CLINICAL STUDY PROTOCOL published: 14 August 2019 doi: 10.3389/fnagi.2019.00216 Effects and Mechanisms of Cognitive, Aerobic Exercise, and Combined Training on Cognition, Edited by: Henriette van Praag, Health, and Brain Outcomes in Florida Atlantic University, United States Physically Inactive Older Adults: The Reviewed by: Agnieszka Z. Burzynska, Projecte Moviment Protocol Colorado State University, United States Alba Castells-Sánchez 1,2,3 , Francesca Roig-Coll 1 , Noemí Lamonja-Vicente 1,2,3 , Laura Serra, Marina Altés-Magret 1 , Pere Torán-Monserrat 4 , Marc Via 1,2,3 , Alberto García-Molina 5 , Fondazione Santa Lucia (IRCCS), Italy José Maria Tormos 5 , Antonio Heras 4 , Maite T. Alzamora 4 , Rosa Forés 4 , Guillem Pera 4 , David Raichlen, Rosalia Dacosta-Aguayo 1† , Juan José Soriano-Raya 1,2 , Cynthia Cáceres 6 , The University of Arizona, Pilar Montero-Alía 4 , Juan José Montero-Alía 4 , Maria Mercedes Jimenez-Gonzalez 4 , United States Maria Hernández-Pérez 6 , Alexandre Perera 7 , George A. Grove 8 , Josep Munuera 9 , *Correspondence: Sira Domènech 10 , Kirk I. Erickson 8 and Maria Mataró 1,2,3* Maria Mataró 1 Department of Clinical Psychology and Psychobiology, University of Barcelona, Barcelona, Spain, 2 Institut mmataro@ub.edu de Neurociències, University of Barcelona, Barcelona, Spain, 3 Institut de Recerca Pediàtrica, Hospital Sant Joan de Déu, † Present address: Barcelona, Spain, 4 Unitat de Suport a la Recerca Metropolitana Nord, Fundació Institut Universitari per a la Recerca Rosalia Dacosta-Aguayo, a l’Atenció Primària de Salut Jordi Gol i Gurina, Mataró, Spain, 5 Institut Guttmann, Institut Universitari de Neurorehabilitació, Center for Neuropsychology Universitat Autònoma de Barcelona, Barcelona, Spain, 6 Department of Neurosciences, Hospital Universitari Germans Trias i and Neurosciences Research, Kessler Pujol, Barcelona, Spain, 7 B2SLab, Departament d’Enginyeria de Sistemes, Automàtica i Informàtica Industrial, Universitat Foundation, East Hanover, NJ, Politècnica de Catalunya, Barcelona, Spain, 8 Department of Psychology, University of Pittsburgh, Pittsburgh, PA, United States United States, 9 Diagnostic Imaging Department, Fundació de Recerca, Hospital Sant Joan de Déu, Barcelona, Spain, 10 Institut de Diagnòstic per la Imatge, Hospital Universitari Germans Trias i Pujol, Barcelona, Spain Received: 14 March 2019 Accepted: 30 July 2019 Published: 14 August 2019 Introduction: Age-related health, brain, and cognitive impairment is a great challenge Citation: in current society. Cognitive training, aerobic exercise and their combination have been Castells-Sánchez A, Roig-Coll F, shown to benefit health, brain, cognition and psychological status in healthy older adults. Lamonja-Vicente N, Altés-Magret M, Torán-Monserrat P, Via M, Inconsistent results across studies may be related to several variables. We need to García-Molina A, Tormos JM, better identify cognitive changes, individual variables that may predict the effect of Heras A, Alzamora MT, Forés R, these interventions, and changes in structural and functional brain outcomes as well Pera G, Dacosta-Aguayo R, Soriano-Raya JJ, Cáceres C, as physiological molecular correlates that may be mediating these effects. Projecte Montero-Alía P, Montero-Alía JJ, Moviment is a multi-domain randomized trial examining the effect of these interventions Jimenez-Gonzalez MM, Hernández-Pérez M, Perera A, applied 5 days per week for 3 months compared to a passive control group. The aim of Grove GA, Munuera J, Domènech S, this paper is to describe the sample, procedures and planned analyses. Erickson KI and Mataró M (2019) Effects and Mechanisms of Cognitive, Methods: One hundred and forty healthy physically inactive older adults will be Aerobic Exercise, and Combined randomly assigned to computerized cognitive training (CCT), aerobic exercise (AE), Training on Cognition, Health, and Brain Outcomes in Physically combined training (COMB), or a control group. The intervention consists of a 3 month Inactive Older Adults: The Projecte home-based program 5 days per week in sessions of 45 min. Data from cognitive, Moviment Protocol. Front. Aging Neurosci. 11:216. physical, and psychological tests, cardiovascular risk factors, structural and functional doi: 10.3389/fnagi.2019.00216 brain scans, and blood samples will be obtained before and after the intervention. Frontiers in Aging Neuroscience | www.frontiersin.org 1 August 2019 | Volume 11 | Article 216 Castells-Sánchez et al. Aerobic-Cognitive Training: Moviment Protocol Results: Effects of the interventions on cognitive outcomes will be described in intention-to-treat and per protocol analyses. We will also analyze potential genetic, demographic, brain, and physiological molecular correlates that may predict the effects of intervention, as well as the association between cognitive effects and changes in these variables using the per protocol sample. Discussion: Projecte Moviment is a multi-domain intervention trial based on prior evidence that aims to understand the effects of CCT, AE, and COMB on cognitive and psychological outcomes compared to a passive control group, and to determine related biological correlates and predictors of the intervention effects. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT03123900. Keywords: computer-based cognitive training, aerobic exercise, neuroplasticity, neuroimaging, biomarkers, physically inactive, aging, fitness INTRODUCTION networks (Klingberg, 2010; Jolles et al., 2013; Kim et al., 2017) and connectivity of the hippocampus (Lisanne et al., 2017) and Walk, learn, be active, do! A large number of messages posterior DMN (De Marco et al., 2016) have also been described. about healthy behaviors to reduce age-related functional These structural and functional changes appear to be directly decline has flooded into our daily lives. Aging is related to related to the types of trained tasks (Taya et al., 2015). Despite major risk of cardiovascular diseases, metabolic syndrome, this, the biological pathways by which CCT produces these mitochondrial dysfunction, obesity, sarcopenia, and consequent effects remain poorly understood in humans. Shao et al. (2015) higher inflammation, oxidative stress, and brain and cognitive hypothesized that these mechanisms might be related to brain impairment (Sallam and Laher, 2016). Healthy aging has become neuroplasticity. According to Hebb (1949), a group of neurons a matter of interest for the scientific community and for that are repeatedly and simultaneously activated will tend to most people and governments that stand for social health form stronger associations. This framework suggests that CCT policies. Since the aged population is expected to triple by may influence cognition by promoting the strength of synaptic 2100 and will represent 29% of people in the world (United connections (Patterson et al., 1996; Taya et al., 2015). Based on Nations Department of Economic Social Affairs Population animal models, Valenzuela and Sachdev (2009) suggested that Division, 2017), we need policies and strategies that enhance brain-derived neurotrophic factor (BDNF) and nerve growth independence and quality of life while considering economic, factor (NGF) might be the molecules promoting cell survival and social, environmental, and personal determinants as well as proliferation after cognitive stimulation in humans. health and social services (World Health Organization [WHO], Physical activity (PA), defined as any body movement 2002, 2015). Cognitive training and aerobic exercise are two produced by skeletal muscles that results in energy expenditure lifestyle interventions that have proved to produce positive effects (Caspersen et al., 1985), promotes health, cognitive and on health (Cotman et al., 2007; Sallam and Laher, 2016), reduce psychological benefits (DiLorenzo et al., 1999; Penedo and cognitive impairment (Harada et al., 2013), and delay the onset Dahn, 2005). Exercise, which is considered a planned, structured of dementia (Hall et al., 2009). However, questions about which, and repetitive subtype of PA that aims to improve physical when and why remain unclear. fitness (Caspersen et al., 1985), produces an acute body reaction Gates and Valenzuela (2010) define cognitive training as that includes increased energy expenditure, repetitive muscle an intervention consisting of repeated practice of standardized contractions and an inflammatory and oxidative response (van exercises targeting a specific cognitive domain or domains. Praag et al., 2014; Sallam and Laher, 2016). Different types of Computerized cognitive training (CCT) has emerged as a new exercise, applied in a regular manner, may produce different tool to systematically apply these exercises. CCT facilitates the physiological, brain and cognitive benefits (Barha et al., 2017; administration by allowing investigators to adapt the content and Cabral et al., 2019). Several systematic reviews conclude that challenge of the task to individual performance and including aerobic exercise (AE), the type of exercise that involves oxygen visual engaging interfaces (Lampit et al., 2014; Shao et al., 2015). consumption and movement of large groups of skeletal muscles There is evidence that CCT may maintain or improve global during a sustained period of time (Chodzko-Zajko et al., 2009; cognitive function and specific trained functions such as verbal Thomas et al., 2012), may improve executive function, processing memory (Shao et al., 2015; Barban et al., 2016; Bahar-Fuchs speed, attention and memory in healthy older adults (Etnier et al., et al., 2017), processing speed (Kueider et al., 2012; Lampit et al., 1997; Colcombe and Kramer, 2003; Paterson and Warburton, 2014; Shao et al., 2015), and executive function (Kueider et al., 2010; Smith et al., 2010; Guiney and Machado, 2012; Karr 2012; Barban et al., 2016). Brain related benefits such as increases et al., 2014; Scherder et al., 2014; Lü et al., 2016; Barha et al., in gray matter volume of default-mode network (DMN) areas 2017; Northey et al., 2017). However, other reviews reported (De Marco et al., 2016), functional activity of frontal-parietal that the evidence was too limited to draw firm conclusions Frontiers in Aging Neuroscience | www.frontiersin.org 2 August 2019 | Volume 11 | Article 216 Castells-Sánchez et al. Aerobic-Cognitive Training: Moviment Protocol (Snowden et al., 2011; Cox et al., 2016; Brasure et al., 2017; memory performance (Erickson et al., 2009; Szabo et al., 2011) Sáez de Asteasu et al., 2017) or reported no significant effects and bigger caudate nucleus and nucleus accumbens (Verstynen of exercise on cognition (Angevaren et al., 2007; Kelly et al., et al., 2012). However, Rosano et al. (2010) and Smith et al. (2011) 2014; Young et al., 2015). Regular AE has direct effects on did not find a significant association between PA and gray matter our body: higher oxygen and glucose consumption related to volume. Sexton et al. (2016) systematically reviewed the effects increased energy expenditure, and reduction of body fat and of exercise on white matter volume – global, local, lesions, and increased muscle strength, which have been hypothesized as microstructure – and found cautious support for this association specific pathways for the physiological relationship between given the fact that evidence was inconsistent. Recent research exercise and cognitive function (Cotman et al., 2007; van Praag aims to identify the effect of exercise on functional connectivity. et al., 2014; Sallam and Laher, 2016; Stimpson et al., 2018). CRF has been associated with higher general efficiency and lower The increase of energy expenditure reduces visceral fat that may local efficiency and executive function performance (Kawagoe lead to less production of interleukin-6 (IL-6), tumor necrosis et al., 2017). Brain network modularity at baseline may predict factor alpha (TNF-alpha) and an increase of M2:M1 macrophage the effects of exercise intervention (Baniqued et al., 2018). ratio and the release of adiponectin. Energy expenditure is also Other variables have been identified as potential modifiers of related to higher glucose consumption which may be related to the association between exercise and cognition. Groups with a better energy metabolism and insulin sensitivity and reducing higher percentage of women (Barha and Liu-Ambrose, 2018) resistance to leptin and insulin (van Praag et al., 2014). The or APOE E4 genotype carriers (Etnier et al., 2007) may benefit activity in the muscles induces IL-ra, IL-10, and heat shock more from exercise. proteins (HSP), reducing the inflammatory environment while The combination (COMB) of PA and cognitive stimulation suppressing IL-1 and TNF-alpha and upregulating IL-15 and may induce greater cognitive benefits compared to each promoting the reparation of the vessels to facilitate blood flow intervention separately (Kraft, 2012; Curlik and Shors, 2013; and, as a consequence, oxygen and nutrient circulation (Sallam Fissler et al., 2013; Bamidis et al., 2014; Law et al., 2014; Lauenroth and Laher, 2016). Skeletal muscles may also improve the use et al., 2016). However, Shatil (2013) found improvements only of lipids instead of glycogen in energy expenditure processes. on those participants engaged in cognitive training, single Exercise increases circulating HDL and reverses cholesterol or combined. Zhu et al. (2016) replicated these results in a transport, reducing cholesterol levels in blood (Mann et al., systematic review of twenty studies, concluding that COMB 2013). The activity in the cardiovascular system produces laminar may have a small positive effect only when compared to a shear stress on vascular endothelial cells which may be related control and physical activity group but not to a cognitive to the downregulation of oxidative processes, and activates the intervention. To our knowledge, the specific cognitive benefits of hypothalamic-pituitary-adrenal axis which triggers the release COMB, in sequence or dual task, remain unknown; undefined of glucocorticoids that may help to inhibit the inflammatory “greater effects” or “more enduring” are usually hypothesized. system. The anti-oxidative response is mediated by redox- General cognitive function (Oswald et al., 2006; Shatil, 2013), sensitive transcription factors: NF-KB and AP-1, which reduce executive function (Anderson-Hanley et al., 2012; Theill et al., RONS, and PGC-1, which promotes mitochondrial biogenesis 2013; Barcelos et al., 2015; Eggenberger et al., 2015), processing (Sallam and Laher, 2016). Laminar shear stress is also related speed (León et al., 2015), memory (Fabre et al., 2002) and to greater release of insulin growth factor (IGF) and vascular vocabulary (Schmidt-Kassow et al., 2013) performance may endothelial factor (VEGF) which benefits the cardiovascular tend to benefit more from a COMB. However, evidence is system, helping to repair the body vasculature and promoting not consistent across trials and negative results have also been greater blood flow, brain angiogenesis and neurogenesis (Cotman found in these same domains (Fabre et al., 2002; Oswald et al., et al., 2007; Sallam and Laher, 2016; Stimpson et al., 2018; 2006; Legault et al., 2011; Anderson-Hanley et al., 2012; Linde Cabral et al., 2019). IGF promotes the release of BDNF in the and Alfermann, 2014; Rahe et al., 2015). Li et al. (2014) and brain, which has been identified as one of the principal factors Pieramico et al. (2012) reported that a multimodal intervention mediating the effect of exercise on cognition. BDNF may support produced a reorganization of functional connectivity between newborn cells, regulate synaptic changes and facilitate long- the DMN areas. Shah et al. (2014) identified higher verbal term potentiation which may be related to the identified brain memory related to increased glucose metabolism in the brain changes and cognitive benefits (Stimpson et al., 2018; Cabral in the COMB group only. In order to explain these potential et al., 2019). Cardiorespiratory fitness (CRF), the health-related greater benefits, Olson et al. (2006) and Fabel et al. (2009), component of physical fitness reflecting these parameters, has based on animal models, hypothesized that neuroplasticity may shown to be related to better cognitive function in healthy adults be facilitated by exercise and guided by cognitive training. The (Colcombe and Kramer, 2003). However, Etnier et al. (2006) anti-inflammatory, anti-oxidative stress and cardiovascular and and Young et al. (2015) could not find the relationship between neural repairing responses related to regular PA may enhance changes in CRF and changes in cognition in their systematic cell proliferation through BDNF. Cognitive stimulation may reviews. Erickson et al. (2014) found a positive relationship promote the survival of newborn cells and regulate synaptic between PA or CRF and gray matter volume in older adults in changes (Hebb, 1949). prefrontal, temporal and parietal areas (Erickson et al., 2007; Systematic reviews and papers cited before, independently Gordon et al., 2008; Weinstein et al., 2012). Higher levels of of the intervention, reported inconsistencies across results CRF have been also related to greater hippocampus volume and which likely relate to genetic and environmental variables of Frontiers in Aging Neuroscience | www.frontiersin.org 3 August 2019 | Volume 11 | Article 216 Castells-Sánchez et al. Aerobic-Cognitive Training: Moviment Protocol participants; type, duration and schedule of assessments; type, 1. All intervention conditions will positively impact duration, frequency, intensity and adherence of interventions; psychological and subjective daily functional performance as well as methodological issues of the design, such as assessed by questionnaires compared to controls. type of control group and statistical approaches (Kraft, 2012; 2. Aerobic exercise and COMB will similarly increase CRF Young et al., 2015; Gates et al., 2019). These discrepancies and energy expenditure in daily activity compared to challenge a clear theoretical model and lead to different cognitive and control conditions. conclusions and the identification of potential moderators 3. All intervention conditions will positively impact the even at the systematic and meta-analytic analysis level. structure and function of the brain assessed by whole These issues highlight the need to better identify not only brain analyses, structures of interest and white matter the cognitive effects of these interventions but also the lesions volume and microstructure, cortical thickness and individual variables that may predict them and the brain functional connectivity compared to a control group. changes and physiological molecular correlates that may be 4. Aerobic exercise and COMB will improve immunity, mediating any benefits. reduce inflammation and improve vascular risk factors Projecte Moviment is a multi-domain randomized trial that compared to cognitive and control conditions. addresses the effect of CCT, AE, and COMB on cognition and 5. Individual variables (i.e., sex, age, cognitive psychological status in healthy physically inactive older adults baseline, CRF baseline) will predict the effect of the compared to a passive control group. We also aim to identify interventions on cognition. variables that may predict the effects of the intervention and the 6. Changes in cognition will be related to specific changes in underlying brain changes and physiological molecular correlates secondary outcomes depending on the intervention. that may mediate the effects. The purpose of this paper is to describe the protocol in accordance with SPIRIT Guidelines. METHODS AIMS OF THE STUDY Study Oversight and Schedule Projecte Moviment is a multi-center, single-blind randomized The primary objective of Projecte Moviment is to examine controlled trial that started November 2015 with the aim of the effect of CCT, AE, or COMB on cognitive outcomes in recruiting 140 participants distributed in four parallel groups healthy physically inactive older adults. The primary hypotheses (one control group, n = 20; three intervention groups, n = 40 sustaining this goal are: each). All participants give their written informed consent and are assessed at baseline and 3 months later, immediately after 1. Computerized cognitive training – 5 times per week for the intervention (Figure 1). This study is led by the Faculty of 3 months – will improve general cognitive function as Psychology of the University of Barcelona in collaboration with well as trained cognitive functions (executive function, Institut Universitari d’Investigació en Atenció Primària Jordi Gol, processing speed and memory) measured by composite Hospital Germans Trias i Pujol and Institute Guttmann; it was scores using a battery of validated neuropsychological tests approved by the responsible ethics committees following the at 3 months compared to a control group. Declaration of Helsinki. 2. Aerobic exercise – 5 times per week for 3 months – will improve executive function, attention-processing speed and memory measured by composite scores using a Participants Participants are 140 community dwelling physically inactive battery of validated neuropsychological tests at 3 months healthy adults aged 50–70 years from Barcelona. Inclusion and compared to a control group. exclusion criteria are detailed in Table 1. Multiple strategies are 3. Combined training – 5 times per week for 3 months – applied to recruit participants: distribution of posters and flyers, will show greater improvements in general cognitive publication of press releases in local media (newspapers, radio, function, executive function, attention-processing speed and TV), presentations in local community organizations, list and memory measured by composite scores using a of patients of general physicians and volunteers from previous battery of validated neuropsychological tests at 3 months studies. Participants are enrolled in primary care centers and can compared to a control group. voluntarily withdraw from the project at any time. The secondary objectives of Projecte Moviment are: (a) to determine the effects of these interventions on psychological Assessments status and subjective performance on daily activities, CRF, brain Potential participants are screened by phone and an on-site structure and function and physiological molecular correlates; personal interview; if eligible, informed written consent is (b) to identify genetic, demographic, physiological and brain obtained. Assessments are conducted in a clinical environment variables that might predict the effect of the intervention; (c) to and organized into three appointments that take place at identify the association between cognitive effects and other baseline – within 2 weeks prior to the start of the intervention, psychological, physiological correlates. Specific hypotheses for and again at 3 months within 2 weeks after the completion of each objective will be specified in each article when reporting the intervention (Table 2). (1) Medical assessment (30 min): results. General secondary hypotheses include: review of medical history and current health status including Frontiers in Aging Neuroscience | www.frontiersin.org 4 August 2019 | Volume 11 | Article 216 Castells-Sánchez et al. Aerobic-Cognitive Training: Moviment Protocol FIGURE 1 | Projecte Moviment study design. CCT, computer-based cognitive training; AE, aerobic exercise; COMB, combined training. TABLE 1 | Inclusion and exclusion criteria for Projecte Moviment. in the Hospital Germans Trias i Pujol. All subjects receive an actimeter the first and last week of intervention to track their Inclusion criteria Exclusion criteria daily activity and determine if participants meet the intervention Aged 50–70 years Current participation in any cognitive training protocol. The same team of psychologists, which administers activity or during last 6 months > 2 h/week cognitive tests, and nurses, who collect general health data, follow ≤120 min/week of physical Diagnostic of dementia or mild cognitive the protocol in all the centers. activity during last 6 months impairment Mini-Mental State Examination Diagnostic of neurological disorder: stroke, (MMSE) ≥ 24 epilepsy, multiple sclerosis, traumatic brain Randomization injury, brain tumor Participants are randomly assigned to the groups stratified by sex, Montreal Cognitive Assessment Diagnostic of psychiatric illness current or age, and education. The allocation sequence consists of a random 5-min (MoCA 5-min) ≥ 6 during last 5 years list of these variables all combined and was generated by a Competency in Catalan or Geriatric Depression Scale (GDS-15) > 9 statistician. The intervention staff is responsible for the allocation Spanish and informs participants at the first intervention visit. Assessors Adequate visual, auditory, and Consumption of psychopharmacological drugs are blinded to the sequence and the group assignment of the fine motor skills current or during last 5 years; or more than 5 years throughout life participants. Blinding will only be broken for medical reasons. Acceptance of participation in History of drug abuse or alcoholism current or the study and signature of the during last 5 years; or more than 5 years Intervention informed consent throughout life; >28 men and >18 woman unit The intervention consists of a 3 months program, 5 days per of alcohol/week week in sessions of 45 min. At baseline all participants receive History of chemotherapy oral and written information about their specific intervention, Contraindication to magnetic resonance imaging an actimeter with brief instructions, and a follow-up diary to monitor the intervention. They are also asked to register hours MMSE (Blesa et al., 2001); MoCA 5-min (Wong et al., 2015); GDS-15 (Martínez et al., 2002). of sleep during the first and last week of the intervention. AE and COMB groups are also trained to monitor the intensity of their activity using the Borg Rating of Perceived Exertion Scale cardiovascular risk factors and blood extraction between 8 (BRPES) (Borg, 1982) while CCT and COMB conditions are and 9:30 AM following an overnight fast. (2) Cognitive informed about the computer program. A follow-up calendar is assessment and physical status (2.5 h): administration of a battery also created to determine adherence and any interfering events. of neuropsychological tests, psychological health, subjective All participants receive phone calls every 2 weeks, a mid-point performance, daily activities and PA questionnaires and a intervention visit after 6 weeks and a final visit (Table 2). treadmill fitness test. In order to control the effects of acute exercise, participants are advised not to exercise prior to all Computerized Cognitive Intervention (CCT) appointments and cognitive tests are conducted before the CRF The intervention program consists of a set of multi-domain test. (3) Magnetic Resonance Imaging (MRI) scans (45 min): cognitive tasks targeting executive function, visual and verbal administration of a neuroimaging protocol to acquire structural memory and sustained, divided and selective attention using and functional data of the brain. All assessments are carried out a computerized telerehabilitation platform called Guttmann in two primary care centers except MRI scans that are performed NeuroPersonal Trainer (GNPT , Spain; Solana et al., 2014; R R Frontiers in Aging Neuroscience | www.frontiersin.org 5 August 2019 | Volume 11 | Article 216 Frontiers in Aging Neuroscience | www.frontiersin.org Castells-Sánchez et al. TABLE 2 | Assessments. Enrollment and screening Baseline assessments (within 2 weeks prior to Intervention Post-intervention assessments (within the start of the intervention) 2 weeks after the completion of the intervention) Telephone Visit 1: Visit 2: Visit 3: Visit 4: Visit 5: Initial Visit 6: Mid- Visit 7: Final Visit 8: Post- Visit 9: Post- Visit 10: Post- screening Screening Baseline Baseline Baseline intervention intervention intervention intervention intervention intervention assessment assessment assessment assessment assessment assessment First review of criteria X Montreal Cognitive X Assessment 5-min (MoCA 5-min) Information of study X X Exhaustive review of X criteria Informed consent form X Mini-Mental State X X Examination (MMSE) Geriatric Depression X X Scale (GDS-15) Medical history X General health status X X Blood extraction X X 6 Battery of X X1 neuropsychological tests Psychological health X X and daily activities scales Physical activity X X questionnaire (VREM) Cardiorespiratory X X fitness (Rockport 1-mile walk test) Aerobic-Cognitive Training: Moviment Protocol Magnetic resonance X X imaging Information about X August 2019 | Volume 11 | Article 216 intervention Follow-up adherence X X questions2 Actimeter3 (Polar X X Loop R ) Intervention follow-up X X X diary4 1 All of tests except vocabulary subtest; 2 This information is also collected in phone calls every 2 weeks between visits; 3 Participants carry the actimeter the first and last week of training; 4 Participants record the diary every day during the intervention; MoCA 5-min (Wong et al., 2015); MMSE (Blesa et al., 2001); GDS-15 (Martínez et al., 2002); VREM – Reduced Minnesota leisure time physical activity questionnaire (Ruiz et al., 2012); Rockport 1-mile walk test (Kline et al., 1987). Castells-Sánchez et al. Aerobic-Cognitive Training: Moviment Protocol Solana et al., 2015). The cognitive functions trained are all the assessments. Instructions for each intervention include assessed with the battery of neuropsychological tests. However, healthy advice to prevent injuries. Participants can also contact the specific training tasks differ from the task performed the intervention staff for any problems or pain that they may in the assessment. GNPT includes a variety of exercises experience. Adverse events occurring during the intervention are designed by neuropsychologist based on cognitive paradigms. monitored in a diary and sent to a physician in case of medical The GNPT platform calculates an individual profile based on R incident. Participants will be excluded from the trial based on age, educational level and the results of the neuropsychological medical recommendation. assessment. The demand of the tasks is adjusted according to the performance of previous activities, which allows the software to design a new activity plan adapted to the participant level in DATA MANAGEMENT AND RESULTS each cognitive domain. Training is done individually at home for 45 min per session. Participants without access to a personal Data Quality computer or Internet can perform the intervention in the health A computerized database is used to collect and organize all care center. The software records the numbers of sessions and data. Data is collected without personal identifying information performance in activities automatically. using a code assigned by the assessor and researchers will only have access to this information in case of an incident. Data Aerobic Exercise (AE) from all participants will be collected regardless of whether the The training program is based on international guidelines of participant withdraws from the intervention or not. Assessments, physical exercise (World Health Organization [WHO], 2010). individual reports and databases will be double-checked. We will Participants are instructed to walk briskly in one continuous bout follow Data Quality Assessment Checklist and Recommended (45 min for 5 days, 225 min per week); intensity and duration are Procedures (DQA; USAID, 2014) that assesses a variety of initiated in a stepwise manner in order to reduce the possibility dimensions as validity, reliability, timeliness, precision and of injury. The first week they must walk 30 min at 9–10 on the integrity. Regarding interventions parameters, we will assess BRPES (Borg, 1982) considered light intensity. Time is increased the coherence between personal diaries, phone-call follow-ups to 45 min with the same intensity during the second week. During and actimeter. We will analyze if compliance is related to the rest of the program (10 weeks), they maintain the 45 min and expected physical changes. In addition, if we identify any issues, increase the intensity of the activity to a moderate-high effort that we will inform and apply any required statistical procedures corresponds with 12–14 in the same scale. Subjects are trained to control them. to use the BRPES (Borg, 1982) and to record this intensity and frequency of activity in a diary. Outcomes Combined Training (COMB) Primary Outcomes This group receives both the CCT and the AE intervention. To address the primary hypothesis, an extensive They follow the same previously described instructions for neuropsychological battery was designed by Projecte Moviment. each condition. Participants can organize both tasks at their Each test has been selected for its psychometric qualities and convenience, always applied in a single continuous bout of 45 min high relevance in the area of study. These tests provide measures each at any moment of the day. This results in 90 min of daily of multiple functions: executive functions, visuospatial abilities, activity, 5 times per week. We did not set any restriction about memory, language, attention and processing speed. We will the order of the tasks during the day or time-point at which they calculate z-score composites from normalized raw data for each had to be applied. cognitive domain and a global cognitive function score as a sum of all domains (Table 3). Control Group Participants in the control group are on the waiting list for Secondary Outcomes 3 months and are asked to keep their normal lifestyle. Once the Several domains are assessed to test secondary hypotheses. Main control condition is finished, they have the option to start one outcomes and measures are described in Table 4. of the interventions (CCT, AE, or COMB). Data of this optional Cognitive decline screening activity will not be included in the trial as they are not considered Montreal Cognitive Assessment 5 min (Wong et al., 2015) and participants during this period. Mini-Mental State Examination (Blesa et al., 2001) assess global cognitive function as relevant markers of cognitive decline. Safety Considerations In order to anticipate, prevent and answer medical or personal Psychological health and daily activity issues of the participants, several considerations will be taken Questionnaires ask for depressive symptoms and emotional into account. First, all the assessments are reviewed by the status, sleep quality and subjective performance in daily corresponding health professional before randomization to activities. These outcomes will test the potential effect of the ensure safety during the intervention. Abnormalities identified interventions to enhance perceived psychological status and are reported and these participants are rerouted to the functionality which may be related to cognitive effects and other corresponding healthcare service. Participants receive reports of secondary outcomes. Frontiers in Aging Neuroscience | www.frontiersin.org 7 August 2019 | Volume 11 | Article 216 Castells-Sánchez et al. Aerobic-Cognitive Training: Moviment Protocol TABLE 3 | Primary outcomes: variables and measures. Outcome/Variable Outcome measure Composites 1st level Composites 2nd level Tests – Subtest Executive function Inhibition Stroop – Interference Z score Working memory WAIS III – Backward span Z score TMT – B Z score Fluency Letter fluency Z score Category fluency Z score Visuospatial function Visuospatial ROCF – Copy accuracy Z score Memory Verbal memory RAVLT – Total learning Z score RAVLT – Recall II Z score Visual memory ROCF – Memory accuracy Z score Language Language WAIS III – Vocabulary Z score BNT (15 items) Z score Attention – Speed Attention WAIS III – Forward span Z score WAIS III – Digit symbol coding Z score WAIS-III – Symbol search Z score Speed TMT – A Z score ROCF – Copy time Z score Stroop test (Golden, 2001); WAIS-III, Wechsler Adult Intelligence Scale (Wechsler, 2001); TMT, Trail Making Test (Tombaugh, 2004); Verbal fluency tests (Peña-Casanova et al., 2009); ROCF, Rey-Osterrieth Complex Figure (Rey, 2009); RAVLT, Rey Auditory Verbal Learning Test (Schmidt, 1996; Marqués et al., 2013); BNT, Boston Naming Test (Goodglass et al., 2001). TABLE 4 | Secondary outcomes: variables and measures. Variable/Outcome Outcome measure General cognitive function Montreal Cognitive Assessment 5-min (MoCA 5-min) Z score Mini-mental State Examination (MMSE) Z score Psychological health Daily activity Geriatric Depression Scales (GDS-15) Z score Modified version of Visual Analog Mood Scale (VAMS) Z score Short Informant Questionnaire on Cognitive Decline in the Elderly (S-IQCODE) Z score Pittsburg Sleep Quality Index (PSQI) Z score Clinical Outcomes in Routine Evaluation-Outcome Measure (CORE-OM) Z score Fitness Cardiorespiratory fitness (Rockport 1-mile walk test) VO2 max Physical activity Reduced Minnesota leisure time physical activity questionnaire (VREM) METs Actimeter activity parameters (Polar Loop R ) Hours, steps, km, kcal Actimeter sleeping parameters (Polar Loop R ) Hours, % Health status Weight, height, and waist diameter Kg, cm Blood pressure mm Hg Hypertension, diabetes, and dyslipidemia Yes/No Tobacco and alcohol use Yes/No, Units Blood sample data Hemogram Conventional units Biochemistry in plasma Conventional units Cortisol ng/mL Genetics – Apolipoprotein E (APOE) E4+/E4- Genetics – Brain Derived Neurotrophic Factor (BDNF) Met+/Met- Cytokines ng/mL Neuroimaging T1-weighted Volume T2-weighted turbo inversion Volume Susceptibility weighted imaging Volume Resting state Z score Diffusion tensor imaging (DTI) Fractional Anisotropy Index MoCA 5-min (Wong et al., 2015); MMSE (Blesa et al., 2001); GDS-15 (Martínez et al., 2002); VAMS (Stern et al., 1997); S-IQCODE (Morales et al., 1992); PSQI (Rico and Fernández, 1997); CORE-OM (Trujillo et al., 2016); Rockport 1-mile walk test (Kline et al., 1987); VREM (Ruiz et al., 2012); MET (Metabolic Equivalent of Task). Frontiers in Aging Neuroscience | www.frontiersin.org 8 August 2019 | Volume 11 | Article 216 Castells-Sánchez et al. Aerobic-Cognitive Training: Moviment Protocol Aerobic fitness (4) Susceptibility-weighted imaging with T2 – fl3d sequence CRF is assessed by the Rockport 1 mile walk test. Participants are (TR/TE: 28/20 ms, slices: 88); (5) Resting state imaging with a instructed to walk on a treadmill for 1 mile adjusting their speed gradient echo planar imaging sequence (TR/TE: 2000/25 ms, in order to be as fast as possible without running (Technogym , R slices: 39, thickness: 3 mm, volumes: 240); (6) Diffusion tensor Italy). Maximal aerobic capacity (VO2 max) will be estimated imaging, echo planar imaging (voxel: 2 × 2 × 2 mm, TR/TE: with the linear regression reported by Kline et al. (1987). CRF 10200/89 ms, 64 directions, 1 acquisition). On one side, estimation is a well-known measure of cardiovascular health. structural and functional brain outcomes may help identify the We expect to describe the relationship between CRF and the molecular changes that are related to changes in brain volume, physiological blood measures as well as how change in CRF relate microstructure and connectivity between groups. On the other, to brain and cognitive outcomes. we aim to identify if changes in the MRI outcomes are associated with cognitive changes. Physical activity Other parameters from the follow-up such us adherence and Information about energy expenditure of PA performed during type of adverse events will be described. the last month is obtained by the Reduced Minnesota leisure time PA questionnaire (Ruiz et al., 2012). Polar Loop actimeter R Analyses (Polar Electro, NY, United States) registers daily PA (hours, Power Analysis steps, km, kcal) and sleeping (hours, %) parameters. Energy The sample size was determined considering previous studies expenditure is the very first consequence of exercising. We aim (Erickson et al., 2011) and the effect size and the standard error to identify if baseline energy expenditure is related to baseline of cardiovascular interventions on all cognitive tasks reported in a CRF and describe how the change in energy expenditure is related previous meta-analytic study (Colcombe and Kramer, 2003). We to physiological molecular correlates, CRF and to brain and also considered the following assumptions: bilateral contrasts and cognitive outcomes. an effect size of 0.4 using the Tukey–Kramer multiple comparison Health status test at 0.05 significance level with a common standard deviation A nurse registers demographic data, blood pressure, within a group of 0.3. In order to have at least 80% statistical anthropometrics measurements, and cardiovascular risk factors. power to answer the 3 primary aims of the project, we need Demographic data will allow us to control the influence of 18 subjects in the control group and 36 for CCT, AE, and individual variables. We expect that weight loss could be related COMB groups, respectively. Assuming 10% of lost to follow up to the physiological blood markers and to primary outcomes or (Rahe et al., 2015), we need a total sample size of 139 subjects other secondary outcomes. The reduction of cardiovascular risk (control group n = 19, intervention groups n = 40). Sample factors is an indirect measure of better cardiovascular health that power has been computed using PASS 14 Power Analysis and has been related to exercise. Sample Size Software. Blood-sample data Statistical Analyses Hemogram, biochemical parameters, and lipidic profile will Addressing the primary objective, statistical procedures will be be quantified in a common blood test. Cortisol will be performed with IBM SPSS Statistics 24 and R Environment. The analyzed in plasma and genetic biomarkers in APOE (SNPs distribution of raw scores will be examined in order to assess rs429358 and rs7412) and BDNF (rs6265) genes will be data quality (i.e., outliers, skewness) and we will obtain sample determined in the buffy coat fraction. Finally, a set of 105 z-scores for all cognitive tests. Five primary domains will be cytokines will be studied semi-quantitatively with The Proteome calculated by adding z-scores – executive function, memory, Profiler HumanTM XL Cytokine Array (R&D Systems, MN, language, attention-speed, and visuospatial function – which will United States). Biomarkers with relevant differences within and be split into nine secondary domains in order to assess specific between groups will be analyzed quantitatively using an ELISA changes within each domain – inhibition, fluency, working immunoassay method. We have chosen relevant genetic variables memory, verbal memory, visual memory, language, attention, and physiological molecular markers that have been related to speed and visuospatial function (see Table 3). Domains will be exercise interventions. We expect to detect changes at 3 months based on the literature (Strauss and Spreen, 1998; Lezak et al., and describe any type of relationship with cognitive outcomes. 2012) given the fact that a principle component analysis would not be appropriate for our sample size. Neuroimaging In order to test our primary hypotheses, we will conduct Magnetic Resonance Imaging will be obtained in a Siemens an intention-to-treat (ITT) analysis considering data from all Magnetom Verio Symo MR B17 (Siemens Healthineers, randomized participants, including those that complete and Erlangen, Germany). The protocol includes: (1) T1-weighted drop-out, in order to prevent attrition bias. An adequate method multi-planar reformat sequence (voxel: 0.9 × 0.9 × 0.9 mm, of imputation will be applied and informed. Parametric or TR/TE: 1900/2.73 ms, slices: 192; thickness: 0.9 mm); (2) T2- non-parametric tests will be chosen regarding the fitting of weighted turbo spin-echo sequence (voxel: 0.7 × 0.5 × 3 mm, data to statistical requirements of the tests and we will follow TR/TE: 6000/74 ms, slices: 35, thickness: 3 mm); (3) a coherent pipeline to explore variance: (a) comparison of T2-weighted turbo inversion recovery magnitude (voxel: baseline values between groups to identify potential variables to 1 × 0.8 × 3 mm, TR/TE: 9000/99 ms, slices: 44, thickness: 3 mm); adjust further analyses; (b) comparison of variables at different Frontiers in Aging Neuroscience | www.frontiersin.org 9 August 2019 | Volume 11 | Article 216 Castells-Sánchez et al. Aerobic-Cognitive Training: Moviment Protocol time-points for each group to identify the independent effect potential cognitive and psychological improvements depending of each condition; (c) identification of significant cross-time on adherence, characteristics of the intervention and other correlations in order to determine whether it is necessary to individual variables. control for baseline measures; (d) interaction between conditions Projecte Moviment aims to overcome some of the limitations and time-points to compare interventions. Sex, age, and years of underlined in relevant reviews (Daskalopoulou et al., 2017; education will be considered covariates beforehand and a two- Carrion et al., 2018). First, we examine several cognitive domains tailed p-value < 0.05 will be set as the significant threshold and multiple dimensions of health collecting information at and the corresponding correction for multiple comparisons different levels of measure. This fact will allow us to examine will be applied. In a second phase, we will define a per- the effect on different cognitive domains. We will be able to protocol (PP) sample including only subjects that finished the identify other related variables that may explain the results intervention with at least 80% adherence and we will reproduce and differences between groups at a molecular level. To our the same pipeline. In case of high disparity between ITT knowledge, it is one of the first trials to propose a high- and PP results, we will analyze potential variables related to frequency program, 5 days per week for 3 months in an ecological that discrepancy. environment. We chose a short period of time, used in other We will analyze our secondary hypotheses following the trials (Pereira et al., 2007; Renaud et al., 2010; Maass et al., 2015; same pipeline in the per-protocol sample to guarantee that Cabral et al., 2019), but with a higher frequency to examine we will be studying the effects of the intervention on the if we can observe the same or greater biological changes and previously described outcomes. We will examine potential equivalent or greater related cognitive improvements. A home- mediator effects through relationships between primary and based non-reimbursed participation may help us to determine secondary outcomes accounting for the intervention condition if adherence patterns and effects are like center-based rewarded using adequate correlational methods and linear mixed models. interventions which might be helpful for clinical guidelines. We Structural neuroimaging data will be first processed studying will also control the influence of many demographic variables whole brain, hippocampus and frontal lobe volumes and white through the eligibility criteria of the sample and age and sex matter microstructure. In a second phase, connectivity and balanced groups. white matter lesions will be analyzed. Data will be published in Nevertheless, we are aware of the limitations of the several papers where detailed procedures and software packages current study. Highly demanding home-based interventions will be described. during a short period of time may result in low adherence and an insufficient amount to test our hypotheses about effects on cognition. Intention to treat and per protocol DISCUSSION analyses will help us to describe discrepancies and control attendance. We are also collecting data at a molecular, Healthy aging is a current social challenge. Lifestyle behaviors structural and behavioral level in order to identify the effect such as cognitive training and exercise have a positive impact of the intervention at multiple biological and behavioral on health, brain and cognition with the possibility of greater levels. Despite the short duration, Stimpson et al. (2018) benefits when they are combined. Despite this evidence, there proposed a timeline of the effects of exercise intervention are still many questions remaining unanswered. Questions with changes in the blood and brain parameters within about the type of activity, length, frequency, duration, and 3 months. In addition, literature suggested that middle- intensity required to observe a cognitive effect, the potential age adults and healthy participants may lead to null results individual predictors of response to the intervention, the (Erickson et al., 2014; Young et al., 2015). We believe that relationship between physiological molecular correlates, and replication and deeper examination and understanding structural and functional brain changes and cognitive and of discrepancies is needed. These and future limitations, psychological benefits remain unclear. Projecte Moviment is a will be considered when analyzing, interpreting and multi-domain intervention trial based on prior evidence that publishing all results. aims to understand the effects of CCT, AE, and COMB on Projecte Moviment aims to report results through at least cognitive and psychological outcomes compared to a passive 6 publications in peer-reviewed journals without restrictions control group and determine related biological correlates as well to positive or negative results. Conclusions will also be as significant predictors of their effect. We aim to describe what presented in oral communications and posters at national and type of change these specific interventions may produce on international conferences. We will inform participants and biological, cognitive and psychological outcomes at 3 months. the general community through educative releases. Projecte These results may support the literature that is currently Moviment aims to reach health professionals to support examining the timeline of the effects of these interventions the translation of the results of the current study into (Stimpson et al., 2018; Cabral et al., 2019) on cognition and clinical practice. trying to identify potential related modifiers (Barha et al., 2017; Future research will also include a large study of gene Northey et al., 2017). We expect to find changes in physiological expression and metabolites in this sample following big data molecular correlates as well as structural and functional brain analytic strategies under the concept of omics to provide a outcomes within each intervention group and determine how deeper understanding of the biological mechanisms related to they differ across groups. Those changes may be related to these interventions. Frontiers in Aging Neuroscience | www.frontiersin.org 10 August 2019 | Volume 11 | Article 216 Castells-Sánchez et al. Aerobic-Cognitive Training: Moviment Protocol ETHICS STATEMENT All authors reviewed the manuscript and provided the final approval for the manuscript. This study was carried out in accordance with the recommendations of SPIRIT Guidelines with written informed consent from all subjects. All subjects gave written informed FUNDING consent in accordance with the Declaration of Helsinki. The protocol was approved by the Bioethics Commission of the Projecte Moviment is a project funded by the Spanish University of Barcelona (IRB00003099) and Clinical Research Ministry of Economy and Competitiveness under two grants: Ethics Committee of IDIAP Jordi Gol (P16/181). Neuroplasticity in the adulthood: physical exercise and cognitive training (PSI2013-47724-P) and Integrative omics study on the neurobiological effects of physical activity and AUTHOR CONTRIBUTIONS cognitive stimulation (PSI2016-77475-R). It has also been rewarded with three pre-doctoral fellowships (FPU014/01460, MM conceptualized the study and contributed to the study design FI-2016, and FI-2018). and implementation as Principal Investigator. PT-M and KE made substantial contributions to the design and content of the trial. MV, MTA, RF, GP, RD-A, JS-R, CC, AP, GG, JM, and SD ACKNOWLEDGMENTS contributed to the design of the trial from their area of expertise. 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Psychiatry 17, 179–187. doi: 10.1097/ JGP.0b013e3181953b57 Copyright © 2019 Castells-Sánchez, Roig-Coll, Lamonja-Vicente, Altés-Magret, van Praag, H., Fleshner, M., Schwartz, M. W., and Mattson, M. P. (2014). Exercise, Torán-Monserrat, Via, García-Molina, Tormos, Heras, Alzamora, Forés, Pera, energy intake, glucose homeostasis, and the brain. J. Neurosci. 34, 15139–15149. Dacosta-Aguayo, Soriano-Raya, Cáceres, Montero-Alía, Montero-Alía, Jimenez- doi: 10.1523/jneurosci.2814-14.2014 Gonzalez, Hernández-Pérez, Perera, Grove, Munuera, Domènech, Erickson and Verstynen, T. D., Lynch, B., Miller, D. L., Voss, M. W., Prakash, R. S., Mataró. This is an open-access article distributed under the terms of the Creative Chaddock, L., et al. (2012). Caudate nucleus volume mediates the link between Commons Attribution License (CC BY). The use, distribution or reproduction in cardiorespiratory fitness and cognitive flexibility in older adults. J. Aging Res. other forums is permitted, provided the original author(s) and the copyright owner(s) 2012, 1–11. doi: 10.1155/2012/939285 are credited and that the original publication in this journal is cited, in accordance Wechsler, D. (2001). WAIS-III. Escala de Inteligencia de Wechsler Para Adultos. with accepted academic practice. No use, distribution or reproduction is permitted Madrid: TEA Ediciones. which does not comply with these terms. Frontiers in Aging Neuroscience | www.frontiersin.org 14 August 2019 | Volume 11 | Article 216