A multi-center prospective, open-label, parallel-group randomized controlled trial is conducted to investigate the cognitive-protective efficacy of a novel, diabetes-specific virtual reality (VR)-based cognitive training system integrated with diet management modules, relative to frequency- and duration-matched traditional paper-and-pencil cognitive training, in adults aged 45-80 years with T2DM and amnestic/mixed mild cognitive impairment (MCI). A total of 40 eligible participants are randomly assigned 1:1 to either the intervention group (24 weeks of individualized VR training with dynamic difficulty, 2 sessions/week, 45-60 minutes/session) or the active control group (standardized paper-and-pencil cognitive tasks). All participants maintain stable glucose-lowering regimens for ≥3 months and receive standardized weekly diabetes health education. The primary endpoint is the between-group difference in the change in MoCA total score from baseline to the 24-week follow-up. Secondary endpoints include changes in individual cognitive domains (memory, executive function, attention, processing speed), Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) Score , Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13) Score , Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) Score, olfactory threshold/identification/recall, brain structural volumes and resting-state functional connectivity (assessed via 3.0T fMRI), glycemic control (HbA1c, fasting/postprandial glucose), lipid profile, body composition, sleep quality, anxiety and depressive symptoms, and diabetes self-management behaviors. The safety and participant adherence to the VR intervention are also systematically monitored.
As China's aging population continues to grow, type 2 diabetes Mellitus (T2DM) has become a serious health threat to the country's elderly. The risk of dementia rises rapidly with age among T2DM patients. Mild cognitive impairment (MCI) is a critical transitional stage between normal aging and dementia; early intervention can effectively slow disease progression and reduce the risk of developing dementia. Against this backdrop, non-pharmacological interventions such as cognitive training have become a key pillar of early intervention due to their high safety profile and ease of implementation. Traditional paper-and-pencil cognitive training is limited by the lack of immersive, real-world scenarios and unsatisfactory patient compliance. Virtual reality technology, with its immersive and interactive features, has shown favorable outcomes in cognitive rehabilitation for MCI patients. Nevertheless, specialized VR cognitive training programs tailored for T2DM combined with MCI are currently lacking. This study aims to evaluate the cognitive-protective efficacy of a customized VR-based cognitive training system integrated with diabetes self-management modules in adults with T2DM and MCI. The system combines multi-sensory cognitive training with diabetes diet management education to improve cognitive function, metabolic parameters and diabetes self-management ability simultaneously. The safety and participant adherence of this customized VR training system are also verified systematically in the trial. A total of 40 eligible participants are enrolled and randomized in a 1:1 ratio to either the VR cognitive training group or the traditional paper-and-pencil cognitive training group. The intervention period lasts 24 weeks. All participants maintain stable glucose-lowering regimens for no less than 3 months before enrollment and throughout the trial, and receive standardized weekly diabetes health education. Weekly follow-ups are conducted via verbal communication, telephone or WeChat to monitor glycemic control, adverse events and training adherence. Participants in the VR cognitive training group use a customized VR cognitive training system developed by the research team. The system is equipped with an HTC VIVE Pro Eye head-mounted display, handheld controllers, spatial positioning base stations and a 360° rotating seat, and its supporting software is developed based on the Unity3D engine. Individualized training plans are generated according to participants' metabolic parameters including height, weight, physical activity level and diabetes duration, and training difficulty is adjusted dynamically based on task completion rate and response time of each session. The training consists of four core modules: (1) VR supermarket/canteen module, which combines diabetes diet management training with executive function, memory and calculation ability training; (2) multi-sensory object finding and difference detection module for the training of attention, visual span and cross-modal association ability; (3) mindfulness healing garden module, which relieves negative emotions through virtual natural scenes, soothing audio and relaxing scents; (4) comprehensive cognitive training module targeting memory and processing speed via digit span test, trail making test and other tasks. Training is delivered twice a week, with each session lasting 45 to 60 minutes. Participants in the control group receive frequency- and duration-matched paper-and-pencil cognitive training under full guidance from research staff throughout each session. Assessments are performed at baseline and upon completion of the 24-week intervention, with interim follow-ups arranged at the 8th, 16th and 24th weeks to evaluate training adherence and diabetes self-management ability. The primary endpoint is the between-group difference in the change in Montreal Cognitive Assessment (MoCA) total score from baseline to week 24. Secondary endpoints cover changes in domain-specific cognitive functions (assessed by the Repeatable Battery for the Assessment of Neuropsychological Status \[RBANS\], digit span test, Stroop Color-Word Test and Trail Making Test), olfactory function (olfactory threshold, identification and recall scores), brain structural measurements and resting-state functional network connectivity (assessed via 3.0T functional magnetic resonance imaging \[fMRI\]), glycemic and lipid metabolic parameters (HbA1c, fasting and postprandial blood glucose, insulin, C-peptide and lipid profile), body composition, sleep quality, anxiety and depressive symptoms, as well as diabetes self-management behaviors. Safety assessments include monitoring the type, incidence, severity and causality of adverse events throughout the trial, together with regular detection of vital signs and laboratory indicators including liver and kidney function.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
NONE
Enrollment
40
Device: Customized VR Cognitive Training System Participants will receive individualized VR cognitive training using the research team-developed system, which consists of an HTC VIVE Pro Eye head-mounted display, handheld controllers, spatial positioning base stations, and a 360° rotating seat, with software developed on the Unity3D engine. Training plans are generated based on patients' metabolic parameters (height, weight, physical activity level, diabetes duration), and difficulty is dynamically adjusted according to each session's task completion rate and response time. The training includes four core modules: (1) VR supermarket/canteen (integrating diabetes diet management); (2) multi-sensory object finding/difference detection; (3) mindfulness healing garden (multi-sensory emotional regulation); (4) comprehensive cognitive training (digit span, trail making tests). Training will be administered twice weekly for 45-60 minutes per session for 24 weeks.
Device: Traditional Paper-and-Pencil Cognitive Tasks Participants will complete standardized paper-and-pencil cognitive training tasks targeting the same cognitive domains (memory, attention, executive function, processing speed) as the VR group. Training will be administered twice weekly for 45-60 minutes per session for 24 weeks, with full guidance from trained research staff throughout each session to ensure standardization.
Department of Endocrinology, the Affiliated Drum Tower Hospital of Nanjing University Medical School
Nanjing, Jiangsu, China
RECRUITINGChange in cognitive function (evaluated by MoCA score)
Whether MoCA scores in the two groups of Type 2 diabetes mellitus patients with MCI after intervention were different from those before treatment and the difference of changes between the two groups. The MoCA scale evaluates overall cognitive function, with a total score of 30. Generally, subjects scoring ≥26 points are considered as normal cognition,while between 19-25 points as mild cognitive impairment. An extra point is added If the subject has less than 12 years of education.
Time frame: Baseline , Week24
Chang in Immediate Memory(evaluated by RBANS score)
The immediate memory assessment primarily consists of two tests: (1) vocabulary learning and (2) story memory. The vocabulary learning task involves five rounds of serial learning to assess the ability to progressively encode verbal information; the story memory task involves the immediate retelling of a logical story to assess the ability to encode contextual information. All raw scores from the subtests must be converted to age-corrected standard scores (mean = 10, standard deviation = 3) to eliminate the influence of age on cognitive scores; the score for each cognitive domain is calculated by summing the age-corrected standard scores of its subordinate subtests and then directly converting this sum to the standard score for that cognitive domain using a conversion table (mean = 10, standard deviation = 3).
Time frame: Baseline , Week24
Change in Visual-Spatial/Structural Ability(evaluated by RBANS score)
The Visual-Spatial/Structural Ability Assessment primarily consists of two tests: (1) Figure Reproduction and (2) Line Orientation. Figure Reproduction requires the subject to trace complex geometric figures, assessing visuomotor coordination and spatial structuring abilities; Line Orientation requires matching lines with identical angles, assessing the ability to judge two-dimensional spatial relationships. All raw scores from the subtests must be converted to age-corrected standard scores (mean = 10, standard deviation = 3) to eliminate the influence of age on cognitive scores; the score for each cognitive domain is calculated by summing the age-corrected standard scores of its subordinate subtests and then directly converting this sum to the standard score for that cognitive domain using a conversion table (mean = 10).
Time frame: Baseline , Week24
Change in verbal function (evaluated by RBANS score)
The verbal function assessment primarily consists of two tests: (1) Picture Naming and (2) Semantic Fluency (Animal Naming). The Picture Naming test involves naming 30 pictures of common objects to assess vocabulary retrieval speed; the Semantic Fluency test involves naming as many animals as possible within one minute (a type of category fluency) to assess the activation and retrieval capabilities of the semantic network. All raw scores from the subtests must be converted to age-corrected standard scores (mean = 10, standard deviation = 3) to eliminate the influence of age on cognitive scores; the score for each cognitive domain is calculated by summing the age-corrected standard scores of its subordinate subtests and then directly converting this sum to the standard score for that cognitive domain using a conversion table (mean = 10, standard deviation = 3).
Time frame: Baseline , Week24
Change in delayed memory(evaluated by RBANS score)
The delayed memory assessment primarily consists of four tests: (1) Delayed Word Recall, (2) Delayed Story Recall, (3) Delayed Picture Recall, and (4) Delayed Word Recognition. The Delayed Word Recognition task requires participants to identify 10 previously learned words from a set of 20 distractor words, thereby assessing the integrity of memory storage. The core assessment functions include the ability to store information long-term, the ability to retrieve memories, and the ability to consolidate memories; All raw scores from the subtests must be converted to age-corrected standard scores (mean = 10, standard deviation = 3) to eliminate the influence of age on cognitive scores; the score for each cognitive domain is calculated by summing the age-corrected standard scores of its subordinate subtests and then directly converting this sum to the standard score for that cognitive domain using a conversion table (mean = 10, standard deviation = 3).
Time frame: Baseline , Week24
Change in attention(evaluated by RBANS score)
The attention assessment primarily consists of two tests: (1) Digit Span (including forward and backward subtests) and (2) Digit Coding. Digit Coding requires participants to pair numbers with symbols one-to-one within 90 seconds, assessing visual information processing speed and visuomotor coordination. The core assessment functions include immediate auditory memory span, auditory working memory, visual information processing speed, and visuomotor coordination; All raw scores from the subtests must be converted to age-corrected standard scores (mean = 10, standard deviation = 3) to eliminate the influence of age on cognitive scores; the score for each cognitive domain is calculated by summing the age-corrected standard scores of its subordinate subtests and then directly converting this sum to the standard score for that cognitive domain using a conversion table (mean = 10, standard deviation = 3).
Time frame: Baseline , Week24
Change in Overall Cognitive Function(evaluated by RBANS score)
The RBANS Overall Cognitive Function score is calculated by summing the standard scores from the five cognitive domains described above; The core assessment focuses on the subject's overall cognitive functioning level and the severity of cognitive impairment. After summing the standard scores from the five cognitive domains, the total is directly converted using a look-up table to a Total Scale Score (TSS; mean = 100, standard deviation = 15). This scoring system aligns with internationally accepted IQ scoring systems and provides an intuitive reflection of the subject's overall cognitive status.
Time frame: Baseline , Week24
Changes in Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB) Scores
The changes in Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB) scores from baseline to week 24 will be compared between the VR cognitive training group and the traditional cognitive training group. The score range is 0 to 18, with higher scores indicating more severe cognitive and functional impairment.
Time frame: Baseline, 24 weeks
Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13) Score Change
The change in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13) score from baseline to week 24 will be compared between the VR cognitive training group and the traditional cognitive training group. The score ranges from 0 to 85, with higher scores indicating more severe cognitive impairment.
Time frame: Baseline, 24 weeks
Change in Diabetes Self-Care Activities (SDSCA) Score
The Summary of Diabetes Self-Care Activities (SDSCA) assessment primarily consists of 11 items across 6 dimensions: general diet, healthy eating, regular exercise, blood glucose monitoring, foot care, and medication adherence. Its core assessment function is to measure the frequency with which people with diabetes have performed various self-management behaviors over the past 7 days; All items are scored on a 0-7 scale (representing the number of days the behavior was performed over the past 7 days). The score for each dimension is calculated as the mean of the corresponding items, and the total score is the mean of all items, with a score range of 0-7. A higher score indicates better adherence to diabetes self-management behaviors.
Time frame: Baseline , Week8, week16, Week24
Change in Resting-State Functional MRI
Assessment of baseline brain functional state. Key metrics: amplitude of low-frequency fluctuations (ALFF), regional coherence (ReHo), and functional connectivity within the default mode network and executive control network. Data are corrected for head motion and physiological noise, and data with excessive head motion (translation \> 2 mm / rotation \> 2°) are excluded.
Time frame: Baseline , Week24
Change of Olfactory function
Whether the scores of olfactory threshold, identification and memory of the two groups after intervention were higherthan those before treatment and the difference of changes between the two groups. Olfactory testing was performed using Olfactory Function Assessment by Computerized Testing (OLFACT) (Osmic Enterprises, Inc.). Based on the University of Pennsylvania Smell Identification Test (UPSIT), OLFACT tests were computerized, standardized, and self-administered. Higher scores indicated better ability to detect odors. Threshold testing was performed by a series of binary dilutions of n- butanol solution in light mineral oil, and scores ranged from 1 to 14. Identification and memory tests included two tasks: task A with 10 different odors, and task B with 20 odors (with 10 same odors in the task A). Each participant was asked to identify each odor from four pictures in tasks A and B and to indicate whether each was old or new in task B. There was a 10-min break in-between.
Time frame: Baseline , Week24
Change in blood glucose
Change in fasting blood glucose from baseline to Week 24 will be assessed using laboratory testing.
Time frame: Baseline, Week 24
Change in Glycated Hemoglobin
Change in glycated hemoglobin (HbA1c) from baseline to Week 24 will be assessed using laboratory testing.
Time frame: Baseline, Week 24
Change in liver function
Change in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) from baseline to Week 24 will be assessed using laboratory testing.
Time frame: Baseline, Week 24
Change in kidney function
Change in Serum Creatinine(Ucr),Urea,Uric Acid(UA),Glomerular Filtration Rate (eGFR) from baseline to Week 24 will be assessed using laboratory testing.
Time frame: Baseline, Week 24
Change in blood lipid levels
Change in high-density lipoprotein cholesterol (HDL-C) , low-density lipoprotein cholesterol (LDL-C), Total cholesterol(TC), triglyceridesfrom(TC) from baseline to Week 24 will be assessed using laboratory testing.
Time frame: Baseline, Week 24
Change in insulin and C-peptide levels at fasting and 120 minutes after a meal
Change in insulin and C-peptide levels at fasting and 120 minutes after a meal from baseline to Week 24 will be assessed using laboratory testing.
Time frame: Baseline, Week 24
Percent Change in Body Weight From Baseline
Percent change in body weight from baseline to Week 24 will be compared between two groups .
Time frame: Baseline, Week 24
Change in waist and hip measurements
Change in waist and hip measurements from baseline to Week 24 will be assessed using standardized anthropometric measurement.
Time frame: Baseline, Week 24
Change in Body Composition and Fat Distribution
Changes in body composition and fat distribution will be assessed by body fat percentage using anthropometric measurements and body composition analysis.
Time frame: Baseline, Week 24
Change in Controlled Attenuation Parameter
Change in controlled attenuation parameter (CAP) from baseline to Week 24 will be assessed using transient elastography.
Time frame: Baseline, Week 24
Change in Liver Stiffness Measurement
Change in liver stiffness measurement (LSM) from baseline to Week 24 will be assessed using transient elastography.
Time frame: Baseline, Week 24
Change in Hospital Anxiety and Depression Scale (HADS) Score
The Hospital Anxiety and Depression Scale (HADS) primarily consists of two subscales with a total of 14 items: (1) the Anxiety Subscale (HADS-A, 7 items); (2) Depression Subscale (HADS-D, 7 items); Its core function is to screen for and quantify the severity of anxiety and depressive states in non-psychiatric patients, effectively distinguishing between symptoms of physical illness and those of mood disorders; All items are scored on a 4-point scale ranging from 0 to 3. The total score for each subscale ranges from 0 to 21, and the total scale score is the sum of the two subscales (0-42). Higher scores indicate more severe anxiety or depressive symptoms. Clinical cutoffs: 0-7 points is normal, 8-10 points indicates a suspected mood disorder, and 11-21 points indicates a definite mood disorder.
Time frame: Baseline , Week24
Change in Self-Rating Anxiety Scale (SAS) Score
The Self-Rating Anxiety Scale (SAS) primarily consists of 20 items covering subjective feelings of anxiety, physical symptoms, restlessness, and autonomic dysfunction; its core function is to assess the severity of participants' subjective anxiety symptoms and their dynamic changes before and after intervention; All items are rated on a 4-point scale from 1 to 4 (with 5 items reverse-scored). Raw scores are multiplied by 1.25 and rounded to the nearest whole number to obtain a standard score, with a range of 25-100 points; a higher score indicates more severe anxiety symptoms; Clinical cutoff scores: \<50 points is normal, 50-59 points is mild anxiety, 60-69 points is moderate anxiety, and ≥70 points is severe anxiety.
Time frame: Baseline , Week24
Change in Functional Activities Questionnaire-9 (FAQ-9) Score
The Functional Activities Questionnaire-9 (FAQ-9) primarily assesses nine items related to instrumental activities of daily living: using the telephone, shopping, meal preparation, housework, laundry, using public transportation, taking medication regularly, managing finances, and going out alone; The core assessment function is the subject's instrumental activities of daily living (IADL) ability, making it a sensitive tool for distinguishing between normal aging and functional impairment caused by mild cognitive impairment; All items are scored on a 4-point scale ranging from 0 to 3 (0 = completely independent; 3 = completely dependent on others), with a total score ranging from 0 to 27; a higher score indicates more severe impairment in instrumental activities of daily living; the clinical cutoff is ≥5, indicating significant functional impairment.
Time frame: Baseline , Week24
Change in Pittsburgh Sleep Quality Index (PSQI) Score
The Pittsburgh Sleep Quality Index (PSQI) primarily assesses seven core components: subjective sleep quality, time to fall asleep, total sleep time, sleep efficiency, sleep disturbances, use of sleep medications, and daytime dysfunction. Its core function is to provide a comprehensive evaluation of overall sleep quality and various sleep-related issues over the past month. Each component is scored on a scale of 0-3, with a total score ranging from 0 to 21. A higher score indicates poorer sleep quality; the clinical cutoff is ≥7, indicating the presence of a clinically significant sleep disorder.
Time frame: Baseline , Week24
Changes in Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) Scores
The ADCS-ADL is a scale consisting of 23 items, including 6 basic ADL (bADL) items and 17 instrumental ADL (IADL) items. The change in ADCS-ADL scores from baseline to week 24 will be compared between the VR cognitive training group and the traditional cognitive training group.The total score ranges from 0 to 78, with lower scores indicating greater severity of cognitive impairment.
Time frame: Baseline，24 weeks
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.