Effects of 24-week Computerized Cognitive Training in Patients With MCI and AD

Effects of 24-week Computerized Cognitive Training on Microbiota-gut-brain Axis in Patients With Mild Cognitive Impairment and Mild Alzheimer's Disease: a Randomized Controlled Trial

This study aims to testify multi-domain effects of computerized cognitive training in patients with mild cognitive impairment and mild Alzheimer's disease through multi-dimensional evaluation.

This study aimed to elucidate the neural process enhancement and remodulation in gut microbes resulting from older adults with MCI and mild AD in a randomized controlled trial of a 24-week computerized cognitive training (CCT) program. After recruitment and baseline assessments, pairs of participants with MCI and mild AD would be randomly allocated into the corresponding subgroup. Participants in CCT group will receive a computerized multidomain cognitive training program (www.66nao.com) and will be required to complete at least 30 minutes of training per day (3 cycle of 5 2-min tasks), 5 days a week for 24 weeks. Adherence to the intervention will be supervised by an independent researcher. The number of training days and training hours per day will be recorded. Patients in control group received treatment as usual (TAU) for 24 weeks. The neuropsychological measures will be performed at baseline, follow-up at 4 weeks, 12 weeks, and 24 weeks; functional Near-Infrared Spectroscopy (fNIRS) data and fecal samples will collected at baseline and 24 weeks.

computerized cognitive training, functional near-infrared spectroscopy, mild cognitive impairment, Alzheimer's disease, brain-gut-microbiota axis, gut microbiota

After recruitment and baseline assessments, pairs of participants with MCI and mild AD will be randomly allocated into either the CCT group and the control group. Participants in CCT group will receive a multidomain adaptive computerized cognitive training program (www.66nao.com) for 24 weeks. Patients in control group will receive treatment as usual (TAU) for 24 weeks.

Since it will not be possible to blind the participants because the experimental and control interventions have to be explained to them and their caregivers before randomization. The single blinding will be applied to researchers who conducted the measurements to minimize the potential assessor biases. Blinding will be also maintained for data management, outcome assessment, and data analysis.

Adaptive computerized cognitive training program (www.66nao.com) and the intensity is at least 30 minutes of training per day (3 cycle of 5 2-min tasks), 5 days a week for 24 weeks.

Patients in control group will receive TAU for 24 weeks, which includes (1) regular medication management from the Memory Clinic, if applicable; (2) basic health education at each follow-up (face to face) and twice per month on the internet.

Participants in intervention group will receive a multidomain, adaptive computerized cognitive training program (www.66nao.com) and will be required to complete at least 30 minutes of training per day (3 cycle of 5 2-min tasks), 5 days a week for 24 weeks. Multidomain coverage paradigms include working memory, calculation, processing speed, attention, executive function, and short-term and long-term memory.

Patients in control group will receive TAU for 24 weeks, which includes (1) regular medication management from the Memory Clinic, if applicable; (2) basic health education at each follow-up (face to face) and twice per month on the internet .

The Alzheimer's Disease Assessment Scale- cognitive subscale (11 items) will be used to evaluate global cognition and served as the primary outcome measure. The minimum and maximum values are 0 and 70 respectively, and higher scores mean a worse outcome.

The Auditory Verbal Learning Test (minimum to maximum: 0-45) will be applied, and higher scores mean a better outcome for the scale.

The Free and Cued Selective Reminding Test (minimum to maximum: 0-48) will be applied, and higher scores mean a better outcome for the scale.

The Trail Making Test (minimum to maximum: 0-24) will be applied, and higher scores mean a better outcome for the scale.

The Digital Span Test (minimum to maximum: 0-10) will also be applied, and higher scores mean a better outcome for the scale.

The Clock Drawing Test (minimum to maximum: 0-15) will be applied, and higher scores mean a better outcome for the scale.

The Boston Naming Test (minimum to maximum: 0-30) will be applied, and higher scores mean a better outcome for the scale.

The Verbal Frequency Test (minimum: 0, no maximum) will also be applied, and higher scores mean a better outcome for the scale.

The Neuropsychiatric Inventory (minimum to maximum: 0-144) will be used, and higher scores mean a worse outcome for the scale.

The 30-Geriatric Depression Scale (minimum to maximum: 0-30) will be used, and higher scores mean a worse outcome for the scale.

The Instrumental Activities of Daily Living scale (minimum to maximum: 0-31) will be used, and higher scores mean a worse outcome for this scale.

The Clinical Dementia Rating scale (sum of boxes, minimum to maximum: 0-18) will be used, and higher scores mean a worse outcome for this scale.

The regions of interests (ROIs) are selected as the Brodmann Area (BA) 9 and 46 (overlapping the dorsolateral prefrontal cortex, DLPFC), left Brodmann Area 6 (overlapping pre-Motor and Supplementary Motor Cortex, PM-SMC), and right Brodmann Area 45 (overlapping pars triangularis Broca's area). For each resting-state dataset of fNIRS, functional connectivity (FC) will be analyzed by Spearman's correlation between the time series of each ROI-to-ROI pair.

Fecal samples will be collected from patients in standard 300 mL sterilin tubes and frozen immediately at -80°C. Patients will be asked to produce the first-morning sample for consistency and to avoid alcohol the previous 24 h. After 16S rRNA high-throughput sequencing, the diversity analysis of species under a sample (α-diversity) of the bacteria on Genus, will be analyzed in R.

After 16S rRNA high-throughput sequencing, the cluster analysis between different samples (β-diversity) will be analyzed in R.

After 16S rRNA high-throughput sequencing, the compositional analysis of bacteria on genus will be analyzed in R.

Inclusion Criteria: between 55 and 90 years of age; a Clinical Dementia Rating (CDR) score of 0.5 or 1; at least three months of stable doses if receiving antidementia medication or mood-stabilizing medication for mild AD participants; primary school education and above; accompanied by a consistent caregiver (at least 5 days/week); informed consent. Exclusion Criteria: factors that might preclude completion of assessments; severe psychiatric illness and the use of antidepressants; any condition that would preclude completion of training and follow-up tests; other disorders that would affect cognition.

With publication of research articles, de-identified data collected for the study, including individual participant data, can be made available to interested parties on reasonable request, and if in line with privacy regulations. Data can be requested at least 18 months after publication of the research articles, with a proposal by sending an e-mail to Dr. Yang Lü.

With publication of research articles, de-identified data collected for the study, including individual participant data, can be made available to interested parties on reasonable request, and if in line with privacy regulations, with a proposal by sending an e-mail to Dr. Yang Lü.