. Patient and proxy ratings were poorly correlated, particularly in patients with more advanced AD. However, proxy ratings displayed the validity and reliability across the entire range of AD severity needed to detect long-term changes relevant to economic evaluation. Further longitudinal research of patient and carer HR-QOL based on multidimensional measures of outcome and utilities is needed.

Model-based economic evaluation in Alzheimer's disease: a review of the methods available to model Alzheimer's disease progression.

OBJECTIVE: To consider the methods available to model Alzheimer's disease (AD) progression over time to inform on the structure and development of model-based evaluations, and the future direction of modelling methods in AD. METHODS: A systematic search of the health care literature was undertaken to identify methods to model disease progression in AD. Modelling methods are presented in a descriptive review. RESULTS: The literature search identified 42 studies presenting methods or applications of methods to model AD progression over time. The review identified 10 general modelling frameworks available to empirically model the progression of AD as part of a model-based evaluation. Seven of these general models are statistical models predicting progression of AD using a measure of cognitive function. The main concerns with models are on model structure, around the limited characterization of disease progression, and on the use of a limited number of health states to capture events related to disease progression over time. None of the available models have been able to present a comprehensive model of the natural history of AD. CONCLUSIONS: Although helpful, there are serious limitations in the methods available to model progression of AD over time. Advances are needed to better model the progression of AD and the effects of the disease on peoples' lives. Recent evidence supports the need for a multivariable approach to the modelling of AD progression, and indicates that a latent variable analytic approach to characterising AD progression is a promising avenue for advances in the statistical development of modelling methods.