This study is a prospective single-blind randomized controlled non-inferiority trial. The Consolidated Standards of Reporting Trials (CONSORT) flowchart for enrollment and randomization is shown in Figure 1. After recruitment, participants will be contacted and will undergo in-person baseline assessment (T0) using the below-listed tests (see evaluation of the participants section and Table 1). Participants who meet the inclusion criteria will be enrolled and randomized to one of two groups: HomeCoRe and CoRe. For both the groups, the intervention will consist of a 6-week program (3 sessions/week, each lasting ~45 min). Follow-up in-person neuropsychological assessments will be scheduled at the end of the rehabilitation program (T1) and after 6 (T2) and 12 months (T3).

Participants will be recruited from the Dementia Research Center outpatient services and Neurorehabilitation Unit of the IRCCS Mondino Foundation (Pavia, Italy) and screened for eligibility criteria through a clinician evaluation made by an expert neurologist.

The inclusion criteria for participants will be:

The exclusion criteria will be:

Medication intake for dementia and/or past cognitive rehabilitation treatments will be not considered as exclusion criteria given that these factors are not expected to affect the outcome of this study. Any pharmacological treatment ongoing must be stable across the entire period of this study protocol.

Table 1 lists the evaluation battery (neuropsychological assessment, questionnaires and scale, and participant-centered outcomes) across testing sessions. Each evaluating session would last about 90 min per participant and will be carried out in a hospital setting.

After baseline assessment, we will generate random numbers through the use of a computer algorithm (https://www.random.org/) from a uniform distribution in the range 0–1, dividing the range in two equal intervals and assigning each participant to the group corresponding to the sampled number (1:1 ratio), within strata defined by diagnosis (Mild or Major Neurocognitive Disorders). Neuropsychologists carrying out cognitive evaluations will be blinded to group allocation.

Both the CoRe and HomeCoRe are research software tools developed within a long-lasting collaboration between clinicians from the IRCCS Mondino and bioengineers from the University of Pavia. At the moment, the tools are limited to Italian speaking participants. The tools allow a participant-tailored intervention aimed at stimulating several cognitive abilities (e.g., logical-executive functions, attention/processing speed, working memory, and episodic memory) through a series of sessions of exercises (see Table 2 for details). Their use is time-saving for the therapists, as they are ready to use and do not require a continuous manual setting of exercises for each training session. This is because, once the therapist has remotely set up the treatment plan, exercises take place in an adaptive mode across all the sessions. In particular, during their dynamic generation, performance data of an individual participant are analyzed in order to set the appropriate difficulty level. Performance data of the participants refer to the response accuracy normalized according to the number of aids that the participant required to solve the task. Furthermore, for each exercise and each level, thresholds are defined to allow difficulty levels to progressively increase in order to stimulate neural plasticity (6, 45, 46). In addition, the system calculates an overall “Weighted Score” (WS), taking into account the correctness of the answers, the execution time, and the difficulty of the exercises. The WS informs the therapist about each performance of the participant in a single value. Hence, WS represents a useful and advantageous index that can be used to assess both the overall outcome of a training session and the global trend of the rehabilitation (see Figure 2).

Both the CoRe and HomeCoRe require a personal computer equipped with a touch screen. HomeCoRe is installed on a laptop (password protected and encrypted) that is supplied to participants by the therapist, while CoRe is installed on a desktop PC located in the hospital setting. Both the HomeCoRe and CoRe will be installed on the personal computer by an expert engineer and under the supervision of the Information Technology (IT) department—IRCCS Mondino. CoRe, being an in-person treatment, will be then performed under therapist monitoring; HomeCoRe, being home based, will/could be performed under caregiver monitoring. In particular, before the beginning of HomeCoRe treatment, participants and possible caregivers will be trained together at the hospital on the use of the rehabilitation tool at home. This is in order to account for possible differences in baseline technological skills. Then, during the training sessions, participants, with the possible support of their caregivers, will go through each exercise of the treatment until they feel familiar with the use of the device. During the rehabilitative program at home, remote technical support will be available when requested. To this aim, participant will be provided with the support team contacts. The treatment sessions, both in the CoRe and HomeCore, can be paused in case of fatigue of the participant and resumed at a later time.

Differently from CoRe, HomeCoRe architecture includes two main components, namely, therapist side and participant/caregiver side and a communication system (HomeCoRe server). The therapist-side dashboard allows remotely setting and monitoring all the parameters of the treatment plan (e.g., frequency and duration of the plan, type of exercises, difficulty level). The interface of the participant/caregiver is very simple and it allows to view/execute the exercises of the day and to send the results to the therapist (see Figure 3).

The HomeCoRe system can be used online or offline in the case that the internet connection of the participant is not available. In the online mode, the communication between the therapist side and participant side takes place automatically through a dedicated communication protocol managed by the HomeCoRe server, while in the offline modality, some manual operations are required for loading the therapeutic plan offline and save result report on an external memory support (e.g., USB key or hard disk). In any case, the communication with the therapist is asynchronous.

As the primary outcome measure, we will consider the change in global cognitive functioning, measured using the MMSE at T1 compared to T0. Secondary outcome measures will be longitudinal changes in all the neuropsychological tests, questionnaires and scales (T1, T2, and T3 vs. T0 when applicable according to Table 1). Secondary outcome measures will include also participant-centered outcomes to assess those aspects that are most important for the participants and the subjective evaluation of intervention success at T1.

This study will involve human participants, cognitive rehabilitation interventions, data collection, elaboration, and abstraction used for the evaluation of the two therapeutic options. In addition to ethical approval, all the procedures and the data managed have been approved by the Data Protection Officer of the IRCCS Mondino who guarantees compliance to the GDPR. The information provided when presenting the informed consent to the participants will be given in a language appropriate to the individual level of understanding. Participants will also be encouraged to ask questions before signing the informed consent.

To the best of our knowledge, HomeCoRe should not have any potential negative impact on the participant. The investigator will communicate any possible, unforeseen, and adverse event to the Ministry of Health. With respect to payment policies for participants, the amount of compensation and the method and timing of disbursement must be consistent with the laws, regulations, and guidelines of the region in which this study is conducted and must not improperly influence a decision of the participant to participate. This study is a no-profit study and, in Italy, the national legislation refers that it is forbidden to offer or request any kind of financial benefit for the participation in a clinical experimental trial.

Since participants are expected to interact with a rehabilitation tool (the HomeCoRe application), one possible issue could be frustration in case of lack of ability to cope with that technology. However, this risk will be mitigated, before the beginning of HomeCoRe treatment, thanks to specific training sessions on the use of this application that will be delivered to participants (and possible caregivers) (see CoRe/HomeCoRe software architecture section). Moreover, the interface fully complied with the guidelines for human–computer interaction, to make the user interface as easy as possible.

This RCT will allow to implement and assess the effectiveness of a TR tool targeting participants with cognitive decline. HomeCoRe aims to provide participant-tailored cognitive intervention directly at home, also when needed to extend the duration of cognitive programs started in the hospital setting and to reduce the dropout rate. The availability of effective and feasible TR modalities will address the paucity of healthcare personnel dedicated to cognitive rehabilitation within the neuropsychology services, thus increasing the offer to a wider population. It will also provide a modality to ensure care continuity also during COVID-19 pandemic crises.

This study has some limitations that need to be acknowledged. In particular, participants with scanty computer familiarity and without a compliant caregiver could be excluded by the use of TR, representing a selection bias for this kind of intervention (55). However, there is also evidence about the possibility of using telemedicine devices in participants with early cognitive impairment living alone. It seems that compliance of the participants depends on the level of monitoring remotely received (56). In addition, it is important to consider that user-friendly developed TR tools can produce benefits in participants and also caregivers (57).