the apathy item of the NPI scale and the cognitive inertia item of the APADEM-NH of patients in the NAO group. This results replicate previous studies were, despite a lack of methodological rigor, it is apparent that non-pharmacological interventions have the potential to reduce apathy in dementia (Brodaty and Burns, 2012). In the second phase, no statistically significant difference in measures of apathy was found. An explanation could be that apathy in institutionalized patients with advanced dementia seems to increase in time (Wetzels et al., 2010) and therapeutic interventions may have a window in mild and moderate dementia, but not in advanced dementia (López and Agüera-Ortiz, 2014). In the day care center, there was no statistically significant difference in apathy.

Analysis of the NPI scores of all patients in this study reveals a random assortment of changes that were minimal at best. Statistically significant changes were observed in:

	- Impairment in delusions and
	- Improving in apathy (Phase 1 nursing home), total score and irritability/lability (day care center)
	- Impairment in irritability/lability (nursing home), hallucinations (Phase 2 nursing home) and disinhibition (vs. the DOG group)
	- Improving in night-time behavior disturbances (vs. the DOG group).
	- Impairment in hallucinations, irritability/lability

Measures of irritability on the NPI item in the nursing home groups at baseline for Phase 2 showed statistically significant differences between groups, which casts some doubt on the significance of the follow up results.

The changes observed in hallucinations and in the DOG group were produced more by the improvement in the other therapeutic groups, than by its impairment.

A decrease in agitation after the use of animal assisted interventions has been described in the literature (Churchill et al., 1999; Richeson, 2003; O'Neil et al., 2011; Bernabei et al., 2013), as a decrease in behavioral symptoms after the use of a therapy dog during the day time hours (*p <* 0*.*05) with no significant differences during the evening hours (McCabe et al., 2002). Behavioral improvement, as defined by a reduction in anxiety and aggressiveness, has also been previously reported after the use of PARO (Shibata and Coughlin, 2014). These previous findings were not replicated in this study.

# **Limitations**

The study was designed in order to minimize any potential biases: 3 months of therapy were used in order to decrease the novelty effect, the raters and statistician were blinded, several recording sessions were held before the study began to get the patients and therapists used to the presence of the camera and decrease the Hawthorne effect, interaction between ACRSF regular caregivers and the robots and dogs was avoided to reduce potential informant bias, and while active participation in the therapy sessions was encouraged in order to decrease selection bias patients were not forced to interact with the therapist or the tools.

Throughout the study, several participants left the center or unit or died, and several patients joined the study late. Most of these changes did not occur during the interventions. Some participants were only evaluated once, due to hospitalization, illness or absence from the center: only 1.6% of participants were lost to follow up in the first year and 2.3% in the second.

This study was a pilot study in a sample, not representative of the general population, with a low number of participants. The changes after the use of the three new tools were minimal, and some of the statistical significant changes may be false positives, due to the high number of comparisons made and to the relatively small sample sizes. It is not possible to conclusively state that these tools were the cause of the changes seen, because of several possible confounding factors (i.e., differences in participants' pharmacologic regimens or type of dementia). However, these factors were controlled for, and will be investigated in future research.

In the nursing home, randomization was done by unit, not by individual participant. Although individual randomization would have been optimal, it would have required moving residents to different units for the sessions and would have introduced major changes in the daily routines and environments of the participants. Additionally, the environments and the characteristics of the individuals in units of the same dementia level are very similar. Baseline evaluation showed no difference between any of the nursing home groups on any of the measures (except in irritability in the nursing home in Phase 2), indicating that there is no significant difference between people who live in different units in the variables analyzed in this study.

# **Concluding Remarks**

In a controlled pilot study of parallel groups in institutionalized patients with moderate/severe dementia comparing 3 months of assisted therapy with:

# **References**

animal-shaped robot group and increased night-time behavior disturbances in the dog group.

In a study of robot therapy sessions for patients with moderate/severe dementia cared for at a day care center, participants showed improvements in irritability and global neuropsychiatric symptoms after participating in sessions with the humanoid robot, but not after sessions with the animalshaped robot.

# **Future Studies**

Randomized controlled trials are needed with a larger amount of patients, in order to better understand the effects of robots and dogs on the therapy of people with dementia.

Additionally, new scales that are internationally validated and more sensitive and specific are needed, in order to detect the slight changes in behavior, emotion and cognition that were observed during the session but were not significant enough to appear in the analysis.

As a result of this study, our team is going to focus on the use of humanoid robots in cognitive therapy for people with mild dementia and in the use of pet robots for people with moderate to severe dementia.

# **Grants**

This study received grants from the Spanish Ministry of Science and Innovation (PI10/02567) and the Spanish Ministry of Health, Social Policy and Equality (IMSERSO 231/2011).

# **Acknowledgments**

Thank you to the patients and their families and friends, for their cooperation to make feasible research programs like this one. The authors want to acknowledge for their collaboration to the rest of the members of the Robotherapy Working Group: Miguel Ángel Fernández Blázquez, Marina Ávila Villanueva, Belén Frades Payo, Isabel Ramos García, Isabel Cruz Orduña, Luis Ignacio Casanova Peño, Sara Saiz Bailador, Belén González Lahera, Susana Morales Martínez, Lidia Espada Raboso, Gema Melcon Borrego, Cristina Martín Carmona and Raquel Díaz Rodríguez. Special thanks to Hydra-Sata Association and Bocalan Foundation for making the third year of the study possible by training the therapists, providing the therapy dogs, and attending every session. Thank you to the "Association of users and friends of the guide dogs of Madrid" who were unable to participate in this study despite great enthusiasm and desire to. The authors also recognize the staff of the ACRSF and CIEN Foundation who helped to carry out this program. And thank you to Sloane Heller for the language assessment.

apathy in institutionalized persons with dementia: the APADEM-NH. *Am. J. Geriatr. Psychiatry* 23, 149–159. doi: 10.1016/j.jagp.2013.01.079

Bemelmans, R., Gelderblom, G. J., Jonker, P., and de Witte, L. (2012). Socially assistive robots in elderly care: a systematic review into effects and

Agüera-Ortiz, L., Gil-Ruiz, N., Cruz-Orduña, I., Ramos-García, I., Osorio, R. S., Valentí-Soler, M., et al. (2015). A novel rating scale for the measurement of

effectiveness. *J. Am. Med. Dir. Assoc*. 13, 14–120.e1. doi: 10.1016/j.jamda.2010. 10.002

**Conflict of Interest Statement:** The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

*Copyright © 2015 Valentí Soler, Agüera-Ortiz, Olazarán Rodríguez, Mendoza Rebolledo, Pérez Muñoz, Rodríguez Pérez, Osa Ruiz, Barrios Sánchez, Herrero Cano, Carrasco Chillón, Felipe Ruiz, López Alvarez, León Salas, Cañas Plaza, Martín Rico, Abella Dago and Martínez Martín. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.*

# 'Kitchen and cooking,' a serious game for mild cognitive impairment and Alzheimer's disease: a pilot study

*Valeria Manera1, Pierre-David Petit 1, Alexandre Derreumaux 1, Ivan Orvieto2, Matteo Romagnoli 2, Graham Lyttle3, Renaud David1,4 and Philippe H. Robert 1,4\**

*1 EA CoBTeK/IA (Cognition Behavior Technology), Institut Claude Pompidou, University of Nice Sophia Antipolis, Nice, France, 2 Testaluna S.r.l., Milano, Italy, 3 Kainos Evolve Ltd., Belfast, UK, 4 Centre Edmond et Lily Safra pour la Recherche sur la Maladie d'Alzheimer – Centre Mémoire de Ressources et de Recherche – Institut Claude Pompidou – CHU de Nice, Nice, France*

### *Edited by:*

*P. Hemachandra Reddy, Texas Tech University, USA*

### *Reviewed by:*

*Cristina Muscio, Fondazione Europea Ricerca Biomedica – Centro Eccellenza Alzheimer – Ospedale Briolini, Italy Ioannis Tarnanas, University of Bern, Switzerland*

### *\*Correspondence:*

*Philippe H. Robert, Centre Edmond et Lily Safra pour la Recherche sur la Maladie d'Alzheimer – Centre Mémoire de Ressources et de Recherche – Institut Claude Pompidou – CHU de Nice, 10 Rue Molière, 06000 Nice, France<EMAIL_ADDRESS>
> *Received: 14 January 2015 Accepted: 22 February 2015 Published: 17 March 2015*

### *Citation:*

*Manera V, Petit P-D, Derreumaux A, Orvieto I, Romagnoli M, Lyttle G, David R and Robert PH (2015) 'Kitchen and cooking,' a serious game for mild cognitive impairment and Alzheimer's disease: a pilot study. Front. Aging Neurosci. 7:24. doi: 10.3389/fnagi.2015.00024* Recently there has been a growing interest in employing serious games (SGs) for the assessment and rehabilitation of elderly people with mild cognitive impairment (MCI), Alzheimer's disease (AD), and related disorders. In the present study we examined the acceptability of 'Kitchen and cooking' – a SG developed in the context of the EU project VERVE (http://www.verveconsortium.eu/) – in these populations. In this game a cooking plot is employed to assess and stimulate executive functions (such as planning abilities) and praxis. The game is installed on a tablet, to be flexibly employed at home and in nursing homes. Twenty one elderly participants (9 MCI and 12 AD, including 14 outpatients and 7 patients living in nursing homes, as well as 11 apathetic and 10 non-apathetic) took part in a 1-month trail, including a clinical and neuropsychological assessment, and 4-week training where the participants were free to play as long as they wanted on a personal tablet. During the training, participants met once a week with a clinician in order to fill in self-report questionnaires assessing their overall game experience (including acceptability, motivation, and perceived emotions). The results of the self reports and of the data concerning game performance (e.g., time spent playing, number of errors, etc) confirm the overall acceptability of Kitchen and cooking for both patients with MCI and patients with AD and related disorders, and the utility to employ it for training purposes. Interestingly, the results confirm that the game is adapted also to apathetic patients.

Keywords: serious game, Alzheimer disease, mild cognitive impairment, apathy, executive functions

# Introduction

The term dementia indicates a decline in mental ability severe enough to interfere with activities of daily life (Dubois et al., 2010). Due to the increasing average lifespan, the occurrence of dementia has risen dramatically, thus engendering high socio-economic costs. For this reason, the early detection and the treatment of dementia are considered as a research priorities (Ballard et al., 2011). Dementia is characterized by the presence of cognitive symptoms, such impaired memory, attention, orientation and executive functions, which are often associated to behavioral and psychological symptoms, such as apathy or agitation (Aalten et al., 2003). Dementia can result from different causes, the most common being Alzheimer's disease (AD), and it is often preceded by a predementia stage, known as mild cognitive impairment (MCI), characterized by a cognitive decline greater than expected for an individual's age, but which does not interfere notably with activities of daily life (Petersen et al., 1999; Gauthier et al., 2006).

Serious games (SG) – which are digital applications specialized for purposes other than entertaining (such as educating, informing, or enhancing cognitive and/or physical functions) – are now widely recognized as promising non-pharmacological tools to help assess and evaluate patients' functional impairments, as well as to help the patients' treatment, stimulation, and rehabilitation (Robert et al., 2014). Boosted by the publication of a Nature letter showing that video game training can enhance cognitive control in older adults (Anguera et al., 2013), there is now a growing interest in developing SG specifically adapted to people with AD and related disorders. Preliminary evidence shows that SG can successfully be employed to train physical and cognitive abilities in people with AD, MCI, and related disorders. McCallum and Boletsis (2013) performed a literature review of the experimental studies conducted to date on the use of SG in neurodegenerative disorders. In summary, the results of the 15 reported studies suggest that: (1) physical games (or exergames, i.e., games that promote physical fitness) can positively affect several health areas of the players with mild AD and MCI, such as balance and gait (Padala et al., 2012), and voluntary motor control (Legouverneur et al., 2011); (2) cognitive games (i.e., games which target cognitive improvement) can improve a number of cognitive functions, such as attention and memory (Stavros et al., 2010; Weybright et al., 2010; Rosen et al., 2011) and visuo-spatial abilities (Yamaguchi et al., 2011); (3) both physical and cognitive games can have a positive impact on social and emotional functions, for instance they can improve the mood and increase positive affect and sociability (Weybright et al., 2010; Boulay et al., 2011; Yamaguchi et al., 2011) and reduce depression (Férnandez-Calvo et al., 2011).

Despite these promising results, a number of studies showed that elderly people and people with AD have problems in using many of the SG currently available on the market. Their difficulties include problems in getting familiar with the game technology and embarrassment about using the tools designed for the game (e.g., Wollersheim et al., 2010; Legouverneur et al., 2011). Furthermore, certain games were considered too demanding or even risky for elderly people (e.g., Sohnsmeyer et al., 2010). These difficulties derive from the fact that most of the SG currently employed have been developed for entertainment purposes (e.g., the Nintendo Wii Fit, Wii Sports, and Big Brain Academy) and with a "typical healthy user" in mind. To overcome this problem, SG targeting specifically AD and related disorders are starting to emerge (e.g., Benveniste et al., 2010; Nor Wan Shamsuddin et al., 2011; Tarnanas et al., 2013).

The purpose of the present paper is to report the results of a feasibility study conducted with patients with MCI and AD and related disorders with the game "Kitchen and cooking," a SG game developed in the context of the European FP7 project VERVE (Vanquishing Fear through e-inclusion, http://verveconsortium.eu/). Kitchen and cooking is born from the tight collaboration between clinicians and game designers. Based on a recent survey showing that food is the most interesting topic for elderly people living in nursing homes (Leone et al., 2012), we developed the game based on a cooking plot, where participants can play different scenarios/recipes. Kitchen and cooking targets executive functions, specifically planning abilities, but includes also activities training attention and object recognition, as well as praxis. Following the recommendations of Robert et al. (2014) and Fua et al. (2013), the game can keep track of participants' performance overtime, and thus can be employed also for assessment purposes. Furthermore, it takes into account the users' impairments: for instance, after a number of errors, the user is helped with some prompts. Finally, it is installed on a tablet, which is an inexpensive and easy to use interface that can be employed anywhere.

In order to test how the SG is used in different environments, we included both outpatients and patients living in nursing homes. Furthermore, we included both apathetic and nonapathetic patients, as one challenges of the project VERVE was to develop new technologies to support the treatment of people with apathy associated to aging, or to neurological disorders.

# Materials and Methods

### Participants

Nine MCI patients (seven female and two male; mean age = 75.8 years; SD = 9.1; age range = 60–84) and 12 patients with AD or related disorders (eight female, four male; mean age = 80.3 years; SD = 6.3; age range = 70–90) voluntarily participated in this study. Patients were recruited either at the Nice Research Memory Center and CoBTeK research unit (CMRR), located at the Institut Claude Pompidou (MCI: *N* = 6, AD: *N* = 8) or in a nursing home working with the CMRR (MCI: *N* = 3, AD: *N* = 4). MCI diagnosis was conducted according to the National Institute on Aging and Alzheimer Association group clinical criteria (Albert et al., 2011), and the AD diagnosis was made according to the NINCDS ADRDA criteria (McKhann et al., 1984). Participants were not included if they had an active episode of major depression, if they had major perceptual (visual or auditory) impairments, rigidity or trembling (according to the UPDRS III; Fahn and Elton, 1987) or epilepsy. The mini mental state exam (MMSE) was used to evaluate the level of cognitive impairment for each group (Folstein et al., 1975). AD patients scored between 15 and 24 (*M* = 18.4, SD = 3.2) and MCI patients scored from 24 to 30 (*M* = 27.2, SD = 1.9). The presence of apathy was evaluated by means of the diagnostic criteria for apathy (Mulin et al., 2011), and the criteria have been used to divide the population in apathetic versus non-apathetic subjects. In addition, the severity of apathy was assessed using the Apathy Inventory – clinician version (Robert et al., 2009), a 12 point scale evaluating the presence of reduced initiation, interest, and emotional blunting.

Characteristics of MCI and AD subjects are presented in **Table 1**. The age, level of education, and gender distribution were not significantly different between the two groups. All participants gave their informed written consent before beginning the study. The study was performed in compliance with the Declaration of Helsinki, and was approved by the local ethics committees.

### Materials and Procedure

A flowchart summarizing the study procedure with the different experimental sessions is reported in **Figure 1**. Participants performed a 4-week training with 'Kitchen and cooking' game installed on a tablet. During the training, participants were asked to play at home as much as they wanted, and they meet five times with a trained clinician. During the inclusion visit, after signing the informed consent, participants underwent the cognitive and functional assessment (see below). During the first session with the clinician (S1), they underwent a preliminary game training for Kitchen and cooking, in which the clinician showed all the ingredients/objects used in the different scenarios (in order to ensure that the objects were recognizable), and showed which gestures needed to be performed to complete the different game actions. Second, participants played one of the available scenarios in front of the clinician, who provided additional explanations (if necessary) in order to allow the participant to successfully complete the scenario. Finally, participants completed some self-report questionnaires to assess the game acceptability and interest. The homework for week 1 was to play as much as they wanted to the scenario seen in S1 (participants were allowed to try and play other scenarios, if they wanted). After 1-week participants meet again with the clinician (S2) and played with him the scenario played in S1, together with a new scenario, which represented the

homework for week 2. The structure of S3 and S4 sessions was identical to that of S2, and every week participants exercised on a new scenario. During the last session with the clinician (S5), taking place at the end of week 4, participants played again the scenario performed during week 4, and they completed the same self-report questionnaires assessing the game acceptability and interest administered after S1.

### Cognitive and Functional Assessment

Global functioning was evaluated during the inclusion visit by means of the MMSE, the Instrumental Activities of Daily Living scale (IADL; Mathuranath et al., 2005) and the Independence in Activity of Daily Living index (ADL; Katz et al., 1970).  Executive functions (specifically, selective attention, and inhibition control) were evaluated using the interference scores from the Victoria Stroop Test (Word/Dot and Interference/Dot, Bayard et al., 2011). Memory performance was evaluated by means of the Visual Association Test (VAT; Lindeboom et al., 2002).

### 'Kitchen and Cooking' Game

"Kitchen and cooking" game is a SG developed in the context of the European FP7 project VERVE (Vanquishing Fear through einclusion, http://verveconsortium.eu/), a project which aimed to develop new technologies to support the treatment of people at risk of social exclusion, either because of fear and apathy associated with aging, or because of a neurological disorder. The CMRR and the CoBTeK team designed the cognitive task embedded in the game. The game was developed by Testaluna s.r.l. (Milan, Italy), and Kainos Evolve Ltd (Belfast, UK) developed the game interface used by the clinicians.

*Group comparisons were made using Mann–Whitney U test (\*p < 0.05) and chi-square (\*p < 0.05) for categorical testing.*

Kitchen and cooking is based on a cooking plot, where participants can play four different scenarios/recipes: pizza, yogurt cake, chicken breast in cream sauce, and finally salmon wrap. In each scenario, participants need: (a) to select the correct ingredients from the fridge and cupboards, a searching task with engages object recognition and sustained attention (*gnosis* activity); (b) to plan which actions need to be performed, and in which order, a task requiring planning abilities (*executive functions* activity); and finally, to perform specific gestures to accomplish each action (e.g., to rotate the finger to mix the ingredients), a task which requires praxis abilities (*praxis* activity). Depending on the scenario, the number of objects to be recognized ranges from 5 to 7, the number of executive functions activities ranges from 5 to 8, and the number of praxis ranges from 7 to 13.

The game can keep track of the time spent playing a scenario and of the time spent on each of the game activities (gnosis, executive functions, and praxis), of the total number of scenarios played (successfully completed or not), and of the number of errors performed in each game activity.

A demo showing Kitchen and cooking can be seen on the website of the Association Innovation Alzheimer, at the following link: http://www.innovation-alzheimer.fr/projets-en/verve-en/

### Self Report Questionnaires

At the end of S1 and S5 participants were administered self-report questionnaires concerning the game experience. Specifically, the perceived satisfaction was assessed through a 10 cm analogical scale, in which participants were asked to bisect a line ranging from 'not satisfied at all' to 'really satisfied' in order to indicate their degree of satisfaction for the game. Perceive interest was assessed through a 4 item 1–7 Likert scale adapted from Gourlan et al. (2013). Similarly, motivation was evaluated through an adaptation of the scale proposed by Gourlan et al. (2013), a 24-item 0–7 Likert scale which measures separately intrinsic motivation (e.g., "I play because it is fun") and external motivation ("I play because my friends/family members say I should"). Experienced emotions were assessed through the PANAS scale (Watson et al., 1988), a 20-item 0–5 Likert scale evaluating separately self-reported positive and negative emotions. Finally, fatigue was evaluated through the French adaptation of the Piper Fatigue Scale (11 rating questions, scale 0–10; Gledhill et al., 2002).

### Statistics Analyses

All statistical analyses were computed using SPSS 20.0. In order to verify the acceptability of the intervention, we computed: (a) the number of participants that successfully completed the training; (b) the mean scores of the acceptability questionnaires administered after S1 and S5; (c) the mean time spent playing, and the number of scenarios played (in total and at home). Group comparisons were performed using diagnosis (MCI vs. AD), residence (outpatients vs. patients in nursing home) and presence of diagnostic criteria for apathy (yes vs. no) as independent between-subject factors. As the distribution of the data was not normal, group comparisons were performed using nonparametric Mann–Whitney *U* test. Comparisons between the acceptability questionnaires after S1 and S5 were performed using paired-sample *t*-tests.

In order to verify whether the assessment of the different game activities (gnosis, executive functions, and praxis) was in line with the classical functional and neuropsychological assessment, we computed for each participant the mean time spent to complete a scenario, and the errors and mean time spent on each game activity in S1 (first session), and we submitted them to separate Mann–Whitney *U* test, with diagnosis (MCI vs. AD), residence (outpatients vs. patients in nursing home) and presence of diagnostic criteria for apathy (yes vs. no) as independent between-subject factors. We also compute correlations between the time spent on each game activity in S1 and the classical cognitive and functional assessment using Pearsons' correlation coefficient (two-tails).

Finally, in order to verify if game activities improved with training, for each scenario we compared the time spent to perform each activity (gnosis, executive functions, and praxis) during the first session (S1, S2, S3, or S4 depending on the scenario and participant) and the next session (1 week after) using pairedsample *t*-tests. Group comparisons on the improvement scores (difference in time spent on an activity between two consecutive sessions) were performed with Mann–Whitney *U* test using diagnosis (MCI vs. AD), residence (outpatients vs. patients in nursing home) and presence of diagnostic criteria for apathy (yes vs. no) as independent between-subject factors. We also computed Pearsons' correlations between game improvement scores and the total time spent playing during the training.

### Results Cognitive, Functional, and Behavioral Assessment

Demographic, cognitive, and functional characteristics of the patients are presented in **Table 1**. Compared to MCI participants, AD participants had significantly lower MMSE scores (*p <* 0.001) and IADL-E (*p* = 0.028), confirming the presence of a significant impairment in the activities of daily living. Furthermore, participants were slower at the TMT A (*p* = 0.015), more sensitive to interference in the Victoria Stroop Test – Word/Dot index (*p* = 0.023), and scored lower at the VAT memory task (*p <* 0.001) compared to MCI participants. Finally, AD participants had a higher Apathy Inventory compared to MCI participants (*p* = 0.041). However, no significant difference between groups was found concerning the presence of diagnostic criteria for apathy (χ2 = 2.29, *p* = 0.130). No significant difference between groups was found for the ADL, and the Victoria Stroop Test – Interference/Dot index.

### Intervention Acceptability

### Training Completion and Self-Report Questionnaires

The 4-weeks training was successfully completed by 20 out of 21 participants (one participant abandoned the study after the

### first week). The results of the self-report questionnaires (mean scores between S1 and S5) showed that, as a group, participants reported to be highly satisfied concerning the game experience (Mean = 8.2/10, SD = 1.3), interested by the game (Mean = 17.1/28, SD = 5.6), and motivated by the activity. Specifically, intrinsic motivation (Mean = 3.9/7, SD = 1.3), was significantly higher than external motivation [Mean = 2.5/7, SD = 1.2; *t(*15*)* = 4.37, *p* = 0.001]. Furthermore, participants reported to be not very fatigued (Mean = 3.7/10; SD = 1.2), and to have experienced more positive emotions (PANAS pos, *M* = 2.7/5; SD = 0.8) than negative emotions [PANAS neg, *M* = 1.4/5, SD = 0.6, *t(*18*)* = 5.86, *p <* 0.001]. The interest, satisfaction, motivation (intrinsic and extrinsic) fatigue, and experienced emotions (positive and negative) did not change from S1 to S5 (*t* ranging from 0.15 to 1.8, *p*s ranging from 0.092 to 0.880), thus confirming the overall positive evaluation of the game also after a repeated training.

Results according to diagnosis, residence, and presence of diagnostic criteria for apathy are shown in **Table 2**. Group comparisons revealed that AD participants reported to be significantly more satisfied compared to the MCI participants (*p* = 0.043). Furthermore, apathetic participants reported to experience fewer positive emotions (*p* = 0.008) compared to nonapathetic participants. No difference in the self-report scales was found between outpatients and patients living in nursing homes (all *p*s *>* 0.323).

### Game Experience

The acceptability of the intervention was corroborated also by the data concerning the time that patients spent playing, and the number of scenarios played. During the 4-week trial participants played a mean of 55.8 scenarios (SD = 64.9; range = 10–284), for a mean playtime of more than 5 h (5h22m; SD = 4h19m; range = 32m–17h40m), corresponding to a mean of 1h21m

*Results of the self report questionnaires (mean between S1 and S5), number of scenarios and total time played by MCI vs. AD patients, outpatients vs. patients living in nursing homes, and by apathetic vs. non-apathetic patients according to the Apathy diagnostic criteria. Results in bold indicate a significant difference at the Mann–Whitney U test (p < 0.05).*

hours per week. Almost 85% of the scenarios were played at home (Mean = 47.4, SD = 64.3), for a mean playtime at home of 3h48m (SD = 4h19m range = 0m–16h28m). Over 70% of the scenarios were successfully completed (Mean = 70.2%, SD = 25%; range = 18.2%–100%).

Results according to diagnosis, residence, and presence of diagnostic criteria for apathy are shown in **Table 2**. No significant difference in the number of scenarios (*p* = 0.422) or time played (*p* = 0.808) was found between MCI and AD participants. Outpatients played more scenarios compared to patients in nursing home (*p* = 0.031), but the difference in the time spent playing did not reach statistical significance (*p* = 0.224). Interestingly, apathetic patients played longer than non-apathetic patients (*p* = 0.016), while no difference in the number of scenarios played was found (*p* = 0.654).

### Game Assessment

### Time for Scenario Completion, Gnosis, Executive Functions, and Praxis

Results according to diagnosis, residence and presence of diagnostic criteria for apathy are shown in **Table 3**. AD participants took significantly longer to complete a scenario compared to MCI participants (*p* = 0.004). Furthermore, the first time a scenario was played with the clinician (*t*0), AD participants were significantly slower in the gnosis (*p* = 0.002), executive functions (*p* = 0.046), and praxis activities (*p* = 0.006) compared to MCI participants, and made more errors in the praxis activity (*p* = 0.046) thus suggesting that the game assessment was sensitive to differences in the level of general cognitive impairment. AD participants were significantly slower than MCI participants also when the scenario was played again with the clinician after 1 week of training at home (*t*1; gnosis time, *p* = 0.002; executive functions time, *p* = 0.003; praxis time, *p* = 0.004). No difference in the errors was found (all *p*s *>* 0.056). No difference in the

### TABLE 3 | Game assessment.

mean time spent to complete a scenario, gnosis, executive functions, and praxis time/errors was found between outpatients and patients living in nursing homes (all *p*s *>* 0.157), nor between apathetic and non-apathetic participants (all *p*s *>* 0.175).

### Correlations Between Classical Cognitive Assessment and Game Assessment

The game gnosis time in S1 showed a significant correlation with the MMSE [*r(*20*)* = −0.68, *p* = 0.001], the TMT A time [*r(*20*)* = 0.59, *p* = 0.006], thus confirming that the object search and selection task can be considered a good proxy for attentional processes. As expected, the game executive functions time showed a significant correlation with the Victoria Stroop Test [Word/Dot index, *r(*20*)* = 0.70, *p* = 0.001; Interference/Dot index, *r(*20*)* = 0.55, *p* = 0.013], an index of inhibition control. Finally, the praxis time correlated significantly with the MMSE [*r(*20*)* = −0.53, *p* = 0.016] and with both indexes of the Victoria Stroop Test [Word/Dot index, *r(*20*)* = 0.71, *p <* 0.001; Interference/Dot index, *r(*20*)* = 0.60, *p* = 0.005]. No other significant correlation was found (all *p*s *>* 0.153).

# Improvement in the Game Activities During the Training

Every scenario was played with the clinician twice: the first time to practice the recipe (*t*0, in S1, S2, S3, or S4 depending on the scenario and participant), and the second time 1 week later (*t*1), before practicing another recipe. As the scenarios differ in length and complexity, we could not compare performance in S1 and S5, and we compared instead, for each scenario, performance in *t*0 and *t*1. Comparisons between the game assessment made during *t*0 and *t*1 revealed no differences in the gnosis time (*p* = 0.115), but a significant reduction is praxis and executive function time, with participants becoming faster in the praxis (*p* = 0.001) and executive functions activities from the practice to the follow up round (*p* = 0.017). No difference in the number of errors was

*Mean time to complete a scenario, and mean time spent on each game activity in t0 (first time a scenario was played with the clinician) and t1 (1 week later) for MCI vs. AD patients, outpatients vs. patients living in nursing homes, and by apathetic vs. non-apathetic patients. Results in bold indicate a significant difference at the Mann–Whitney U test (p < 0.05).*

found for any of the activities (all *p*s *>* 0.519). The improvement in the executive functions was greater for MCI compared to AD patients. Specifically, MCI participants showed a more consistent reduction in the time spent in the activity (*p* = 0.010; see **Figure 2**) and in the mean number of errors (*p* = 0.025) in *t*1 vs. *t*0 compared to AD participants. Furthermore, outpatients improved in the gnosis (reduction of time from *t*0 to *t*1) more than patients living in nursing home (*p* = 0.14). No significant difference between apathetic and non-apathetic patients was found.

A significant correlation was found between the improvement in the gnosis and the praxis [*r(*20*)* = 0.55, *p* = 0.013], and between the praxis and the executive functions [*r(*20*)* = 0.68, *p* = 0.001], thus suggesting that participants that became faster in the gnosis and executive functions became also faster in the praxis. The correlation between gnosis and executive functions did not reach statistical significance [*r(*20*)* = 0.43, *p* = 0.057].

A significant correlation was found between the time spent playing during the 4-week training and the improvement shown in the gnosis [*r(*20*)* = 0.52, *p* = 0.020] and executive functions time [*r(*20*)* = 0.46, *p* = 0.040], thus suggesting that gnosis and executive functions (as assessed by the game) could be improved by exercise. The correlation between time spent playing and improvement in the praxis time was in the same direction, but did not reach statistical significance [*r(*20*)* = 0.36, *p* = 0.124].

# Discussion

The results of the present feasibility study confirm that Kitchen and cooking was acceptable and interesting for both patients with MCI and AD. This interpretation is confirmed by the fact that 20 out of 21 participants successfully completed the 4-week training, and by the fact that participants rated the game experience as interesting, reported to be highly satisfied and motivated by the game, to experience more positive emotions than negative emotions, and not to be fatigued both at the beginning and at the end of the training. Moreover, participants played a mean of almost one and a half hours per week (corresponding to 14 scenarios),

thus suggesting that they played also outside the meetings with the clinician. Interestingly, there was a huge variability in the playing time: while a few participants played almost only with the clinician, some others played up to 70 scenarios per week, thus suggesting that the game most probably met their interest, and was particularly adapted to them. This variability in the playing time confirms that adaptation to the patients' interest and level impairment is a key challenge in designing SGs with training purposes (Robert et al., 2014).

We are convinced that a critical factor in the success of the intervention was the presence of the clinician. We designed Kitchen and scenario as a tool to help the patient to train outside the clinical consultation, but the periodic supervision of the clinician is necessary to explain the functioning to the patient and the family, keep track of the evolution of the performance, to adapt the intervention step by step to the patients' changing needs and to maintain the motivation.

Another interesting finding was that we found a significant difference in the number of scenarios played depending of the place of residence, with outpatients playing significantly more compared to patients in nursing home. The proportion of AD/MCI was not significantly different between outpatients and patients living in nursing home, suggesting that the level of impairment was similar in the two groups, and thus was not the critical variable in explaining the effect. One possible explanation concerns the level of initial engagement/commitment to the training. Outpatients needed to come to the Memory consultation five times during the 4-week training, which implies that they were very committed when they decided to take part in the study. On the contrary, for patients living in nursing homes the trainings with the clinician took place in the nursing home, which makes possible that some participants accepted even if they had a lower commitment. Another possibility is that outpatients played more because they were followed more closely by a family caregiver. The level of external motivation reported at the beginning and at the end of the training (e.g., "I play because my friends/family say I should") did not differ between the two groups. However, it is possible that the simple sharing experience stimulated patients to play more.

The major limitation of these results is the small number of participants included in the study. The study was designed as a pilot experiment most specifically oriented to a feasibility target. In addition, it was important in order to fit the European commission requirement to include both outpatients and patients living in nursing home. This is obviously of interest, but it increases the heterogeneity of the population.

### A Serious Game for Apathy

Apathy is one of the most common neuropsychiatric symptoms of AD and related disorders, occurring in almost 65% of dementia patients (Ferri et al., 2005; König et al., 2014). Apathy is associated with a higher degree of global functional impairment (Doron et al., 2013) and therefore to a loss of autonomy in activities of daily living (Boyle et al., 2003; Robert et al., 2009). One of the challenges of the project VERVE was to design SG that, due to their playful nature, may be particularly adapted to target apathetic patients. The results of this feasibility study suggest that Kitchen and cooking was adapted to apathetic participants. Indeed, apathetic participants reported to be as interested, motivated, and satisfied by the game experience as non-apathetic participants, a result which in interesting on its own. Critically, apathetic patients played *more* during the 4-week training compared to non-apathetic patients, suggesting that they were not impaired in this specific goal-directed activity. At a first glance, this may seem counterintuitive. A possible explanation concerns the fact that non-apathetic participants have more interests and external activities compared to apathetic participants, and thus had less time that they wish to dedicate to the game. Future studies including qualitative interviews may be useful to corroborate this interpretation.

### Kitchen and Cooking as an Assessment Tool

Correlation analysis revealed that performance in the different game activities was consistent with performance in the classical functional and neuropsychological tests. Specifically, the game gnosis time at the beginning of the training correlated with the TMT A time, thus confirming that the object search and selection task can be considered a good proxy for attentional processes, and the game executive functions time showed a significant correlation with the Victoria Stroop Test, an index of inhibition control. Furthermore, AD participants spent more time to complete a scenario compared to MCI participants, and were slower in the gnosis, praxis, and executive functions time, thus suggesting that the assessment made with Kitchen and scenario was in line with that made using classical assessment instruments.

This SG was not designed to substitute the classical functional, behavioral, and neuropsychological assessment. However, the present results suggest that it may be useful to complement classical assessment methods. For instance, it could be easily employed to track the evolution of executive functions and attentional deficits overtime. Furthermore, due to its playful nature, it may be particularly adapted to patients whose performance is strongly influenced by test anxiety. For instance a heavily impaired performance at the classical tests associated to preserved functioning in the SG activity may prompt the clinician to be more cautious in the interpretation of the test results.

## Kitchen and Cooking a Training Tool

The results of the training suggest that performance in the different game activities could be improved overtime. After 1 week of practicing on a scenario, participants became faster in both executive functions activity and praxis activity. Our training was designed to test feasibility and not the improvement in

# References

performance, so we did not ask participants to play every scenario in the first (S1) and last session (S5) with the clinician, meaning that we were unable to quantify exactly the improvement observed over 4 weeks. However, as patients were able to improve significantly their performance in 1 week, it is likely that the improvement in performance between S1 and S5 would be even more pronounced. This hypothesis is supported by the finding that participants who played more improved more in the game activities, specifically in the gnosis and executive functions.

Interestingly, MCI participants improved significantly more in the executive functions activity compared to AD participants. These results supports the view that early interventions targeting predementia stage are more effective in training cognitive abilities such as executive functions (REF), and suggest that Kitchen and cooking (employed as a training tool) may be specifically adapted to people with MCI.

# Conclusion

Kitchen and cooking is a SG game developed with the tight collaboration between clinicians and game designers in the context of the European FP7 project VERVE. This study suggests that Kitchen and cooking was acceptable, interesting and motivating for both patients with MCI and AD, and that it was adapted also to apathetic participants. This suggests that Kitchen and cooking could be an additional tool for clinicians in order to stimulate apathetic patients. Given these promising results, we are going to use the game in clinical practice, and propose the game to the patients coming for consultation to our Memory clinic and to the patients in the day centers, with a special focus on apathetic patients showing a loss or reduction in self-initiated behaviors, but preserved environmental-stimulated behaviors (Robert et al., 2009). This will allow us to collect additional data on the usability and acceptability of the game, and on its efficacy over longer training periods. Also, in order to allow the patients to select among a variety of activities, and to meet the interests of a wider variety of patients, we aim at creating new SGs.

# Acknowledgments

This study was supported by a grant from the FP7 European Commission Seventh Framework Programme VERVE project (Vanquishing fear and apathy through e-inclusion: http://www.verveconsortium.com/) and by the Innovation Alzheimer association.

due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. *Alzheimers Dement.* 7, 270–279. doi: 10.1016/j.jalz.2011. 03.008

Anguera, J. A., Boccanfuso, J., Rintoul, J. L., Al-Hashimi, O., Faraji, F., Janowich, J., et al. (2013). Videogame training enhances cognitive control in older adults. *Nature* 501, 97–102. doi: 10.1038/ nature12486

Yamaguchi, H., Maki, Y., and Takahashi, K. (2011). Rehabilitation for dementia using enjoyable video-sports games. *Int. Psychogeriatr*. 23, 674–676. doi: 10.1017/S1041610210001912

**Conflict of Interest Statement:** The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

*Copyright © 2015 Manera, Petit, Derreumaux, Orvieto, Romagnoli, Lyttle, David and Robert. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.*

# Clinical trial design of serious gaming in mild cognitive impairment

Cristina Muscio1, 2 \*, Pietro Tiraboschi 3 , Ugo P. Guerra4 , Carlo A. Defanti 1 and Giovanni B. Frisoni 5, 6

1 Fondazione Europea Ricerca Biomedica, Centro Eccellenza Alzheimer, Ospedale Briolini, Bergamo, Italy, 2 Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy, 3 Division of Neurology V/Neuropathology, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milan, Italy, 4 Fondazione Poliambulanza, Nuclear Medicine Department, Brescia, Italy, 5 Laboratory of Epidemiology, Neuroimaging and Telemedicine, IRCCS Centro San Giovanni di Dio-Fatebenefratelli, Brescia, Italy, 6 Memory Clinic and LANVIE - Laboratory of Neuroimaging of Aging, University Hospitals and University of Geneva, Geneva, Switzerland

Keywords: serious games, Alzheimer's disease, mild cognitive impairment, biomarker enrichment strategy, outcome measures, clinical trials

# Introduction

The "Global Impact of Dementia: 2013–2050" (Alzheimer's Disease International, 2013), released ahead of the December 2013 G8 Dementia Summit in London, estimated that 44.35 million people in the world were living with dementia in 2013. This number was predicted to increase to 75.6 million in 2030, and 135.5 million in 2050. This dramatic increase will have profound implications for social and economic costs (Alzheimer's Disease International, 2010). Since the most common dementia subtype (50–75%)is Alzheimer's disease (AD), its early detection and clinical effectiveness of its prevention and treatment represent a major public health concern and have been identified as a research priority (Alzheimer's Disease International, 2009; Ballard et al., 2011; Foster et al., 2014).

### Edited by:

Philippe Robert, University of Nice Sophia Antipolis, France

### Reviewed by:

Alexandra König, EA CoBTek CHU de Nice - Université de Nice Sophia Antipolis, France Julian Alvarez, Lille1 University, France Francois Bremond, Inria, France

### \*Correspondence:

Cristina Muscio<EMAIL_ADDRESS>
Received: 18 January 2015 Accepted: 23 February 2015 Published: 11 March 2015

### Citation:

Muscio C, Tiraboschi P, Guerra UP, Defanti CA and Frisoni GB (2015) Clinical trial design of serious gaming in mild cognitive impairment. Front. Aging Neurosci. 7:26. doi: 10.3389/fnagi.2015.00026

Recently, there has been a growing interest in employing Information and Communication Technologies (ICT) to evaluate patient's cognitive and functional impairment for early detection of AD (Wan Shamsuddin et al., 2011; Tarnanas et al., 2014). Beyond being important for assessment, ICT can also play a key role in the patient's treatment, stimulation, and rehabilitation (Robert et al., 2014). This is the idea underlying the current use of Serious Games (SGs), which are a broader reapplication of videogames resources integrating gaming and serious purposes. Lately, a few studies have started to investigate the efficacy of SGs used as an ICT intervention, which target cognitive decline, in people with AD and mild cognitive impairment (MCI). Until now, however, rigorous studies are still lacking. To overcome the current methodological issues and to evaluate the efficacy of SGs in secondary prevention (that currently is being pursued and is considered one of the potentially attainable goals of treatment, Foster et al., 2014), the purpose of the present opinion paper is to highlight the importance of defining harmonized SGs parameters, and to propose the implementation of biomarkers as enrichment strategy and outcome measures in SGs trial design. We will now review the history and state-of-art types and use of SGs, before describing in more detail our proposal.

# History of Serious Games: Origin, Typologies, Target

SGs are games designed for a primary purpose other than entertainment, enjoyment or fun (Michael and Chen, 2005). The historical origin of this oxymoron dates back to Neo-Platonists, who referred the term "serio ludere" to light-hearted approach in literature dealing with serious matters (Manning, 2004). The first use of SG oxymoron close to its current use seems to be in book written (Abt's, 1970), even though with a more extensive meaning. In fact, a SG could indeed be a computer game, a game, a role-playing game or even an outdoor game (Alvarez and Djaouti, 2012). The SG term in a digital context was firstly used in 2002, with the start of the Serious Game Initiative led by David Rejeski and Ben Sawyer in the US (De Gloria et al., 2014).

To date, SGs have been applied in many sectors, including education, training, defense, health, communications, marketing, politics, and the list is continually expanding (Alvarez and Djaouti, 2012). Since SGs addresses a set of markets, they are constituted by a wide variety of different types. Considering the dual nature of SGs, a system that classifies SGs according to both the "serious" and the "game" dimensions was proposed by Djaouti et al. (2011)1 . This model has classified 3080 SGs so far.

Examples of SGs include (see Alvarez and Djaouti, 2012, for a review): (i) military games, commonly dedicated to tactical and strategic training as well as recruitment for the army; (ii) edugames for educational and training purposes, also usable in a school context; (iii) advergames, where the gameplay is centered around a commercial message; (iv) newsgames that are based on current events or certain journalistic issues; (v) SGs dedicated to health sector aimed to improve player's cognitive or physical abilities; etc.

SGs do not target exclusively young gamers. A considerable proportion (20–29%) of regular digital gamers are indeed older than 50 years (ESA, 2011; BIU, 2014). In this respect, it is worth noting the increase by 32% in the number of US females gamers aged 50 and older from 2012 to 2013 (ESA, 2014). Because the number of elderly people who play video games in the past decades has steadily increased and is predicted to grow further (Robert et al., 2014), even small beneficial effects may have significant public health implications (Alzheimer's Disease International, 2014).

# The State-of-Art Use of Cognitive Serious Games with Healthy Older Adults and Ad Patients

The cognitive effect of SGs played by older adults has not yet been studied thoroughly (Weybright et al., 2010; Alzheimer's Disease International, 2014). In the context of research focused on successful cognitive aging and on the possibility to modify the cognitive decline normally associated with healthy aging (Zinke et al., 2014), anyway, SGs have been demonstrated to be a motivating tool with some beneficial effects in improving cognitive functions in healthy older adults (Nouchi et al., 2012; Anguera et al., 2013). In the study reported by Anguera et al. (2013), indeed, it's worth mentioning that: (i) SG improved both trained and untrained cognitive abilities, which is commonly referred to as a transfer effect, that is the effect due to a training not only on skills or performance that are trained, but also on skills or performance that are not trained (Nouchi et al., 2012); (ii) untrained abilities that improved were sustained attention and working memory, which are known to be involved in everyday functioning; and (iii) performance gains remained stable 6 months after training without booster sessions. This transfer effect of SG on the improvement of executive functions and processing speeds in the elderly has been also demonstrated with a short-term training (Nouchi et al., 2012), suggesting that a possible transfer effect from laboratory-based tasks to real world ones may be expected. Neurophysiological findings support training-induced neuroplasticity as the mechanistic basis of these SG effects (Anguera et al., 2013).

However, whether AD patients or population at high risk for developing AD (i.e., MCI) may benefit from SGs is unknown (Robert et al., 2014).

Recently, some studies have started to employ SGs with people with AD and MCI as a cutting-edge cognition-focused intervention (**Table 1**). Cognition-focused interventions fall under the broader umbrella of non-pharmacological interventions, and can be defined as interventions that directly or indirectly target cognitive functioning as opposed to interventions that focus primarily on behavioral, emotional or physical functions (Bahar-Fuchs et al., 2013). These interventions are typically designed to promote intellectual stimulation and minimize cognitive impairment (Weybright et al., 2010). Progressive decline of cognitive functions is indeed a clinical feature of AD and has been found to be associated with impairment in activities of daily living (Tomaszewski Farias et al., 2009). Thus, intervention aimed at prevention and rehabilitation of such decline may promote a longer independent life at home and decrease the burden of dementia on patients and families.

Despite the promising results and the increasing interest in applying cognitive SGs to AD/MCI patients, rigorous feasibility and efficacy studies are still lacking, partly reflecting the only recent interest in employing SGs in cognitively impaired patients (Robert et al., 2014). The main methodological issues are: limitation of randomized controlled studies and lack of harmonized procedures (i.e., absence of standardized SG parameters such as when, where and with whom SGs have to be played), as well as small sample size and questionable choice of patient selection and outcome measures. However, these issues are common in studies addressing cognition-focused interventions (Woods et al., 2012; Bahar-Fuchs et al., 2013).

## Future Perspectives

### Definition of Harmonized SGS Parameters

To overcome the current lack of harmonized procedures, one important aspect to be taken into account in the SG trial design includes the definition of parameters such as when, where and with whom SGs are more adapted to be played by AD/MCI patients.

According to the recommendations reported in (Robert et al., 2014), SGs for MCI patients' stimulation could be considered adapted to be used both everyday and once a week; at home, in day centers and in the nursing homes; with a therapist, a professional caregiver and a family caregiver.

In our opinion, SG trials should take into account these methodological recommendations, and assess SG feasibility and efficacy due to when, where, with whom SG is played by patients.

1http://serious.gameclassification.com

patients.

TABLE

As far as "with whom" is concerned, we think that it could also be interesting to study SGs played by multiple players physically copresent or by online patients connected from remote locations. One of SG strengths is indeed its possible role in promoting social interactions among patients with cognitive impairment (Robert et al., 2014).

### Biomarkers as Enrichment Strategy and Outcome Measures

 group.

> It is generally estimated that up to one third of patients enrolled in AD trials do not have AD (Delrieu et al., 2014), leading to dilution of observable treatment effects (Aisen, 2011). However, AD pathology can be identified in living subjects through pathophysiological markers indicative of abnormal amyloid deposition that, in addition to a specific cognitive profile, moves a patient from a status of MCI of undetermined etiology to that of prodromal AD (Dubois et al., 2014). CSF Aβ1-42 and/or PET-amyloid imaging, as well as hippocampal atrophy on MRI, have indeed been qualified as enrichment biomarkers to enroll predemented AD subjects in regulatory clinical trials (see EMA/CHMP/SAWP/893622/2011 and EMA/CHMP/SAWP/809208/2011 qualification opinions). Inclusion of biomarkers into clinical trials for treatment of early AD has until now been recommended for pharmacological studies alone. However, both pharmacological and nonpharmacological studies can share the same issues that may have contributed to their failures (Doody et al., 2014; Salloway et al., 2014), including for example misdiagnosis of patients and insensitivity of outcome measures.

> To overcome the above-mentioned limitations of cognitionfocused interventions pertaining to patient selection and outcome measures, and to evaluate the efficacy of SG in secondary prevention, we propose to implement in the SG trial design: (i) a biomarker enrichment strategy to enroll MCI due to AD, and (ii) the use of biomarkers as outcome measures in combination with clinical ones.

> A biomarker enrichment strategy would be expected to support screening out non-AD cases and screening in AD ones, reducing the diagnostic inaccuracy at enrollment and, thus, minimizing the masking of treatment effects that occurs when misdiagnosed patients are recruited (Morris and Selkoe, 2011). Once identified MCI due to AD using enrichment biomarkers, it could also be relevant to randomize these patients after stratifying them into different groups based on positivity on one or more biomarkers, in order to evaluate a possible differential effect of SG on MCI subjects presumably at different pre-dementia stages of the AD process. MCI patients with brain amyloidosis and neurodegeneration are indeed at higher risk of dementia in the following years. According to the current pathophysiologic model of AD (Jack et al., 2010), they might be at a more advanced disease stage (Prestia et al., 2013). For this reason, a SG effect dependent on single or multiple biomarker positivity could be hypothesized and taken into account for defining optimal SG protocols. Patients with MCI could also be stratify into two groups based on positivity or negativity of biomarkers, in order to investigate whether cognitively impaired subjects devoid of AD pathology might have a greater benefit due to less severe neuronal injury

TABLE

1

Continued

and, consequently, greater brain reserve (Stern, 2009). Finally, it could be interesting to verify if there is an association between biomarkers and methodological parameters cited in the previous subparagraph: for instance, can patients with a single positive biomarker or negativity of biomarkers take advantage from SGs played at lower time intensity (e.g., once at week) or alone at home compared with patients with multiple positive biomarkers or positivity of biomarkers, respectively?

Some studies in AD and MCI patients have shown that MRI and FDG-PET biomarkers may be more sensitive to change than clinical measures, as reported by Caroli et al. (2014) but regulatory agencies have not yet recognized biomarkers as surrogate outcome measures. This cautious approach is due to the requirement that, to be recognized as surrogate outcome measures, biomarker changes should reliably predict detectable clinical changes (Aisen, 2011). Unfortunately, the results of randomized clinical trials with anti-beta amyloid drugs (Abeta vaccine AN1792 and bapineuzumab) have until now shown no clinical efficacy despite a change in biomarkers. On the other hand, use of biomarkers would allow studies with fewer participants, shorter durations, lower costs, and with the possibility to control for the specificity of disease-modifying effect (Morris and Selkoe, 2011; Food and Drug Administration: Draft Guidance for Industry. Alzheimer's Disease: Developing Drugs for the Treatment

## References

of Early Stage Disease, 2013). Recent non-pharmacological studies that have incorporated hippocampal atrophy as biomarker outcome have found a disease-modifying benefit of aerobic exercise in early AD over 6 months (Honea et al., 2014), suggesting that similar results could also be found applying physical and cognitive SGs.

# Conclusions

If the presumed beneficial effects of SGs will be demonstrated by robust studies, the potential societal impact will be huge considering the very high prevalence of cognitive impairment due to AD, the popularity of video games played by baby-boomers now at risk of dementia, the current lack of effective treatments, and the cost-effectiveness of these enjoyable interventions. Moreover, video games already marketed to older adults for maintaining cognitive health may be seen as a scale up of a prevention program in a high-risk subgroup of the population (Alzheimer's Disease International, 2014). SGs may represent a motivating, low-barrier, engaging and sustainable method to improve or at least delay the decline in specific social, sensory-motor, cognitive and emotional functions of elderly people (Wiemeyer and Kliem, 2012).

**Conflict of Interest Statement:** The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2015 Muscio, Tiraboschi, Guerra, Defanti and Frisoni. This is an openaccess article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

# Reliability of a novel serious game using dual-task gait profiles to early characterize aMCI

*Ioannis Tarnanas1\*, Sotirios Papagiannopoulos1, Dimitris Kazis1, Mark Wiederhold2, Brenda Widerhold3 and Magda Tsolaki1*

*1 3rd Department of Neurology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece, 2 Division of Cognitive and Restorative Neurology, Virtual Reality Medical Center, San Diego, CA, USA, 3 Virtual Reality Medical Institute, Brussels Life Sciences Incubator, Catholic University's Woluwe Campus, Brussels, Belgium*

Background: As the population of older adults is growing, the interest in a simple way to detect characterize amnestic mild cognitive impairment (aMCI), a prodromal stage of Alzheimer's disease (AD), is becoming increasingly important. Serious game (SG) based cognitive and motor performance profiles while performing everyday activities and dual-task walking (DTW) "motor signatures" are two very promising markers that can be detected in predementia states. We aim to compare the consistency, or conformity, of measurements made by a custom SG with DTW (NAV), a SG without DTW (DOT), neuropsychological measures and genotyping as markers for early detection of aMCI.

### *Edited by:*

*Valeria Manera, University of Nice Sophia Antipolis, France*

### *Reviewed by:*

*Cristina Muscio, Fondazione Europea di Ricerca Biomedica, Italy Pedro Gamito, Lusophone University, Portugal*

### *\*Correspondence:*

*Ioannis Tarnanas, Gerontechnology and Rehabilitation Group, University of Bern, CH-3010 Bern, Switzerland<EMAIL_ADDRESS>
> *Received: 19 January 2015 Accepted: 26 March 2015 Published: 22 April 2015*

### *Citation:*

*Tarnanas I, Papagiannopoulos S, Kazis D, Wiederhold M, Widerhold B and Tsolaki M (2015) Reliability of a novel serious game using dual-task gait profiles to early characterize aMCI.*

> *Front. Aging Neurosci. 7:50. doi: 10.3389/fnagi.2015.00050*

Methods: The study population included three groups: early AD (*n* = 86), aMCI (*n* = 65), and healthy control subjects (*n* = 76), who completed the custom SG tasks in three separate sessions over a 3-month period. Outcome measures were neuropsychological data across-domain and within-domain intra-individual variability (IIV) and DOT and NAV latency-based and accuracy-based IIV. IIV reflects a transient, withinperson change in behavioral performance, either during different cognitive domains (across-domain) or within the same domain (within-domain). Test–retest reliability of the DOT and NAV markers were assessed using an intraclass correlation (ICC) analysis.

Results: Results indicated that performance data, such as the NAV latency-based and accuracy-based IIV, during the task displayed greater reliability across sessions compared to DOT. During the NAV task-engagement, the executive function, planning, and motor performance profiles exhibited moderate to good reliability (ICC = 0.6–0.8), while during DOT, executive function and spatial memory accuracy profiles exhibited fair to moderate reliability (ICC = 0.3–0.6). Additionally, reliability across tasks was more stable when three sessions were used in the ICC calculation relative to two sessions.

Discussion: Our findings suggest that "motor signature" data during the NAV tasks were a more reliable marker for early diagnosis of aMCI than DOT. This result accentuates the importance of utilizing motor performance data as a metric for aMCI populations where memory decline is often the behavioral outcome of interest. In conclusion, custom SG with DTW performance data provide an ecological and reliable approach for cognitive assessment across multiple sessions and thus can be used as a useful tool for tracking longitudinal change in observational and interventional studies on aMCI.

Keywords: mild cognitive impairment, early diagnosis, motor performance, virtual reality, test–retest reliability, Alzheimer's disease

# Introduction

Even though a number of risk factors for sporadic Alzheimer's disease (AD), the most common type of dementia, have been discussed (e.g., diagnosis of mild cognitive impairment (MCI), hippocampal atrophy, family history of AD, apolipoprotein-E ε4 allele [APOE-ε4]), one of the most well-documented risk factors for the disease is increasing age (Ferreira et al., 2014; Naj et al., 2014). Neurodegenerative changes such as atrophy, which is characteristic of AD, and occasionally of other dementing diseases such as fronto-temporal lobar dementia (FTLD) or Hippocampal Sclerosis, have a relatively long pre-morbid asymptomatic period (Lindberg et al., 2012a; Pelletier et al., 2013). At the same time, despite the fact that no cognitive symptoms may be obvious during the pre-morbid period, by the time AD is diagnosed, sufficient neuronal injury has occurred such that reversal of the disease is perhaps unlikely (Petersen, 2003; Lindberg et al., 2012b; Lockhart et al., 2012). This has therefore raised considerable interest in the prodromal stage of AD, involving revised criteria for diagnosing an early clinical stage of AD ("MCI due to AD," aMCI or MCI-AD; Dubois and Albert, 2004; Michon, 2009; Sperling et al., 2011) and "Prodromal AD"(Albert et al., 2011) and incorporating biomarkers to increase the certainty of the diagnosis (Dickerson et al., 2013).

The accuracy of early diagnosis for dementia is increasingly important for both therapeutic and scientific investigations. Many of the early-onset dementias are treatable, and the presentation of the common degenerative diseases of late life, such as AD, can be different when presenting in the fifth or sixth decade. The currently available diagnostic tests have moved the field closer to early diagnosis of AD; however, differential diagnosis is broad, and a definitive diagnosis is made only with the development of clinical dementia and the presence of amyloid plaques and neurofibrillary tangles at autopsy (Snowden et al., 2011). An ideal AD biomarker should be able to satisfy the following criteria: the ability to diagnose AD with high sensitivity and specificity as confirmed by the gold standard of autopsy validation, detect early-stage disease, and track the progression of AD and monitor disease progression or therapeutic efficacy (McKhann et al., 2011). This understanding could offer the potential for tailored treatments and a specific diagnosis for both early-onset and late-onset dementia. MCI-AD, or aMCI, is a term used to describe early AD signs that precede functional and cognitive impairment (Sperling et al., 2011) and may be clinically indistinguishable from what is described as "probable AD" (Albert et al., 2011; Dickerson et al., 2013). Epidemiological studies have suggested that the most common form of aMCI is a multiple deficit syndrome with memory impairment and a 10–15% annual risk of conversion to AD (Portet et al., 2006). According to some recent studies, MCI individuals with amnestic syndrome of the hippocampal type (HaMCI), compared to those with the amnestic syndrome of the non-hippocampal type (NHaMCI), are the leading at-risk subgroup of the MCI population for the development of dementia due to AD (Sarazin et al., 2007). However, it is still controversial whether the tests designed to detect hippocampal amnestic syndrome (Duara et al., 2013), such as atrophy of the hippocampus in the CA1 subfield region (Burger, 2010; Fletcher et al., 2014), are superior to other tests for the detection of early-stage dementia (Albert et al., 2011; McKhann et al., 2011). Yet, in addition to the atrophy of hippocampus only in the CA1 subfield region experts recently developed the harmonized protocol for the manual segmentation of the whole hippocampus (Prestia et al., 2013, Alzheimers Dementia). Indeed, after a harmonization effort lasted 4 years and funded by the Alzheimer's Association, world experts converged onto the harmonized segmentation protocol, which. the European Medicines Agency has qualified as an enrichment biomarker to enroll mild and moderate as well as predemented AD subjects in regulatory clinical trials.

Besides the usefulness of cued recall as a diagnostic tool for aMCI and AD (De Jager et al., 2010; Kelemen and Fenton, 2010; Carlesimo et al., 2011; Chechko et al., 2014), emerging evidence has demonstrated the value of walking stability and variability analysis as an early indicator of aMCI and AD (Persad et al., 2008; Gillain et al., 2009; Theill et al., 2011; Montero-Odasso et al., 2012; Muir et al., 2012). More specifically, prospective studies over periods of five and 6 years in cohorts of 427 and 603 older subjects over 70 years of age demonstrated that initial quantitative measures of gait, such as velocity, variability, and frequency can predict the risk of developing dementia (Waite et al., 2005; Verghese et al., 2007; Montero-Odasso et al., 2014). However, the relationship between cognitive function in everyday abilities and gait variables in conditions other than normal walking (NW) is insufficiently understood in people with aMCI. In everyday activities, there are numerous dual-task walking (DTW) situations that require active involvement of the visual system (Al-Yahya et al., 2011). Observing how people walk while they perform a secondary task with a high demand on attention, i.e., a dual-task paradigm, has been used to assess interactions between cognition and gait. Executive function is often implicated in DTW because subjects must walk and adapt to new and/or complex situations that involve working memory, mental inhibition, and mental flexibility. In addition, less efficient executive functions in older adults have shown significant contribution to impairments in spatial memory, especially when spatial interference is high (Holden and Gilbert, 2012).

Another concept that has recently attracted the attention of researchers and clinicians is that of cognitive frailty. Recent work has defined cognitive frailty as a multi-dimensional geriatric syndrome characterized by the simultaneous presence of both physical frailty and cognitive impairment without the presence of a concomitant neurological disease (see Kelaiditi et al., 2013 for a review). Cognitive frailty is viewed as a potential precursor of neurodegenerative processes (Duron et al., 2014). However, few studies have made the link between motor fragility reflected by a reduction in walking velocity and cognitive fragility reflected by an early alteration in executive function and have hypothesized that alteration in motor performance could occur before detection of cognitive impairment (Perrochon et al., 2013).

In a similar vein, recent studies have shown that increased cognitive intra-individual variability (IIV) across accuracy scores from neuropsychological tests, representing different cognitive domains (across-domain IIV), might serve as a biomarker of cognitive frailty occurring before detection of prodromal AD (Kälin et al., 2014). More particularly, latency- (variability across response time performance scores) and accuracy-based IIV (variability across accuracy scores – correct vs. wrong responses) have reportedly been associated with functional decline (Dixon et al., 2007; Morgan et al., 2012), incident dementia (Holtzer et al., 2008), and probable AD (Brewster et al., 2012). A more recent study compared within- and across-domain IIV and APOE genotype between healthy control subjects (HCS), MCI, and AD in a single comparative study and found that withindomain IIV may constitute a cognitive marker for the detection of prodromal AD at the MCI stage, whereas across-domain IIV may detect beginning AD at the MCI stage (Kälin et al., 2014).

In this context, computerized cognitive assessments, such as serious games (SGs), can ideally be applied to detect subtle changes in both DTW and IIV between HCS and aMCI performance profiles (Robert et al., 2014). There is already evidence that SG can be successfully employed for the characterization of episodic and prospective memory profiles in MCI and AD (Werner et al., 2009; Weniger et al., 2011; Plancher et al., 2012) or even early screening for aMCI (Tarnanas et al., 2013, 2014). According to the literature, SG interactions require coordination of information by eliciting medium to high cognitive control, such as inhibition of external stimuli or processing speed (e.g., reaction time at interactive events), which is believed to be affected by aging (De Lillo and James, 2012; Korsch et al., 2014). Very recently, an innovative DTW concept for detecting cognitive impairment eliciting medium to high cognitive control, called the Walking Stroop Carpet, was demonstrated by Perrochon et al. (2013), but to our knowledge, this is the first study reporting on a complex everyday activities SG employing DTW, which might indicate prodromal AD.

The aim of this study was to (1) systematically evaluate the reliability of two SGs—a high cognitive control, requiring inhibition of external stimuli, and planning a virtual day-out task without DTW (DOT) and a high cognitive control, requiring inhibition, navigation task with DTW (NAV)—and (2) explore the stability of test–retest measurements as a factor of the number of SG sessions.

# Materials and Methods

### Participants

A total of 270 participants (HCS *n* = 100, aMCI *n* = 80, and AD *n* = 90) were considered for analysis from ongoing studies at the 3rd Neurological Clinic of the Aristotle University of Thessaloniki, Greece and from the Greek Association for Alzheimer Disease and Related Disorders (GAADRDs) Memory Clinics, belonging to the 3rd Neurological Clinic of the Aristotle University of Thessaloniki. The study was carried out in accordance with the Declaration of Helsinki, and the participants were recruited from the outpatient population of the GAADRD Memory Clinics or by advertisement in the local media. All subjects had complete cognitive baseline data acquired between January 2010 and April 2013 with written informed consent obtained prior to study participation. From the original HCS sample, 24 subjects were excluded from the analyses due to alcohol abuse (*n* = 2), dropout (*n* = 6), and medication (*n* = 16). Also, 15 aMCI and six early AD subjects were also excluded due to dropout after the initial assessment. Thus, a total of 76 HCS, 65 aMCI, and 86 early AD patients were eligible for the analyses.

Amnestic MCI was diagnosed according to the criteria of Winblad et al. (2004), and all diagnoses were made by a multidisciplinary team under the supervision of an experienced psychiatrist. The diagnosis was made if the patient met the following criteria: (1) memory complaint, (2) abnormal memory for age, (3) normal activities of daily living, (4) normal general cognitive function, and (5) not demented. Structural magnetic resonance imaging (MRI) data were also available in our aMCI cases in order to exclude other conspicuous brain abnormalities that could account for cognitive decline. The diagnosis of AD was done according to the International Working Group (IWG-2) criteria considering three main markers: abnormal neuropsychological assessment, medial temporal atrophy on MRI, and abnormal Abeta42 or tau protein concentrations in the CSF (Dubois et al., 2014). Additionally, all three groups (HC, aMCI, and early AD) were screened for disorders, which could potentially produce cognitive impairment, i.e., depression; psychiatric, neurological, and other diseases. Such subjects were excluded if there were such disorders or medication use potentially affecting cognition. Furthermore, it was ascertained that all participants had normal or corrected to normal vision. All participants but three older adults were right-handed, according to the Edinburgh Handedness Inventory (Oldfield, 1971).

## Neuropsychological and Psychomotor Examination

All subjects were assessed with a standardized neuropsychological test battery. The neuropsychological test battery consisted of multiple tests covering the following cognitive domains: working and episodic memory, executive function, attention/psychomotor processing speed, language, and visualconstructive abilities. The Mini–Mental State Examination (Folstein, 1975) was used to assess global cognitive functioning. For episodic memory, the Grober–Buschke scale was used (Grober et al., 1988; Carlesimo et al., 2011). Short-term memory and working memory were investigated using a digit span forward test (Ramsay and Reynolds, 1995). Tests of executive functioning included verbal fluency and category fluency (the Set Test; Isaacs and Akhtar, 1972), Stroop (Stirling, 1979), and the TMT B (Tombaugh, 2004). Long term memory was assessed with the Rey Auditory Verbal Learning Test (RAVLT; Rosenberg et al., 1984). We determined impairment if at least one score per domain was 1.5 SD below group means compared to test-specific normative data.

In addition to the neuropsychological examination, participants also completed a baseline psychomotor evaluation in order to exclude physical frailty or other forms of physical disability that might affect the reliability of both DTW and across-domain and within-domain latency- and accuracy-based IIV across SG performance profiles, such as arthritis. The psychomotor examination included a number of simple and complex measures addressing the ability to understand and perform with accuracy specific physical performance tasks. These tasks included the following: (a) "Gait-speed" was measured as the time (to 0.1 s) required for a participant to walk a 4.6-m course at his or her usual pace after starting from a standstill and recorded by stopwatch, and b) the "Finger-Tapping Test" measured both the dominant and non-dominant hand using a computerized screening test, which measured finger tapping speed for a given duration of 10 s.

### Quantitative Gait Assessment

We performed a baseline motor evaluation of single-task spontaneous walking for 10 m in a normal environment on an 8-m electronic walkway (GAITRite-R , CIR Systems Inc, Sparta, NJ, USA). This tool is equipped with a portable, pressure-sensitive electronic walkway [793 cm × 61 cm × 0.6 cm (L × W × H)] which provides data for both spatial and temporal gait parameters. The simple-task trial consisted of walking the length of the mat at the participant's usual pace. For the dual-task trials, participants walked at their usual pace, with no instruction to prioritize the gait or cognitive task, while doing the following cognitive tasks aloud: (i) counting backward from 100 by ones and (ii) naming animals. To balance and minimize the effects of learning and fatigue, the order of the dual tasks was randomized. Allowing both gait and cognitive tasks to vary provides a better representation of daily living activities, and the reliability of this protocol in people with MCI has been previously established (Montero-Odasso et al., 2009).

### SG Hardware Setup

The SG used is patent pending (XtremeVRI AG, Winterthur, Switzerland) and used mobile phone based Augmented Reality (AR) in order to present cognitive tasks and record all behavioral and kinetic responses while the subject navigated the AR environment inside his house (**Figure 1**).

### DOT and NAV Tasks

The novel SG used in this study consisted of two modules simulating complex activities of daily living (CADL): the 3D immersive reality day-out complex task without DTW (DOT) and the 3D immersive reality spatial NAV. The DOT was a complex task breakdown followed by a rehearsal exercise of a virtual apartment building fire evacuation drill. The drill included six different scenarios of increasing difficulty, where participants navigated the virtual environment using a first-person perspective and simple hand pointing gestures for forward, backward, and left, and right lateral movement, respectively. They could also use natural finger pointing and grabbing gestures in order to select, pick, drop, and move objects inside the virtual environment and had to complete each within 8 min. All participant movement within the virtual building was recorded at 10 Hz and represented as a series of *x*, *y*, *z* coordinates, with actions annotated and time stamped.

The DOT naturalistic actions script was based on an ordered list of right and wrong actions that was prepared by an occupational psychologist and was used to examine executive function and prospective memory as well as planning and reasoning in a complex emergency routine. The fire evacuation drill setting had six different simulated fire situations (from easy to more difficult) taking place at a virtual apartment block with three levels and five apartments per level. The task put a medium to high load on the cognitive control processes with which older adults prioritize, organize, initiate, and complete a number of

subroutines (e.g., pick-up the phone and call the fire department, sound the fire-alarm) in order to evacuate safely and in the fastest possible way from an apartment level (e.g., second floor) to the ground area (e.g., determine and gather information on the size of the fire, avoid smoke, avoid wrong actions like using the elevator). In this sense, DOT is a complex activity of daily living, which previous research showed is a valid and reliable indicator of cognitive decline in elderly persons (Tarnanas et al., 2013).

The NAV task took place at the same virtual apartment block but with the player challenged in different aspects of executive function, such as volition, self-awareness, planning, inhibition of dominant response, and external distraction during response control, and dual-task coordination. The goal at difficulty level 1 was to navigate from point A to point B, after the route was demonstrated by a first-person perspective camera walkthrough without iteration. The NAV task took place with six levels of difficulty, with the addition of one more point of destination per difficulty level—for example, level 3 has three points to reach, level 4 has four, etc. Each level had a starting position (start) and an end position (goal) and multiple ways to arrive from start to goal. Participants were asked to make their way from start to goal in the shortest time possible. The NAV task placed a medium to high demand on higher order cognitive control processes, such as following a mental strategy to reach the goal with performance monitoring while inhibiting environmental stressors, such as virtual characters forcing the player to choose a less familiar route or interact with distractors in the virtual environment, a process which typically involves cognitive control.

According to the literature, interactions such as the DOT and NAV tasks, require participants to follow a mental strategy and monitor their performance by eliciting medium to high cognitive control, such as inhibition of external stimuli or processing speed (e.g., reaction time at interactive events; Kelemen and Fenton, 2010). This coordination of information to select appropriate behavioral responses is believed to be affected by aging (Korsch et al., 2014).

The order of participating in either the DOT or NAV tasks was random, and both started after each participant had 5 min to read written instructions detailing the task, virtual building layout, and task rules. Then, participants practiced the virtual environment using gestures to move around the building and completed 3 practice runs involving object collection, button pressing, unlocking the stairwell door with a key code, and folder sorting. This also allowed participants to familiarize themselves with the building. None of the practice runs were used in the main task. The practice session took in total approximately 20 min.

Participants played all difficulty levels of DOT and NAV in a baseline session (Visit 1), again all levels at a 1-month postbaseline session (Visit 2), and finally all levels at a 3-month post-baseline session (Visit 3). A total of three sessions were measured in order to assess test–retest reliability.

# Computation of IIV of DOT and NAV Performance

In order to apply IIV computations to the DOT and NAV performance profile data, we first had to categorize the performance profiles into accuracy-based and latency-based data. Since NAV was a more complex task than DOT, we conducted a principal component analysis (PCA) of participants' performance data on the cognitive variables at their initial visit in order to create composite IIV measures. We then used the Spearman's correlations to identify three accuracy- based and three latencybased performance categories, explained bellow, which place medium to high demands on higher order cognitive abilities for both DOT and NAV. Across-domain IIV was calculated with tasks representing different cognitive domains, while within-domain IIV was calculated with tasks representing cognitive control. Additionally, in order to avoid ceiling or floor effects, we added performances from each difficulty level and calculated a total performance profile from all difficulty levels per cognitive domain and category above in order to prevent suppressing variation at the extreme ends of the distribution.

To calculate DOT across-domain accuracy-based IIV, we used accuracy scores from three data categories, each representing a different cognitive domain: (1) spatial memory accuracy measured as the correct route selection, such as the nearest emergency exit or route for the evacuation of the virtual apartment building, according to the memorized virtual building layout; (2) planning accuracy measured as the correct order of subroutines execution, such as first sounding the fire alarm and then calling the fire department; and (3) executive functions accuracy measured as successful subroutines completion, such as sounding the fire alarm.

NAV across-domain accuracy-based IIV was calculated using accuracy scores from three data categories, each representing a different cognitive domain: (1) spatial memory accuracy measured as correct route selection, such as the nearest route for navigating from start to goal, according to the memorized virtual building layout; (2) planning accuracy measured as the correct order of subroutines execution, such as first going to point B and then to point C before goal; and (3) executive functions accuracy measured as successful subroutines completion, such as reaching each point from start to goal.

For calculating DOT within-domain accuracy-based IIV, we used accuracy performance data from three categories, each representing executive functions and eliciting recruitment of cognitive control processes. We calculated: (1) omissions of the subroutines, (2) repetition of the same subroutine, and (3) perseverations of incorrect order while performing the subroutines before completing the given script per difficulty level. According to the literature, virtual reality-based navigation, and interactions, such as the DOT task process, require participants to generate, maintain, and monitor a plan and to select and establish specific responses—therefore, accessing cognitive control (Cushman et al., 2008).

Accordingly, for calculating NAV within-domain accuracybased IIV, we used accuracy performance data from: (1) omissions of the destination points between start and goal, (2) repetition of the same destination point, and (3) perseverations of incorrect order while navigating to the goal before completing the given script per difficulty level. Participants needed to maintain a goal while inhibiting a routine response in favor of a less familiar one, a process which typically involves cognitive control (West et al., 2002).

The DOT across-domain latency-based IIV was calculated using performance data from the participant's timed response within three data categories, each representing a different cognitive domain: (1) total time to complete the navigation route per difficulty level, according to the memorized virtual building layout; (2) total time to complete the order of emergency evacuation subroutines execution; and (3) time of execution through acceleration data, such as "fast hand pointing gestures," per subroutine completion.

In order to calculate the NAV across-domain latency-based IIV, we used performance data from the participant's timed response at: (1) total time to complete the navigation route per difficulty level; (2) gait frequency at interactive events, such as avoidance of moving obstacles and distractors; and (3) gait parameters such as stride length, distance, and variability of stride while completing the navigation per destination point.

DOT within-domain latency-based IIV was calculated using timed response performance data from the following categories, eliciting recruitment of cognitive control processes: (1) reaction time of "navigation gestures" usage, measured as the time elapsed between the virtual character idle state and the next immediate "direction command"; (2) reaction time of "interaction gestures" usage, measured as the time elapsed between the virtual character idle state and the next immediate interaction response to the virtual environment, such as "open door action"; and (3) reaction time at interactive events, such as avoidance of moving obstacles.

Finally, to calculate NAV within-domain latency-based IIV, we used timed response performance data from the following categories, eliciting recruitment of cognitive control processes during DTW: (1) gait velocity during the navigation, measured as the time elapsed between the virtual character idle state and the next immediate "direction command"; (2) cadence, measured as steps per minute between the virtual character idle state and the next immediate interaction response to the virtual environment, such as "open door action"; and (3) time in double support during interactive events, such as avoidance of distractors and moving obstacles.

Following the work described in recent studies (Nesselroade and Salthouse, 2004; Kälin et al., 2014), we calculated the intraindividual standard deviation (ISD) across each individual's performance profile data in order to compute IIV. Starting from the accuracy-based IIV and the HCS group, we log-transformed performance data in order to achieve normal distribution and multiplied by -1 to adjust for scaling difference. This process generated for HCS standardized residuals representing adjusted accuracy and latency scores with a mean of 0 and variance of ∼ 1. We used the General Linear Model to estimate effects associated with age, education, gender, and potential interactions. The model parameters were used to predict accuracy scores in aMCI and early AD subjects. We then calculated standardized residuals for aMCI and early AD subtracting the predicted from the observed accuracy scores and dividing it by the model's SE. Similar to the work of Kälin et al. (2014), we used the intra-individual mean (IIM) across residuals underlying acrossdomain IIV (across-domain IIM) and across residuals underlying within-domain IIV (within-domain IIM) as covariates in all relevant analyses in order to address the association between ISD and mean performance.

Accordingly, for the latency-based IIV we followed data preparation procedures similar to those of Bielak et al. (2010). We removed the high and low outliers in reaction time from each performance profile category for each participant. We defined high outliers as the individual reaction times that were greater than 3 SD more than the person's mean reaction time and low outliers as individual reaction times less than 3 s. After the outliers were removed, we recalculated mean RT and within-person ISDs for each participant. In order to remove the effect of mean RT from the ISDs, since mean RT is positively associated with variability, and age is associated with slower reaction times (Anstey et al., 2007), we regressed the ISDs on mean RT and collected standardized ISD residuals. Finally, the ISDs of all variables were normally distributed, and we calculated the across-domain IIV and within-domain IIV composite scores of the standardized residuals.

### Genotyping Data

We used restriction isotyping to classify participants as either carriers (APOE ε2/ε4, ε3/ε4, and ε4/ε4) or non-carriers of the APOE ε4 allele. A similar approach is also described in another IIV study (Kälin et al., 2014).

# Statistics

All analyses were performed as two-tailed tests using the statistical analysis software package PASW 18.0 for Windows. We used univariate analysis of variance (ANOVA) to perform the group comparisons of normally distributed demographic, raw, and adjusted performance data applying Sidak *post hoc* tests correcting for multiple comparisons. Not normally distributed variables were analyzed with Kruskal–Wallis tests followed by Mann–Whitney tests corrected for multiple comparisons, and categorical variables were analyzed with Pearson's chi-square test. Difference in across- and within-domain IIV was analyzed with univariate analyses of covariance (ANCOVA) in order to evaluate group-wise differences with the diagnostic group treated as the main effect. The influences of age, gender, and education as well as across- and within-domain IIM were also used as covariates to control for influences on IIV. To calculate the effect of the IIV type (accuracy- vs. latency-based), we used multivariate analyses of covariance (MANCOVA), and to account for the unbalanced designed we applied Sum of Square Type III. We calculated significant group effects using a Sidak *post hoc* test correcting for multiple comparisons. Finally, all parametric analyses were performed with a significance level of *p <* 0.05, while a significance level of *p <* 0.017 (0.05/3 = 0.017) was applied for non-parametric analyses.

Following a recent study (Montero-Odasso et al., 2014), gait variability was calculated as the coefficient of variation for stride time: CV = (SD of stride time/mean stride time) × 100. Gait velocity (cm/s) and stride time variability (CVst, %) were measured during the NAV dual-task trials.

We assessed the test–retest reliability with the intraclass correlation coefficient (ICC) as defined by Shrout and Fleiss (1979). This form of ICC utilizes a two-way ANOVA in which both the SG performance data and participants are treated as random effects to assess reliability at a single point in time. Using this model, test–retest reliability was characterized as excellent (ICC N 0.8), good (ICC 0.6–0.79), moderate (ICC 0.4–0.59), fair (ICC 0.2–0.39), or poor (ICC b 0.2; Kam et al., 2012). We assessed the stability of ICC using three SG data collection sessions by calculating the ICC values from the first two sessions and comparing them to the values from all three sessions.

# Results

The baseline demographic details are summarized in **Table 1**, including IIV computations from the baseline neuropsychological performance.

In general we observed a main effect between diagnostic groups and IIV [*F(*2*,*225*)* = 7.87; *p* = 0.001; η2 = 0.07]. We also observed that IIV in general was influenced by age [*F(*1*,*225*)* = 4.21; *p* = 0.03; η2 = 0.03] and by IIM, although the effect size was not significant [*F(*1*,*225*)* = 3.63; *p* = 0.06; η2 = 0.02], but not by education [*F*(1*,*225*)* = 0.12; *p* = 0.72; η2 = 0.00] or gender [*F(*1*,*225*)* = 1.78; *p* = 0.27;

† *Free recall: sum of the three free recalls.*

‡*Analyses of covariance, means adjusted for gender, age, and education and across- or within-domain IIM.*

∗*p < 0.05,* ∗∗*p < 0.001.*

*HCS, healthy control subjects; MCI, mild cognitive impairment; AD, Alzheimer's disease; MMSE, mini-mental state examination; TMT, trail making test; IIM, intra-individual mean; IIV, intra-individual variability.*

η2 = 0.007]. Groups did not differ in years of education (*F(*2*,*225*)* = 1.30, *p* = 0.33) or distribution of gender [χ2 *(*2*)* = 0.29, *p* = 0.89]. HCS and aMCI did not differ in age [*t(*225*)* = −1.36, *p* = 0.36].

## Accuracy-Based Comparisons Between Across-Domain and Within-Domain IIV

The accuracy-based IIV at both DOT and NAV was not influenced by education [*F(*1*,*225*)* = 2.41; *p* = 0.13; η2 = 0.01), gender [*F*(1*,*225*)* = 2.12; *p* = 0.10; η2 = 0.01], or IIM [*F(*1*,*225*)* = 1.20; *p* = 0.19; η2 = 0.01] but differed among diagnostic groups [*F(*2*,*225*)* = 5.75; *p* = 0.001; η2 = 0.06] and slightly by age [*F(*1*,*225*)* = 1.06; *p* = 0.05; η2 = 0.02]. The early AD group revealed in general higher across-domain IIV than both the aMCI group (*p* = 0.001; 95% CI = 0.17–0.88) and HCS group (*p* = 0.001; 95% CI = 0.18–0.99), whereas IIV did not differ significantly between the aMCI and HCS groups (*p* = 0.71; 95% CI = –0.16–0.31). Within-domain IIV was not influenced by age [*F(*1*,*225*)* = 0.056; *p* = 0.82; η2 = 0.00] but was higher in the early AD group compared to the HCS group (*p* = 0.006; 95% CI = 0.12– 0.85) and was not significant between the early AD and the aMCI groups (*p* = 0.374; 95% CI = 0.142–0.582). In addition, we found a strong trend for higher withindomain IIV in the aMCI group than in the HCS group (*p* = 0.051; 95% CI = –0.02–0.27). To avoid statistical issues associated with two missing trials for the DOT group, grouplevel ISD values were imputed for missing data (*<*3% of the total data). **Figure 2** summarizes the accuracy-based IIV results.

## Latency-Based Comparisons between Across-Domain and Within-Domain IIV

The latency-based IIV at both DOT and NAV was also not influenced by education [*F(*1*,*225*)* = 2.43; *p* = 0.15; η2 = 0.01], gender [*F(*1*,*225*)* = 2.21; *p* = 0.13; η2 = 0.01], or IIM [*F(*1*,*225*)* = 1.19; *p* = 0.20; η2 = 0.01] but differed among diagnostic groups [*F(*2*,*225*)* = 5.71; *p* = 0.001; η2 = 0.06] and age [*F(*1*,*225*)* = 1.51; *p* = 0.02; η2 = 0.03]. The across-domain latency-based IIV differed between the early AD and aMCI groups (*p* = 0.001; 95% CI = 0.22–1.07) as well as between the AD and HCS groups (*p* = 0.001; 95% CI = 0.24–1.29) and also between the aMCI and HCS groups (*p* = 0.001; 95% CI = 0.26–1.30). Within-domain latency IIV was found to be higher in the early AD group compared to the aMCI group (*p* = 0.001; 95% CI = 0.19–0.85) and the HCS group (*p* = 0.001; 95% CI = 0.16–0.82) and also between the aMCI and HCS groups (*p* = 0.001; 95% CI = 0.20–0.97). **Figure 3** summarizes the accuracy-based IIV results.

## Accuracy-Based IIV vs. Latency-Based IIV

In order to evaluate whether there was a relationship between the accuracy- and latency-based IIV scores and the SG task, a MANCOVA was performed with IIV type (accuracy- or latencybased) and task (DOT and NAV) included as covariates. There was a significant main effect of the IIV type for the group [*F(*2*,*225*)* = 29.9; *p* = 0.001; η2 = 0.41], but not for task, age, education, or gender.

In addition, ANCOVA was performed in order to calculate a difference score by subtracting within- from across-domain IIV while treating age, education, and gender as covariates. For the accuracy-based IIV, we found only a tendency toward

(IIV) scores between diagnostic groups: intra-individual standard deviation (ISD) representing mean across-domain IIV for DOT and NAV as well as mean within-domain IIV for DOT and NAV per diagnostic group (HCS, healthy control subjects; MCI, mild cognitive impairment;

AD, Alzheimer's disease). Error bars display 95% confidence interval for the mean with p values based on Sidak *post hoc* tests following analyses of covariance for the comparison of means adjusted for age, years of education and gender as well as mean across-domain performance (A) and mean within-domain performance (B), respectively.

higher across-domain IIV—not within-domain IIV—in each group (HCS: M = 0.21, SD = 0.76; MCI: M = 0.08, SD = 0.81; AD: M = 0.38, SD = 0.95). On the other hand, the latency-based IIV revealed no significant differences between IIV scores across diagnostic groups [*F(*2*,*225*)* = 4.32; *p* = 0.16; η2 = 0.15].

# Associations between IIV, Genotype, and Neuropsychological Tests

Correlations are given in **Table 2**. The relationship between IIV, neuropsychological tests, and APOE status was explored in a subsample with available genotypes. We performed ANCOVAs to compare IIV scores between ε4 carriers and non-carriers within each group by treating gender as a covariate in aMCI. We calculated the general across-domain IIV and found that it did not vary with APOE status in HCS [*F(*1*,*75*)* = 0.412; *p* = 0.37; η2 = 0.003], MCI [*F(*1*,*51*)* = 0.316; *p* = 0.54; η2 = 0.008], or AD [*F(*1*,*33*)* = 0.012; *p* = 0.87; η2 = 0.00]. Similarly, the withindomain IIV did not vary as a function of APOE status in early AD [*F(*1*,*33*)* = 0.219; *p* = 0.67; η2 = 0.01], but there was a significant effect of APOE status in HCS [*F(*1*,*75*)* = 4.393; *p* = 0.04; η2 = 0.04] and aMCI [*F(*1*,*51*)* = 2.399; *p* = 0.05; η2 = 0.03], which indicated increased within-domain IIV in these groups.

### Reliability of Performance-Based IIV Data

**Figure 4** for the DOT task and **Figure 5** for the NAV task summarize the reliability data. ICC values were calculated using all three SG sessions for both the accuracy- and latency-based IIV of the DOT and NAV tasks. Results showed that, in general, accuracybased IIV elicits fair to moderate reliability (ICC 0.33–0.57) for both the DOT and NAV tasks. In addition, accuracy-based ICC values increased after all three SG sessions for the DOT task, but the NAV task elicited an average ICC decrease of 0.15 (SEM = 0.04). In contrast, latency-based IIV for both the DOT and NAV tasks exhibited good to excellent reliability measures (ICC 0.69–0.85) after all sessions.

# Discussion

A major problem in studying aging is how to separate the effects of aging from disease, and the two most pressing clinical questions relate to etiology and prognosis. In this study, we examined SG with and without DTW performance data and applied acrossand within-domain accuracy-based and latency-based IIV measures in order to reliably differentiate between HCS, aMCI, and early AD. Specifically for the SG with DTW, we found increased IIV for both across- and within-domain IIV in early AD vs. HCS, aMCI vs. HSC, and in early AD vs. aMCI, consistent with a recent study (Phillips et al., 2013). In addition, and consistent with the literature on within-domain IIV (Duchek et al., 2009; Schroeter et al., 2012) placing more demands on cognitive control processes, we also found SG with DTW latency-based within-domain IIV being increased in early AD vs. HCS, aMCI vs. HCS, and early AD vs. aMCI, which is found to be a sensitive early marker of cognitive impairment (MacDonald et al., 2012; Kälin et al., 2014). High IIV has been linked to an increased probability that an individual with aMCI will become demented within 2.5 years (Tales et al., 2012).

When one investigates SG-based human navigation—in particular, the strategies implemented in a complex everyday way-finding task—one must also consider the role of vision in walking. In order to maintain a regular walking velocity in the SG, subjects must anticipate visualizing the destination route and process the responses upstream without having to stop. During the NAV task, each way-point had several action points as well as distractors and required several hesitant jerky movements to process them. Using the IIV measures, we were able to verify

### TABLE 2 | Cognitive measures per diagnostic group, IIV, and APOE genotype (means with SDs).

† *Data shown are calculated standardized residuals of cognitive test scores for MCI and AD by using parameter estimates for age, education, and gender in HCS.* ‡*Analyses of covariance, means adjusted for gender, age, education, and across- or within-domain IIM.*

∗*p < 0.05.*

*HCSs, healthy control subjects; MCI, mild cognitive impairment; AD, Alzheimer's disease; MMSE, mini–mental state examination; TMT, trail making test; IIM, intra-individual mean; IIV, intra-individual variability.*

that NAV task interference is preserved in dual-task conditions, consistent with other recent studies, i.e., (Perrochon et al., 2013).

The role of vision in gait control during locomotion has been demonstrated by other studies, especially when the environment is enriched with visual information (Chapman and Hollands, 2006, 2007). During NAV, this mechanism triggered a modification in gait parameters, such as a reduction in velocity and frequency, and more so by an increase in double support time. At the same time, others have suggested that elders with reduced cognitive ability have more difficulty identifying the environment, and it is necessary to fixate more to have a maximum of visual information (Di Fabio et al., 2005). In another study, Scherder et al. (2011) demonstrated that one can predict a change in walking control and motor performance in subgroups of patients with dementia pathology using the concept of "last in-first out," —that is, the neuronal circuits that mature late would be the first to deteriorate in neurodegenerative pathology. In that study, subjects with frontotemporal or vascular dementia had difficulties at the motor level in coordinating complex foot movements and planning movements associated with early degeneration of the anterior cingulate cortex and dorsolateral prefrontal cortex. In another study, Gwin et al. (2011) performed an electroencephalogram on a subject walking on DTW and noted activation of the anterior cingulate cortex during placement of the foot, similar to the detection of an error in placing the foot on the floor and correction of its trajectory. During the NAV task, one could imagine that there is a conflict at the level of the anterior cingulate cortex, which simultaneously manages performance of the cognitive task and correct placement of the foot. This conflict at the level of the anterior cingulate cortex could be increased in early AD because this cerebral zone is often prematurely deteriorated in patients with dementia.

We also examined the stability of measurements. Our results found at both the SG accuracy- and latency-based measures an increased IIV, suggesting a breakdown of cognitive control functions early in prodromal AD. More precisely, across- and within-domain accuracy-based IIV differed between each group, underlying the differences in cognitive control required by the DOT and NAV tasks. Consistent with other studies (Kälin et al., 2014), we also found that accuracy-based within-domain IIV was increased in early AD and aMCI vs. HCS and appeared to constitute a reliable marker for the detection of prodromal AD at the MCI stage. We also found that accuracy-based across-domain IIV was increased in early AD vs. aMCI and HCS and may be used to separate early AD from the aMCI stage.

Furthermore, since higher IIV has been found in tasks requiring cognitive control to be influenced by gender, by task-related processing load and processing speed (MacDonald et al., 2009; Phillips et al., 2013; Kofler et al., 2014), previous studies found that MCI subjects who later converted to dementia were found to have higher IIV than non-converters. Consistent with this study and the literature on latency-based within-domain IIV (Duchek et al., 2009; Schroeter et al., 2012) placing more demands on cognitive control processes, we also found latency-based withindomain IIV being increased in early AD vs. HCS, aMCI vs. HCS, and early AD vs. aMCI.

Additionally, we found increased within-domain IIV in HCS and aMCI ε4 carriers vs. non-carriers, whereas there was no ε4 related change in IIV in the early AD group. Contrary to findings reported by others (Duchek et al., 2009; Kälin et al., 2014) who only found an increased latency-based IIV in a cognitive control task in HCS ε4 carriers vs. non-carriers, we also found increased latency-based IIV in aMCI ε4 carriers vs. non-carriers. One reason for our findings might be that, in contrast to the previous studies, we examined the relationship between accuracy- and latency-based intra-individual differences in trial-to-trial variability. Another reason might be that the SG performance data are sensitive enough to detect subtle changes in IIV at both the HCS and aMCI stages. However, such interpretations should be treated with caution as it is already known that the frontal lobe constitutes a brain region that manifests ε4-effects very early in the disease (Filbey et al., 2010). Since the frontal lobe is believed to be the basis of IIV (MacDonald et al., 2009), our findings add evidence to recent studies (Kälin et al., 2014) and further support the relationship between within-domain IIV and APOE status.

In order to assess the reliability of performance data IIV, we analyzed the stability of test–retest measurements for both the DOT and NAV tasks using ICC values. Given that longitudinal change in IIV among accuracy and response time is thought to be particularly important and robust in signaling the risk of cognitive impairment and dementia (Vaughan et al., 2013), this result underscores the importance of utilizing response time data as a metric for memory processes, especially in aMCI populations where memory decline is often the behavioral outcome of interest.

In summary, our results demonstrated that SG with DTW performance profiles data represents another aspect of cognition that underlies age-related differences in cognitively demanding tasks independently of mean reaction time and executive function. Importantly, our findings confirmed that impaired cognitive control processes, especially in terms of latency, as measured with NAV performance profiles, produce stable inconsistencies across IIV in cognitive control-sensitive tasks, and hence can act as a predictor of greater cognitive decline.

Consistent with other studies, we found intra-individual differences in cognitive domains, both cross-sectional as well as longitudinal, which can be used for early detection and intervention. Recently, evidence for a strong association between IIV and frontal gray and white matter integrity changes on MRI scans (volumetric decline, demyelination, and hyperintensities) due to age-related changes in cerebral bold flow, vascular injury, or neurological conditions such as AD (Jackson et al., 2012; Lövdén et al., 2013; Radanovic et al., 2013) support the idea of frontal system disruptions underlying increased IIV in aMCI and early AD.

Our study has strengths but also limitations. One limitation was the small variability of the education profiles of our groups, which were all considered to be highly educated older adults. Although recent studies (Kälin et al., 2014) found no effect between education and IIV, this risk was addressed by treating education and within- and across-domain IIM as covariates in all analyses. Furthermore, the outcome of interest in the present study was the ISD calculated across tasks, and thus we assume the risk to be minimal. Another limitation was the correlation of SG performance profile data with neuropsychological tasks that might not exclusively assess the same cognitive functions. Specifically, the NAV task required motor performance with complex cognitive abilities, such as processing speed, visuoconstruction, and inhibition, among other cognitive control functions. Neuropsychological tasks, such as the TMT, the Letter and Category Fluency task, the Stroop Test, and the RAVLT place fewer demands on cognitive control processes, which might have influenced the significance of our correlations. Finally, the motor performance seen in subjects with aMCI is likely to be linked to early degeneration of the dorsolateral prefrontal cortices as well as the anterior cingulate cortex, and these subjects would be susceptible to progressive dementia pathology, such as frontotemporal and vascular dementia and not only AD. Brain imaging will be used in a future study to confirm or refute this hypothesis.

Despite these limitations, SG with DTW might useful in everyday clinical practice. Compared to other non-invasive biomarkers such as MRI, using SG performance data in clinical practice could optimize the diagnosis of AD at the early stage of the disease and would provide the greatest benefit in terms of cost and risk compared with other techniques. Finally, we suspect that integrating this type of dual-tasking with training programs or physical therapy, in an acute training design, might delay cognitive and motor decline in the elderly. However, further examination using different custom SG tasks in a longitudinal design is needed to provide more specific information about their preventive value.

# Author Contributions

For the work described in this manuscript, IT developed and implemented the DAT and NAV system, performed manuscript drafting and statistical analysis. DK performed data collection and analysis. MT and SP performed the recruitment of participants and drafted the Ethical Approval. IT, BD and MD conceived the study and participated in its design, and coordinated the Grant funding. All authors did read and approve the final manuscript.

# Acknowledgments

This research was funded by the University of Bern, Serious Game project at the ARTORG Center for Biomedical Engineering Research and the European project PharmaCog (Prediction of cognitive properties of new drug candidates for neurodegenerative diseases in early clinical development). The Serious Game project started in 2013, and it is one of the most ambitious research projects for the use of serious games in the early screening of dementia and cognitive exercising that can delay the onset of the disease. PharmaCog started at 2010, and it is a partnership of 32 academic and industry actors from seven countries and is one of the most ambitious European projects for tackling bottlenecks in Alzheimer's disease research and drug discovery. We would also like to thank the personnel from the Greek Association for Alzheimer Disease and Related Disorders (GAADRD) Memory Clinics and especially Dr. Anthoula Tsolaki, MD, for their support in data acquisition.

# References

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impairment: a precursor to dementia? *J. Alzheimers. Dis*. 32, 457–466. doi: 10.3233/JAD-2012-120505

**Conflict of Interest Statement:** The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

*Copyright © 2015 Tarnanas, Papagiannopoulos, Kazis, Wiederhold, Widerhold and Tsolaki. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.*

# Detecting early egocentric and allocentric impairments deficits in Alzheimer's disease: an experimental study with virtual reality

*Silvia Serino1\*, Francesca Morganti2, Fabio Di Stefano3 and Giuseppe Riva1,4*

*1 Applied Technology for Neuro-Psychology Lab, Istituto Auxologico Italiano, Milan, Italy, 2 Department of Human and Social Sciences, University of Bergamo, Bergamo, Italy, 3 Ospedale Castelli Verbania, Verbania, Italy, 4 Department of Psychology, Università Cattolica del Sacro Cuore, Milan, Italy*

### *Edited by:*

*Valeria Manera, University of Nice Sophia Antipolis, France*

### *Reviewed by:*

*Johannes Schröder, Section of Geriatric Psychiatry at the University of Heidelberg, Germany Ioannis Tarnanas, University of Bern, Switzerland*

### *\*Correspondence:*

*Silvia Serino, Applied Technology for Neuro-Psychology Lab, Istituto Auxologico Italiano, Via Magnasco, 2 20149 Milan, Italy<EMAIL_ADDRESS>
> *Received: 01 December 2014 Paper pending published:*

*21 January 2015 Accepted: 01 May 2015 Published: 20 May 2015*

### *Citation:*

*Serino S, Morganti F, Di Stefano F and Riva G (2015) Detecting early egocentric and allocentric impairments deficits in Alzheimer's disease: an experimental study with virtual reality. Front. Aging Neurosci. 7:88. doi: 10.3389/fnagi.2015.00088* Several studies have pointed out that egocentric and allocentric spatial impairments are one of the earliest manifestations of Alzheimer's Disease (AD). It is less clear how a break in the continuous interaction between these two representations may be a crucial marker to detect patients who are at risk to develop dementia. The main objective of this study is to compare the performances of participants suffering from amnestic mild cognitive impairment (aMCI group), patients with AD (AD group) and a control group (CG), using a virtual reality (VR)-based procedure for assessing the abilities in encoding, storing and syncing different spatial representations. In the first task, participants were required to indicate on a real map the position of the object they had memorized, while in the second task they were invited to retrieve its position from an empty version of the same virtual room, starting from a different position. The entire procedure was repeated across three different trials, depending on the object location in the encoding phase. Our finding showed that aMCI patients performed significantly more poorly in the third trial of the first task, showing a deficit in the ability to encode and store an allocentric viewpoint independent representation. On the other hand, AD patients performed significantly more poorly when compared to the CG in the second task, indicating a specific impairment in storing an allocentric viewpoint independent representation and then syncing it with the allocentric viewpoint dependent representation. Furthermore, data suggested that these impairments are not a product of generalized cognitive decline or of general decay in spatial abilities, but instead may reflect a selective deficit in the spatial organization Overall, these findings provide an initial insight into the cognitive underpinnings of amnestic impairment in aMCI and AD patient exploiting the potentiality of VR.

Keywords: virtual reality, egocentric representation, allocentric representation, mild cognitive impairment, Alzheimer's disease

# Introduction

Given the rise in life expectancy and concomitant growth of the aging population (aged 65 and over), the prevalence of dementia is expected to increase dramatically. It is estimated that the number of the elderly affected by Alzheimer's disease (AD), which is the most common type of dementia, will reach 115.4 million by 2050 (Prince et al., 2013). Accordingly, the identification of early indicators of cognitive decline in the elderly is becoming a worldwide health policy priority. In parallel with continuous research of well-validated biomarkers of AD processes, cognitive assessment continues to provide reliable cognitive indicators that are crucial for better definition, for both early and differential diagnosis, for improving the design of clinical trials, and for offering the chance of prevention treatments. The early impairment in episodic memory is traditionally considered the first sign of AD (Weintraub et al., 2012). Episodic memory is the ability to encode, store and then retrieve personal past events characterized by a specific time and place ("what," "where," and "when"), and with a reference to the individual themselves as participants of those events (Tulving, 1985, 2001, 2002). Indeed, the core feature of episodic memory is the *autonoetic consciousness*, namely the subjective and conscious experience of mentally reliving an event (Tulving, 2001). From a cognitive standpoint, this first-person perspective is the default mode for information processing, and corresponds to egocentric spatial representations (Vogeley et al., 2004). There are two types of spatial representations, defined on the basis of the reference used to encode and store spatial information: egocentric and allocentric representations (Paillard, 1991; Klatzky, 1998).

Egocentric spatial representations are constituted by subjectto-object spatial relations, since spatial information is acquired and processed using the self as the reference (self-centered). These transient spatial representations are integrated in posterior parietal area 7a (Zipser and Andersen, 1988; Pouget and Sejnowski, 1992; Lester and Dassonville, 2014). On the other hand, allocentric spatial representations are constituted by object-to-object spatial relations, since spatial information is stored using objects and/or environmental features as reference (world-centered). Hippocampal place cells are supposed to be responsible for the long-term storage of the allocentric representations of space (O'Keefe and Dostrovsky, 1971; Ono et al., 1993; Ekstrom et al., 2003).