key: cord-0851632-fcincqi2 authors: Rodrigo, Adrián; Trigueros, Paloma; Jamilis, Laura; Alegret, Montserrat; Rodríguez, Octavio; Tárraga, Lluís; González‐Pérez, Antonio; Kramberger, Milica; Winblad, Bengt; Visser, Pieter Jelle; Jessen, Frank; Campo, Laura; Boada, Mercè title: Identification of undiagnosed dementia cases using a web‐based pre‐screening tool: The MOPEAD project date: 2021-04-15 journal: Alzheimers Dement DOI: 10.1002/alz.12297 sha: 660321abf75889d3a3d65c25a1152e0b17310783 doc_id: 851632 cord_uid: fcincqi2 INTRODUCTION: Innovative patient engagement models are required to identify people with prodromal and mild Alzheimer's disease who are “hidden” in their communities and not normally found in a memory clinic setting. METHODS: A marketing campaign and a web‐based pre‐screening tool were used to identify individuals at risk of dementia in five European countries. Harmonized clinical evaluation of these patients was performed in participating memory clinics within the MOPEAD project. RESULTS: A total of 1487 individuals completed the pre‐screening, with 547 of them found to be at risk of dementia (36.8%). Among the subset of 91 patients with a positive pre‐screening result that underwent full clinical evaluation, 49 (53.8%) were diagnosed with either mild cognitive impairment or Alzheimer's disease. CONCLUSION: This novel web‐based pre‐screening tool showed to be a valid strategy to identify undiagnosed people with cognitive impairment. Dementia is a devastating condition with a rapidly increasing prevalence. Projections based on social and demographic trends worldwide suggest that the number of cases could triple in the next 25 years. 1 In response, the World Health Organization has made dementia research in management and prevention a global health priority. 2 One of the problems we face when fighting dementia is that a large proportion of people with cognitive decline remain undiagnosed or "hidden" in their communities. Although there is limited evidence exploring the impact of timely diagnosis of Alzheimer's disease (AD), some reported benefits include delayed institutionalization, improved patient/carer quality of life, and access to timely counseling and social support. 3 However, in most health systems, dementia is underdiagnosed, and diagnosis typically occurs at a relatively late stage in the disease process. Furthermore, it has been hypothesized that one of the reasons for the disappointing results of clinical trials in patients with AD could be the limited effect of these drugs when irreversible neuronal damage has already occurred. 4 Therefore, diagnosing patients at early stages of the disease would not only be beneficial for them but could also be crucial in finding new effective treatments. However, the current lack of treatment options to revert the condition, along with the poor knowledge of possible social care interventions, discourages general practitioners' efforts to reach an early diagnosis 5, 6 and dissuades patients from seeking care. The scarcity of patients with early diagnosis impedes the development of effective treatments, and at the same time this lack of treatments makes it difficult to implement screening programs to identify patients in early stages of dementia. To break this loop, a paradigm shift in AD diagnosis is needed, moving toward earlier diagnoses. This shift requires an effort to increase patient engagement and find "hidden" prodromal AD, mild cognitive impairment (MCI), and mild dementia cases. 7 The Models of Patient Engagement for Alzheimer's Disease (MOPEAD) project aims to raise awareness of this problem and explores different ways to promote diagnosis at early stages of the disease. 8 These mechanisms include the use of (1) innovative internet-based pre-screening tools, (2) open-house initiatives at memory clinics, (3) primary care engagement, and (4) tertiary care engagement through diabetes clinics. This paper describes the methodology and the results of the first strategy, known as RUN1, which comprises an online campaign targeted to individuals between 65 and 85 years of age, who are directed to a webbased examination to detect people who may have cognitive impairment. The aim of this study was to assess the validity of this method for identifying patients with MCI or AD dementia among the elderly population. The internet and social media are tools commonly used to look for medical information. 9 This made us consider the use of online marketing We designed a landing page that adapted its appearance to the browser's regional configuration. Individuals were presented with information about cognitive decline and their potential participation in the study in their local languages. Once they agreed to participate in the study, individuals were asked to provide basic demographic data (age, sex, and educational level), and were redirected to a website where they could perform two cognitive tests, the Paired Only individuals between 65 and 85 years of age according to demographic information and no previous diagnosis of cognitive impairment reported were eligible to undergo this pre-screening. 8 People surfing the internet could be the participants themselves, but also a friend or a family member interested in their cognitive assess- The initial choice of Google's advertising platform was based on the predominance of Google as a search engine in participating countries. A set of country-specific dementia-related keywords was selected based on the reported frequency of these words in Google searches and local investigator criteria (Table S1 in supporting information). It is important to note that the cost per click is determined by market forces (based on bids placed by competing campaigns). Hence it fluctuates with time and varies for different words in different target locations. Given the limited resources, the marketing campaign needed to adapt to these changes to maximize the effect of the investment in each target location during the study period. Changes to the marketing campaign (such as keywords being used, the design or content of the ads/landing pages, or reinforcing the campaign for specific countries) were adopted during the study period if deemed necessary. A maximum of 33 consecutive patients with a positive pre-screening per study center was planned to undergo a clinical diagnostic evaluation with a common homogeneous protocol across all sites and countries to ensure the resulting data are comparable. The evaluation has been described elsewhere. 8 (9) neuroimaging evaluation. We aimed to recruit 100 individuals per country in this initiative, with 33 of them completing the clinical evaluation. We estimated that this sample size allowed us to detect differences of 65% or larger in the positive pre-screening rates between participating countries in the four pre-screening initiatives evaluated within the MOPEAD project (power = 80%, two-sided alpha = 0.01). The distribution of age groups, sex, and education among study subjects across countries and sources of traffic was compared using chisquare tests. Mean age was also estimated and compared using analysis of variance (ANOVA) tests. Unconditional logistic regression models were used to explore the following probabilities: completing the prescreening process, obtaining a positive pre-screening result, being evaluated at the memory clinics, and confirming a positive pre-screening result after clinical diagnostic examination at the memory clinics. To obtain adjusted estimates for the contribution of each factor, the following variables were introduced simultaneously in these models: age groups, sex, education, traffic source, and country of origin. The webtool was designed taking into account an ethical perspective and protecting data privacy from the very design. Approval from institutional review boards (IRBs) was obtained in all participating countries. IRBs in Germany and the Netherlands required changes to the online platform, which delayed the rollout of the campaign, and, more importantly, forced individuals to go through additional steps to agree to participate in the study. The campaign started in July 2018 in Spain, Sweden, and Slovenia; in In total, 23,565 euros were invested to generate traffic to the landing pages of the study centers. This figure results from multiplying the cost of each ad (which varies) by the number of individuals that clicked on the ad who were redirected to the landing pages (i.e., traffic). Of note, throughout the campaign >15 million individuals were exposed to the ads while surfing the web, irrespective of whether they clicked on it or not. The distribution of traffic sources in each site (Table 1) has a great impact on the costs of the campaign, as well as the market price of these ads in the different locations. The distribution of the cost of the different strategies also differed by country ( Figure S2 . Also, we found that while females comprised more than two thirds of all participants from Slovenia, in Spain there were slightly more males than females (Table 2 ). We also observed that Individuals who reached the landing page via Facebook ads tended to be younger, and more frequently of female sex than those recruited via Google display ads, Adwords, or those from unpaid traffic sources (Table S2 in supporting information) . When the size of the target population was considered, we found that in Slovenia, the campaign was able to achieve a complete prescreening in 456 of every 100,000 individuals in the target population. The corresponding estimates for Spain, Sweden, the Netherlands, and Germany were 60, 42, 19, and 3 pre-screened patients per 100,000 individuals, respectively. We were able to explore the factors associated with completing the pre-screening. As seen in Table 3 , compared to those aged below 70 years, older age groups were between 20% and 40% more likely to complete the pre-screening, while sex and education did not seem to have an effect. Individuals recruited via Facebook were more likely to According to the results of the pre-screening, a total of 547 individuals were at risk of dementia (36.8%). As seen in Table 4 , older age and lower education were the most important predictors of a positive screening. Traffic source and country of origin did not seem to be associated with the screening result. Details on the results of the screening tests have been reported in a previous communication. 19 A subset of all individuals with a positive pre-screening could be contacted and evaluated in the memory clinic to confirm or discard this result (n = 91, 16.7%). We found that those aged 70 to 74 years and those from Sweden were more likely than others to be evaluated in the memory clinic (Table S3 in The results of this study show that web-based pre-screening campaigns targeting the elderly population represent a valid method to identify individuals with MCI or prodromal AD that could possibly have remained undiagnosed or be diagnosed at a later stage. Timely diagnosis is crucial because it grants patients and their families access to counseling and social support, and promotes clinical research aimed at finding a definitive cure for this devastating disease. Our study found that more than one half of those individuals with a positive pre-screening result were confirmed as MCI/AD in a clinical diagnostic evaluation performed at specialized memory clinics. It is important to note that the validity of this online pre-screening tool was similar irrespective of age. To put this result into context, we should note that the percentage of individuals diagnosed with MCI/AD among par- ticipants of an open-house initiative performed before the MOPEAD study began in one of the study centers was 37%. 20 This result is well below the lower limit of our PPV estimate, even though prevalence among participants on a web-based tool is expected to be lower due to their younger age. It is also important to establish to what extent this initiative, which included a marketing campaign and an online pre-screening tool, was effective in reaching our target population. Online campaigns, including social media such as Facebook, are increasingly being used to recruit individuals to participate in health studies. Most of these studies specifically target young adults or even adolescents, in areas such as human immunodeficiency virus, pregnancy outcomes, etc. 21 However, in instances in which broader populations have been targeted (e.g., smoking cessation trials), 22 from these countries). However, in general, our results suggest that these online strategies can be effective in the elderly, despite the limited use of internet. Furthermore, the effectiveness of these strategies is expected to increase as internet use becomes more common in this population. We should keep in mind that internet use in the elderly has risen rapidly in the last years and will likely continue to grow. Note that in the United States, internet use among the elderly went from 22% in 2004 to 67% in 2016. 24 Thus, the potential of web-based tools to identify individuals at risk and promote early diagnosis of MCI/AD is appreciable. In fact, there are several ongoing initiatives, like the Brain Health Registry, an online study recruiting AD patients but also healthy individuals who are interested in neuroscience research. Participating subjects provide their health and lifestyle information by answering a questionnaire and take periodic online brain tests, which are used to identify potential participants for ongoing clinical trials. 25 The APT Webstudy is another online registry specifically designed to identify individuals who may be at higher risk for developing dementia among patients aged 50 to 85 years who take online tests every 3 months. 26 Finally, the MindCrowd is an online research study in which healthy individuals aged 18 years and older register to take a PAL online test and who might be contacted in a second phase for future memory studies. 27 To enhance the dissemination of these initiatives, marketing campaigns that involve advertising costs are used. In our study, the advertising cost per visit to the landing page ranged between 0.20 and 0.46 euros depending on the country and the proportion of paid traffic. Our ability to translate these visits into study subjects that complete the pre-screening process determines the cost-effectiveness of the strategy. We were successful in doing so in Spain, Sweden, and especially in Slovenia. However, we were not in Germany and the Netherlands. While the campaigns were relatively successful in attracting peoples' attention in these countries (in fact, Germany was the second country in number of visits), the additional steps required clearly discouraged participation in the study. Therefore, one of the conclusions of this study is that these initiatives will not be effective when the burden of participation in these online pre-screening tools is excessive, as reflected by the cost per individual completing the pre-screening in the Netherlands and especially in Germany. Also, we noted that the Facebook campaign led to higher participation rates than others, and this should be considered for future initiatives. Furthermore, we learned that to be successful these strategies should be able to adapt the prescreening tool and web-based referrals system to the logistics, health policies, and cultural idiosyncrasies of local memory clinics. Our study has some limitations. Comparing the effectiveness of the campaign in the different countries, our traffic sources, we should keep in mind the dynamic nature of the campaign, with changes mainly driven by costs and performance. Also, internet use among the elderly is not equal across participating countries. Interestingly the countries where the initiative was more successful, Spain and Slovenia, have the lowest estimated use of internet among the elderly (28% and 31%, respectively) which emphasizes the great performance of the campaign in these two countries. 23 Along these lines, it is important to note that study participants do not comprise a sample representative of all individuals aged 65 to 85 years for many reasons. Clearly those with memory complaints will be more likely to search for dementiarelated information on the internet and therefore to participate in the study. Furthermore, individuals who regularly use the internet differ in many ways (e.g., age, sex, and education) from those who do not. However, we should point out that our study does not intend to estimate the prevalence of impaired cognition in the general population, but to assess the ability of this webtool to identify individuals at high risk of dementia among study participants. Another limitation is that the platform used to administer the cognitive tests is not available in mobile phones, which represent a large percentage of devices used by the target population. Future initiatives should consider using mobile phonecompatible platforms to avoid this problem. Finally, given the observational nature of our study we cannot assume that all new diagnoses identified during the study are a direct consequence of this initiative, as some individuals could have been diagnosed at some point even if they had not participated in the study. In summary, the results of the study confirm the validity of this online method to identify MCI and early AD cases. Furthermore, we open-house initiative in the same participating memory clinics, a primary care-based strategy, and a tertiary care-based strategy through diabetes clinics) will allow us to contextualize these results and determine whether one strategy should be favored over the others. World Alzheimer report 2015: the global impact of Dementia | Alzheimer's disease international Dementia: a global health priority -Highlights from an ADI and World Health Organization report Timely diagnosis for Alzheimer's disease: a literature review on benefits and challenges Testing the right target and right drug at the right stage Factors affecting timely recognition and diagnosis of dementia across Europe: from awareness to stigma Diagnosis and disclosure of dementia-a comparative qualitative study of Irish and Swedish General Practitioners Patient engagement: the fundació ACE framework for improving recruitment and retention in Alzheimer's disease research The MOPEAD project: advancing patient engagement for the detection of "hidden" undiagnosed cases of Alzheimer's disease in the community Evaluating the process of online health information searching: a qualitative approach to exploring consumer perspectives A comparative study of visuospatial memory and learning in Alzheimer-type dementia and parkinson's disease Early detection and differential diagnosis of Alzheimer's disease and depression with neuropsychological tasks Using voxel-based morphometry to examine the relationship between regional brain volumes and memory performance in amnestic mild cognitive impairment Hippocampal dysfunction in patients with mild cognitive impairment: a functional neuroimaging study of a visuospatial paired associates learning task. Neuropsychologia Association between CSF biomarkers, hippocampal volume and cognitive function in patients with amnestic mild cognitive impairment (MCI) Characterization of cognitive function with the cantab in individuals with amnestic mild cognitive impairment in relation to hippocampal volume, amyloid, and tau status: preliminary baseline results from the PharmaCog/european-ADNI study Normative data from linear and nonlinear quantile regression in CANTAB: cognition in mid-to-late life in an epidemiological sample The Clinical Dementia Rating (CDR): current version and scoring rules P4-603: interim analysis of online screening as a recruitment strategy for the models of patient engagement in Alzheimer's disease (mopead) initiative. Alzheimer's Dement Influence of sampling and recruitment methods in studies of subjective cognitive decline Recruiting for health, medical or psychosocial research using Facebook: systematic review Exploring the viability of using online social media advertising as a recruitment method for smoking cessation clinical trials A review of Internet use among older adults Alzheimer Prevention Trials (APT) Webstudy. n.d This project has received funding from the Innovative Medicines Ini- Laura Campo is a full-time employee of Eli Lilly Italia S.p.A. and shareholder of Eli Lilly. Additional supporting information may be found online in the Supporting Information section at the end of the article.