### Baseline profiling
At baseline, demographics (sex, age, years of education), as well as medical history (comorbidities, pharmacological treatment, surgeries), will be collected. In addition,participants will be profiled in terms of:
* previous and current risk factors for dementia with the CogDrisk Dementia Risk® short form [24]: a 51-item survey assessing the principal risk factors informative of the propensity to develop dementia conditions,such as obesity,cholesterol,diabetes,stroke,traumatic brain injury,hypertension,insomnia,depression,physical activity,cognitive activity,loneliness,fish consumption,smoking,and atrial fibrillation. A high score suggests a greater risk for dementia.
* cognitive reserve proxies with the Cognitive Reserve Index questionnaire [25]: a 20-item tool collecting lifetime cognitive-stimulating experiences linked with cognitive resilience. The questionnaire allows for obtaining a total score, and three subscores specific for education, working activity, and leisure time, which are interpreted as the higher score, the greater level of reserve.Scores of 70, 85, 115, and 130 indicate low, medium-low, medium-high, and high levels of reserve, respectively.
* Familiarity and perceived competence with technology with an ad-hoc questionnaire [26]: a 12-item questionnaire divided into two sections, assessing the frequency of use of technologies in the last year, and the level of competence the individual perceives while using the technology, on a 5-point Likert scale. Two separate scores (range 1-5) are derived, with a higher score suggesting a greater familiarity and competence.* Cognitive impairment severity with the Clinical dementia Rating scale [27]: an informant-based semi-structured interview to the person with cognitive complaint and his/her caregiver (such as a family member) grading the level of cognitive difficulties on a 5-point Likert scale, encompassing six domains: memory, orientation, judgment and problem-solving, community affairs, home and hobbies, and personal care. A global score is computed, ranging from 0 to 3, with 0 indicating no dementia, 0.5 related to questionable dementia, such as the MCI, 1 suggesting mild dementia, 2 indicating moderate dementia, and 3 related to severe dementia. Furthermore, for each domain evaluated, a sub-score ranging from 0 (no dementia) to 18 (severe dementia) is calculated.
### Outcome measures
#### Primary outcomes
Primary outcomes will be the Patient Activation Measure®-13I (PAM®13-I [28, 29]), and the Montreal Cognitive Assessment scale (MoCA [22]).
PAM®13-I: A 13-item tool measuring an individual’s knowledge, skills, and confidence in effectively managing their health and healthcare on a 5-point Likert scale. The scale explores four stages of activation: (1) individuals’ beliefs about the relevance of their role, (2) their confidence and knowledge to take action, (3) taking action, (4) maintaining direction during stressful situations. The total score derives from the sum and standardization of items to a metric ranging from 0 to 100, with 100 suggesting a greater activation. Individuals classified in the lowest activation level typically lack awareness of their role in managing their health, demonstrate limited health-related knowledge, and possess underdeveloped self-management abilities. In contrast, those in the highest activation level exhibit proactive health be
Assessments Employed
Yoni 48-item task (Yoni-48 [36, 37])
A performance-based computerized test assessing social cognition, particularly Theory of Mind (ToM). participants are shown 48 visual stimuli, where a cartoon-like character (Yoni) in the middle of the screen is referring with eye gaze or/and emotional expression to one of the four surrounding elements/characters, and thay are required to select the ones Yoni is referring to. In total, 42 stimuli assess ToM, while the others are control items. The 42 stimuli are divided into items assessing affective or cognitive ToM,and first-order or second-order ToM. The test allows computing two global scores,adjusted based on Italian norms (Isernia et al., 2023): the accuracy index (ACC, range 0-1) and the response time index (RT, range 0-1), with higher scores suggesting greater performance. Furthermore,subscores may be derived: affective ToM (range 0-21),cognitive ToM (range 0-21),first-order ToM (range 0-16),and second-order ToM (range 0-26).
mood
Beck Depression Inventory II (BDI-II [38])
A 21-item self-report questionnaire assessing the presence of clinical depression symptoms on a 4-step Guttman’s response scale. The BDI-II allows extracting a total score ranging 0 to 63, and two subscores evaluating cognitive and non-cognitive symptoms. A greater score is associated with a more severe deflection of mood tone. Generally, a BDI-II score of 16 is suggested as a cut-off.
Positive Affect and Negative Affect Schedule (PANAS [39])
A 20-item self-report scale evaluating positive and negative affective states (positive affect – PA- and negative affect – NA- subscales). NA and PA subscales refer to 10 items,positive or negative states,respectively,which are rated on a 5-point Likert response scale assessing the intensity with which the participant feels them (from point 1,very slightly,to 5,extremely). The overall PANAS score is calculated by summing the ratings for the items within each subscale, yielding separate PA and NA scores. A higher score reflects a greater intensity of the affective states.
State-trait Anxiety Inventory (STAI-Y state [40])
A 20-item self-report scale assessing the state anxiety on a 4-point Likert scale rating the frequency of anxiety symptoms (from 1, Almost never, to 4, Almost always). Total score ranges from 20 to 80, with a score of 40 commonly used to determine probable clinical anxiety. A higher score indicates a greater anxiety level.
Quality of life
EuroQol 5-dimensions 5-levels [41]
A standardized Guttman’s scale assessing five dimensions of quality of life, mobility, self-care, usual everyday activities, pain/discomfort, and anxiety/depression. Each domain is rated on a 5 step Guttman’s scale.In addition, a global self-reported evaluation of health is required on a VAS tool ranging from 0 to 100 with 0 indicating the “worst health you can imagine” and 100 “the best health you can imagine”.
MRI markers
Changes in structural and functional neuroplasticity mechanisms will be evaluated through Magnetic Resonance Imaging (MRI) with a 3 Tesla Siemens Prisma scanner (Erlangen, Germany) equipped with a 64-channel head/neck coil. The MRI protocol will include following sequences: (1) 3D sagittal magnetization-prepared rapid acquisition with gradient echo (MPRAGE) sequence (repetition time (TR) = 2300 ms, echo time (TE) = 3.1 ms, in-plane resolution = 0.8 × 0.8 mm2, acquisi
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clinical Trial: investigating a Novel Intervention for Cognitive Dysfunction
This clinical trial aims to evaluate the efficacy and safety of a novel intervention for individuals experiencing cognitive dysfunction. The study will employ a randomized, double-blind, placebo-controlled design to assess the impact of the intervention on cognitive performance, brain structure and function, and overall quality of life. The trial will also prioritize understanding the user experience, acceptability, and sustainability of the intervention.
Trial Design and Methodology
The study will enroll a diverse cohort of participants diagnosed with cognitive impairment. Participants will be randomly assigned to receive either the active intervention or a placebo. The intervention will be administered over a specified period, with regular assessments conducted throughout the trial to monitor progress and identify any adverse effects.
Key Assessment Measures
A extensive battery of assessments will be used to evaluate the intervention’s effects.These include:
- Cognitive Assessments: Standardized neuropsychological tests will measure various cognitive domains, including memory, attention, executive function, and processing speed.
- MRI Scans: Magnetic Resonance Imaging (MRI) will be used to assess changes in brain structure and function. Specific MRI markers will be analyzed to identify potential neurobiological mechanisms underlying the intervention’s effects.
- behavioral Measures: Assessments of daily functioning, mood, and quality of life will provide a holistic understanding of the intervention’s impact.
- User Experience & Acceptability: Qualitative and quantitative data will be collected to evaluate participant satisfaction, ease of use, and adherence to the intervention protocol.
- Sustainability: Long-term follow-up assessments will evaluate the durability of treatment effects and the feasibility of integrating the intervention into routine clinical practice.
Data Analysis
Statistical analysis will be performed using appropriate methods, including analysis of variance (ANOVA), t-tests, and non-parametric tests. Correlation and regression models will be used to investigate the association between MRI markers and behavioral measures, as well as between baseline characteristics and outcome measures. An alpha threshold of 0.05 will be considered for statistical importance.
Communication of Trial Results
The results of the trial will be disseminated through multiple channels to ensure broad accessibility and impact.
- Project Meetings: Participants, healthcare professionals, and relevant stakeholders, such as patient advocacy groups, will be informed through presentations at dedicated project meetings.
- Scientific Dissemination: Findings will be presented at scientific meetings and published in peer-reviewed journals.
- Trial Registry: Trial results will be reported in the ClinicalTrials.gov registry.
- Public Communication: Press releases and summaries will be shared via institutional websites and social media platforms to reach a wider audience.
Frequently Asked Questions (FAQ)
What is a randomized, double-blind, placebo-controlled trial?
This type of trial is considered the gold standard in clinical research. “Randomized” means participants are assigned to groups by chance. “Double-blind” means neither the participants nor the researchers know who is receiving the active intervention and who is receiving the placebo. “Placebo-controlled” means one group receives a dummy treatment (placebo) to compare against the active intervention.
What is MRI and why is it being used in this trial?
Magnetic Resonance Imaging (MRI) is a non-invasive imaging technique that uses strong magnetic fields and radio waves to create detailed images of the organs and tissues in the body. In this trial, MRI will be used to examine changes in brain structure and function that may be associated with the intervention.
How will participant data be protected?
All participant data will be handled with strict confidentiality and in accordance with relevant privacy regulations,such as