EMRESERVA to Enhance Cognitive Reserve in Multiple Sclerosis
Condition: Cognitive Change
Study type: Observational

Summary: 
      Multiple Sclerosis(MS) is an immunological degenerative disease that affects central nervous
      system causing cognitive impairment, which is one of the most disabling symptoms in MS.
      Cognitive reserve may influence manifestations of 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,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, best treatment of
      cognitive impairment in MS may be a proactive prevention of cognitive decline in first place
      Through the application of the EM-Reserva program 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: 
      The cognitive profile is homogeneous in MS. This neuropsychological profile is characterised
      by impairment of memory ,speed of information processing, attention and executive functions.
      Periodic cognitive explorations are necessary to assess evolution of patients with MS. This
      evaluation helps to establish a neuropsychological profile which could help to study
      cognitive and emotional symptoms of MS. Therefore, using reliable cognitive tests could
      enable to study neuropsychological disorders associated with MS.

      Impact of cognitive impairment on daily routine of people with MS can be diverse and is one
      of major causes of disability in MS. Therefore is vital to stablished which is the role of
      cognitive and brain reserve and if they could explain inconsistency between structural damage
      and cognitive functions in MS.

      Attention, information processing speed, working memory, and verbal fluency have a positive
      impact in cognitive reserve. Therefore, our goal is to assess whether EM-Reserva specific
      cognitive program have a positive impact in these cognitive functions and maybe could prevent
      onset of cognitive impairment.

      According to Sumowski and Leavitt three activities have a strong association with enhancement
      of cognitive reserve.

        1. 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).

        2. Aerobical physical exercises

        3. Activities that promote social relationships.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.

      Therefore, is proposed to evaluate cognitive impact of the "EMReserva" specific cognitive
      training to maintain or improve cognitive functions in patients with MS compared to a
      standard cognitive training. A five-month (20 weeks) intervention program is proposed to
      evaluate efficacy of cognitive training programs in patients with MS. Cognitive performance
      improvement has been found after 5-15 weeks (28-32) of cognitive training. On the other hand,
      musical techniques had been used in cognitive rehabilitation for 24-36 weeks (33-36)

      OBJECTIVES(enter elsewhere) METHODS(enter elsewhere) This is a pragmatic, unicentric,
      observer-blinded Randomized Controlled Trial (RCT) comparing cognitive rehabilitation
      programme EM-Reserva (intervention) with usual cognitive care alone(control).

      This 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.

      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 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:

        1. Cognitive leisure tasks 1) Reading books. 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.

        2. 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.

        3. 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...) Physical exercises will be done using a virtual platform,
      conducted by a non-blinded Neurophysioterapist specialized in MS. 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. 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. Patients will perform Brief Repeatable
      Neuropsychological Test Battery for MS (BRB-N), which evaluates verbal and visual memory,
      attention, information processing speed and prefrontal functions.Other test such as 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) and
      Trail Making Test A-B (TMT A-B) will be also perform.

      To asses executive functions other tests will be used, such as Working Memory Index test
      (WAIS-IV),Tower of London,Controlled Oral Word Association Test (COWAT),Wechsler Abbreviated
      Intelligence Scale, Cognitive Reserve Questionnaire (CRQ).

      In order to evaluate the effect of the programme quality of life test all patients will
      perform Multiple Sclerosis International Quality of Life questionnaire (MusiQoL-54) ,PDQ
      (Perceived Deficit Questionnaire), Modified fatigue impact scale (MFIS-5) and The Beck
      Depression Inventory (BDI)

      WORK PLAN

        1. To select 58 patients who met inclusion/exclusion criteria (VISIT 0). They will be
           randomized in two groups (Intervention/Control) and stratified taking in account the
           punctuation in Cognitive Reserve Questionnaire and age, in a randomized 1:1 masked
           manner.

        2. VISIT 1 (+/- 3m from VISIT 0), evaluate 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).Administer MSQOL-54, BDI and BAI and PDQ-5
           tests.

        3. VISIT 2 (6 m +/- 1 month) evaluate 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). Administer MSQOL-54, BDI and BAI and
           PDQ-5 tests.

        4. VISIT 3(12 m +/- 1 month) evaluate cognitive performance in both groups with 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
      manifestations of cognitive dysfunctions.

      After administration of EMReserve program, cognitive improvement with enrichment of cognitve
      reserve is expected. This fact may be reflected in neuropsychological assessment scores of
      patients who were included in the program whereas measures of patients who undergo
      non-specific program 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.

      If the EMReserva program proves to be effective in improving 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 prevention of cognitive impairment in patients
      affected by MS 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.
    

Intervention name(s): EMRESERVA
Intervention type(s): Behavioral
Intervention description(s): training program will be carried out in groups (up to 6 patients) who will meet one hour once a week for 5 months.
Observational model: Other
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        Patients under follow-up in the Multiple Sclerosis unit, diagnosed with RRMS (according to
        the revised McDonald 2017 criteria) and without cognitive impairment will be selected. The
        presence or absence of cognitive impairment will be determined according to Amato´s
        criteria, and defined as the absence of a failure on at least two BRB-N tests, with scores
        of at least 1.5 SD below the scores of healthy controls