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.
Aged 45-80 years; gender is not restricted;
Participants must meet the diagnostic criteria for diabetes outlined in the *Chinese Guidelines for the Prevention and Treatment of Type 2 Diabetes (2020 Edition)*, namely: patients exhibit typical symptoms of diabetes and meet one of the following conditions: 1) HbA1c ≥ 6.5%; 2) Fasting blood glucose ≥7.0 mmol/L. Fasting is defined as no caloric intake for at least 8 hours; 3) 2-hour postprandial blood glucose ≥11.1 mmol/L following an oral glucose tolerance test; 4) Random blood glucose ≥11.1 mmol/L;
Stable glycemic control regimen for 3 months or longer;
Completed a systematic neuropsychological assessment and meets Petersen criteria for Mild Cognitive Impairment, satisfying the following conditions: 1) The patient or a caregiver subjectively perceives a decline in cognitive function; 2) Assessment results indicate impairment in one or more cognitive domains; 3) There is mild impairment in complex instrumental activities of daily living, but the patient maintains independence in basic activities of daily living; 4) Does not yet meet the diagnostic criteria for dementia;
Suffering from other dementia-related neurological disorders (such as Alzheimer's disease, Parkinson's disease, etc.) or severe mental illness;
History of central nervous system disorders, including traumatic brain injury, intracranial hemorrhage, acute cerebral infarction, etc.;
Severe sinusitis, space-occupying lesions in the nasopharynx, or congenital disorders affecting the sense of smell,or a history of trauma;
Glaucoma, severe dry eye syndrome, uncorrected strabismus, severe diabetic retinopathy,or severe motion sickness, making the user unable to tolerate VR devices;
Parallel
VR-Based Cognitive Training Plus Standard Diabetes Care
DeviceDevice: 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.
Traditional Paper-and-Pencil Cognitive Training Plus Standard Diabetes Care
Other interventionDevice: 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.
Change 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.
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).
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).
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).
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).
Change in Simulator Sickness Questionnaire (SSQ)
Assesses the severity of VR-related motion sickness, comprising 16 items related to physical discomfort (headache, dizziness, nausea, etc.). It uses a 4-point rating scale from 0 to 3 (0 = no symptoms, 3 = severe), with a total score ranging from 0 to 48. Cutoff scores: \<5 points = no discomfort; 5-12 points = mild; 13-24 points = moderate (requires pause for adjustment); ≥25 points = severe (terminate intervention).
Change in VR Experience Acceptance Scale
Based on the Technology Acceptance Model, this scale comprises 15 items across 5 dimensions: perceived usefulness, perceived ease of use, perceived enjoyment, user experience, and intention to use. A 5-point Likert scale is used (1 = strongly disagree, 5 = strongly agree). Dimensional and total scores are calculated as the mean of the corresponding items; higher scores indicate better acceptance.
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The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School
Lead sponsor
Nanjing Lanyuan Community Health Service Center
Collaborator
Nanjing Meiyuan Xincun Community Health Service Center
Collaborator
Nanjing Dayingbi Community Health Service Center
Collaborator
