The Cognitive Protective Effect of VR-based Cognitive Training in Type 2 Diabetes Patients With Mild Cognitive Impairment

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.

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).

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).

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).

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).

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).

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.

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.

Assess the function of the olfactory-cognitive pathway. Key metrics: activation intensity in the piriform cortex, hippocampus, and orbitofrontal cortex under gradient-concentration odor stimulation; functional connectivity of the olfactory network. Analysis using a GLM model; multiple comparisons corrected using the GRF method (voxel P < 0.001, cluster P < 0.05).

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.

Change in fasting blood glucose from baseline to Week 16 will be assessed using laboratory testing.

Change in glycated hemoglobin (HbA1c) from baseline to Week 16 will be assessed using laboratory testing.

Change in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) from baseline to Week 16 will be assessed using laboratory testing.

Change in Serum Creatinine(Ucr),Urea,Uric Acid(UA),Glomerular Filtration Rate (eGFR) from baseline to Week 16 will be assessed using laboratory testing.

Change in high-density lipoprotein cholesterol (HDL-C) , low-density lipoprotein cholesterol (LDL-C), Total cholesterol(TC), triglyceridesfrom(TC) from baseline to Week 16 will be assessed using laboratory testing.

Change in insulin and C-peptide levels at fasting and 120 minutes after a meal from baseline to Week 16 will be assessed using laboratory testing.

Percent change in body weight from baseline to Week 4, Week 8, Week 12 and Week 16 will be compared between two groups .

Change in waist and hip measurements from baseline to Week 4, Week 8, Week 12 and Week 16 will be assessed using standardized anthropometric measurement.

Changes in body composition and fat distribution will be assessed by body fat percentage using anthropometric measurements and body composition analysis.

Change in controlled attenuation parameter (CAP) from baseline to Week 16 will be assessed using transient elastography.

Change in liver stiffness measurement (LSM) from baseline to Week 16 will be assessed using transient elastography.

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.

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.

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.

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.

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.

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).

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.