Telemedicine has developed rapidly during the COVID-19 pandemic and is now integrated into the clinical practice of many hospitals. Telemedicine offers many advantages, and even after the end of the pandemic, many patients still choose to undergo healthcare visits remotely. However, the rapid expansion of telemedicine may be associated with the risk of providing patients with unvalidated and uncontrolled telehealth solutions, potentially negatively impacting their health. In this study, the researchers aim to investigate the effectiveness of remote cognitive training in patients with mild-to-moderate Alzheimer's disease (AD) using tablets equipped with virtual reality-based cognitive exercises. The investigators also aim to evaluate the impact of online supervision of cognitive training by a neuropsychologist and to compare the costs and burden of home-based versus hospital-based cognitive training in patients with AD. This project will define the optimal modalities for cognitive telerehabilitation to ensure validated protocols for the continuity of care in AD.
This project aims to use new technologies and telemedicine to ensure continuity of care and slow cognitive decline in patients with Alzheimer's disease (AD). The investigators also aim to reduce caregiver burden and healthcare costs for the national healthcare system. The investigators hypothesize that patients provided with a VRRS tablet and undergoing autonomous cognitive training as an adjunct to cognitive telerehabilitation will achieve better cognitive outcomes than patients who do not receive a VRRS tablet. The investigators also hypothesize that patients receiving both forms of cognitive training-autonomous training using the VRRS tablet combined with online cognitive telerehabilitation supervised by a professional neuropsychologist-will show greater improvements in cognitive function than patients who do not receive online cognitive telerehabilitation. This is a prospective, interventional, randomized, single-blind, monocentric clinical study. Study population: 48 patients with AD (MMSE score 18-24) and one caregiver for each patient (48 caregivers in total). To minimize potential bias, the neuropsychologist responsible for patient and caregiver assessments will be blinded to treatment allocation. Patients will be randomized in a 1:1:1 ratio to one of the following treatment groups: * Intervention Group 1:\*\* 16 patients provided with a VRRS tablet to perform autonomous home-based cognitive training (5 days per week), in addition to online cognitive telerehabilitation sessions supervised by a neuropsychologist at San Raffaele Hospital twice weekly. * Intervention Group 2:\*\* 16 patients provided with a VRRS tablet to perform autonomous home-based cognitive training (5 days per week), without neuropsychologist-supervised cognitive telerehabilitation. * Comparator Group 3:\*\* 16 patients receiving online cognitive telerehabilitation sessions supervised by a neuropsychologist twice weekly. These patients will not receive a VRRS tablet for home use. No interim analysis is planned. Study design: Each group will undergo a 3-month intervention according to the following schedule. Group 1: Autonomous home-based cognitive training using the VRRS tablet for 1 hour per day, 5 days per week. Remote cognitive telerehabilitation sessions supervised by a neuropsychologist twice weekly. Group 2: Autonomous home-based cognitive training using the VRRS tablet for 1 hour per day, 5 days per week. No cognitive telerehabilitation sessions. Group 3: Remote cognitive telerehabilitation sessions supervised by a neuropsychologist twice weekly. No VRRS tablet and no additional autonomous home-based cognitive training. \- Study visits: Patients and caregivers will attend the following visits: 1. Enrolment. 2. Screening (Day 1) and treatment initiation. 3. Post-treatment assessment (after 3 months of treatment). 4. Follow-up assessment (3 months after completion of treatment). * Methods of data collection The following data will be collected: * patients' neuropsychological performance; * electroencephalographic (EEG) activity; * caregivers' mental health and caregiver burden; * system usability; * costs associated with telerehabilitation and cognitive training. * Assessment of patients' neuropsychological performance: Patients will undergo a comprehensive neuropsychological assessment at three time points: baseline, after the 3-month treatment period, and at the 3-month follow-up. The assessment battery will include: * Montreal Cognitive Assessment (MoCA) (primary outcome): a screening tool for cognitive impairment providing a total score and six domain-specific index scores (Memory, Executive Function, Attention, Language, Visuospatial Ability, and Orientation). Total scores range from 0 to 30, with scores ≥26 generally considered normal. * Mini-Mental State Examination (MMSE). * Quality of Life in Alzheimer's Disease (QoL-AD). * Geriatric Depression Scale (GDS). * Attention Matrices. * Raven's Progressive Matrices. * Token Test. * Semantic Fluency Test. * Phonemic Fluency Test. * Naming Test. * Word-Picture Naming Test. * Digit Span Test (forward and backward). * Corsi Block-Tapping Test. * Rey Complex Figure Test. * Trail Making Test. * EEG assessment: Five minutes of resting-state EEG will be recorded using 32-channel EEG caps before and after the intervention to perform time-frequency analyses. * Assessment of caregivers' mental health and burden: * Beck Depression Inventory-II (BDI-II). * Zarit Burden Interview. Assessment of system usability: System Usability Scale (SUS). Usability will be evaluated in terms of effectiveness, efficiency, and user satisfaction. \- Assessment of the costs of telerehabilitation and cognitive training: The following cost components will be analysed: * healthcare professional costs (neuropsychologist); * outpatient clinic costs; * telemedicine equipment costs for both patients and the hospital; * patients' travel costs; * cognitive training equipment costs; * caregiver burden; * system usability. Any future research involving the collected data will require prior approval from the Ethics Committee (EC).
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
48
Online sessions of cognitive telerehabilitation, twice a week, supervised by a neuropsychologist based at the San Raffaele hospital.
Patients equipped with VRRS tablets to undergo autonomous home-based cognitive training (5 days a week).
Montreal Cognitive Assessment (MoCA)
MoCA is a screening instrument to detect cognitive impairment. It generates a total score and six domain-specific index scores: (1) Memory, (2) Executive Functioning, (3) Attention, (4) Language, (5) Visuospatial, and (6) Orientation. The total possible score is 30 points; a score of 26 or above is considered normal, while scores below 26 may indicate cognitive impairment. Increase in MoCA scores meaning improvement in cognitive functioning.
Time frame: (1) before telerehabilitation, (2) at the end of the 3-month rehabilitation period, and (3) 3 months following the end of treatment.
Electroencephalographic (EEG) activity
Patients' electroencephalographic activity: 5 min of resting state EEG will be recorded using a 32 channel cap in order to perform time-frequency analyses before and after training. EEG power in the alpha, beta and theta rangers will be analyzed.
Time frame: (1) before telerehabilitation, (2) at the end of the 3-month rehabilitation period, and (3) 3 months following the end of treatment.
Caregivers' mental status
\- Beck Depression Inventory-II (BDI): 21-item self-report instrument assessing the common cognitive symptoms of depression. BDI is considered a valid and reliable instrument for depression screening in the general population. The BDI is scored by summing the highest ratings for each of the 21 items. Each item is rated on a 4-point scale ranging from 0 to 3, and the total scores can range from 0 to 63. BDI total scores ranging from 0 to 13 represent "Minimal" depression; total scores from 14 to 19 represent "Mild" depression; total scores from 20 to 28 represent "Moderate" depression; and total scores from 29 to 63 represent "Severe" depression.
Time frame: (1) before telerehabilitation, (2) at the end of the 3-month rehabilitation period, and (3) 3 months following the end of treatment.
Caregivers' burden
Zarit Burden Interview: a standardized, 22-item assessment tool used by healthcare professionals to measure the subjective burden experienced by caregivers of individuals with chronic illnesses or dementia. It evaluates the emotional, physical, social, and financial impacts of caregiving to identify individuals at risk for burnout. It contains 22 questions rated on a 5-point scale (0 = Never, 1 = Rarely, 2 = Sometimes, 3 = Quite frequently, 4 = Nearly always). The total score ranges from 0 to 88, with higher scores indicating greater perceived strain.
Time frame: (1) before telerehabilitation, (2) at the end of the 3-month rehabilitation period, and (3) 3 months following the end of treatment.
System usability
System Usability Scale (SUS): a reliable, 10-item questionnaire used in research to quickly measure the perceived usability of a product, software, or website. Usability measurements consider different aspects: effectiveness (users can successfully achieve their goals), efficiency (how much effort and resources are spent to achieve those goals) and satisfaction (the experience was satisfactory). Participants rate 10 statements (alternating positive and negative) on a 5-point scale (1 = Strongly Disagree, 5 = Strongly Agree), covering areas like ease of use, consistency, and complexity. A SUS score does not represent a percentage. Instead, scores are generally understood using standardized benchmarks and grading scales: (1) 80.3: Excellent (Grade A); (2) 71 - 80: Good (Grade B); (3) 68: Okay/Average; (4) 51 - 68: Poor (Grade C/D); (5) \<51: Worst Imaginable (Grade F).
Time frame: At the end of the 3-month rehabilitation period.
Telerehabilitation's costs
The total costs for 3 months of telerehabilitation will be evaluated. Costs related to the following elements will be summed up: * pay for a neuropsychologist twice a week, for 3 months; * telemedicine equipment costs for patients (tablet, internet) * telemedicine equipment costs for the hospital (computer, internet, room).
Time frame: At 3 months follow-up.
Mini Mental State Examination (MMSE)
The MMSE is a 30-point, 11-question screening tool used by clinicians to assess cognitive impairment. It evaluates functions like memory, orientation, attention, language, and visuospatial skills, taking just 5 to 10 minutes to administer. It is most commonly used to detect conditions like dementia or track cognitive decline over time. The MMSE covers several key domains of mental ability to establish a comprehensive overview of a person's present cognitive performance: Orientation (10 points), registration (3 points), Attention and Calculation (5 points), Recall (3 points), Language and Visual Construction (9 points). Scores are tallied out of 30, with higher scores indicating better cognitive function. A score of 24 or higher is generally considered normal, while scores below that threshold suggest varying levels of cognitive impairment.
Time frame: (1) before telerehabilitation, (2) at the end of the 3-month rehabilitation period, and (3) 3 months following the end of treatment.
Quality of Live in Alzheimer's Disease (QoL-AD)
The QOL-AD is a 13-item questionnaire designed to assess-through both the patient and the caregiver-the quality of life (QOL) of patients diagnosed with Alzheimer's disease (AD). The scale comprises 13 items measuring physical condition, mood, memory, functional abilities, interpersonal relationships, the ability to participate in meaningful activities, financial situation, and global assessments of self and overall QOL. Items are rated on a four-point scale, with descriptors ranging from 1 (poor) to 4 (excellent). Separate scores are calculated for patients and caregivers and then combined into a composite score (QoL-AD CS), in which patient ratings are weighted twice as heavily as caregiver ratings.
Time frame: (1) before telerehabilitation, (2) at the end of the 3-month rehabilitation period, and (3) 3 months following the end of treatment.
Geriatric Depression Scale (GDS)
The most widely used rating scale for assessing depressive symptoms in frail elderly patients and patients with dementia. The scale consists of 15 binary-response questions (yes or no), each scored as 1 or 0. The final score ranges from 0 (no depressive symptoms) to 15 (probable presence of depression).
Time frame: (1) before telerehabilitation, (2) at the end of the 3-month rehabilitation period, and (3) 3 months following the end of treatment.
Attention matrices
Attentional Matrices is a classic paper-and-pencil diagnostic tool primarily used to assess selective visual attention and visual scanning. It requires patients to rapidly identify and cross out target numbers hidden among distractors within a strict time limit. The test typically consists of three separate matrices containing rows and columns of random digits. The patient is handed a sheet and given a brief timeframe (usually 45 seconds) to scan the matrix and cross out specific, pre-defined target numbers. The task becomes progressively complex across the three matrices.
Time frame: (1) before telerehabilitation, (2) at the end of the 3-month rehabilitation period, and (3) 3 months following the end of treatment.
Raven's Progressive Matrices (RPM)
RPM are a widely used, non-verbal psychometric assessment designed to measure fluid intelligence, abstract reasoning, and problem-solving skills. It evaluates an individual's ability to deduce relationships, identify patterns, and impose meaning on complex, abstract visual information. Test-takers are presented with a series of visual matrices-typically 3 × 3 geometric patterns-with one piece missing. The goal is to identify the underlying logical rule governing the pattern and select the correct missing piece from a set of multiple-choice options. The test is "progressive" because the visual puzzles begin simply and become increasingly difficult, demanding more complex cognitive operations to solve as the test goes on.
Time frame: (1) before telerehabilitation, (2) at the end of the 3-month rehabilitation period, and (3) 3 months following the end of treatment.
Token test
The Token Test is a standardized neuropsychological assessment used to evaluate receptive language disorders (auditory comprehension). It requires patients to follow increasingly complex spoken commands to manipulate small, colored plastic shapes (tokens). During the assessment, 20 physical tokens-featuring combinations of two shapes (circles and squares), two sizes (large and small), and five colors (red, blue, green, yellow, and white)-are placed in front of the patient. The test is typically divided into six sections of increasing difficulty: Simple commands: "Touch the red circle"; Complex/Two-part commands: "Touch the large green square and the small red circle"; Relational commands: "Touch the red circle with the blue sqaure". While the original test by A widely used short version consists of 36 commands. Points are awarded for correct manipulations. Lower or cutoff scores (e.g., 25 or below on the 36-item version) indicate varying levels of receptive language impairments.
Time frame: (1) before telerehabilitation, (2) at the end of the 3-month rehabilitation period, and (3) 3 months following the end of treatment.
Semantic and phonemic fluency
emantic and phonemic fluency are critical neuropsychological tests evaluating language and executive functions like working memory, mental flexibility, and strategy generation. Semantic fluency requires producing words within a specific category (e.g., animals), heavily relying on temporal lobe networks and semantic memory. Phonemic fluency requires generating words starting with a specific letter (e.g., F, A, S), taxing frontal lobe executive systems and phonological knowledge. The primary score is the sum of all valid, unique words generated within the 60-second limit.
Time frame: (1) before telerehabilitation, (2) at the end of the 3-month rehabilitation period, and (3) 3 months following the end of treatment.
Naming
Naming test evaluates an individual's ability to retrieve and articulate the names of visually presented objects or pictures. It is primarily used to diagnose anomia (word-finding difficulty) and localize language impairments caused by stroke, traumatic brain injury, or neurodegenerative diseases like Alzheimer's.
Time frame: (1) before telerehabilitation, (2) at the end of the 3-month rehabilitation period, and (3) 3 months following the end of treatment.
Word-picture naming test
It is a core neuropsychological evaluation that asks a patient to verbally identify common objects, animals, or actions shown in pictures. It is used to measure lexical retrieval (word finding), semantic memory, and speech fluency. The examiner presents a series of line drawings or photographs one by one. The patient is asked to state the name of the object as quickly and accurately as possible.
Time frame: (1) before telerehabilitation, (2) at the end of the 3-month rehabilitation period, and (3) 3 months following the end of treatment.
Digit Span test
The Digit Span test is a core neuropsychological assessment of memory. It features two parts: Digits Forward, which measures passive short-term verbal memory and attention by requiring verbatim repetition, and Digits Backward, which assesses executive working memory by demanding mental manipulation and sequence reversal. Digits Forward: The examiner reads a random sequence of numbers aloud (e.g., "5-8-2-1") at a rate of one digit per second. The participant must repeat the sequence in the exact same order. Digits Backward: The examiner reads a sequence of numbers, and the participant must repeat the sequence in reverse order (e.g., if the examiner says "3-9-2", the correct response is "2-9-3").
Time frame: (1) before telerehabilitation, (2) at the end of the 3-month rehabilitation period, and (3) 3 months following the end of treatment.
Hospital-based cognitive training costs
The total costs for 3 months of cognitive rehabilitation in the outpatient clinic of the San Raffaele Hospital (Milan, Italy) will be evaluated. Costs related to the following elements will be summed up: * pay for a neuropsychologist twice a week, for 3 months; * cognitive training equipment costs for the hospital (computer, rehabilitation material, outpatient room). * costs related to patients' travel to and from the hospital.
Time frame: At 3 months follow-up.
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