Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring 11 (2019) 231-247 Diagnostic Assessment & Prognosis What outcomes are important to patients with mild cognitive impairment or Alzheimer’s disease, their caregivers, and health-care professionals? A systematic review Claire Tochela,*, Michael Smitha, Helen Baldwina,b, Anders Gustavssonc,d,e, Amanda Lya, Christin Bexeliuse, Mia Nelsona, Christophe Bintenerf, Enrico Fantonig, Josep Garre-Olmoh, € urkl, Olin Jansseni, Christoph Jindraj, Isabella F. Jørgensenk, Alex McKeownb, Buket Ozt€ Anna Ponjoanh,m, Michele H. Potashmann, Catherine Reedo, Emilse Roncancio-Diazg, Stephanie Vosi, Cathie Sudlowa, on behalf of the ROADMAP consortium a Centre for Medical Informatics, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK b University of Oxford, Oxford, UK c Quantify Research, Stockholm, Sweden d Department of Neurobiology, Care Sciences & Society, Karolinska Institute, Stockholm, Sweden e F. Hoffmann-La Roche Ltd., Basel, Switzerland f Alzheimer Europe, Luxembourg City, Luxembourg g GE Healthcare, Life Sciences, Amersham, UK h Girona Biomedical Research Institute (IdibGI), Girona, Catalonia, Spain i Department of Psychiatry & Neuropsychology, School for Mental Health & Neuroscience, Alzheimer Center Limburg, Maastricht University, Maastricht, the Netherlands j Department of Psychiatry, University of Oxford, Oxford, UK k Novo Nordisk Foundation Center for Protein Research, Faculty of Health & Medical Sciences, University of Copenhagen, Copenhagen, Denmark l Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark m Vascular Health Research Group (ISV-Girona), Institut Universitari d’Investigacio en Atencio Primaria Jordi Gol (IDIAP Jordi Gol), Barcelona, Catalonia, Spain n Biogen, Cambridge, MA, USA o Eli Lilly and Company Limited, Windlesham, UK Abstract Introduction: Clinical trials involving patients with Alzheimer’s disease (AD) continue to try to identify disease-modifying treatments. Although trials are designed to meet regulatory and registra- tion requirements, many do not measure outcomes of the disease most relevant to key stakeholders. Methods: A systematic review sought research that elicited information from people with AD, their caregivers, and health-care professionals on which outcomes of the disease were important. Studies published in any language between 2008 and 2017 were included. Results: Participants in 34 studies described 32 outcomes of AD. These included clinical (memory, mental health), practical (ability to undertake activities of daily living, access to health information), and personal (desire for patient autonomy, maintenance of identity) outcomes of the disease. Discussion: Evidence elicited directly from the people most affected by AD reveals a range of disease outcomes that are relevant to them but are not commonly captured in clinical trials of new treatments. Ó 2018 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer’s Association. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/ 4.0/). Conflicts of interest: A.G. is a partner of Quantify Research, providing *Corresponding author. Tel.: 144 131 651 7867; Fax: 144 131 650 consultancy services to pharmaceutical companies and other private and 3891. public organizations and institutions. A.G.’s contribution to ROADMAP E-mail address: ctochel@ed.ac.uk was on behalf of Roche Pharmaceuticals. C.B. (Alzheimer Europe) received an Honoraria from ProLog Wissen GmbH, Cologne, Germany, for a cogni- tive training program. https://doi.org/10.1016/j.dadm.2018.12.003 2352-8729/Ó 2018 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer’s Association. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 232 C. Tochel et al. / Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring 11 (2019) 231-247 Keywords: Alzheimer’s Disease; Mild cognitive impairment; Outcomes; Systematic review; Qualitative; Quantitative; Qual- ity of life; Memory; Activities of daily living; Autonomy; Burden; Patients; Caregivers; Healthcare professionals 1. Background 2. Methods Dementia has a substantial global impact, affecting The systematic review protocol is available in the PROS- over 46 million people in 2015 and costing an estimated PERO database (https://www.crd.york.ac.uk/PROSPERO/ US $818 billion [1]. Alzheimer’s disease (AD) is the display_record.php?RecordID575722). most common cause of dementia, accounting for 50- 70% of cases [2,3]. AD is typically characterized by 2.1. Search strategy impairments in memory, executive functions, and activities of daily living (ADLs), but the range and We developed a search strategy for the MEDLINE data- impact of symptoms and outcomes across the base, balanced for sensitivity and specificity, and adapted disease spectrum are diverse. The underlying causes of it for use in Embase, CINAHL, and PsycINFO (Table S1). AD and effective treatments for the disease remain We developed groups of search terms for each research ques- elusive [3,4]. tion using input from ROADMAP partners. We combined Clinical trials involving patients with AD continue to terms related to AD across the disease spectrum, stakeholder try to identify disease-modifying treatments. However, groups and study methods, with terms related to outcomes although such trials may meet regulatory and registration and priority (for research question 1) and separately with requirements, they may not provide convincing evidence terms related to a meaningful delay of disease (for research of relevance to patients, caregivers, or health-care pro- question 2). We combined all searches to remove duplicates. fessionals. Some trials are criticized for using inappro- We searched for gray literature using “Alzheimer” in combi- priate or inadequately sensitive endpoints [4,5], and it nation with “outcome” or “progression”, applying date is often unclear how much stakeholder input, other limits 2008-2017 on relevant websites (Table S1). than that of regulators, is applied in the selection of We included relevant studies regardless of language by trial endpoints [5]. arranging translation into English by colleagues. We sought Helping key stakeholders to understand which AD out- additional relevant studies through manual searches of key comes are most relevant and what constitutes a meaning- articles’ citation lists and checking relevant conference ab- ful delay in disease progression could help researchers stracts for full publications. develop and evaluate relevant, effective treatments and improve health services and care [6]. This systematic re- 2.2. Study screening, quality appraisal, and selection view, conducted on behalf of the international consortium We established specific inclusion and exclusion criteria to Real World Outcomes Across the AD Spectrum for Better guide the selection of relevant studies for inclusion and Care (ROADMAP; https://roadmap-alzheimer.org/), screened the titles and abstracts of all retrieved citations aimed to collate all available evidence about prioritization (Table 1). Two members of the research team independently of AD outcomes and criteria for meaningful disease pro- screened the first half of the retrieved citations, with 95% gression from the perspective of patients, caregivers, and agreement on decisions to include/exclude (Cohen’s kappa, health-care professionals. ROADMAP partners will seek 0.53 [0.42-0.64]). A discussion of discrepancies with a third to match these to “real-world evidence” sources, member of the team revealed that most disagreements were including disease registries, population-based cohort due to the appraiser including potentially relevant articles studies, and electronic health records documenting routine that did not meet all inclusion criteria. The risk of missing rele- patient care. vant evidence was considered to be low; hence, one research We sought evidence from studies covering a spectrum team member screened the remaining half of the citations. from prodromal AD and mild cognitive impairment (MCI) Two members of the team independently used published to confirmed AD dementia [7]. We sought research studies tools with our inclusion and exclusion criteria to appraise that elicited information from stakeholders, addressing the the full text of articles that passed screening for relevance following research questions: and quality. Checklists from the Clinical Appraisal Skills 1. Which outcomes of AD across the spectrum are prior- Program were used to appraise qualitative studies (http:// itized by patients, caregivers, and health-care profes- www.casp-uk.net/casp-tools-checklists) and the National sionals? Institute of Health for quantitative studies (https://www. 2. What do these stakeholders consider a meaningful nhlbi.nih.gov/health-topics/study-quality-assessment-tools). delay in progression of AD across the spectrum? Discrepancies were discussed by the team and resolved C. Tochel et al. / Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring 11 (2019) 231-247 233 Table 1 Inclusion and exclusion criteria Included all relevant studies which elicited information from an included stakeholder group which answered one or both research questions from the perspective of one (or more) of the following groups: 2patients with AD across the spectrum; 2people caring informally for individuals with AD across the spectrum, including, but not limited to, family members, unpaid caregivers, and advocates; 2health-care professionals or clinicians looking after patients with AD across the spectrum, including, but not limited to, neurologists, geriatricians, psychiatrists, family doctors, nurses, therapists, professions allied to medicine, and formal, paid caregivers/support workers, where results could be differentiated from informal, unpaid, or familial caregivers.  used an appropriate and explicit research methodology to gather the required research data, including the use of surveys, focus groups, or interviews to gather views directly from subjects  met a minimum quality threshold  were published between 2008 and 2017, inclusive Excluded all relevant studies which  did not allow information related to AD across the spectrum to be distinguished from other conditions such as stroke, multiple sclerosis, and epilepsy, or other causes of dementia and cognitive impairment, unless they occurred as AD comorbidities  only included information on patients with dementia or cognitive impairment caused by a condition other than AD or dementia of an undefined or nonspecific etiology  did not provide sufficient data to answer the research questions, such as commentaries, opinion pieces, or conference abstracts  failed to provide the required information (year of publication, title, abstract) for filtering when extracted from the source  reported on AD outcomes as measured by diagnostic tools or interventions without including the views of one of our stakeholder groups on their importance. Abbreviation: AD, Alzheimer’s disease. through consensus. Through iterative discussion, we estab- perspective of the relevant stakeholder group. In studies lished a minimum quality threshold for inclusion, agreeing where outcomes were directly ranked for priority, the top to exclude studies with incomplete descriptions of recruit- 50% of outcomes were included. In studies where outcomes ment or analysis or unclear reporting of results which did were surveyed for importance but not ranked in the order of not allow appraisal of their rigor. priority, outcomes that were deemed important by over 50% of participants were included. In studies adopting qualitative 2.3. Data extraction methods, outcomes that were grouped into themes by au- thors or that recurred frequently in participant quotations For each included study, one member of the research team completed data extraction, noting the research approach, were included. recruitment methodology, participant stakeholder demo- graphics, disease stage, data analysis and synthesis methods, 3. Results research findings, and conclusions (Table S2). At least one additional member of the team verified the extracted data. Of the 3772 citations identified in the deduplicated searches, we excluded 3653 at title/abstract screening and 2.4. Data synthesis process a further 92 after full-text screening (Fig. 1). In addition to the 27 studies that passed full-text review and quality We extracted quotations and other study findings that appraisal, we further found seven studies meeting all inclu- referred to outcomes or meaningful delay of AD across the sion criteria through citation searching key articles and disease spectrum. We sought feedback from consortium col- follow up of relevant conference abstracts. No additional leagues to group specific outcomes into overarching do- studies were found through the gray literature search. mains (e.g., memory within the cognition domain) (Table 2). Because many outcomes were multifaceted and some 3.1. Study characteristics overlapped domains, we placed each outcome where it fitted best according to clinical nosology (e.g., grouping behav- The 34 included studies (representing 32 distinct research ioral, mental, and neuropsychiatric outcomes as used in in- projects) were conducted in 13 countries (Fig. 2). Individual ternational classification systems [8]) and previous studies involved between four and 1116 participants. Twenty ROADMAP activities [9]. studies recruited patients with MCI or AD dementia, 23 re- To allow integration of evidence emerging from studies cruited caregivers, and six recruited health-care profes- using a range of different methodologies, we established a sionals (the majority of whom were generalist or specialist framework for deciding which of the outcomes discussed physicians and community or nursing home nurses; details within each study should be considered important from the are shown in Table 3). No studies included the views of Table 2 234 Domains and outcomes: the number of included studies in which each outcome was considered important and the number of countries involved in those studies No. of studies in which the The overall no. of studies No. of countries outcome was considered in which the outcome was represented in important by: considered important relevant studies Overarching domain Outcome Definition Patients Caregivers HPs (range: 1-11) (range: 1-10) Cognition Memory/slowing of forgetfulness Recalling names, events, and dates; 5 6 1 10 6 C. Tochel et al. / Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring 11 (2019) 231-247 general forgetfulness; slowing of memory loss Language and communication Verbal and written communication, such 3 3 - 6 3 as verbal fluency and object naming General cognitive health Cognitive functioning without explicitly 1 1 1 2 2 referring to a specific cognitive function Judgment and insight Ability to retain an intuitive 2 1 - 2 1 understanding of oneself and of the disease process Executive functions Planning, multitasking, and focused 2 - - 2 2 concentration Functioning and dependency Activities of daily living (ADLs) Competent and independent ability to 3 7 2 10 7 complete instrumental (cooking meals, housekeeping, managing finances) and basic (using the toilet, eating meals, dressing, self-hygiene) ADLs Driving Legal implications and issues 1 1 1 2 2 surrounding surrendering the patient’s license Maintaining hobbies Continued ability to partake in preferred 3 1 - 3 3 leisure activities and hobbies Eating behaviors Appetite or frequency of eating - 2 - 2 3 Patients’ independence and autonomy The ability to function as an autonomous 7 4 1 10 7 individual, both physically and psychologically Social engagement Socialization and social support 2 1 - 3 3 Physical health and mobility Physical health, fitness, and mobility 2 1 - 3 3 Behavioral and neuropsychiatric Mental health Changes in affect and irritation, 3 5 1 10 6 symptoms of anxiety, depression, and reality distortion Maintaining identity or personality Personality traits, knowledge, or 4 4 1 9 7 emotional bonds with others Challenging and distressing behaviors Verbal or physical aggression, anger, and - 5 1 6 4 injurious behaviors Apathy General engagement with their 1 3 - 3 1 environment and an interest, motivation, or enthusiasm for everyday life Sleep patterns Patterns or the duration and frequency of - 2 1 3 2 sleep Self-efficacy Patients’ belief and confidence in their - 1 - 1 1 abilities Patient length and the quality of life Patient quality of life Living with dignity, leading a fulfilling 2 3 1 6 7 life, and an overall sense of satisfaction with life Length of patient life Longevity and staying healthy for as long 1 - - 1 1 as possible Caregiver-oriented outcomes Caregiver burden The burden associated with care, 1 8 1 9 8 C. Tochel et al. / Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring 11 (2019) 231-247 including a loss of social life, time spent caring, stress, mental and physical impact, and giving up work or study Family participation in care Family members drifting apart since - 5 2 6 8 diagnosis of the illness, an unequal share of caregiving duties, and the importance/positives of involving family in the caregiving process Caregiver social support Need for social support as a caregiver, the - 5 1 6 8 reported benefits of providing support to fellow caregivers via shared understanding, barriers to seeking social support, the importance of seeking social support from family members, and information regarding the support services that caregivers use Spouses’ “duty” to care Belief that it is the “duty” of the spousal 1 2 1 3 2 caregiver to provide care to their ill partner because of the marital bond Quality of patient/caregiver relationship Strain placed on marital and parental 2 2 - 4 3 relationships Caregiver quality of life Changes to lifestyle, freedom, physical - 2 - 2 6 burden, and emotional impact that affect life as a whole Health, social care, and treatment- Health services and disease information Disease information provided at various 5 8 2 11 10 related outcomes health services, availability and relevance of provided information, quality of communication between health-care professionals, patients, and caregivers Stability of symptoms and general Treatment expectations or controlling 1 4 1 5 7 symptom control symptoms at a level that enables functionality Delaying entry into institutional care Stay in their own home for as long as 1 1 2 4 3 possible Medication side effects The importance of limiting the side 1 2 - 2 6 effects Certainty of diagnosis Accuracy of diagnosis 2 1 - 2 2 (Continued ) 235 236 C. Tochel et al. / Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring 11 (2019) 231-247 No. of countries patients living with preclinical or prodromal AD or with AD relevant studies represented in (range: 1-10) at the severe end of the spectrum. Qualitative methods were used in 23 studies [10,12,14- 21,23,25,28-33,36,40-43], nine used quantitative methods 3 [11,22,24,27,34,35,37-39], and two used mixed methods [13,26] (Table 3). Six studies included explicit prioritization in which the outcome was The overall no. of studies of outcomes through ranking or survey responses from considered important stakeholders [11,22,24,27,34,38]; the rest included relevant material in the form of quotations and themes from (range: 1-11) interviews or focus groups that was used to infer the Domains and outcomes: the number of included studies in which each outcome was considered important and the number of countries involved in those studies (Continued ) importance of outcomes from stakeholder perspectives [10,12-21,23,25,26,28-33,35,37,39-43]. 4 Only three of the 34 included studies provided any evi- dence on stakeholders’ views about criteria for a meaningful HPs No. of studies in which the delay in disease progression [10,37,39]. Evidence was - outcome was considered sought on either the duration of such a delay or the Caregivers symptoms delayed in their onset or worsening, which would be considered meaningful. These studies gathered important by: 3 data via stakeholder interviews and clinical assessments of cognition. Patients 1 3.2. Outcomes of AD across the spectrum Anticipated, perceived, or actual labeling psychological, and societal effects of Table 2 lists 32 outcomes across seven domains which or stereotyping because of the AD process, alongside the emotional, experiencing such stigmatization emerged from the included studies, indicating which stake- holder(s) considered them important, the number of studies in which the outcome was described by each stakeholder group, and the number of countries from which participants were recruited. Fig. 3 shows the overlap by the stakeholder group. The most consistent evidence across the stakeholder Definition groups is summarized in the following section, including illustrative quotations and other relevant findings. 3.2.1. Outcomes raised by all stakeholder groups Eight outcomes, spanning all seven overarching domains, Abbreviations: AD, Alzheimer’s disease; HPs, health-care professionals. were considered important by all stakeholder groups. They emerged from between six and eleven studies, from a range of evidence types (Table 2). The impact and importance of memory decline was considered in relation to MCI and AD. This encompassed recalling names and dates and a general sense of forgetful- ness. “.it gets . frustrating to not be able to finish a con- Outcome versation without at least having one instance where I Stigma don’t remember a certain item, a name or place” (patient with MCI) [21]. “I was losing my mother—she was forget- ting people, how to do the most basic things. forgetting who she was” (familial caregiver of AD patient) [20]. The ten studies [10,12,14,18-21,31,36,38] reporting this were conducted in North and South America and Europe. Overarching domain ADLs and loss of functioning included completion of routine activities, such as independently managing cooking, Social issues finances, and self-hygiene. Evidence for significance in rela- Table 2 tion to MCI and AD came from ten studies [10,11,14,15,19,22,28,30,36,38] conducted in North and C. Tochel et al. / Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring 11 (2019) 231-247 237 Fig. 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart showing citation numbers in each stage of the screening process. Abbreviations: AD, Alzheimer’s disease; MCI, mild cognitive impairment. South America, Europe, and Asia. “Improve ADLs so far as up.. call the police” (professional describing main topics you know... buttoning up a shirt or closing a zipper” emerging after early AD diagnosis) [14]. (physician regarding expectations of treatment) [10]. “A The importance of maintaining patient independency and big issue is car driving.. we have to fight that they give autonomy was discussed in relation to MCI and AD in ten Fig. 2. Map showing the number of studies recruiting participants from countries around the world (some studies included participants from more than one country and so are enumerated on the map more than once; see Table 3). Darker shading implies a larger number of studies within a country, as shown on the scale beneath the map. Table 3 238 Summary of characteristics and results of included studies Findings Participant numbers according to First author; location (language) stakeholder type and AD/MCI patient Methods of data collection and Research question 1: reported Research question 2: definition of a (reference) status analysis outcomes meaningful delay Andersen; Canada (English) [10] Mild AD patients: n 5 4 Qualitative: semistructured interviews, AD patients: memory, general AD patients: positive results of AD caregivers: n 5 4 30-60 minutes, thematic analysis cognitive health treatment indicated by slowed rate C. Tochel et al. / Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring 11 (2019) 231-247 AD HPs: n 5 11 (nurses, physicians, AD caregivers: stability of symptoms of memory loss or improvement in pharmacists) and general symptom control cognitive function AD HPs: stability of symptoms and AD caregivers: positive results general symptom control, delaying indicated by stabilized symptom/ entry into care, patient social halting of deterioration engagement, patient QoL, ADL, AD HPs: positive results indicated by apathy stabilization of symptoms to defer requirement to leave home, retention of ability to be socially engaged, improvement in cognitive or physical function Barrios; USA (English) [11] MCI patients: n 5 16 Quantitative: ranking of 12 outcomes MCI patients: before the intervention, MCI caregivers: n 5 33 (study 1), from 1 (most important) to 12 (least MCI patients ranked patient n 5 16 (study 2) important) depression as significantly less important (mean rank 7.9) than the MCI caregivers (mean rank 4.2; P , .01) MCI caregivers: ADL, patient self- efficacy, patient mental health, caregiver QoL, patient QoL; Note: caregiver burden and caregiver depression were ranked as the outcomes with the least priority by the caregivers. Beard; USA (English) [12] MCI/mild AD patients: n 5 17 Qualitative: 14 focus groups conducted MCI/AD patients: patients’ mental MCI/AD caregivers: n 5 68 throughout the USA using a health, independence and common interview guide, grounded autonomy, social engagement, theory physical health and mobility, judgment, and insight MCI/AD caregivers: patient independence and autonomy, memory Blieszner; USA (English) [13] MCI caregivers: n 5 86 Mixed methods: individual, face-to- MCI caregivers: patients’ apathy, face interviews, thematic analysis patients’ sleep patterns, caregiver burden, quality of patient-caregiver relationship, family participation in care, health services, and disease information Bronner; Germany (English) [14] Mild AD patients: n 5 5 Qualitative: individual, face-to-face AD patients: patient independence and AD caregivers: n 5 6 semistructured interviews, autonomy, spouses’ “duty” to care, AD HPs: n 5 13 (physicians, social categorical content analysis health services, and disease engagement workers, legal information guardians, nurses, paid caregiver) AD caregivers: memory, family participation in care AD HPs: ADL, patients’ independence and autonomy, driving, patients’ mental health, maintaining identity or personality, spouses’ “duty” to care, caregiver burden, health C. Tochel et al. / Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring 11 (2019) 231-247 services and disease information, caregiver social support, delaying entry into care Cheng; China (English) [15] AD caregivers: n 5 57 (for patients Qualitative: tape recorded diaries, AD caregivers: ADL, eating behaviors, with mild to moderate AD) thematic analysis stigma, spouses’ “duty” to care, caregiver social support, access to health services and disease information, patient QoL, caregiver burden Dai; China (English) [16] MCI caregivers: n 5 13 Qualitative: individual, in-depth MCI caregivers: general cognitive interviews, grounded theory health, patient independence and autonomy, patient mental health, stigma, health services, and disease information Dean; UK (English) MCI patients: n 5 23 Qualitative: individual, in-depth MCI patients: memory, language and (a) [17] Study (b) added MCI caregivers: semistructured interviews, thematic communication, maintaining (b) [18] n 5 20 analysis hobbies, patient social engagement, patients’ mental health, maintaining identity or personality, caregiver social support, stigma, certainty of diagnosis, access to health services and disease information; (b) MCI caregivers: health services and disease information, stigma, caregiver social support Frank; UK, US, Spain (English) [19] Mild to moderate AD patients: n 5 18 Qualitative: focus groups with AD patients: ADL, patient AD caregivers: n 5 46 caregivers and patients, thematic independence, and autonomy analysis AD caregivers: memory, caregiver social support Gelman; USA (English) [20] AD caregivers: n 5 10 Qualitative: counseling sessions were AD caregivers: memory, patient sleep conducted, categorical content patterns, spouses’ “duty” to care, analysis caregiver burden, family participation in care, health services, and disease information Gordon; USA (English) [21] MCI patients: n 5 25 Qualitative: mixture of focus groups MCI patients: memory, language and and individual meetings, thematic communication, executive analysis functions Hauber; USA and Germany (English) AD caregivers: n 5 400 (USA) and Quantitative: 15 best-worst scaling AD caregivers: ADL, eating behaviors [22] 403 (Germany) questions that correspond to 10 activities from the Disability Assessment for Dementia 239 (Continued ) Table 3 240 Summary of characteristics and results of included studies (Continued ) Findings Participant numbers according to First author; location (language) stakeholder type and AD/MCI patient Methods of data collection and Research question 1: reported Research question 2: definition of a (reference) status analysis outcomes meaningful delay Hulko; Canada (English) [23] Mild to severe AD patients: n 5 4 (not Qualitative: participant observation AD patients: patients’ independence possible to differentiate by AD sessions, in-home interviews, and and autonomy, quality of patient- C. Tochel et al. / Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring 11 (2019) 231-247 stage) focus groups, grounded theory caregiver relationship, health services, and disease information Jones; France, Germany, Italy, Spain, AD caregivers: n 5 250 (50 from each Quantitative: surveys consisting of a AD caregivers: caregiver burden, UK (English) [24] location) series of attitudinal statements caregiver QoL, family participation AD HPs: n 5 500 (100 from each requiring a response on a Likert in care location), half specialists (e.g., scale AD HPs: caregiver QoL, health neurologist/neuropsychiatrist) and services and disease information, half generalists. family participation in care Joosten-Weyn; Netherlands (English) MCI patients: n 5 8 Qualitative: individual interviews, MCI patients: executive functions, [25] grounded theory physical health and mobility, patient independence and autonomy, patient mental health, maintaining identity or personality Kunneman; Netherlands (English) [26] MCI patients: n 5 1; mild AD: n 5 2; Mixed methods: focus groups, content MCI/AD patients: certainty of AD: n 5 3 analysis diagnosis, health services, and MCI/AD caregivers: n 5 6 disease information MCI/AD caregivers: certainty of diagnosis Kurz; Brazil, Canada, France, Mild to moderate AD patients: n 5 502 Quantitative: survey AD patients: stability of symptoms and Germany, Spain, USA (English) (w100 from each of USA, France, general symptom control, [27] Germany, Spain, Brazil) medication side effects, health AD caregivers: n 5 614 (as above, services and disease information, w100 from Canada) patient QoL AD caregivers: caregiver social support, medication side effects, health services, and disease information Lenardt; Brazil (Portuguese) [28] AD caregivers: n 5 14 (patients with Qualitative: semistructured interviews, AD caregivers: ADL, challenging and mild to moderate AD) taxonomic analysis distressing behaviors, caregiver burden, maintaining identity or personality Lu; USA (English) [29] MCI caregivers: n 5 10 Qualitative: open-ended interviews, MCI caregivers: language and interpretive phenomenological communication, patient analysis independence and autonomy, challenging and distressing behaviors, maintaining identity or personality, caregiver burden, quality of patient/caregiver relationship Lu; USA (English) [30] MCI patients: n 5 9 (7 male) Qualitative: focus groups, content MCI patients: ADL, patients’ MCI caregivers: n 5 9 analysis independence and autonomy MCI caregivers: language and communication, ADL, patients’ mental health MacRae; Canada (English) Mild AD patients: n 5 8, (b) added one Qualitative: in-depth, semistructured AD patients: memory, patient (a) [31] further patient with AD (total n 5 9) interviews, thematic analysis independence and autonomy, (b) [32] delaying entry into care, C. Tochel et al. / Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring 11 (2019) 231-247 maintaining identity or personality, stigma, length of patient life, patient QoL, length of patient life Malthouse; UK (English) [33] Mild AD patients: n 5 5 Qualitative: open-ended interviews, AD patients: patients’ independence AD caregivers: n 5 5 thematic analysis and autonomy AD caregivers: physical health and mobility, patients’ mental health Naumann; Germany (German) [34] AD caregivers: n 5 35 Quantitative: 25 outcomes (referred to AD caregivers: language and as ‘benefit aspects’) were ranked for communication, delaying entry into priority. Average scores for each care, challenging and distressing item were calculated. behaviors, stability of symptoms and general symptom control, patient QoL Oremus; Canada (English) [35] AD caregivers: n 5 216 (patients with Quantitative: questionnaire, regression AD caregivers: medication side effects mild (81%) or moderate (19%) AD analysis Pavarini; Brazil (Portuguese) [36] AD caregivers: n 5 14 (patients with Qualitative: interviews, categorical AD caregivers: memory, ADL, probable, mild AD) content analysis caregiver burden, health services and disease information, patients’ social engagement, patients’ mental health, patients’ challenging and distressing behaviors, family participation in care Rockwood; Canada (English) [37] AD HPs: number and specialty not Quantitative: clinical assessment using At group-level analysis, a 4-point stated ADAS-Cog at 8-week intervals over improvement was significantly Mild to moderate AD patients: n 5 99 24 weeks compared to changes on related to improvements on other AD caregivers: n 5 99 other assessments (PGAS, CGAS, assessments. Worsening scores CIBIC1) measured by clinician were nonsignificantly related to interview clinical changes. At individual level, there was substantial variability, with around half misclassified; often when ADAS- Cog detected no change, clinically meaningful effects could be detected. Ropacki; USA (English) [38] MCI patients: n 5 25 Quantitative: focus groups, categorical MCI patients: memory, language and MCI caregivers: n 5 25 content analysis communication, judgment and insight, ADL, maintaining hobbies, driving, patient apathy, patient sleep patterns, patient mental health, caregiver burden, maintaining identity and personality 241 (Continued ) Table 3 242 Summary of characteristics and results of included studies (Continued ) Findings Participant numbers according to First author; location (language) stakeholder type and AD/MCI patient Methods of data collection and Research question 1: reported Research question 2: definition of a (reference) status analysis outcomes meaningful delay MCI caregivers: memory, judgment and insight, ADL, maintaining C. Tochel et al. / Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring 11 (2019) 231-247 hobbies, driving, patient apathy, patient sleep patterns, challenging and distressing behaviors, maintaining identity or personality, caregiver burden Schrag; UK (English) [39] Mild AD patients: n 5 181 Quantitative: ADAS-Cog compared to ADAS-Cog scores among those with a AD HPs: number and specialty not clinician-assessed memory and clinically relevant change at stated, all based within nonmemory cognitive function 6 months were between 3.1 and 3.8. neuroimaging initiative sites using FAQ and CDRS Scores in those without a clinical change were between 1.9 and 2.0. Minimally, clinically relevant changes determined to be 3 points. Smith; Australia (English) [40] AD patients: n 5 5 Qualitative: in-depth, semistructured AD patients: stability of symptoms and AD caregivers: n 5 6 interviews, thematic analysis general symptom control Smith; Canada (English) [41] AD caregivers: n 5 17 (16 patients Qualitative: in-depth narrative AD caregivers: maintaining identity or with early to moderate AD, 1 with interviews conducted, grounded personality, stability of symptoms, moderate to severe AD) theory and general symptom control Sorensen; Denmark (English) [42] Patients with mild AD: n 5 11 Qualitative: semistructured interviews, AD patients: maintaining hobbies, grounded theory maintaining identity or personality, quality of patient-caregiver relationship Yektatalab; Iran (English) [33] AD HPs: n 5 14, clinical and social Qualitative: interviews with open- AD HPs: challenging and distressing caregivers for residents in a nursing ended questions, descriptive content behaviors, family participation in home analysis care Abbreviations: AD, Alzheimer’s disease; ADAS-Cog, Alzheimer’s Disease Assessment Scale-Cognitive Subscale; ADL, activities of daily living; CDRS, Clinical Dementia Rating Scale; CIBIC1, Clinician Interview-Based Impression of Change plus caregiver input; CGAS, clinician Goal-Attainment Scaling; FAQ, functional activities questionnaire; HPs, health-care professionals; MCI, mild cognitive impairment; PGAS, patient/carer Goal-Attainment Scaling; QoL, quality of life. C. Tochel et al. / Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring 11 (2019) 231-247 243 Fig. 3. Overlap of outcomes according to the stakeholder group which raised their importance and the number of studies in which they appeared. studies [12,14,16,19,23,25,29-31,33] from North America, emotional bonds with others. “My best friend [husband Europe, and Asia. This concept went beyond functional with MCI] has gone. He is part of me, but he is no longer capacity to the ability to self-govern, preserving both the same person. I really miss him” [29]. physical and psychological autonomy. “The issue is [they] The impact of the disease through caregiver burden was want to maintain [their] autonomy. [They] don’t want to be discussed in relation to MCI and AD in nine studies [13- patronised” (health-care professional for AD patients) [14]. 15,20,24,28,29,36,38] carried out in North and South The impact of mental health issues, such as anxiety, America, Europe, and Asia. “I quit my job, my house, to depression, and reality distortion, was mentioned in relation take care of her. I do not go to the cinema, I do not go out to MCI and AD, with evidence from ten studies for a walk, I do not go to the shopping mall, I do not go to [11,12,14,16,18,25,30,33,36,38] conducted in North and the hairdresser” (caregiver of AD patient) [28]. South America, Europe, and Asia. When asked which key The importance of health services and disease informa- areas should be targeted in an intervention for MCI, tion (and its absence) was discussed by all stakeholder spousal caregivers believed that targeting depression was groups in relation to MCI and AD in eleven studies [13- important [30]. 17,20,23,24,26,27,36] from North and South America, The importance of maintaining patient quality of life Europe, and Asia. “If there is something I don’t (QoL) (encompassing the concepts of living a fulfilled and understand, I will go on [the computer] and look it up. I dignified life) was highlighted in relation to MCI and AD; just want to be able, [if] something happens, [to] take care evidence came from six studies [10,11,15,27,31,34] of him as far as [possible] in every situation .” (caregiver conducted in North and South America, Europe, and Asia. of an AD patient) [13]. In one study, caregivers of patients with MCI ranked patient QoL as the most important outcome from a 3.2.2. Outcomes raised by both patients and caregivers predetermined list of twelve outcomes [11]. Patients and caregivers mentioned the importance of re- Maintenance of patients’ identity and personality was taining language and communication functions in relation discussed in relation to MCI and AD in nine studies to MCI and AD. This included cognitive aspects of verbal [14,18,25,28,29,31,38,41,42] carried out in North and and written communication, such as verbal fluency and ob- South America and Europe. This related to the ject naming. Evidence came from six studies preservation of personality traits, knowledge, and [18,21,29,30,34,38] conducted in North America and 244 C. Tochel et al. / Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring 11 (2019) 231-247 Europe, including one study in which familial caregivers of disease over time, and none comprehensively defined what AD patients ranked “improvement to communication constituted a meaningful delay in disease progression from abilities” as the fourth most important of a predetermined stakeholders’ perspectives. One study involving patients list of 25 outcomes [34]. with mild AD described changes in symptomatology Patients and caregivers dealing with MCI and AD dis- without specific reference to time periods (e.g., slowing cussed the importance of maintaining a quality patient-care- memory deterioration and retaining ability to undertake giver relationship. Evidence emerged from four studies ADLs) [10] (details are shown in Table 3). Two studies [13,23,29,42] conducted in North America, Europe, and involving patients with mild to moderate AD referred to dis- Asia. “My husband gets angry with me when I can’t ease progression in terms of cutoff points on the AD Assess- remember things we have decided to do. He talks a lot ment Scale-Cognitive describing 3- [39] or 4-point changes about it. Sometimes I think that it is worse for him than for [37] as clinically meaningful. Authors of both these studies me” (a patient with AD) [42]. emphasized that although these changes may be significant The impact of experiencing stigma due to AD emerged in when analyzed at a group level, there was a substantial vari- four studies [15,16,18,31] conducted in North America, ation among individuals and their experienced symptoms at Europe, and Asia. Stakeholders described anticipated, any given score on the scale. perceived, and overt stereotyping because of AD. “We haven’t discussed this, but I get the feeling that [my husband] wouldn’t like that, because there is a certain amount of 4. Discussion stigma attached to dementia. So no, I haven’t” (wife of an AD patient when asked about seeking social support) [18]. Our systematic review provides a framework of real- world outcomes which represents the voices of stakeholders 3.2.3. Outcomes mentioned by both health-care personally impacted by AD across the spectrum of disease, professionals and caregivers adding a different perspective to the previous work based Both health-care professionals and caregivers discussed on AD trial outcomes and their measures [44,45]. the difficulty of dealing with challenging and distressing Important outcomes included clinical aspects of the behaviors in relation to MCI and AD, such as verbal or disease, e.g., memory and mental health, and social physical aggression. Evidence came from six studies aspects, such as the devastating impact of caregiver burden. [28,29,34,36,38,43] conducted in North and South Other frequently observed important outcomes reflect America, Europe, and Asia. “If you don’t have patience practical challenges such as accessing AD information or here, you won’t last for even 2 months because of patients’ the ability to complete ADLs alongside personal aspects yelling and their aggression” (a paid caregiver of AD such as maintenance of patient autonomy, identity, and QoL. patients) [43]. Our review identified the importance of several outcomes The benefits of caregiver social support and the chal- consistent with those typically assessed in clinical trials, lenges of accessing it were discussed in relation to MCI such as cognition and ADLs. However, we revealed the and AD, with evidence from six studies [14,15,17-19,27] importance of several additional outcomes that are infre- from North and South America, Europe, and Asia. “I quently assessed in clinical trial settings, including preserva- started to realize that I should get someone to talk to when tion of the patient’s personality or the accessibility of health feeling helpless sometimes. I felt better after letting services and disease information. These concepts may be everything out from within” (a caregiver of AD patients) [15]. captured by patient reported outcome and experience mea- Patients dealing with MCI and AD described the impor- sures [46], which can be used to describe and evaluate the tance of maintaining family participation in care throughout effectiveness of treatments and quality of care, respectively, the disease process to preserve relationships and spread duties. and their use may enhance patient and carer engagement This emerged in six studies [13,14,20,24,36,43] conducted in with—and so recruitment to—clinical trials. North and South America, Europe, and Asia. “He (the patient) Stakeholders prioritized outcomes with tangible and loved his sister so much, and now she won’t even call to see directly observable effects on the daily lives of patients how he’s doing. She’s angry that I keep insisting there’s and caregivers. Disease biomarkers (e.g., those based on something wrong, and that he ‘took my side’ because he tau or amyloid, structural neuroimaging measures, or combi- hasn’t called her. But of course he can’t call her. This is nation of these) are now incorporated into research diag- tearing the family apart.” (a caregiver of an AD patient) [20]. nostic criteria and therefore commonly used to assess Outcomes discussed less frequently are described in interventions in clinical trials [2]. These were not mentioned Table 2 and Fig. 3. by stakeholders, although the desire for certainty of diag- nosis was identified in two studies. It is possible that clinical biomarker-based outcomes were not flagged as being impor- 3.3. Meaningful delay tant because of the sparsity of data from health-care profes- Only three included studies [10,37,39] reported relevant sionals (six of the 34 included studies), the lack of data from statements or data relating to changes in outcomes of the people with prodromal or severe AD, and/or the relatively C. Tochel et al. / Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring 11 (2019) 231-247 245 new and tentative nature of the evidence linking biomarkers is better focused on aspects of AD most important to the peo- to clinical symptomatology. ple affected by it. Although we identified a substantial body of research re- As there was limited evidence to define a “meaningful porting on the importance of various outcomes to stake- delay in AD disease progression” from any of the stake- holders, no reliable conclusions relating to the definition of holders’ perspectives, further research is essential to explore a meaningful delay in AD progression could be drawn. this important issue at different stages of the AD spectrum. The available evidence highlighted the difficulty of using AD outcomes of importance in preclinical and severe stages scales to determine clinically relevant or meaningful change of the disease should also be explored. because these are not accurate or predictive of symptoms at Our findings will help future researchers meet the chal- the individual level, suggesting the need for further investi- lenge of designing and undertaking optimized clinical trials gation of this issue. with the greatest potential to provide treatments for AD which mitigate its most devastating effects at a personal and social level. 4.1. Strengths and limitations This review benefitted from the multidisciplinary team of Acknowledgment researchers and experts across Europe who conducted the This project has received funding from the Innovative Med- work and contributed at key decision-making stages. icines Initiative 2 Joint Undertaking under the grant agree- The inclusion of studies published in multiple languages ment no.: 116020 (“ROADMAP”). This Joint Undertaking in different countries (although few from developing coun- receives support from the European Union’s Horizon 2020 tries) improves the generalizability of the evidence, and its research and innovation program and EFPIA. methodological heterogeneity adds confidence by incorpo- rating outcomes that emerged from a range of study types. Supplementary data This combined evidence facilitates a complete understand- Supplementary data to this article can be found online at ing of stakeholder perspectives. https://doi.org/10.1016/j.dadm.2018.12.003. Although our search strategy was relatively sensitive, it may not have captured all relevant material. We used the term “patient” with condition terms to identify individuals with AD across the spectrum, so relevant studies may have RESEARCH IN CONTEXT been missed which used terms such as “person” or “subject”. We found no studies that addressed the opinions of patients or corresponding stakeholders at the severe end of the AD 1. Systematic review: The authors searched four databases spectrum. Given the time-intensive and complex nature of (Medline, Embase, CINAHL, and PsycINFO) and on- qualitative work and the requirement of appropriate consent line sources of gray literature for research published procedures, it would be practically and ethically difficult to in any language which elicited the views of stakeholders conduct such research. We also did not capture the opinions to identify clinical and nonclinical outcomes of Alz- of former caregivers of people with AD. Both groups repre- heimer’s disease which were important to them. sent important missing voices in the evidence presented. The interpretation of research evidence into outcomes and their 2. Interpretation: There was consistent evidence across categorization into domains may have obscured some rele- stakeholder groups, countries where studies were vant concepts. For example, language and communication based, and study methodologies. Overall, 32 out- may have been captured by the broader “cognition” domain comes encompassed by seven broad domains were from the perspective of health-care professionals. uncovered, reflecting impacts across the spectrum of the disease. There was more evidence for the importance of patient memory, activities of daily 5. Conclusions living, quality of life, independence and autonomy, mental health, maintaining identity and personality, Our systematic review provides evidence about the out- caregiver burden, and access to health services and comes of MCI and mild to moderate AD dementia which disease information. are of importance to patients, caregivers, and health-care 3. Future directions: Understanding which real-world professionals. It demonstrates that although current clinical outcomes of Alzheimer’s disease are most relevant trials typically assess some of these, others are rarely to patients, caregivers, and health-care professionals included as outcomes. Involving these varied and nuanced should help guide future research to develop relevant, AD outcomes in the trial design would be a substantial chal- effective treatments and improve health services. lenge, but as they reflect distinct, important aspects of the experience and burden of the disease, they could help ensure that successful treatments or evaluation of the quality of care 246 C. Tochel et al. / Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring 11 (2019) 231-247 References [20] Gelman CR. ’La Lucha’: the experiences of Latino family caregivers of patients with Alzheimer’s disease. Clin Gerontologist 2010; 33:181–93. [1] Prince MJ. World Alzheimer Report 2015: the global impact of de- [21] Gordon MF, Lenderking WR, Duhig A, Chandler J, Lundy JJ, mentia: an analysis of prevalence, incidence, cost and trends. Alz- Miller DS, et al. 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