RESEARCH ARTICLE The Barcelona Brain Health Initiative: Cohort description and first follow-up Gabriele Cattaneo ID1,2*, David Bartrés-Faz1,3, Timothy P. Morris1,4, Javier Solana Sánchez ID1,2, Dı́dac Macià1,3, Josep M. Tormos1,2, Alvaro Pascual-Leone1,5 1 Institut Guttmann, Institut Universitari de Neurorehabilitació adscrit a la UAB, Badalona, Barcelona, Spain, 2 Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain, 3 Departament de Medicina, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, Barcelona, Spain, 4 Berenson-Allen Center for Noninvasive Brain Stimulation, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States of America, 5 Hinda and Arthur Marcus Institute for Aging Research, Hebrew SeniorLife, a1111111111 Harvard Medical School, Boston, MA, United States of America a1111111111 a1111111111 * gcattaneo@guttmann.com a1111111111 a1111111111 Abstract The Barcelona Brain Health Initiative is a longitudinal cohort study that began in 2017 and aims to understand and characterize the determinants of brain health maintenance in middle OPEN ACCESS aged adults. A cohort of 4686 individuals between the ages of 40 and 65 years free from any Citation: Cattaneo G, Bartrés-Faz D, Morris TP, neurological or psychiatric diseases was established, and we collected extensive demo- Solana Sánchez J, Macià D, Tormos JM, et al. (2020) The Barcelona Brain Health Initiative: Cohort graphic, socio-economic information along with measures of self-perceived health and life- description and first follow-up. PLoS ONE 15(2): styles (general health, physical activity, cognitive activity, socialization, sleep, nutrition and e0228754. https://doi.org/10.1371/journal. vital plan). Here we report on the baseline characteristics of the participants, and the results pone.0228754 of the one-year follow-up evaluation. Participants were mainly women, highly educated, and Editor: Stephen D. Ginsberg, Nathan S Kline with better lifestyles compared with the general population. After one year 60% of partici- Institute, UNITED STATES pants completed the one-year follow-up, and these were older, with higher educational level Received: July 26, 2019 and with better lifestyles in some domains. In the absence of any specific interventions to- Accepted: January 22, 2020 date, these participants showed small improvements in physical activity and sleep, but Published: February 11, 2020 decreased adherence to a Mediterranean diet. These changes were negatively associated with baseline scores, and poorer habits at baseline were predictive of an improvement in life- Copyright: © 2020 Cattaneo et al. This is an open access article distributed under the terms of the style domains. Of the 2353 participants who completed the one-year follow-up, 73 had been Creative Commons Attribution License, which diagnosed with new neurological and neuropsychiatric diseases. Changes in vital plan at fol- permits unrestricted use, distribution, and low-up, as well as gender, sleep quality and sense of coherence at baseline were shown to reproduction in any medium, provided the original be significant risk factors for the onset of these diagnoses. Notably, gender risk factor author and source are credited. decreased in importance as we adjusted by sleep habits, suggesting its potential mediator Data Availability Statement: All relevant data are effects. These findings stress the importance of healthy lifestyles in sustaining brain health, within the paper and supporting information files. and illustrate the individual benefit that can be derived from participation in longitudinal Funding: The research leading to these results has observational studies. Modifiable lifestyles, specifically quality of sleep, may partially medi- received funding from “la Caixa” Foundation (grant agreement n˚ LCF/PR/PR16/11110004), and also ate the effect of other risk factors in the development of some neuropsychiatric conditions. from Institut Guttmann and Fundació Abertis. David Bartrés-Faz was funded by the Spanish Ministry of Economy and Competitiveness (MINECO; PSI2015-64227-R) and the Spanish Ministry of Science, Innovation and Universities (RTI2018-095181-B-C21) research grants. Josep PLOS ONE | https://doi.org/10.1371/journal.pone.0228754 February 11, 2020 1 / 22 The Barcelona Bain Health Initiative follow-up M. Tormos was partly supported by INNOBRAIN Introduction (COMRDI15-1-0017). Ad-Salutem Institute, Sodexo S.A., I.C.A Informática y Comunicaciones The World Health Organization (WHO) makes it plain: “Neurological and mental disorders Avanzadas, Neuroelectrics, Corporació Catalana de are the greatest threat to public health”, and it projects that they will be responsible for over Mitjans Audiovisuals, Club Metropolitan, Casa half of the world-wide economic impact of disability by 2050. Unless we develop interventions Ametller, and Agència de Qualitat i Avaluació to minimize the impact of emotional distress, learning disabilities, cognitive decline, brain and Sanitàries de Catalunya-AQuAS are commercial mental illnesses, society will face an unsurmountable crisis. Therefore, sustaining brain health companies supporting the Barcelona Brain Health Initiative and this study. The funders had no role in and reducing the impact of neurological and psychiatric diseases is arguably the greatest chal- study design, data collection and analysis, decision lenge of biomedical research for the 21st century. Indeed a systematic review of the literature to publish, or preparation of the manuscript. reveals that if one were to identify a cohort of healthy individuals between 40 and 65 years of Competing interests: We have the following age, over the course of a decade, 26% would become diagnosed with neurological or psychiat- interests: Dr. A. Pascual-Leone serves on the ric diseases [1](see Fig 1). scientific advisory boards for Neuronix, Starlab Among the younger group, particularly women might be expected to be diagnosed with Neuroscience, Neuroelectrics, Magstim, depression [11,12], while among the older group, mild cognitive impairment and dementia Magventure, Constant Therapy, and Neosync; and would be predicted to be the most common diagnoses [2,4,6]. is listed as an inventor on several issued and pending patents on the real-time integration of A growing number of studies have investigated the mechanisms contributing to the preser- transcranial magnetic stimulation with vation of brain structure and function, cognitive performance, and mental wellbeing, as well as electroencephalography and magnetic resonance the role of compensation in the face of injury or disease [13,14]. There is increasing evidence imaging: 1. Method and Apparatus for Recording that some dietary patterns, leisure activity, cognitive stimulating activity, physical activity, as an Electroencephalogram During Transcranial well as other social and psychological activities can promote brain health maintenance and are Magnetic Stimulation. US 6,266,556 B1. associated, for example, with lower risk of dementia (see [15] for a systematic review). Living- (Application 09/067,111; filed Apr 27, 1998) 2. Method and Apparatus for Monitoring a Magnetic stone and collaborators suggested that even beyond the biological or genetic predisposition Resonance Image During Transcranial Magnetic (e.g. Apoe4 allele), dementia could be prevented in up to 35% of the cases through improved Stimulation. US 6,198,958 B1. (Application 09/ control of medical conditions such as hypertension, obesity and diabetes, and attention to 096,725; filed Jan 11, 1998) 3. Method and modifiable risk factors such as education, smoking, physical activity and socialization. Recent Apparatus for Recording an Electroencephalogram interventional studies support this view and suggest that multi-domain lifestyles interventions During Transcranial Magnetic Stimulation.US 6,571,123 B2.(Application 09/746,055; filed Dec may improve mental and cognitive functioning, and be particularly effective in people at risk 21, 2000; prior publication data US 2002/0007128 [16]. Thus, modifiable and non-modifiable factors may interact and ultimately either increase A1 Jan 17, 2002) 4. A. Pascual-Leone And T. Wagner. Transcranial Magnetic Stimulation (TMS) Methods and Apparatus.US 2010/0113959 A1. (Application 10/731892; filed Dec 9. 2003) 5. System and Methods for Applying Signals, Including Contralesional Signals, to Neural Populations. US 2007/0288072 A1. (Application 11/697,696l filed Apr 6, 2007) 6. Transcranial Magnetic Stimulation Methods and Apparatus. US 2010/0210894 A1 2007 Dec 1. 7. Method and System for Safely Guide Interventions in a Procedure where the Substrate is Neural Plasticity. (International Application PCT/ES2008/000677; filed Oct 31, 2008; corresponding US Application US 2011213213. 8. Methods for treating and/or collecting information regarding neurological disorders, including language disorders. US 7,565,199 B2. (Application 10/731,892; filed Dec 9, 2003; provisional application 60/432,073; filed Dec 9, 2002) 9. Method and System for Treating Amblyopia. US 13/200,080. (UR 1-11030- 10035; filed Sept 16, 2010) 10. Non-invasive methods for evaluating cortical plasticity impairments. US 2011/ Fig 1. Graphical representation of the expected survival curve of the cohort for neurological and psychiatric 0224571 A1 (Application 12/947491; filed Nov 16, diseases, based on epidemiological data [1–10]. 2010) 11. Methods for treating and/or collecting https://doi.org/10.1371/journal.pone.0228754.g001 PLOS ONE | https://doi.org/10.1371/journal.pone.0228754 February 11, 2020 2 / 22 The Barcelona Bain Health Initiative follow-up information regarding neurological disorders, or decrease an individual’s risk to develop dementia and other neurological or psychiatric con- including language disorders. US 08050767. ditions [15, 17–19]. (Application 11/935135; filed November 5, 2007) The Barcelona Brain Health Initiative (BBHI) is a longitudinal cohort study started in 2017 12. Device for treating human vision using combined optical and electrical stimulation. with the aim to understand and characterize biological, behavioral and environmental mark- (Application 12/883,423; filed Sep 16, 2010; ers, and their interactions, related with brain health maintenance in middle to old age [1]. In provisional application 60/886,073; filed Jan 22, the first phase of the study, participants completed questionnaires that collected information 2007) 13. A Method for Treating Neuropathic Pain. about socio-demographic, socio-economic, and lifestyles relevant to brain health. We hypothe- (Application 13/197,883; filed Aug 4, 2011) 14. sized that participation in the study might increase awareness of the importance of healthy life- Identification of optimized therapeutic TMS targets for depression based on functional connectivity styles, improving adherence. Here we 1) report baseline characteristics of the cohort and MRI (USSN provisional application 61/648,032 analyze the changes on lifestyles measures after one year of participation in the study, and 2) filed May 16, 2012) 15. System and Method for identify participants who developed new neurological and psychiatric diagnoses and identify Treating Neuropathic Pain. (Application risk factors that contributed to them. EP12380025; filed May 18, 2012) 16. Transcranial magnetic stimulation (TMS) methods and apparatus.- US Patent 20,130,338,424, 2013 17. A Material and methods method and a system for optimizing the configuration of multisite Transcranial current Participants stimulation and a computer-readable medium. US BBHI study participants are community-dwelling individuals, between 40 and 65 years, free nº 14/058,517 (Filed Oct 21, 2013) 18. Identifying from any self-reported neurological or psychiatric diagnosis at the time of recruitment [1]. Individual Target Sites for Transcranial Magnetic Stimulation Applications. Application Number 14/ Participants were recruited by an intensive dissemination and communication campaign 401,296; Filed November 14, 2014. However, their made through different media (TV, radio, newspapers) as well as the most common social potential field of exploitation is not related with the media platforms (Facebook, Twitter, etc.). The engagement of well-known opinion leaders content of the manuscript. Josep M. Tormos is a from the sports, journalism or acting world, who recorded short videos describing the study listed co-inventor in the following patents: 1. A and thus served as ambassadors for the initiative, helped increase the visibility and contributed method for treating neuropatic pain (US 13/ to the recruitment. 197,883) 2. Method and system to safely guide interventions in procedures the substrate whereof People interested in the study enrolled online through the website of the project (https:// is neural plasticity (PCT/ES2008/000677) However, bbhi.cat) by filling out an initial contact form. Upon confirmation of their email, they gave on- he has no ownership of the industrial property for line informed consent to the study which had been approved by the Institutional Review those patents nor is their potential field of Board of the Institute Guttmann neurorehabilitation hospital. Thereafter participants created exploitation related with the content of the their personal profiles and completed an initial on-line questionnaire. manuscript. Ad-Salutem Institute, Sodexo S.A., I.C. A Informática y Comunicaciones Avanzadas, A total of 4,686 participants, mean age = 53.2 years fulfilled inclusion criteria and com- Neuroelectrics, Corporació Catalana de Mitjans pleted the initial online questionnaire. Audiovisuals, Club Metropolitan, Casa Ametller, and Agència de Qualitat i Avaluació Sanitàries de Catalunya-AQuAS are commercial companies Baseline evaluation supporting the Barcelona Brain Health Initiative and Following the initial questionnaire (see Table 1), which had been validated as reported in Cat- this study. There are no further patents, products in taneo et al. 2018, participants were asked to complete several additional validated question- development or marketed products to declare. This does not alter our adherence to all the PLOS ONE naires on-line (between July and December 2017) to further explore their self-perceived policies on sharing data and materials. Table 1. Initial questionnaire administered at enrollment. Self-perceived General PROMIS [22] Health Self-perceived Mental PHQ-4 [23] Health Cognitive Complaints Neuro-Qol [24] Physical activity Physical Activity Questionnaire (PAQ) Sleep Jenkins Sleep Evaluation Questionnaire (JSEQ, [25]) Nutrition Mediterranean Diet Adherence screener (MeDas; [26] Vital Plan Personal growth and Purpose in life subscales of Ryff’s scale of Psychological well- being [27] https://doi.org/10.1371/journal.pone.0228754.t001 PLOS ONE | https://doi.org/10.1371/journal.pone.0228754 February 11, 2020 3 / 22 The Barcelona Bain Health Initiative follow-up Table 2. Subsequent questionnaires characterizing various lifestyle domains. Cognitive Reserve Cognitive Reserve Questionnaire (CRQ, [28]) Physical Activity Godin Leisure Time Physical Activity Questionnaire (GLTPAQ, [29]) Vital Plan The Engaged Living Scale (ELS;[30]) Subjective Self Health Horizon Questionnaire (SHH-Q,[31]) Sense of Coherence scale (SOC; [32]) Ryff scale of Psychological well-being [27] Socialization Lubben Social Network Scale (LSNS; [33]) Sleep Pittsburg Sleep Quality index (PSQI; [34]) Emotional Health Depression Anxiety and Stress Scale (DASS; [35]) Quality of Life The World Health Organization Quality of Life Assessment (WHOQOL-AGE, [36]) Hand dominance Edinburgh Handedness Inventory (EHI, [37]) Bilingualism Questionnaire of bilingualism and multilingualism (BIL, [38]) https://doi.org/10.1371/journal.pone.0228754.t002 quality of life and health, their engagement in cognitive activities, physical activities and social- ization, their habits in nutrition and sleep, their psychological well-being and vital plan, as well as other information (see Table 2). To evaluate Vital plan we consider in particular three dimensions that composed the con- struct of “Meaning in Life”: sense of coherence, purpose in life and engagement with life [20]. The first is a cognitive component, consisting of the ability to make sense of our experiences, the second is motivational and is about having a goal in life, while the third is an affective com- ponent related with satisfaction with life (see [21]). One year follow-up evaluation In November 2018 we conducted a first follow-up evaluation, re-administering the initial questionnaires, with some components expanded (see Table 3). Feedback provided to participants An important methodological aspect of the BBHI is that after completing every questionnaire, participants receive a graphic feedback of their responses as they relate to each one of the areas defined as “brain health pillars”: cognitive function, physical activity, sleep, nutrition, Table 3. Questionnaires administered for the 1-year follow-up. Self-perceived General PROMIS [22] Health Self-perceived Mental PHQ-4 [23] Health Cognitive Complaints Neuro-Qol [24] Physical activity PAQ, International Physical Activity Questionnaire (IPAQ,[39]) Cognitive reserve CRQ [28] Sleep JSEQ [25], STOP-Bang questionnaire [40], Single question RBD [41] Socialization LSNS [33], UCLA Loneliness scale [42] Nutrition MeDas [26] Vital Plan Personal growth and Purpose in life subscales of Ryff’s scale of Psychological well- being [27], Meaning in life questionnaire [43] Alcohol Consumption AUDIT [44] Smoking Pack-year index https://doi.org/10.1371/journal.pone.0228754.t003 PLOS ONE | https://doi.org/10.1371/journal.pone.0228754 February 11, 2020 4 / 22 The Barcelona Bain Health Initiative follow-up socialization and purpose in life [1]. Moreover we periodically publish in our web page tips and news related with brain health and healthy lifestyles in these domains. At the follow-up evaluation participants were given feedback providing the same graphical representation of 6 circle graphs, one for each brain health pillar, but representing now the percentile they occupy when compared with the rest of the BBHI participants of the same gen- der and age bracket (± 5 years; Fig 2). In addition, participants are provided a second form of feedback of their changes over time (Fig 3), where each bar represents the translated score from 0 to 10 for each pillar, so users can easily compare their evolution (inside each bar the date when users responded is shown). Data and statistical analysis Data analysis was performed in consecutive steps. First, a descriptive analysis of the baseline characteristics of all cohort participants was completed. We also explored the association between baseline lifestyles and other medical conditions we ran Spearman correlation and binomial logistic regression analyses. Fig 2. Position of participants respect to other similar participants. https://doi.org/10.1371/journal.pone.0228754.g002 PLOS ONE | https://doi.org/10.1371/journal.pone.0228754 February 11, 2020 5 / 22 The Barcelona Bain Health Initiative follow-up Fig 3. An example of a participant’s change in lifestyle adherence over time: comparison of responses in the first wave of questionnaires and at the follow-up. https://doi.org/10.1371/journal.pone.0228754.g003 To test if there were any differences in baseline scores between those participants who did or did not complete the one-year follow up we used two-sample t test and Chi-squared statis- tics. Third, we assessed possible changes between baseline and follow-up using paired t tests. Next, to explore whether baseline characteristics were predictive of changes over time for each of our variables of interest we regressed its change over time (one-year follow up score— baseline score) on its baseline score. To correct for “regression to the mean”, due to intrinsic noisy nature of the data collecting instruments, we re-ran linear regressions using the changes (subtraction between follow-up and baseline) as dependent variables and the mean between first and second questionnaires’ scores as predictors (after after checking for variance homoge- neity; [45,46]. PLOS ONE | https://doi.org/10.1371/journal.pone.0228754 February 11, 2020 6 / 22 The Barcelona Bain Health Initiative follow-up Finally, to assess the associations between lifestyle and sociodemographic variables and the development of a new neurological of psychiatric diagnosis multiple binomial logistic regres- sion was performed. We report the relative risk as beta coefficients with 95% confidence inter- vals. We additionally performed mediation analysis to determine whether modifiable risk factors mediated the putative effects of non-modifiable factors on a new diagnosis applying Hayes’s mediation model (model 4 [47]) using the PROCESS tool for SPSS [48]. Statistical analyses were performed using SPSS version 20.0 (Statistical Package for Social Sciences, Chi- cago, IL, USA). Results Baseline characterization of the cohort The socio-demographic characteristics of the BBHI cohort are summarized in Table 4. As noted in [1], women (biological sex) are over-represented (66.8% v.s 50.9%), and participants have a higher educational level than the general population of Catalonia (71,7% v.s 41.2%). People living alone are underrepresented (14.0% v.s 23.3%) while other living situations are in line with those of the general population. Occupational status is consistent with the full popu- lation of people of the same age in Catalonia (data from the Statistical Institute of Catalonia; www.idescat.cat), as well as living town situation. Baseline lifestyles Participants performed on average 2 hour of moderate to vigorous aerobic activity per week and only 5.3% of participants showed low adherence to Mediterranean diet; the whole cohort showed a medium to high adherence (mean ± standard deviation = 8.8 ± 2.0) to it. Scores on the Jenkins Sleep Evaluation Questionnaire (8.5 ± 3.8) and Pittsburg Sleep Quality Index (5.7 ± 2.9) indicate a slight trend to poor sleep quality [34]. Socialization instead was quite high (36.1 ± 9.0) and far from the “clinical” risky cut-off of 20 [33]. When we looked at the dis- tribution of scores in Sense of coherence (66.2 ± 11.3), Engagement with life (61.0 ± 9.2) and Ryff psychological well-being (151.4 ± 19.6) only 3-to-3.5% of participants showed scores below mean– 2 standard deviations. Baseline lifestyles and medical conditions When we explored the relation between baseline lifestyles we found significant associations between all of them (all p values �0.01), even if physical activity and adherence to Mediterra- nean were weekly associated to other lifestyles (see Fig 4). Moreover we found that less physical activity and lower sleep quality, measured both with the Jenkins Sleep Evaluation Questionnaire and Pittsburg Sleep Quality Index, were associated with the presence of other medical conditions than neurological and psychiatric ones (see Table 5). The medical conditions we consider for the analysis were: Hypertension, hearth problems or heart attack, hypercholesterolemia, diabetes, chronic pain, hepatitis, cirrhosis, pancreatic problems, sleep apnea, arthritis, chronic nephritis or cancer. 1-year follow-up responders’ profile Of the 4686 participants who completed the baseline set of questionnaires, 2357 completed the one-year follow-up assessment (50%). Participants who complete the one-year follow up questionnaire were older (53.8 ± 6.7; t = -5.70, p<0.001, d = 0.17) compared with those who did not (mean age ± standard PLOS ONE | https://doi.org/10.1371/journal.pone.0228754 February 11, 2020 7 / 22 The Barcelona Bain Health Initiative follow-up Table 4. Socio demographic characteristics of participants broken for biological sex. Men Women Total Mean (SD) Mean (SD) Mean (SD) Age (years) 53.8 (7.0) 53.0 (6.7) 53.2 (6.8) Men Women Total N % N % N % Participants 1555 33,2 3131 66,8 4686 100,0 Marital status Married 1051 67,6 1813 57,9 2864 61,1 Separated/Divorced 229 14,7 592 18,9 821 17,5 Widowed 15 1,0 84 2,7 99 2,1 Never married 260 16,7 642 20,5 902 19,2 Living status Alone 200 12,9 454 14,5 654 14,0 With partner without children 363 23,3 630 20,1 993 21,2 With partner and children 849 54,6 1513 48,3 2362 50,4 With children without partner 64 4,1 386 12,3 450 9,6 With parents 29 1,9 45 1,4 74 1,6 Others 50 3,2 103 3,3 153 3,3 Educational status No studies 1 0,1 0 0,0 1 0,0 Primary 73 4,7 128 4,1 201 4,3 Secondary 437 28,1 689 22,0 1126 24,0 Higher 1044 67,1 2314 73,9 3358 71,7 Occupational status Retired 145 9,3 202 6,5 347 7,4 Unemployed 92 5,9 297 9,5 389 8,3 Part-time 97 6,2 360 11,5 457 9,8 Full-time 1221 78,5 2272 72,6 3493 74,5 Type of work Unqualified manual 50 3,2 92 2,9 142 3,0 Qualified manual 370 23,8 795 25,4 1165 24,9 Professional 369 23,7 1015 32,4 1384 29,5 Manager 529 34,0 730 23,3 1259 26,9 Household monthly income Less than 1,000€ 52 3,3 132 4,2 184 3,9 Between 1,000 and 2,000 € 263 16,9 766 24,5 1029 22,0 Between 2,000 and 5,000 € 938 60,3 1782 56,9 2720 58,0 More than 5,000 € 302 19,4 451 14,4 753 16,1 Living town Small town (less than 2,000 inhabitants) 66 4,2 158 5,0 224 4,8 Town (less than 20,000 inhabitants) 346 22,3 665 21,2 1011 21,6 City (more than 20,000 inhabitants) 572 36,8 1032 33,0 1604 34,2 Big city (more than 500,000 inhabitants) 571 36,7 1276 40,8 1847 39,4 https://doi.org/10.1371/journal.pone.0228754.t004 deviation = 52.7 ± 6.8) and more educated (t = 4.34, p<0.001, d = 0.13), while there were no differences in the gender distribution (X2 = 0.01; p = 0.951). Completers reported better self-perceived emotional (t = 4.78, p<0.001, d = 0.14) and cog- nitive health (t = 3.86, p<0.001, d = 0.11) at baseline. Furthermore, individuals completing the PLOS ONE | https://doi.org/10.1371/journal.pone.0228754 February 11, 2020 8 / 22 The Barcelona Bain Health Initiative follow-up Fig 4. Graphical representations of the correlation’s strength between different lifestyles at baseline. Numbers in the table are ρ coefficients. https://doi.org/10.1371/journal.pone.0228754.g004 follow-up evaluation reported at baseline more physical activity (t = 2.61, p = 0.009, d = 0.08), engagement with life (t = 3.27, p = 0.001, d’ = 0.10) and higher sense of coherence scale scores (t = -3.63, p<0.001, d = 0.12; see Fig 5). 1-year follow up For the participants who completed the one-year follow-up assessment, self-reported lifestyles showed improvements in physical activity (t = -2.27, p = 0.023, d’ = 0.07) and quality of sleep (t = 4.37, p<0.001, d’ = 0.09) while nutrition worsened in the follow-up as compared with baseline (t = 17.14, p<0.001, d’ = 0.30; see Fig 6). However, some of these statistical significant differences were very small in effect size and thus should be interpreted carefully. No change was seen in any of the other questionnaires. We observed that individuals with lower scores at baseline across the different question- naires, tended to exhibit better lifestyle habits (i.e. higher scores) at follow-up. This tendency was however inverted for those with higher ratings at baseline (see Table 6 below). Waterfall plots in Fig 7 represent follow–up changes (y axis) in function of baseline scores (x axis). Bars represent the larger positive and negative change for every baseline score of participants. PLOS ONE | https://doi.org/10.1371/journal.pone.0228754 February 11, 2020 9 / 22 The Barcelona Bain Health Initiative follow-up Table 5. Multiple logistic binomial regression using any medical condition (not neurological or psychiatric) as dependent variable, lifestyles at baseline as independent variables, and gender and age as covariates. Reported val- ues are standardized beta coefficients. Variable B (C.I. 95%) p Physical activity�� 0.95 (0.93–0.97) <0.001 � �� � Sleep quality (JSEQ) 1.04 (1.02–1.07) <0.001 �� � Sleep quality (PSQI) 1.06 (1.03–1.09) <0.001 Mediterranean diet adherence�� 0.99 (0.96–1.03) Engagement with Life�� 1 (0.99–1.01) �� Sense of coherence 1 (0.99–1.01) Purpose in Life�� 1 (0.98–1.02) Cognitive reserve�� 1 (0.98–1.02) Emotional health�� 1 (0.98–1.02) Socialization�� 1.01 (1.00–1.01) � Age 1.11 (1.10–1.12) <0.001 � Gender 0.6 (0.51–0.70) <0.001 � C.I. which do not include 1 are considered statistically significant �� Data were recollected with questionnaires reported in Table 2. https://doi.org/10.1371/journal.pone.0228754.t005 When we tried to correct for regression to the mean we confirmed that in the domains of nutrition and purpose in life people with worse habits at baseline were those who made greater improvements at the one year follow-up, and the opposite was true for those with better habits at baseline (see Table 7 below). New neurological and psychiatric diagnoses at one year follow-up At the one-year follow up assessment we asked participants for new medical conditions that had been diagnosed by their physicians during the last year, since their enrollment in the proj- ect and the completion of the initial survey. Of the 2353 people who responded to the follow-up survey 73 people (3.1%) reported hav- ing been given a formal new diagnosis of neurological or psychiatric condition by their physi- cians (Table 8). As expected for our cohort characteristics, and in line with current epidemiological literature (Ferrari et al., 2013), the most frequent new diagnosis was major depression (76.7%). Also noteworthy are mild cognitive impairment or dementia (8.2%), and Parkinson’s disease (5.5%). Gender (Specifically woman), poor sleep quality and lower sense of coherence at baseline carried significant relative risks for the development of depression (Table 9). In addition, Table 10 shows the relative risk of the change in modifiable lifestyle factors and the emergence of depression. A change in one’s vital plan was significantly associated with a reduced risk of developing a new diagnosis. The mediator effect of modifiable lifestyles over non-modifiable risk factors To investigate the relation between modifiable and non-modifiable risk factor on new diagno- sis of depression we applied mediation models. A preliminary regression and found that gen- der was not related with sense of coherence (p = 0.95), and so no mediation model was performed on these variables. PLOS ONE | https://doi.org/10.1371/journal.pone.0228754 February 11, 2020 10 / 22 The Barcelona Bain Health Initiative follow-up Fig 5. Comparison of baseline lifestyles scores (y axis) of participants who did and did not complete the follow-up (x axis) in a) Emotional health, b) Cognitive health, d) Physical activity, e) Engagement with life, and e) Sense of coherence. https://doi.org/10.1371/journal.pone.0228754.g005 A second analysis revealed that sleep quality significantly and partially mediated the associ- ation between gender and the development of new diagnosis of depression after one year (95% CI, 0.06–0.18; Fig 8). Discussion Over the course of the one-year follow-up we found that older participants, with more educa- tion and better lifestyle habits were more likely to continue to engage with the study. Of those who completed the one-year follow-up, physical activity and quality of sleep improved, whereas adherence to Mediterranean diet decreased. Those with lower baseline scores improved their habits over time, while those with healthier habits at the beginning tended to decrease their adherence to them. Such an effect of participation in observational longitudinal study on modifiable lifestyles and cognitive and mental wellbeing are important to consider in assessing the impact of possible targeted interventions. When we looked at the relation between new diagnosis, baseline characteristics, and change over one year of study participation, we found that a well-defined vital plan appears to offer some protection for a new diagnosis of depression, while female gender, poor sleep quality and low sense of coherence predicted the onset of a new diagnosis. Of these, sleep appears to PLOS ONE | https://doi.org/10.1371/journal.pone.0228754 February 11, 2020 11 / 22 The Barcelona Bain Health Initiative follow-up Fig 6. Comparison of participant’s score at the different lifestyles surveys at the baseline and after one year in a) Physical activity, b) Sleep complaints (scale is inverted), c) Adherence to Mediterranean diet. Error bars represent standard errors. https://doi.org/10.1371/journal.pone.0228754.g006 mediate the relationship between non-modifiable factors, such as gender, and new diagnoses of depression. Baseline characteristics of the cohort Participants were not representative of the general population for socio-demographic factors and lifestyles, probably due to the study methodology (on-line recruitment). As in other cohort studies women are over-represented and participants have higher educational level than the general population [49]. Also the on-line administration of questionnaires may introduced a bias in cohort representativeness and well as possible confounders/limitations. Participants showed at baseline, on average, a medium to high adherence to healthy life- styles. Their 2 hour of moderate to vigorous aerobic activity per week is in line with the 150 minutes of moderate intensity exercise or 75 minutes of vigorous exercise per week recom- mended by the World Health Organization and the American College of Sports Medicine [50, 51]. Adherence to Mediterranean diet was in general quite high and the proportion of people with low adherence to it was less than half of what found in the Catalan population (13.8%; [52]). Socialization levels (score 36.1) were sufficiently high suggesting that in the total cohort, participants were far from “at risk” for social inactivity or isolation (score <20; [33]). Interest- ingly, sleep quality is the worst reported lifestyles and tended to be poorer than what is recom- mended (score <5 at PSQI 4]. For meaning in life, it is difficult to evaluate the significance of the level of Sense of coherence, Engagement with life and Ryff’s psychological well-being Table 6. Linear regressions between habit changes and baseline scores. Number in table are standardized beta coefficient. Physical activity Socialization Purpose in Life Sleep Nutrition �� �� �� �� -0.40 -0.34 -0.32 -0.44 -0.47�� �� p<0.001 https://doi.org/10.1371/journal.pone.0228754.t006 PLOS ONE | https://doi.org/10.1371/journal.pone.0228754 February 11, 2020 12 / 22 The Barcelona Bain Health Initiative follow-up Fig 7. In the x axis of the waterfall plot baseline scores are reported and in the y axis changes between baseline and the follow-up are reported in the different domains: a) physical activity, b) socialization, c) purpose in life, d) sleep and e) nutrition. https://doi.org/10.1371/journal.pone.0228754.g007 scores of participants quantitatively, considering the absence of precise recommendations in literature. This medium to high adherence to some health related lifestyles of our participants reflect the general tendency culturally related of Catalan/Spanish population. For this reason Barce- lona was an ideal location to study the effect of good lifestyle habits on the maintenance of brain health given a lot of the lifestyle pillars we study are inherent in the culture (diet, exercise, socialization for example). When we explored the relation among lifestyles in the different domains we found a strong relation between all of them. People with healthy lifestyles in one domain showed the same degree of healthy lifestyles also in all the others domains. Finally, when we looked at the relation between lifestyles and medical conditions other than neurological and psychiatric ones we found a clear association between and higher level of physical activity and good quality of sleep with less prevalence of medical diagnosis. Retention challenges Retention at the one-year follow-up is clearly a limitation of the study, and is an important issue to explore. About 50% of the participants who enrolled failed to complete the one-year follow-up survey. Such an attrition rate is not far from previous on-line longitudinal studies [53], but higher than longitudinal studies that applied specific retention strategies trying to Table 7. Linear regressions between habit changes and mean scores (first and second questionnaires). Numbers in table are standardized beta coefficient. Physical activity Socialization Purpose in Life Sleep Nutrition -0.02 -0.02 -0.08�� -0.02 -0.06� � p = 0.003 �� p<0.001 https://doi.org/10.1371/journal.pone.0228754.t007 PLOS ONE | https://doi.org/10.1371/journal.pone.0228754 February 11, 2020 13 / 22 The Barcelona Bain Health Initiative follow-up Table 8. Frequency of participant’s new medical conditions that represent an endpoint for the study. Diagnosis N Depression 56 Alzheimer’s disease or Mild cognitive impairment 6 Parkinson’s disease 4 Stroke 2 Multiple Sclerosis 2 Epilepsy 2 Lateral Amyotrophic Sclerosis 1 Schizophrenia/Psychosis 0 TOT 73 https://doi.org/10.1371/journal.pone.0228754.t008 limit drop-outs [54, 55]. Cohorts characteristics seem to be a crucial factor in modulate reten- tion rates, particularly depending by different study modalities employed. Indeed, highly edu- cated women seem to prefer paper and pencil surveys, compared to on-line versions. However, at follow-up, paper and pencil modality showed lower retention rates compared to the on-line version [56]. These and results from other studies have to be taken into account for this and future on-line cohort studies to implement focused and specific retention strategies to limit drop-outs. “One-year follow-up responders” were older, with higher educational level, and reported at the beginning better self-perceived cognitive and mental health, as well as more physical activ- ity and vital plan. This is in line with what has been found in previous longitudinal studies that showed that low educational level, psychological distress and unhealthy life style factors, like physical inactivity, are associated to attrition [57, 58, 59]. This suggests that people with more interest in health maintenance and healthy lifestyles are those who tend to be more engaged in Table 9. Multiple logistic binomial regression using new diagnosis of depression as dependent variable and base- line characteristics of participants as independent variables. Reported values are standardized beta coefficients. Variable B (C.I. 95%) p Age 1.0 (0.9–1.1) � Gender (Women) 4.8 (1.8–12.4) 0.001 Education 1.2 (0.7–2.0) Employment 1.1 (0.8–1.6) Living in a big town 1.0 (0.7–1.4) Family income 0.8 (0.51.2) �� Emotional complaints 0.9 (0.8–1.0) Cognitive complaints�� 1.0 (0.9–1.1) Physical activity�� 1.0 (0.9–1.1) Socialization�� 1.0 (0.9–1.1) Sleep Quality�� 1.1 (1.0–1.2) 0.006 � �� Mediterranean diet adherence 1.1 (0.9–1.3) Engagement with life�� 1.0 (0.9–1.1) Sense of Coherence�� 0.9 (0.9–1.0) 0.003 � �� Purpose in Life 1.0 (0.9–1.1) � C.I. which do not include 1 are considered statistically significant �� Data were recollected in the first questionnaire and by PHQ-4 [23] NeuroQoL [24], LSNS [33], JSEQ [25], MeDAS [26], EWL [30], SOC [32], PIL [27]. https://doi.org/10.1371/journal.pone.0228754.t009 PLOS ONE | https://doi.org/10.1371/journal.pone.0228754 February 11, 2020 14 / 22 The Barcelona Bain Health Initiative follow-up Table 10. Multiple logistic binomial regression using new diagnosis of depression as dependent variable, lifestyles changes at follow-up as independent variables, and gender and age as covariates. Reported values are standardized beta coefficients. Variable B (C.I. 95%) p Physical activity change 1.0 (0.9–1.1) Socialization changes 1.0 (0.9–1.1) � Purpose in Life changes 0.9 (0.9–1.0) 0.05 Sleep quality changes 1.0 (0.9–1.1) Nutrition changes 0.9 (0.7–1.0) � p�0.05 https://doi.org/10.1371/journal.pone.0228754.t010 such studies, probably unavoidably introducing the observed population bias recruiting and bias follow-up in such studies. One year follow-up When we compared the follow-up data with those acquired at baseline we found that over the course of a year participants slightly changed their habits, improving physical activity and sleep, but worsening their adherence to Mediterranean diet. However, these differences, even if statistically significant, were rather small in effect size. We hypothesize that those partici- pants who already have healthy habits did not change them, considering especially that partici- pants that completed the one-year follow-up showed better lifestyles at baseline. In order to test this we explored the relation between the one year change, as the difference between scores at one-year and at baseline, and the baseline characteristic of participants. Results revealed that participants with worst habits at the beginning are those who improved them the most, while those who already had good lifestyles remained stable or even worsened them. We explored the possibility that these results might have been driven by test-retest variability and a regres- sion to the mean phenomenon [45, 60], rather than from real changes in participant’s habits. However, even after correcting for this [46] we still found a negative association between habits Fig 8. JSEQ score as mediator of the association between gender and new diagnosis of depression at the one-year follow-up. Values are B unstandardized coefficients (� p = 0.001; �� p < 0.001); values within parentheses represent total relationship between Gender and new diagnosis when JSEQ are not take into consideration. https://doi.org/10.1371/journal.pone.0228754.g008 PLOS ONE | https://doi.org/10.1371/journal.pone.0228754 February 11, 2020 15 / 22 The Barcelona Bain Health Initiative follow-up at the beginning of the study and improvement over a year, even though is clearly reduced in the magnitude. These negative associations between habits at baseline and follow-up may be related to difficul- ties in maintaining good habits consistently over-time. This interpretation may have relevance for the implementation of multi-domain interventions aiming for simultaneous optimization of mul- tiple lifestyles. Few studies to date have succeeded in such efforts and the present results may be important to consider in the setting of study design. However this interpretation should be taken with caution since as stated previously, the BBHI participants have continued access to ‘brain tips’ and ‘brain news’ through both the public and personalized dedicated web portals of the project. Therefore and beyond the fact that negative associations between baseline and follow up habit sta- tus may be explained by a ‘regression to the mean’ phenomena, we cannot determine if habits change from baseline to follow-up could rather reflect a ‘natural course’ or the effect of a ‘low level of intervention’, because a control group (i.e. participants assessed both at baseline and at follow up but not participating in the BBHI) was not included in our study. Endpoints analysis The one year follow-up survey revealed that 73 participants had been diagnosed in the last year with one of the neurological or neuropsychiatric condition that represents an endpoint for the study. This represents slightly over 3% incidence of new diagnoses for the cohort of previously healthy 40–65 year olds, which is in line with the statistical estimation that we made based on Spanish available epidemiological data for these diseases (Fig 1, [1–10]). Moreover, in line with recent epidemiological reviews [61] and considering the age-range and the high proportion of women in the cohort, the most incident condition was major depression (76.7% of all reported new diagnoses; [1–10]. We explored the relation between lifestyles and participants characteristics and the inci- dence of a new diagnosis of depression. First, we looked at the association between habit changes over the year and diagnosis and we found that increased purpose in life represented a protective factor. Purpose in life is a psychological construct that represent the notion of having a sense of goal and future oriented behavior that may confer more capacity to manage and tolerate changes and demanding temporal situations. Purpose in life is one of the six components of Carol D. Ryff’s prevalent model [62], along with autonomy, personal growth, environmental mastery, positive relationships, and self-acceptance. It has been previously related with biologi- cal risk factors such as inflammatory markers [63], cardiovascular diseases [64], and other health related outcomes [65]. Purpose in life has been also related with cognitive function in healthy adults, mortality, and to the risk of Alzheimer’s disease (AD) and mild cognitive impairment (MCI; [66, 67, 68, 69]). Second we explored if certain baseline modifiable and non-modifiable condition may rep- resent a risk or protective factor. Results revealed that women were at higher risk for diagnosis of depression (see Table 6), while higher levels of sleep quality and Sense of coherence repre- sent protective factors to develop this condition. Considering that almost 80% of the diagnosis was depression these results are not surprising. There is consistent evidence in literature sug- gesting that women are twice as likely to develop depression that man [11, 12], and also sense of coherence and sleep have been previously associated with depression [70, 71]. The role of gender as a risk factor for depression has been related to the more stressful role of women in society and the resulting lower degrees of fulfillment, and the greater vulnerability to negative life events of friends and family given the increase sense of responsibility, copying style and biological response to stress [12, 72]. PLOS ONE | https://doi.org/10.1371/journal.pone.0228754 February 11, 2020 16 / 22 The Barcelona Bain Health Initiative follow-up Sense of Coherence, is not a cultured-bound construct that allows individuals to identify strategies and resources available to manage stressors, and it has been related to a variety of health outcomes, including depression ([71, 73]; see [74] for a review). Sense of coherence is a core component in the salutogenic model of Aaron Antonovsky [75] and is defined as “a global orientation that expresses the extent to which one has a pervasive, enduring though dynamic feeling of confidence that (1) the stimuli deriving from one’s internal and external environ- ments in the course of living are structured, predictable, and explicable; (2) the resources are available to one to meet the demands posed by these stimuli; and (3) these demands are chal- lenges, worthy of investment and engagement’ [76]. Our findings are consistent with studies that argue that a high sense of coherence allows to better cope with stressors and represents a health promoting factor [71] associated with reduced mortality, increased well-being, and reduced incidence of depression [77, 78, 79]. Finally, the relation between sleep disturbance and mental health is well documented in lit- erature, particularly with insomnia. This condition indeed has been consistently related with depression [80, 81, 82] and a recent meta-analysis showed that it is a very strong predictor of this condition [83]. When we looked at the relation between these modifiable and non-modifi- able variables in regards to the risk of a new neurologic or psychiatric diagnosis we found that sleep quality partially mediated the relation between gender and risk of depression. The associ- ation between gender and specific sleep disorders is known and well documented in literature (see [84] for review): women are more likely than men to develop insomnia, restless leg syn- drome and REM sleep disorders, while men are at double the risk of Obstructive Sleep Apnea than women. Given such findings, it is not surprising that part of the risk to develop depres- sion is linked to poor sleep quality. These findings stress the importance of promoting sleep quality in middle age people, par- ticularly in women, and extend to the field of prevention previous results on the positive effect of sleep quality interventions in the treatment of mental health illnesses [85]. Future interven- tion studies should assess the impact of sleep quality promotion programs in reducing the inci- dence of mental health related pathology. Limitation and future directions This study has some possible limitation/confounders. The on-line administration of the ques- tionnaires, as well as representativeness of the cohort and statistical bias may limit the strong of our results. Moreover 93.7% of participants are living in the metropolitan area of Barcelona and are born in Spain (and more than 99% in Europe), and represent a rather homogeneous Caucasian population. The fact that our participants may reflect culturally related of Catalan/Spanish population is a possible limitation in extend our results to other populations. Further studies in other cultural contexts and other regions of the world would be needed to address this issue. On the other hand the big number of participants represents a positive factor and in this sense the retention challenge mentioned above represents a very crucial point for the future of the initiative. During this year participants will continue to respond periodically to new sur- veys and for the end of 2019 they will complete a new 1-year follow up for. This three time points will allow us to exhaustively and in a more complete way confirm our present results and better describe the longitudinal changes in our cohort. Supporting information S1 File. All the data necessaries to replicate the analyses contained in the paper. (XLSX) PLOS ONE | https://doi.org/10.1371/journal.pone.0228754 February 11, 2020 17 / 22 The Barcelona Bain Health Initiative follow-up Acknowledgments A special thanks is extended to all participants and other partners (Ad-Salutem Institute, Sodexo, I.C.A. Informática y Comunicaciones Avanzadas, Neuroelectrics, Corporació Cata- lana de Mitjans Audiovisuals, Club Metropolitan, Casa Ametller, and Agència de Qualitat i Avaluació Sanitàries de Catalunya-AQuAS) for their invaluable collaboration. Author Contributions Conceptualization: Gabriele Cattaneo, David Bartrés-Faz, Timothy P. Morris, Javier Solana Sánchez, Dı́dac Macià, Josep M. Tormos, Alvaro Pascual-Leone. 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