REACT MCI - Repeated Advanced Cognitive Training in Mild Cognitive Impairment

Study Overview
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Brief Summary
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Background: Dementia is a debilitating and devastating disease impacting the individuals, their families, and the health care system. According to the World Health Organization the dementia epidemic could overwhelm the global health care system and undermine social and economic development. Currently, no curative treatment for dementia exists despite immense research activity. The cognitive and functional impairment in dementia, especially Alzheimer's disease (AD), develop slowly decades before clinical signs emerge. This knowledge has led to the recognition of a prodromal period of mild cognitive impairment (MCI), between normal cognition and dementia. This is at present the earliest stage for intervention in dementia; even a short delay in dementia progression will have a large impact on global economy and health care. Objectives: In this clinical multicenter study, we aim to investigate the efficiency and cost-effectiveness of working memory training in MCI. To identify high responders to training analysis of genetic markers, relative's stress and craniospinal clearance will be performed. Participants and methods: This study is a blinded, randomized and controlled trail that will include 213 participants, diagnosed with MCI, included from five Norwegian Memory clinics in four health care regions. The groups will be randomized to either two training periods, one training period or active control. The intervention is computerized working memory training. Neuropsychological status, activities of daily living (ADL), and relative stress and quality of life will be assessed at baseline and 3, 6, 12 ,24 and 48 months after training. Structural MRI will be performed at baseline, and 3 and 6 months after training. For participants in the REACT MCI glymphatics substudy craniospinal clearance will be measured at baseline. A cost-utility analysis will be performed to evaluate if the working memory training is more cost-effective compared to the active control group in the MCI phase, taking a societal perspective.

Official Title
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Repeated Advanced Cognitive Training in Mild Cognitive Impairment (The REACT MCI Study). A Randomized, Controlled Trial.

Conditions
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Mild Cognitive Impairment

Intervention / Treatment
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* Other: Computerized cognitive training.
* Other: Generalized brain training / Active control


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for the REACT MCI study: Diagnosis of MCI, based on the Mayo/winblad criteria or confirmation of current MCI status within the last 6 months before study enrollment. The ability to use and accessibility to an iPad or computer. Fluent in Norwegian. Spinal tap performed and results available Exclusion Criteria for the REACT MCI study: Patients unable to undergo a MRI investigation based on claustrophobia or metal foreign bodies are excluded from the study. Major psychiatric illness and current substance abuse Recent stroke Inclusion Criteria for the REACT MCI Glymphatics substudy: Enrollment in the REACT MCI study Participant allocated to Sorlandet Hospital or Oslo University Hospital Exclusion Criteria for the REACT MCI Glymphatics substudy: Individuals with known allergy against contrast solutions Individuals with other serious allergies Individuals with kidney failure or glomerular filtration rate < 30 Individuals younger than 18 or older than 80 Pregnant or lactating women For individuals >70 years or with medications affecting kidney function the glomerular filtration rate needs to be less than week old.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomization in blocks of six to eight will be performed by the regional research support statistics service to either two training periods, one training period or generalized brain training/active control.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: One training period<br>One training period of 30 minutes of daily adaptive training for 4-5 days a week up for 20- 25 trainings using computerized cognitive training. | Other: Computerized cognitive training.<br>* COGMED RM program (Pearson Inc., UK)<br>|
| Experimental: Two training periods<br>Two training periods of 30 minutes of daily adaptive training for 4-5 days a week up for 20- 25 trainings using computerized cognitive training. | Other: Computerized cognitive training.<br>* COGMED RM program (Pearson Inc., UK)<br>|
| Active Comparator: Active control<br>The generalized brain training group (Active control) will play solitaire 30 minutes daily for 25 sessions | Other: Generalized brain training / Active control<br>* Solitaire<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Working memory training is superior to active control measured by spatial span backwards at 6 months |  | From enrollment until 6 months | 
| Reduced function in the glymphatic system is associated with reduced working memory training effect measured by CT evaluated craniospinal clearance | Craniospinal clearance will be evaluated with a single CT image scan at level with the foramen magnum. | Enrollment to 12 months | 
| Working memory training impact quality of life measure in the participants as compared to active control measured by EuroQOL5D-5L after 12 months. |  | Enrollment to12 months | 
| Working memory training prolongs the MCI phase as compared to active controls | We consider the participants as having dementia when they no longer rapport intact activities of daily living and in addition display reduction of 1.5 standard deviation on test score on two tests on three or more cognitive domains. | Enrollment to 48 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The effect of working memory training is dose related measured by spatial span backwards after 6 months |  | Enrollment to 6 months | 
| Allelic variations in predefined genetic markes influence training effects after 3 months measured by spatial span backwards. | Allelic variations of LMX1a, APOE, AQP4 and/or COMT have in previous publications shown variable impact on working memory training. A statistical model combining these genes will be fitted for this investigation | Enrollment to 3 months | 
| Workin memory training reduces relatives stress scores as compared to relatives stress scores in the active control group after 12 months | Relatives stress score (RSS) is a validated scale measuring the stress for relatives | Enrollment to 12 months | 
| Working memory training reduces QALY associated cost as compared to active controls at 24 months. | The generic outcome in the analysis is QALYs (Quality adjusted life years) derived from the instrument EQ-5D 5L. The second outcome is production loss of the relatives and patients associated with MCI through the progression of dementia The health economic analysis will include following costs: 1) intervention related costs 2) direct costs/health care costs, mainly related to use of health care services, including primary, secondary and tertiary care and health services 3) indirect costs, including work absence for the patients and the relatives of the patients (i.e., productivity loss). Data will be collected through a self-report measures (EQ-5D 5L), and from the Norwegian patient registry. | Enrollment to 24 months | 
| Working memory training reduces QALY associated cost as compared to active controls at 48 months. | The generic outcome in the analysis is QALYs (Quality adjusted life years) derived from the instrument EQ-5D 5L. The second outcome is production loss of the relatives and patients associated with MCI through the progression of dementia The health economic analysis will include following costs: 1) intervention related costs 2) direct costs/health care costs, mainly related to use of health care services, including primary, secondary and tertiary care and health services 3) indirect costs, including work absence for the patients and the relatives of the patients (i.e., productivity loss). Data will be collected through a self-report measures (EQ-5D 5L), and from the Norwegian patient registry. | enrollment to 48 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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computer-based cognitive training