| Outcome Measures: |
Primary: Mild cognitive impairment (MCI) remission rate at week48, MCI mitigation is defined by three criteria: an education-adjusted score of the Montreal Cognitive Assessment (MoCA) ≥26, no cognitive deficits in any cognitive subdomain, and preservation of ability to perform instrumental activity of daily living (IADL) with a Functional Activities Questionnaire (FAQ) score \<5. MoCA test includes attention and concentration, executive function, memory, language, visual structure skills, abstract thinking, calculation, and orientation, with a score range from 0 to 30, plus one point if the participant has 12 years or less of education. Generally, a higher MoCA score reflects a better cognitive function. Sum scores of FAQ range from 0 to 30, with higher scores indicating worse function., The core study spans from baseline to 48 weeks | Secondary: Change of general cognitive function (MMSE) from baseline to 48 and 76 weeks, The MMSE contains a total of 30 items that assess orientation, registration, attention and calculation, recall, and language, with a score range from 0 to 30. Generally, a higher MMSE score reflects a better cognitive function., Baseline, 48 and 76 weeks|Change of general cognitive function (MoCA) from baseline to 24, 48 and 76 weeks, evaluate changes in scores of MoCA. MoCA test includes attention and concentration, executive function, memory, language, visual structure skills, abstract thinking, calculation, and orientation, with a score range from 0 to 30, plus one point if the participant has 12 years or less of education. Generally, a higher MoCA score reflects a better cognitive function., Baseline, 24, 48 and 76 weeks|Change of general cognitive function (RBANS) from baseline to 48 and 76 weeks, evaluate changes in total scores of Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS, Chinese version) is a brief neuropsychological screening battery with established test-retest reliability and age-appropriate normative data, which consists of 12 task tests assessing 5 cognitive domains, namely immediate memory, visuospatial/constructional, language, attention and delayed memory, with a score range from 40 to 160. Generally, a higher RBANS score reflects a better cognitive function., Baseline, 48 and 76 weeks|Change of cognitive subdomains from baseline to 48 and 76 weeks, evaluate changes in scores of each cognitive subdomain in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)., Baseline, 48 and 76 weeks|Change of processing speed from baseline to 48 and 76 weeks, The Trial Making Test (TMT) provides a measure of processing speed, which consists of part A and part B (TMT-A and TMT-B). The time limits for performing the TMT-A and TMT-B are 180 and 300 seconds, respectively. Processing speed is estimated by the sum of the consuming time to complete TMT-A and TMT-B such that less time indicate faster processing speed., Baseline, 48 and 76 weeks|Change of executive function from baseline to 48 and 76 weeks, evaluate changes in consuming time of executive function. The Victoria Stroop Color-Word Test is a well-known measure of executive functioning. There are three indices including Stroop-dot, Stroop-word and Stroop-color word in the test. The color task consists of colored dots; the word task comprises ordinary words that are unrelated to the meaning of color; the color-word task consists of words written in color that indicate the meaning of the color, but the color of these words differs from the meaning of the word itself. The participants were asked to quickly read the color of the dots or Chinese words on the cards. The sum of consuming time taken to read the three cards is used as an index of executive function performance. Less time indicates better executive function., Baseline, 48 and 76 weeks|Change of total brain volume from baseline to 48 and 76 weeks, MRI-derived normalized measures of total brain volume., Baseline, 48 and 76 weeks|Change of grey matter volume from baseline to 48 and 76 weeks, MRI-derived normalized measures of grey matter volume., Baseline, 48 and 76 weeks|Change of white matter volume from baseline to 48 and 76 weeks, MRI-derived normalized measures of white matter volume., Baseline, 48 and 76 weeks|Change of cerebrospinal fluid volume from baseline to 48 and 76 weeks, MRI-derived normalized measures of cerebrospinal fluid volume., Baseline, 48 and 76 weeks|Change of white matter hyperintensity volume from baseline to 48 and 76 weeks, MRI-derived normalized measures of white matter hyperintensity volume., Baseline, 48 and 76 weeks|Change of deep grey subcortical structure volumes from baseline to 48 and 76 weeks, MRI-derived normalized measures of deep grey subcortical structure volumes, which include thalamus, caudate, putamen, pallidum and amygdala., Baseline, 48 and 76 weeks|Change of lobar grey volume from baseline to 48 and 76 weeks, MRI-derived normalized measures of lobar grey volume, which includes frontal, temporal, occipital and parietal., Baseline, 48 and 76 weeks|Change of AD signature region volumes from baseline to 48 and 76 weeks, MRI-derived normalized measures of AD signature region volumes, which include parahippocampal, precuneus, cuneus, entorhinal, inferior parietal lobules and hippocampus., Baseline, 48 and 76 weeks|Change of odor-induced brain activation from baseline to 48 and 76 weeks, All patients underwent odor-induced task fMRI on a 3.0T MR scanner with 222 volumes for task fMRI and 230 volumes for resting-state fMRI. The odor-induced task consisted of "fresh air" "rest" and "scent". Odor-induced brain activation was assessed by a general linear model using Statistical Parametric Mapping 12 (SPM12) software. Following extraction of the three separate conditions "fresh air," "scent," and "rest" from the whole sequence, contrasts were made for each participant between "fresh air \> rest" and "scent \> rest." Odor-induced fMRI data were analyzed in the mask of the olfactory network, including the regions of bilateral parahippocampus, amygdala, piriform cortex, insula, orbitofrontal cortex, hippocampus, and entorhinal cortices., Baseline, 48 and 76 weeks|Change of resting-state functional connectivity from baseline to 48 and 76 weeks, All patients underwent odor-induced task fMRI on a 3.0T MR scanner with 222 volumes for task fMRI and 230 volumes for resting-state fMRI. DPABI software was used to calculate the resting-state functional connectivity (FC) with a seed-based correlation analysis method. Brain areas that showed noticeably different activation of olfactory network among the three groups were selected as seed regions. Then, we extracted the time series of the signal in the seed regions and used these time series to generate voxel-wise FC maps. The parcellation scheme adopted to construct the whole-brain connectivity matrix was built upon the anatomical automatic labeling atlas, which parcellates the brain in 90 regions of interest., Baseline, 48 and 76 weeks|Change of olfactory function from baseline to 48 and 76 weeks, Whether the olfactory threshold scores of the three groups after intervention were higher than those before treatment and the difference of changes between the three 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 13.5., Baseline, 48 and 76 weeks|Change of HbA1c from baseline to 24, 48 and 76 weeks, glycated haemoglobin A1c (HbA1c), Baseline, 24, 48 and 76 weeks|Change of fasting and 2-hour postprandial plasma glucose from baseline to 24, 48 and 76 weeks, fasting and 2-hour postprandial plasma glucose, Baseline, 24, 48 and 76 weeks|Change of fasting and 2-hour postprandial plasma C-peptide levels from baseline to 48 and 76 weeks, fasting and 2-hour postprandial plasma C-peptide levels, Baseline, 48 and 76 weeks|Change of lipid metabolism indicators from baseline to 24, 48 and 76 weeks, lipid profile (triglyceride, total cholesterol, high-density and low-density lipoprotein-cholesterol)., Baseline, 24, 48 and 76 weeks|Change of blood pressure from baseline to 24, 48 and 76 weeks, Systolic and diastolic blood pressure, Baseline, 24, 48 and 76 weeks|Change of body weight from baseline to 24, 48 and 76 weeks, Body weight, Baseline, 24, 48 and 76 weeks|Change of body mass index from baseline to 24, 48 and 76 weeks, Body mass index, Baseline, 24, 48 and 76 weeks|Change of waist circumference from baseline to 24, 48 and 76 weeks, Waist circumference, Baseline, 24, 48 and 76 weeks|Change of hip circumference from baseline to 24, 48 and 76 weeks, Hip circumference, Baseline, 24, 48 and 76 weeks|Change of waist to hip ratio from baseline to 24, 48 and 76 weeks, waist to hip ratio, Baseline, 24, 48 and 76 weeks|Change of basic activities of daily living ability from baseline to 48 and 76 weeks, Basic activities of daily living (BADL) ability measured by the Barthel index. The Barthel Index (Chinese version) measures dependence in 10 basic personal activities of daily living such as showering, feeding, and walking. Ten items are rated, for a maximum score of 100 representing total independence. A "good" score is ≥ 60 points, which indicates that the patient is capable of basic self-care. Moderate dysfunction is defined as a score between 40 and 60, indicating that the patient needs help in daily life. Severe dysfunction is defined as a score between 20 and 40, indicating that the patient is significantly dependent on help in daily living. A score below 20 indicates a total disability in which the patient depends on help for all aspects of daily living. The measure is completed based on input from the direct care worker providing care to the participants on the day testing., Baseline, 48 and 76 weeks|Change of instrumental activities of daily living ability from baseline to 48 and 76 weeks, Instrumental activities of daily living (IADL) ability measured by FAQ scores. The Functional Activities Questionnaire (FAQ, Chinese version) is a standardized assessment of instrumental activities of daily living such as preparing balanced meals and managing personal finances. Sum scores range from 0 to 30, with higher scores indicating worse function. Functional dependence is considered with scores ≥5 points., Baseline, 48 and 76 weeks | Other: Mild cognitive impairment (MCI) remission rate at week76, MCI mitigation is defined by three criteria: an education-adjusted score of the Montreal Cognitive Assessment (MoCA) ≥26, no cognitive deficits in any cognitive subdomain, and preservation of ability to perform instrumental activity of daily living (IADL) with a Functional Activities Questionnaire (FAQ) score \<5. MoCA test includes attention and concentration, executive function, memory, language, visual structure skills, abstract thinking, calculation, and orientation, with a score range from 0 to 30, plus one point if the participant has 12 years or less of education. Generally, a higher MoCA score reflects a better cognitive function. Sum scores of FAQ range from 0 to 30, with higher scores indicating worse function., The extension phase extends from baseline to 76 weeks.
|
