Effects of Exercise Training on Neurotrophic Factors and Subsequent Neuroprotection in Persons with Multiple Sclerosis—A Systematic Review and Meta-Analysis
Abstract
:1. Introduction
2. Methods
2.1. Literature Search
2.2. Selection Criteria
2.3. Screening Process
2.4. Quality Assessment
2.5. Data Extraction
2.6. Meta-Analysis
3. Results
3.1. Screening Process and Study Selection
3.2. Study Quality
3.3. Participants
3.4. Exercise Interventions
3.5. Physiological and Functional Outcome Measures
3.6. Acute Effects of Exercise on Neurotrophic Factors
3.7. Chronic Effects on Neurotrophic Factors
3.7.1. Brain-Derived Neurotrophic Factor (BDNF)
3.7.2. Nerve Growth Factor (NGF)
3.7.3. Ciliary Neurotrophic Factor (CNTF)
3.7.4. Insulin-Like Growth Factor-1 (IGF-1)
3.7.5. Neurotrophin 3 (NT3), 4 (NT4), and 4/5 (NT 4/5)
3.7.6. Glial Cell-Derived Neurotrophic Factor (GDNF)
3.7.7. Platelet-Derived Growth Factor (PDGF)
3.7.8. Vascular Endothelial Growth Factor (VEGF)
3.8. Neuroprotective Effects of Exercise
4. Discussion
4.1. Acute and Chronic Neurotrophic Response to Exercise
4.2. Exercise Modality
4.3. Translation between Neurotrophic Factors and Neuroprotection
4.4. Methodological Considerations
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Study | Study Quality | Sub-Total | Study Reporting | Sub-Total | Total | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | ||||
Abbaspoor et al., 2020 (mixed) | 1 | 0 | 0 | 1 | 1 | 3 | 0 | 0 | 2 | 1 | 0 | 1 | 1 | 5 | 8 |
Askari et al., 2017 (aerobic + resistance) | 1 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 2 | 1 | 0 | 1 | 1 | 5 | 6 |
Banitalebi et al., 2020 (mixed) | 1 | 0 | 1 | 0 | 1 | 3 | 2 | 0 | 2 | 1 | 0 | 1 | 1 | 7 | 10 |
Briken et al., 2016 (aerobic) | 1 | 1 | 1 | 0 | 0 | 3 | 2 | 0 | 1 | 1 | 0 | 1 | 1 | 6 | 9 |
Eftekhari et al., 2018 (Pilates) | 1 | 1 | 0 | 0 | 0 | 2 | 0 | 0 | 1 | 1 | 0 | 1 | 1 | 4 | 6 |
Joergensen et al., 2019 (resistance) | 1 | 0 | 1 | 1 | 0 | 3 | 3 | 0 | 2 | 1 | 0 | 1 | 1 | 8 | 11 |
Khademosharie et al., 2018 (mixed) | 1 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 2 | 1 | 0 | 1 | 1 | 5 | 6 |
Mokhtarzade et al., 2018 (aerobic) | 1 | 0 | 1 | 0 | 1 | 3 | 2 | 0 | 2 | 1 | 0 | 1 | 1 | 7 | 10 |
Naghibzadeh et al., 2019 (mixed) | 1 | 0 | 0 | 0 | 1 | 2 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 1 | 3 |
Ozkul et al., 2018 (mixed) | 1 | 1 | 1 | 1 | 1 | 5 | 3 | 0 | 1 | 1 | 0 | 1 | 1 | 7 | 12 |
Rezaee et al., 2020 (aerobic) | 1 | 0 | 0 | 1 | 0 | 2 | 1 | 0 | 2 | 1 | 0 | 0 | 1 | 5 | 7 |
Savsek et al., 2021 (aerobic) | 1 | 0 | 0 | 1 | 1 | 3 | 2 | 0 | 2 | 1 | 0 | 1 | 1 | 7 | 10 |
Schulz et al., 2004 (aerobic) | 1 | 0 | 1 | 1 | 0 | 3 | 0 | 0 | 2 | 1 | 0 | 0 | 1 | 4 | 7 |
Wens et al., 2016 (mixed) | 1 | 1 | 1 | 1 | 0 | 4 | 3 | 0 | 2 | 1 | 0 | 1 | 1 | 8 | 12 |
Total (across sub-scores) | 14 | 4 | 7 | 7 | 6 | 18 | 0 | 24 | 13 | 0 | 11 | 13 | Median = 8.5 |
Study | MS Participants | Intervention | Type of Training | Neurotrophic Factors Primary Outcome | Physiological and/or Functional Adaptations | |
---|---|---|---|---|---|---|
MS type (RR/SP/PP) Number of participants (m/f%) EDSS (mean/median score or range) Age (mean years or range) TSD (mean years) | Duration (weeks) Sessions/week (s/wk) Session duration (min) Intensity | (yes/no/not reported) Methods for Assessing Neurotrophic Factors Neurotrophic Factor(s) Adaptations | Neuroprotective Adaptations (yes/no/not reported) | |||
Abbaspoor et al., 2020 | RR n = 16 (0/100%) Age: 35.4 EDSS: 3.0 TSD: 10.1 | 1: MIX 2: Control | 8 weeks, 3 s/wk AT (rhythmic): 15–20 min, 55–70% of HRmax 3 s/wk TRX or elastic band or body weight training: 1–2 × 8–14 reps, 1 s/wk | Not reported | Grip strength ↑BG Finger pinch strength 2 min walking distance (↑BG) Walking speed ↑BG Knee ext strength Not reported | |
Methods: Blood samples 48 h before and after intervention. Serum analyzed by ELISA kit (BDNF: Shanghai Crystal Day Biotech Co, China; IGF-1: Mediagnost, Germany). Centrifugation 3000 g for 10 min. Storage −80 °C. | ||||||
Acute: | Chronic: BDNF IGF-1 ↑BG | |||||
Askari et al., 2017 | MS type not reported n = 30 (0/100%) Age: 35.1 EDSS: not reported TSD: not reported | 1: AT 2: RT 3: Control NB: results from AT and RT are pooled into a MIX group. | 8 weeks, 3 s/wk AT (aquatic): 30 min, no intensity reported RT: 30–45 min, 40–70% of 1RM, machines, 2–3 × 10–14 reps | Not reported | Not reported Not reported | |
Methods: Blood samples 48 h before and after intervention. Plasma analyzed with ELISA kit (NT4: Chongqing Biospes Co, China). Centrifugation not reported. Storage −70 °C. | ||||||
Acute: | Chronic: NT4 ↑BG (AT and RT vs control) | |||||
Banitalebi et al., 2020 | RR n = 89 (0/100%) Age: not reported EDSS 0–4: n = 45 EDSS 4.5–6.0: n = 25 EDSS 6.5–8.0: n = 19 TSD: Not reported | 1: MIX 2: Control | 12 weeks, 3 s/wk 100 min (in total) AT (bike or run): 50–70% of HRmax RT (whole body): 40–70% of 1RM, 3 × 12 reps Balance: static + weight shift, no further details reported Pilates: no details reported Stretching: to pain threshold, no further details reported | Not reported | Knee ext strength ↑BG VO2max ↑BG Body fat % ↓BG Not reported | |
Methods: Blood samples before and after intervention (after overnight fasting). Serum analyzed by ELISA kit (BDNF, NT3, NT4/5, GDNF: Boster Bio, CA, US; CNTF: Stabiopharm, Singapore). Centrifugation 500 g for 12 min at 4 °C. Storage −80 °C. | ||||||
Acute: | Chronic: BDNF ↑BG NT3 ↑BG NT4/5 ↑BG GDNF CNTF | |||||
Briken et al., 2016 | SP/PP (31/11) n = 42 (42.9/57.1%) EDSS: 4.9 Age: 50.0 TSD: 16.3 | 1: AT (arm ergometry) 2: AT (bicycle) 3: AT (rowing) 4: Control | 9 weeks, 2–3 s/wk 15–45 min (in total) AT: 120–130% of anaerobic threshold | No (primary outcome: Vo2max) | Vo2max ↑BG (bicycle vs control) 6 min walking distance ↑BG (arm and bicycle vs control) Not reported | |
Method: Blood samples before and after intervention (at rest). Serum analyzed by ELISA kit (BDNF: Promega, WI, US). Centrifugation not reported. Storage −80 °C. | ||||||
Acute: | Chronic: BDNF | |||||
Eftekhari et al., 2018 | RR (Interferon-β) n = 25 (0/100%) EDSS: 2.0–6.0 Age: 33 TSD: not reported | 1: Pilates (mat) 2: Control (waitlist) | 8 weeks, 3 s/wk 30–40 min Pilates: main exercises included hundred, roll-up/-down, single leg circle movements, 1–2 × 3–10 reps (10s per rep) | Not reported | Not reported Not reported | |
Method: Blood samples before and 48h after intervention (in the morning). Serum analyzed by ELISA kit (BDNF: Boster Bio, CA, US). Centrifugation not reported. Storage −80 °C. | ||||||
Acute: | Chronic: BDNF ↑BG | |||||
Joergensen et al., 2019 | RR (Interferon-α or -β) n = 30 (26.7/73.3%) EDSS: 3.0 Age: 44.5 TSD: 7.0 | 1: RT 2: Control (habitual lifestyle) | 24 weeks, 2 s/wk 30 min RT (whole body): 3–5 × 10 reps at 15RM progressing to 6 reps at 6RM | No (primary outcome: total brain volume) | Knee ext + flex EMG ↑BG Knee ext + flex strength ↑BG Brain structure: Total brain volume (↑BG) Cortical thickness ↑BG (4 of 74 subregions) T2 lesion volume + count From Kjolhede et al. 2018 | |
Method: Acute blood samples before and 0, 15, 45, 75, 120 min after one RT session (RT group) or 30 min rest (control group); Chronic blood samples before and after intervention (after overnight fasting at rest in supine position). Plasma analyzed by ELISA kit (BDNF: MyBioSource, CA, US). Centrifugation 1200 g for 10 min at 4 °C. Storage −80 °C. | ||||||
Acute: BDNF | Chronic: BDNF | |||||
Khademosharie et al., 2018 | SP/PP n = 20 (0/100%) EDSS: 3.2 Age: 20–50 TSD: not reported | 1: MIX 2: Control (habitual lifestyle) | 12 weeks, 3 s/wk (2 AT, 1 RT) RT (whole body): 60–80% of 1RM, 2–4 × 8–14 reps AT (rhythmic + jogging): 15–60 min, 40–55% of HRreserve | Not reported | Disability (EDSS) ↓BGBody fat % ↓BG Not reported | |
Method: Blood samples before and 48 h after intervention (after overnight fasting). Serum analyzed by ELISA kit (BDNF: Boster Bio, CA, US; NGF: Eastibiopharm, CA, US). Centrifugation not reported. Storage −80 °C. | ||||||
Acute: | Chronic: BDNF(↑BG) NGF | |||||
Mokhtarzade et al., 2018 | RR n = 61 (34.4/65.6%) EDSS: 1.6 Age: 31 TSD: 7.5 | 1: AT (OW_I) 2: AT (NW_I) 3: Control (OW_C) 4: Control (NW_C) | 8 weeks, 3 s/wk AT (bicycle): 42–66 min, 3 × 10 min upper limbs + 3 × 10 min lower limbs, 60–75% peak power | Not reported | VO2max ↑BG Total body mass BMI Brain structure (blood–brain barrier): S100b ↓BG (NW_I vs control) NSE | |
Method: Blood samples before and after intervention (after overnight fasting). Serum analyzed by ELISA kit (BDNF, NGF: R&D Systems, MN, US; CNTF, PDGF: IBL International, Germany). Centrifugation 3000 g for 12 min at 4 °C. Storage −80 °C. | ||||||
Acute: | Chronic: PDGF ↑BG BDNF ↑BG (NW_I vs control) NGF CNTF | |||||
Naghibzadeh et al., 2019 | RR n = 26 (0/100%) EDSS: 2–4 Age: 33.4 TSD: not reported | 1: MIX 2: Control 3: Swedish massage 4: AT + Swedish massage | 8 weeks, 3 s/wk AT (aquatic): 30 min, walking and jumping, balance etc., no intensity reported | Not reported | Knee flex strength ↑BG (all AT groups vs control) Knee ext strength ↑BG (all AT groups vs control) Grip strength Not reported | |
Method: Blood samples 48 h before and 48 h after intervention. Plasma analyzed by ELISA kit (BDNF: Boster Bio, CA, US; NGF, CNTF: Chongqing Biospes Co, China). Centrifugation not reported. Storage −80 °C. | ||||||
Acute: | Chronic: BDNF NGF ↑BG CNTF | |||||
Ozkul et al., 2018 | RR n = 36 MS (22.2/77.8%) EDSS: 1 Age: 33.8 TSD: 4 | 1: MIX 2: Control 3: Healthy controls (n = 18) | 8 weeks, 3 s/wk AT (treadmill walk): 20–60 min, 60–80% HRmax Pilates: 60 min, multiple exercises, 10–20 reps per exercise | Yes (with suppressors of cytokine signaling proteins) | Postural stability * 6 min walking distance * ↑BG Fatigue severity scale * ↓BG Not reported | |
Method: Blood samples before and after intervention (at rest). Serum analyzed by ELISA kit (BDNF: Shanghai Sunred Biological technology, China). Centrifugation 3000 g for 10 min. Storage −40 °C. | ||||||
Acute: | Chronic: BDNF * | |||||
Rezaee et al., 2020 | RR n = 20 (60/40%) EDSS: 2.4 Age: 28.7 TSD: not reported | 1: AT 2: Control | 6 weeks, 3 s/wk AT (bicycle): 30 min, 60% of VO2max | Yes (with tumor necrosis factor alpha) | Not reported Not reported | |
Method: Acute/chronic blood samples before (in the morning) and immediately after 1st and 18th AT session. Serum analyzed by ELISA kit (VEGF: ZellBio GmbH, Germany). Centrifugation 3000 g for 15 min at 4 °C. Storage −80 °C. | ||||||
Acute: VEGF ↑BG | Chronic: VEGF | |||||
Savsek et al., 2021 | RR n = 28 (82.1/17.9%) EDSS: 2.8 Age: 41 TSD: 11.6 | 1: AT 2: Control (habitual lifestyle) | 12 weeks, 2 s/wk AT (aerobics): 30–40 min (60 min including warm-up and cool-down), 60–70% HRreserve | No (primary outcomes: brain structures) | Disability (EDSS) # Modified fatigue impact scale # Walking speed # ↑BG Brain structure: Total brain volume Gray matter brain volume T2 lesion volume + count Cortical lesion volume + count Active lesion volume + count * ↑BG Substructures ↑BG (5 of 15 substructures) | |
Method: Blood samples before and after intervention (in the morning at rest). Serum analyzed by ELISA kit (BDNF: R&D Systems, MN, US). Centrifugation 3500 g for 5 min. Storage −20 °C. | ||||||
Acute: | Chronic: BDNF # (↑BG) | |||||
Schulz et al., 2004 | RR/SP/PP n = 28 (32/68%) EDSS: 2.3 Age: 39.5 TSD: 11.4 | 1: AT 2: Control (waitlist) | 8 weeks, 2 s/wk AT (bicycle): 30 min, 75% of Wattmax | Not reported | VO2max Not reported | |
Method: Blood samples before and after intervention. Serum analyzed by ELISA kit (BDNF: Promega, WI, US; NGF: sensitive and specific two-site enzyme immunoassay). Centrifugation not specified. Storage −80 °C. | ||||||
Acute: | Chronic: NGF (↓BG) BDNF | |||||
Wens et al., 2016 | RR n = 22 (36.4/63.6%) EDSS: 2.6 Age: 43 TSD: not reported | 1: MIX 2: Control (sedentary) 3: HC (n = 19) | 24 weeks, 5 s/2 wk 45–75 min (in total) AT (bicycle or treadmill): 1–3 × 10 min, 12–14 on BORG20 Scale RT: 1–4 × 10–15 reps, 12–14 on BORG20 Scale | Yes | Knee flex strength ↑BG Knee ext strength ↑BG Fat mass Total body mass Not reported | |
Method: Blood samples before and 48h after intervention (at rest). Serum analyzed by Elisa kit (BDNF: Meso Scale Discovery, MD, US). Centrifugation 3000 g for 10 mn. Storage −80 °C. | ||||||
Acute: | Chronic: BDNF ↑BG | |||||
Summary | n = 473 (n = 366 women) (23/77%) Median EDSS: 2.6 Mean TSD: 9.7 years Mean age: 37.4 years | RT: 1 AT: 5 MIX: 7 Pilates: 1 | 8–24 weeks 2–5 s/wk RT and AT: low-to-high intensity | No. of studies reporting on neurotrophic factors (and ↑BG): Acute: BDNF 1/14 (↑BG in 0/1), VEGF 1/14 (↑BG in 1/1) Chronic: BDNF 12/14 (↑BG in 6/12), IGF-1 1/14 (↑BG in 1/1), NT4 1/14 (↑BG in 1/1), NT3 1/14 (↑BG in 1/1), NT4/5 1/14 (↑BG in 1/1), GDNF 1/14 (↑BG in 0/1), CNTF 3/14 (↑BG in 0/3), NGF 4/14 (↑BG in 1/4), PDGF 1/14 (↑BG in 1/1), VEGF 1/14 (↑BG in 1/1) | No. of studies reporting on physiological/functional outcomes (and ↑BG): 11/14 (↑BG in 10/11; one or more outcomes) No. of studies reporting parallel ↑BG (one or more outcomes) in physiological/functional outcomes and acute neurotrophic factors: 1/2 or chronic neurotrophic factors: 8/11 No. of studies reporting parallel ↑BG (one or more outcomes) in neuroprotection and acute neurotrophic factors: 0/1 or chronic neurotrophic factors: 2/3 |
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Diechmann, M.D.; Campbell, E.; Coulter, E.; Paul, L.; Dalgas, U.; Hvid, L.G. Effects of Exercise Training on Neurotrophic Factors and Subsequent Neuroprotection in Persons with Multiple Sclerosis—A Systematic Review and Meta-Analysis. Brain Sci. 2021, 11, 1499. https://doi.org/10.3390/brainsci11111499
Diechmann MD, Campbell E, Coulter E, Paul L, Dalgas U, Hvid LG. Effects of Exercise Training on Neurotrophic Factors and Subsequent Neuroprotection in Persons with Multiple Sclerosis—A Systematic Review and Meta-Analysis. Brain Sciences. 2021; 11(11):1499. https://doi.org/10.3390/brainsci11111499
Chicago/Turabian StyleDiechmann, Mette D., Evan Campbell, Elaine Coulter, Lorna Paul, Ulrik Dalgas, and Lars G. Hvid. 2021. "Effects of Exercise Training on Neurotrophic Factors and Subsequent Neuroprotection in Persons with Multiple Sclerosis—A Systematic Review and Meta-Analysis" Brain Sciences 11, no. 11: 1499. https://doi.org/10.3390/brainsci11111499