COG-REAGENT: COGnitive tRaining in patiEnts With Amnestic Mild coGnitive impairmENT

Study Overview
=================
Brief Summary
-----------------
This study evaluates the efficacy and mechanism of internet-based cognitive training in patients with amnestic mild cognitive impairment (aMCI). Half of participants will receive multi-domain adaptive internet-based training program, while the other half will receive a fixed, primary difficulty level task.

Detailed Description
-----------------
Background: Alzheimer's disease (AD) is the most common dementia and the major cause for senile dementia. With the increase of life expectancy, AD has become a global problem. However, to date, drug therapies only have modest benefits for patients with AD. Recently, researchers have begun to focus on early intervention of AD at its preclinical stages. Individuals with amnestic mild cognitive impairment (aMCI), often the prodromal stage of AD, report mild short-term memory difficulties but preserved independence in activities of daily living. The aMCI stage is important to slow or even prevent the development of AD. Some previous studies have suggested cognitive training is a potential non-pharmacological intervention for aMCI, however, the results were inconsistent. Thus, investigators will conduct this multi-center randomized controlled trial to explore whether and how cognitive training improves cognitive function in patients with aMCI. Objectives: The first aim of this multi-center single-blinded, randomized controlled trial is to assess whether internet-based cognitive training improves cognitive abilities in patients with aMCI. Furthermore, the second objective is to evaluate the effect of cognitive training on neural plasticity, including brain activation and white matter integrity, which are assessed by functional and structural MRI. Patients and Methods: The study will include 260 patients diagnosed with aMCI from eight centers around China. The patients will be randomized to either a cognitive training group or an active-control group. The intervention is 12-week internet-based cognitive training performed for 40 minutes per day, 4 days a week. Within each task, high accuracy (80%) is required to upgrade to the next difficulty level. The active- control group will receive five processing speed and attention tasks, whose duration also total to 40 min each training day. However, these tasks are set to a fixed, primary difficulty level across the study. Neuropsychological assessments and structural and functional magnetic resonance imaging (MRI) will be performed at the baseline, end of intervention, and 6 months after randomization to measure long-term resilience of the effect. Relevance: Early intervention of aMCI has the potential to delay or even prevent the development of dementia. Some previous studies have suggested cognitive training is a potential non-pharmacological intervention for aMCI, however, the results were inconsistent. Thus, the proposed study is to determine the efficacy of cognitive training in patients with aMCI. Secondly, using functional and structural MRI, this study is to reveal the potential mechanisms underlying cognitive training.

Official Title
-----------------
The Efficacy of COGnitive tRaining in patiEnts With Amnestic Mild coGnitive impairmENT (COG-REAGENT): a Multi-center Randomized Controlled Trial

Conditions
-----------------
Amnestic Mild Cognitive Impairment

Intervention / Treatment
-----------------
* Behavioral: multi-domain internet-based adaptive training program
* Behavioral: active-control program


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Literate Han Chinese, 50-85 years of age with a caregiver that accompanies the subject consistently at least 4 days a week; Complaint and/or informant report of a cognitive impairment lasting for at least 3 months; Clinical diagnosis of MCI according to the MCI core clinical criteria of the National Institute on Aging-Alzheimer's Association (NIA-AA) guidelines; A prominent manifestation of memory deficit with or without other cognitive domain impairments; Mini-Mental State Examination (MMSE) score ≥24, and Clinical dementia rating (CDR) = 0.5, and Normal or slightly impaired activities of daily living as defined by a total score of ≤ 1.5 on the three functional CDR domains (home and hobbies, community affairs, and personal care). Exclusion Criteria: Severe aphasia, physical disabilities, or any other disease that may preclude completion of neuropsychological testing; A medical history of stroke with focal neurological features including hemiparesis, sensory loss, visual field deficits, and evidence of responsible lesions on MRI; Significant white matter lesions (Fazekas score = 3-6); Disorders other than aMCI that may affect cognition; Depression or other psychiatric disorders; Clinically significant gastrointestinal, renal, hepatic, respiratory, infectious, endocrine, or cardiovascular diseases, cancer, alcoholism, drug addiction; Use of medications that may affect cognitive functioning, including tranquilizers, anti-anxiolytics, hypnotics, nootropics, and cholinomimetic agents; Inability to undergo a brain MRI; and Other conditions that in the investigator's opinion might not be suitable for the study.

Ages Eligible for Study
-----------------
Minimum Age: 50 Years
Maximum Age: 85 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cognitive training group<br>Multi-domain adaptive internet-based training program, including processing speed, attention, long-term memory, working memory, flexibility, calculation, and problem solving. 4 x 40 minutes per week, for 12 weeks. | Behavioral: multi-domain internet-based adaptive training program<br>* The training paradigms include a time perception task, visual search task, rapid serial presentation task, delayed match to sample task, paired-associate recall task, attention span task, digit span task, go-no go task, Stroop task, task switching, auditory span task and n-back working memory task. Each task has several difficulty levels. The tasks are grouped in different cognitive domains including: processing speed, attention, perception, long-term memory, working memory, calculation, executive control, reasoning, and problem-solving. Participants in the cognitive training group will complete 40 min of training daily, 4 days a week for 12 weeks. When a high accuracy (80%) is achieved for each task, the level of difficulty will be upgraded for that task.<br>|
| Active Comparator: Active-control group<br>Fixed, primary difficulty level tasks. 4 x 40 minutes per week, for 12 weeks. | Behavioral: active-control program<br>* For the control group, tasks for processing speed and attention are included. Importantly, a fixed, primary difficulty level for all participants in the control group is set.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Montreal Cognitive Assessment | Montreal Cognitive Assessment (MoCA) will be used to evaluate the general cognitive function. MoCA ranges from 0 to 30, and higher value represents a better outcome. | 12 weeks (end of intervention) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-cog, 11-items version). | ADAS-cog 11 scale ranges from 0 to 70, and higher value represents a worse outcome. This study will use ADAS-cog to assess changes in the global cognitive function after intervention. | 12 weeks (end of intervention), 6 months | 
| Change in brain volume and white matter integrity | Structural MRI will be used to measure brain volume and white matter integrity. | 12 weeks (end of intervention), 6 months | 
| Change in brain connectivity | Functional MRI will be used to measure brain connectivity. | 12 weeks (end of intervention), 6 months | 
| Change in Mini-mental State Examination | Mini-mental State Examination (MMSE) will be used to evaluate the general cognitive function. MMSE ranges from 0 to 30, and higher value represents a better outcome. | 12 weeks (end of intervention), 6 months | 
| Change in Montreal Cognitive Assessment | Montreal Cognitive Assessment (MoCA) will be used to evaluate the general cognitive function. MoCA ranges from 0 to 30, and higher value represents a better outcome. | 6 months | 
| Change in memory function | WHO-UCLA Auditory Verbal Learning Test will be used to assess memory function. It ranges from 0 to 45, and higher value represents a better outcome. | 12 weeks (end of intervention), 6 months | 
| Change in Digit span forward | Digit span will be used to assess attention. It ranges from 3 to 10, and higher value represents a better outcome. | 12 weeks (end of intervention), 6 months | 
| Change in Digit span backward | Digit span backward will be used to assess executive function. It ranges from 2 to 8, and higher value represents a better outcome. | 12 weeks (end of intervention), 6 months | 
| Change in Trail Making Test | Trail-Making Test B minus A score will be used to assess executive function. Trail-Making Test B minus A ranges from -150 to 300, higher value represents a worse outcome. | 12 weeks (end of intervention), 6 months | 
| Change in Boston Naming Test | Boston Naming Test will be used to assess language function. It ranges from 0 to 30, and higher value represents a better outcome. | 12 weeks (end of intervention), 6 months | 
| Change in Activities of Daily Living | Activities of Daily Living (ADL) scale will be used to assess the change of life quality. It ranges from 20 to 80. The 20 represents normal life ability and the higher score presents the worse life ability. | 12 weeks (end of intervention), 6 months | 
| Change in Clinical Dementia Rating Scale sum of the boxes | Clinical Dementia Rating Scale sum of the boxes (CDR-SB) will be used to evaluate the general cognitive function. CDR-SB ranges from 0 to 18, and higher value represents a worse outcome. | 12 weeks (end of intervention), 6 months | 
| Change in Quality of Life-Alzheimer's Disease (QoL-AD) Scale | Quality of Life-Alzheimer's Disease (QoL-AD) Scale will be used to evaluate the life quality of the patients. The total score is 13-52, with higher scores indicating better QoL. | 12 weeks (end of intervention), 6 months | 
| Change in Cookie Theft picture description task | Cookie Theft picture description task will be used to evaluate spontaneous discourse. We will analyze the total number of syllables produced, the total number of information units produced, and the total time taken to describe the picture | 12 weeks (end of intervention), 6 months |