EMRESERVA to Enhance Cognitive Reserve in Multiple Sclerosis

Study Overview
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Brief Summary
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Multiple Sclerosis is an immunological degenerative disease that affects the central nervous system causing cognitive impairment as one of the most disabling symptoms, in approximately 40-60% of patients. Cognitive reserve may influence the manifestation of the symptoms of cognitive impairment in MS patients and could justify interindividual differences. Cognitive reserve hypothesis raises that enriching life experiences creates a higher capacity and efficiency of neural networks and protects against cognitive decline in neurological diseases. Scientific evidence demonstrates that older adults with a higher educational or occupational attainment or engagement in cognitively stimulating leisure activities have a reduced risk of dementia.Systematic reviews report little efficacy of pharmacological and behavioral treatments impairment in cognitive functions in MS patients . As such, the best treatment of cognitive impairment in MS may be the proactive prevention of cognitive decline in the first place Through the application of the EM-Reserva program (that contemplates activities that enhance cognitive reserve as cognitive stimulating leisure activities, social relationships and physical exercise), our goal is to evaluate if it is possible to improve cognitive skills of patients with MS without cognitive impairment versus those who undergo non-specific cognitive exercises. In the short and medium term, EM-Reserva program could improve cognitive performance and delay the appearance or modulate the severity of cognitive impairment in the course of the disease

Detailed Description
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The cognitive profile is homogeneous in MS in general, with the time of involvement or degree of involvement being different for each disease form. This neuropsychological profile is characterised by impairment of memory , speed of information processing, attention and executive functions. Periodic cognitive explorations are necessary to assess the evolution of patients with MS. This evaluation helps to establish the neuropsychological profile and details the possible cognitive and emotional patient alterations. The use of reliable and sensitive cognitive tests facilitates the study of neuropsychological disorders associated with MS. The impact of cognitive impairment on the daily lives of people with MS varies greatl. Thus, studies have been found in which patients with minimal physical disability were unable to lead a normal working life due to significant cognitive impairment. According to Rao, people with MS with cognitive dysfunction have greater difficulty in finding employment and enjoying social activities, requiring more personal assistance than people with MS without associated cognitive deficits. Cognitive impairment is therefore one of the major causes of disability in MS and a predictor of restricted participation in daily life. We are currently studying to what extent the potential role of cognitive reserve and brain reserve could explain the inconsistencies found between structural damage or brain dysfunction and cognitive functioning in MS patients. Cognitive reserve is described as the cumulative effect of lifelong intellectual enrichment and includes educational and occupational achievements, lexical abilities and cognitive leisure activities. Attention, information processing speed, working memory, and verbal fluency have a positive impact in cognitive reserve. Therefore, our goal is to assess whether the EM-Reserva specific cognitive program have a positive impact in these cognitive functions and if this stimulation is maintained, it is capable of preventing or slowing the onset of cognitive impairment. According to Sumowski and Leavitt three activities have a strong association with the enhancement of cognitive reserve. Cognitive leisure tasks These activities are 1) reading books, 2) reading magazines or newspapers, 3) producing art (for example, painting, poetry or sculpture), 4) writing non-art productions (for example, a newspaper or a blog), 5) playing a musical instrument, 6) playing structured games (for example, cards, board games, crossword puzzles) and 7) engaging in hobbies (for example, gardening, model building and web design). Aerobical physical exercises Activities that promote social relationships It is known that the brain's ability to improve cognitive reserve depends on several factors, and it is associated with the severity of the brain damage. Gatz and Sumowskihighlighted that the establishment of complex cognitive activities in daily life may be relevant in order to achieve a positive impact in cognitive reserve and delay the onset of cognitive symptoms. These findings provide an opportunity to test whether early intellectual enrichment programs can improve and preserve brain functions and prevent cognitive decline in MS patients. For all the above reasons we propose to evaluate the cognitive impact of the EMReserva specific cognitive training to maintain or improve cognitive functions in patients with MS compared to a standard cognitive training. We propose a five-month (20 weeks) intervention program based on previous studies that have evaluated the efficacy of cognitive training programs in patients with MS. These studies have found results on cognitive performance after a timeframe of cognitive training ranging from 5-15 weeks (28-32). Several studies using musical techniques in cognitive rehabilitation have been performed in a period of time between 24-36 weeks (33-36) OBJECTIVES(enter elsewhere) METHODS(enter elsewhere) This is a pragmatic, unicentric, observer-blinded Randomized Controlled Trial (RCT) comparing the cognitive rehabilitation programme EM-Reserva (intervention) with usual cognitive care alone(control). The trial will be conducted in Multiple Sclerosis Unit of Virgen Macarena Universitary Hospital (UEMAC) in Seville, Spain. Neuropsychologists will check participants' availability to attend groups. Groups of 6 participants who could potentially attend for treatment at the same time and venue were individually randomized to either EM-Reserva'' intervention or usual cognitive care on a 1:1 ratio. Allocation will be stratified by results of Cognitive Reserve Questionnaire. The normative data of the CRC were determined using quartiles. In this way, a score equal to or less than 6 points, which belongs to quartile 1 (≤ C1), would place the subject's degree of cognitive reserve in the lower range. Between 7 and 9 points (C1-C2) would correspond to a cognitive reserve located in the medium-low range, while between 10 and 14 (C2-C3) would be considered mediumhigh. Those scores ≥ 15 points would be classified as a cognitive reserve located in the upper category (≥ C4) (23) The allocation algorithm was held on a secure server using an Internet Based randomization system to obtain treatment allocations for each participant and will be stratified taking in account CRC Quartiles in order to avoid a selection bias. Neuropsychologists and participants will be aware of the group allocation. Neurologists will be blinded to group allocation and will perform SDMT (primary endpoint of the study) Non-specific cognitive exercises included general advice from MS neuropsychologist specialists on how to manage cognitive difficulties and general cognitives exercises to improve cognitive performance elaborated at our MS Unit, using exercises like sudokus, crosswords and labyrinths. This control group will require the completion of at least 30 minutes of cognitive exercises daily from Monday to Friday for 5 months. As a complement, patients will be instructed to read newspapers or magazines at least 15 minutes daily. Specific cognitive rehabilitation program EM-Reserva will be provided by two specialized MS Neuropsychologists in groups of 6 participants who will meet approximately an hour weekly, for 5 months. EM reserva cognitive program includes the following activities: Cognitive leisure tasks 1) Reading books: Reading a book will be recommended for the duration of the cognitive training program. 2) Reading magazines or newspapers daily. 3) Creative tasks type Zentagle drawing, 1 production per week. 4) Writing non-artistic productions: Journal writing or summaries of weekly activities will be recommended. 5) Playing a musical instrument: weekly group piano lessons will be held with a piano keyboard. 6) Playing structured games: Weekly groups will be held to play board games. 7) Participate in socio-cultural activities such as museum visits, exhibitions, etc., once a month. Physical exercises (workout exercises): Group workout will be carried out through a virtual platform three times a week (one hour per session) assisted by a specialized MS Neurophysioterapist. Activities that promote social relationships (social exercises): through group piano teaching lessons, board games for groups and other group activities. The EM Reserva cognitive training program will be carried out in groups (up to 6 patients) who will meet one hour once a week for 5 months. In addition, patients will perform 30 minutes of individual cognitive exercises at home from Monday to Friday (musical exercises with piano/reading/writing...) The physical exercises will be done using a virtual platform, conducted by a non-blinded Neurophysioterapist specialized in the treatment of Multiple sclerosis. Attendance and compliance will be recorded in both intervention/control groups. If participants missed a group session, they could attend early for the following session to catch up on the content they had missed. Compliance with prescribed homework will also be evaluated and recorded. Outcomes assessed at 6 and 12 months after randomization included the SDMT, Brief Repeatable Battery of Neuropsychological Test (BRB-N), Vocabulary WAIS-IV, TMT A/B, WMI WAIS-IV, Tower of London test, phonetic and semantic fluencies (COWAT), MSQOL-54, BDI and BAI and PDQ-5. Questionnaires will be administered by specialized MS Neuropsychologists. The EDSS, number of relapses, number of new/enlarged T2 lesions on cerebral MRI and concomitant medications will also be recorded. This information will be collected by specialized MS Neurologists blinded to intervention (visit 0 and visit 12 months). Study Assessments A specific Cognitive Battery of recognized validity and reliability in this type of patients is used for this purpose.This test is the Brief Repeatable Neuropsychological Test Battery for MS (BRB-N), a battery of cognitive tests that evaluate verbal and visual memory, attention, information processing speed and prefrontal functions, all of which involved in the specific cognitive profile of MS patients. The BRB-N is administered in approximately 20-30 minutes and each of its component tests consists of 15 alternative forms in the original Rao's version, so the battery can be used longitudinally to assess the evolution of cognitive impairment. These tests are: Buschke Selective Reminder test (SRT), 10/36 Spatial recall Test (10/36 SRT),Symbol Digit Modalities Test (SDMT), Paced Auditory serial addition task (PASAT) and Verbal fluency test (FV) (19). Another test that we will use is the Trail Making Test A-B (TMT A-B), We will use another tests that assess executive functions and other areas more deeply, such as the Working Memory Index test (WAIS-IV),the Tower of London,the Controlled Oral Word Association Test (COWAT),The Wechsler Abbreviated Intelligence Scale, The Cognitive Reserve Questionnaire (CRQ). The Multiple Sclerosis International Quality of Life questionnaire (MusiQoL-54) is a multidimensional scale that assesses quality of life, including physical function, pain, general health, vitality, social functions, emotional state, mental health, rest, sexual functions and cognitive activities. The score ranges from 0 to 100 with a higher score corresponding to higher QoL. It is usually self-administered within approximately 15-20 minutes. One of the subscales that we can use in cognitive assessment is the PDQ (Perceived Deficit Questionnaire).Modified fatigue impact scale (MFIS-5) is the abbreviated version of MFIS, it measures the impact of fatigue on cognitive, physical and psychosocial function. It is a self-administered questionnaire that consists of 5 of the 21 items of the MFIS that correlate most strongly with the total score of the MFIS. The Beck Depression Inventory (BDI) is the most widely used measure in the Spanish population for the evaluation of depression in patients with MS. Its use is recommended for this type of patient by the Goldman Consensus Statement on Depression in Multiple Sclerosis. WORK PLAN We will select 58 patients who met the inclusion/exclusion criteria (VISIT 0). They will be randomized in two groups (Intervention/Control) and stratified taking in account the punctuation in the Cognitive Reserve Questionnaire and age, in a randomized 1:1 masked manner. In VISIT 1 (+/- 3m from VISIT 0), we will determine cognitive performance in both groups, using SDMT, (form2), Vocabulary WAIS-IV, TMT A/B, WMI WAIS-IV, TLT, Tower of London test, phonetic and semantic fluencies (COWAT). We will also administer the MSQOL-54, BDI and BAI and PDQ-5 tests. In VISIT 2 (6 m +/- 1 month) we will determine cognitive performance in both groups, using SDMT(Form 3), BRB-N (Form B) , Vocabulary WAIS-IV, TMT A/B, WMI WAIS-IV, TLT, Tower of London test, phonetic and semantic fluencies (COWAT). We will also administer the MSQOL-54, BDI and BAI and PDQ-5 tests. Visit 3 (12 m +/- 1 month) we will determine cognitive performance in both groups with the SDMT (Form 1), BRB-N (Form A) , Wechsler Intelligence Scale Vocabulary subtest (WAIS IV), TMT A-B, work memory index (WAIS), Tower of London test, phonetic and semantic fluencies, and MSQOL-54. Differences in neuropsychological tests before and after cognitive rehabilitation will be evaluated by ANOVA two-factors with replication adn Wilks' Lambda test to test the hypothesis of equality. Each test performance will be adjusted by age, education, and gender. Clinical/demographic data will be assessed in visit 0, visit 2 and visit 3, including sex, age, time of MS evolution, number of relapses, Kurtzke's Expanded Disability Status Scale (EDSS), number of cerebral magnetic resonance T2 lesions and gadolinium enhanced lesions and if they are receiving any Disease Modifying treatment. EXPECTED OUTCOMES Intellectual enrichment is associated with greater protective efficiency of the manifestations of cognitive dysfunctions. After the administration of the EMReserve program, we expect to find a cognitive improvement in functions related to cognitive reserve, reflected in the neuropsychological assessment scores, compared to patients who undergo a non-specific mental exercise program or healthy controls in whom these measures will not be increased. Patients who complete the EMReserva program, due to increased cognitive reserve, will be less likely to develop cognitive impairment at one year from baseline. Given the dynamic nature of this pathology, cognitive programs that go in parallel with the natural history of the disease are necessary. If the EMReserva program proves effective in improving the cognitive capacities involved in cognitive reserve, it would be considered necessary to maintain these cognitive habits throughout life. Therefore, the mental, physical and social exercises based on this program would be implemented as part of the global approach to their disease. The present study aims to invest resources in the prevention of cognitive impairment in patients affected by multiple sclerosis given its high prevalence and the impact on their daily life and quality of life as they are a young working population with high mental demands.

Official Title
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EMRESERVA A Program to Enhace Cognitive Reserve in Patients With Multiple Scleorisis

Conditions
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Cognitive Change

Intervention / Treatment
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* Behavioral: EMRESERVA


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 18-55 years (both inclusive). Relapsing-remitting Multiple Sclerosis (RRMS) according to the 2017 McDonald Revised Criteria with less than 15 years of evolution. Patients with EDSS <3 No cognitive impairment on the Brief Neuropsychological Battery of Rao (BRB-N) (Form A) corrected for age and education performed on the last three months in the MS Unit of Hospital Virgen Macarena (UEMAC) according to Amato´s criteria Able to attend group sessions. Patients able to give written Informed Consent. Exclusion Criteria: Diagnosis of Secondary Progressive or Primary Progressive MS according to McDonald revised criteria (2017) No evidence of relapse or corticosteroid treatment in the 3 months prior to study inclusion. Had vision or hearing problems, such that they were unable to complete the cognitive assessments. Had concurrent severe medical or psychiatric conditions, which prevented them from engaging in treatment and/or Beck Depression Inventory > 20. Involved in other psychological intervention trials.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| control<br>Non-specific cognitive exercises included general advice from MS neuropsychologist specialists on how to manage cognitive difficulties and general cognitives exercises to improve cognitive performance elaborated at our MS Unit, using exercises like sudokus, crosswords and labyrinths. This control group will require the completion of at least 30 minutes of cognitive exercises daily from Monday to Friday for 5 months. As a complement, patients will be instructed to read newspapers or magazines at least 15 minutes daily. | Behavioral: EMRESERVA<br>* training program will be carried out in groups (up to 6 patients) who will meet one hour once a week for 5 months.<br>|
| Intervention EMRESERVA<br>Specific cognitive rehabilitation program EM-Reserva will be provided by two specialized MS Neuropsychologists in groups of 6 participants who will meet approximately an hour weekly, for 5 months.EM reserva cognitive program includes the following activities: Cognitive leisure tasks Physical exercises (workout exercises) Activities that promote social relationships (social exercises) | Behavioral: EMRESERVA<br>* training program will be carried out in groups (up to 6 patients) who will meet one hour once a week for 5 months.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Symbol Digit modality test | Change in mean scores. Asociate display symbol to corresponding number. Number of correct responses in 90 seconds | at month 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Trail Making Test form A and B | change in mean scores | at 6 and 12 months. | 
| Change in BRB-N subtest | Change in mean scores | at 6 and 12 months | 
| Change in Wechsler Intelligence Scale Vocabulary subtest (WAIS IV) mean scores at 6 and Change in Wechsler Intelligence Scale Vocabulary subtest (WAIS IV) mean scores at 6 and Change in Wechsler Intelligence Scale Vocabulary subtest | Change in mean scores | at 6 and 12 months | 
| Change in Work memory index (WAIS) | Change in mean scores | at 6 and 12 months | 
| Change in Tower of London test | Change in mean scores | at 6 and 12 months | 
| Change in Phonetic and semantic fluencies | Change in mean scores | at 6 and 12 months | 
| Change in Multiple Sclerosis Quality of Life-54 (MSQOL-54) questionnaire | Change in mean scores | at 6 and 12 months | 
| Change in Beck depression/anxiety questionnaires | Change in mean scores | at 6 and 12 months | 
| Change in MFIS-5 | Change in mean scores | at 6 and 12 months | 
| Change in Perceived Deficit Questionnaire (PDQ-5) | Change in mean scores | at 6 and 12 months |