Exercise-induced increase in brain-derived neurotrophic factor in human Parkinson's disease: a systematic review and meta-analysis

This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [51]. An a priori protocol [52] was adhered to throughout the review process to minimize risk of bias. An electronic literature search was conducted independently by one of the authors (PH) and a research assistant in the following databases: Medline (Ovid), PubMed (NLM), Embase (Embase.​com), PsycINFO (Ovid), Physiotherapy Evidence Database (PeDro) and the Cochrane library (Wiley). We included the following key words (including MESH): Parkinson’s, Parkinson’s disease AND exercise, exercise training, physical activity, therapy, physical therapy, physical exercise, physical training, exercise-induced, exercise-enhanced AND human, people, person, individual, patient, older, elderly, AND neurotrophic factor, growth factor, brain derived neurotropic factor, neuroplasticity, plasticity, AND trial, intervention, training, treatment OR control, controlled, randomized.

We exclusively focused on studies evaluating the effects of exercise interventions on brain-derived neurotrophic factor in patients with PD. Studies were accepted when: 1) they used human participants with diagnosis of PD, 2) they used a prospective intervention design with or without a control group, 3) they contained physical exercise training or a physical exercise intervention component, 4) they assessed neurotrophic factor(s), 5) they were written in English, 6) they were published in a peer-reviewed journal. Non-human studies, non-physical exercise trials, grey literature, studies using mixed populations, single case studies, studies not specific to PD, and studies without assessment of neurotrophic factors were excluded. The search was conducted up to June 2017.

Initial citation screening (MH, PH) was based on reviewing title and abstract (Level 1 Review) of all database search hits. A second round was implemented (Level 2 review) in which three independent reviewers (EvW, MN, MH) analysed the full manuscripts and performed additional reference tracking. A total of 30 papers were imported into a widely used, web-based, production platform system for reviews (www.​covidence.​org). Disagreements were resolved in a consensus meeting (Fig. 1). Six manuscripts passed onto full data extraction (LEVEL 3 review in covidence.​org). Data on study design, sample size and characteristics, exercise dosing, clinical outcome measures and laboratory results) were extracted manually by two independent data abstractors (MH, MN) and summarized in Table 1. Authors of relevant publications were contacted for data when post intervention means and/or SDs were not reported. When two or more randomized clinical trials were available reporting on the same outcomes, quantitative meta-analysis (i.e., pooling using Hedges’ g) of the findings was performed using Cochrane methodology, in Review Manager 5.3 [53].

Appraisal of individual study methodological quality was based on published quality assessment tools developed jointly by methodologists from NHLBI and Research Triangle Institute International (www.​nhlbi.​nih.​gov/​health-pro/​guidelines/​in-develop/​cardiovascular-risk-reduction/​tools).

The NHLBI Appraisal tools (Additional file 1) includes items for evaluating the internal validity, descriptive criteria and statistical criteria of studies (Additional file 1). A quality rating (‘good’, ‘fair’, ‘poor’) was adapted from the review by Lim et al. [54]. Studies were considered to be of ‘good’ quality if at least 80% of the criteria were met; ‘fair’ quality when 51% to 79% of the criteria were met, and ‘poor’ quality when less than or equal to 50% of the criteria were met. Separate lists of methodological quality criteria were used for randomized controlled trials, uncontrolled pre-post studies and case control studies (Additional file 1).

Two evaluators (MH, MN) independently rated the methodological quality of the included studies using the NHLBI appraisal tools. Next, a kappa statistic was calculated for descriptive purposes and to investigate the agreement between the two evaluators on each appraisal tool (Additional file 1). The kappa values were interpreted using the criteria suggested by Tooth and Ottenbacher [55], <.40 poor agreement, .40 to .60 fair or moderate agreement, .60 to .80 good agreement, and >.80 perfect or excellent agreement. Additionally, we report the exact agreement among the two evaluators before disagreements about scoring were discussed (Additional file 1). Disagreements about scoring were resolved through discussion. If no consensus was reached, a third reviewer (EvW) made the final decision.

For individual RCT’s, we calculated the difference between the pre-to the post-intervention change scores for experimental and control groups. In case of MD-UPDRS-III, we used the mean difference (MD) between the change scores because the same outcome measure was assessed in the trials. For BDNF, reported as serum [56] and plasma levels [57], we used the standardized mean difference (SMD) based on Hedges’ g by calculating the MD, divided by the average population standard deviation (SDi). The MD or SMD values of individual studies were averaged (pooled), resulting in a summary effect size (SES) with corresponding 95% confidence interval (CI). Following Cohen [58] we classified effect sizes into small (<0.2), medium (0.2-0.8), and large (>0.8). The I² statistic was calculated to determine between-study variation [59]. In case of statistical heterogeneity (I² ≥50%,) we applied a random-effects model. For I² <50 % a fixed-effect model was applied.

Two studies, one prospective study on exercise-induced changes in BDNF tyrosine receptor kinase signaling (BDNF-TrkB) [60] and the prospective study by Zoladz and colleagues [61], were excluded from the BDNF level effect size analysis. The study by Fontanesi et al. [60] was excluded from the BDNF meta-analysis analysis because the authors did not report serum or plasma BDNF levels but instead reported BDNF tyrosine receptor kinase signaling. The study by Zoladz et al. [61] was excluded from the BDNF meta-analysis analysis because there was significant overlap in the study participant groups included in the paper by Zoladz et al. [61] and the study participants included in the paper by Marusiak et al. [62] (personal communication with Dr. Marusiak). The more recent candidate paper by Marusiak et al. [62] with the larger sample size (11 healthy controls and 11 patients with PD) was chosen for inclusion.

The subject demographic characteristics, study design, exercise dosing, outcome measures and results are described in Table 1. A total of 100 participants contributed to the studies reported in this review. For the evaluation of physical exercise on BDNF levels, data were aggregated from two RCTs [56, 57] with a total of 52 ambulatory in- and outpatients with mild to moderate idiopathic PD severity, mean 7.0±1.5 years after PD diagnosis and 68±5.6 years (mean±standard deviation) of age at the time of study enrollment. BDNF concentration was assessed by enzyme-linked immunosorbent assay (ELISA) using standardized procedures at the completion of the 28-day intervention in the study by Frazzitta et al. [56] and at the completion of the 90-day intervention in the study by Sajatovic et al. [57]. Percent change BDNF levels were reported from two pre-experimental studies (Marusiak et al. [62], Angelucci et al. [63] Table 1), with a total of 20 ambulatory in- and outpatients with mild to moderate idiopathic PD severity (Hoehn and Yahr stage ≤3, range 1-3), 9.8±6.0 years (range 2-26 years) after PD diagnosis and 66.8±8.3 years of age at the time of study enrollment. BDNF concentration was assessed by ELISA using standardized procedures at the completion of the 30-day intervention in the study by Angelucci et al. [63] and at the completion of the 60-day intervention in the study by Marusiak et al. [62].

Clinical outcomes data were aggregated from two RCTs [56, 57]; and four pre-experimental studies [60‐63] with a total of 100 ambulatory in- and outpatients with mild to moderate idiopathic PD severity (Hoehn and Yahr stage ≤3), 8.4±4.9 years after PD diagnosis, 68.7±6.8 years of age at the time of study enrollment. Methodological quality was scored for the six included studies [56, 57, 60‐63] (Additional file 1).

Across all studies the participant characteristics were relatively homogenous in terms of years of age, PD stage, years since diagnosis, and ambulatory status. The studies were clinically homogenous with regards to including stationary cycling [57, 60‐63] and administration of the MDS-UPDRS motor examination (Part III). Details about “on” or “off” state testing or training were not provided in the study by Fontanesi et al. [60] and Frazzitta et al. [56]. Physical exercise training, clinical outcome evaluations and BDNF testing procedures were conducted during the “on” phase in two studies [57, 63]. Zoladz et al. [61] and Marusiak et al. [62] administered outcome measures during the “off” phase. Differences among studies were noted regarding the use of elliptical machines [60], resistance training [57], physical therapy [56, 63], occupational therapy [60], treadmill training [56, 60, 63], Wii System Fit [63], and stabilometric platform [60]. All except one study reported exercise interventions being delivered by physiotherapists. Sajatovich et al. [57] used a Parkinson peer exercise leader to lead the exercise intervention. The setting for the interventions varied between laboratory [61, 62], hospital-based in-and out-patient [56, 60, 63] and fitness clinic-based [57]. The trial by Sajatovic et al. [57] was conducted in a community-based setting using a group versus an individual self-management program. In the study by Angelucci et al. [63] participants exercised in a group setting. None of the other studies reported details whether a group exercise intervention or an individual approach exercise intervention was used.

BDNF levels assessed with laboratory measures were reported in 2 RCTs [56, 57] (N = 52) and pooling resulted in a significant homogeneous SES (SMD 2.06, 95% CI 1.36 to 2.76; Z = 5.77, P < .000001, I² = 0%, Fig. 2).

MDS-UPDRS-III motor examination scores were reported in 2 RCTs [56, 57] (N = 52) and pooling resulted in a significant heterogeneous SES (MD -5.53, 95% CI -10.42 to -0.64; Z = 2.22, P = 0.03, I² = 94%, Fig. 3). All studies noted statistically significant improvements for clinical outcome measures [56, 57, 60‐63] (Table 1).

Few studies conducted statistical analysis between exercise-induced BDNF blood concentration and scores on clinical outcome measures. Marusiak et al. [62] found a statistically significant association between interval training induced increases in BDNF concentration and decrease in Parkinsonian rigidity. The study by Fontanesi et al. [60] found a statistically significant association between inpatient rehabilitation induced increases in TrkB signaling in the lymphocytes and improvement in MDS-UPDRS total and MDS-UPDRS-II score. The trial by Frazzitta et al. [56] found no correlation between BDNF blood levels and the MDS-UPDRS motor examination score (Part III).

A kappa statistic, which accounts for chance agreements between the two raters, was .62 for the trials by Frazzitta et al. [56] and Sajatovic et al. [57], .55 for the studies by Fontanesi et al. [60], Angelucci et al. [63] and Zoladz et al. [61], and .57 for the study by Marusiak et al. [62]. The percent agreement between the two raters was 72% to 77% (Additional file 1).

Strengths towards the internal validity of the studies included use of masked assessors, and administration of valid and reliable outcome measures. Four studies [56, 57, 60, 61] used assessors masked during the clinical outcomes testing, including the two randomized controlled trials [56, 57]. Five studies administered outcome measures that were valid, reliable and assessed consistently across all study participants [56, 57, 60‐62]. Three studies reported loss to follow-up after baseline testing, which was less than 20% [60‐62].

Deficiencies included the lack of an a-priori justification for the sample size needed to detect an exercise-induced effect on BDNF levels [60‐63], and lack of masking of the assessor conducting the BDNF assays [57, 60‐63]. Additional deficiencies noted were lack of description of adherence to the intervention, short duration of training and short follow-up, lack of details about method used for participant recruitment into study protocol, failure to characterize the cognitive status of patients, failure to describe adverse events, and failure to recruit younger age patients.

Each ‘deficiency’ noted above represents an opportunity for future research and discovery. For example, age and physical exercise intensity may be a rate limiting factor in activity-dependent BDNF neuroplasticity. To address patient age, a future study on the effect of physical exercise on BDNF concentration could compare the response to exercise by age group because younger patients with PD typically display greater baseline physiologic reserve (e.g., VO₂ Maximum) than older patients with PD, and may be able to sustain physical exercise at higher physiologic intensities than older patients.

BDNF assay procedures were reported by all studies. Sajatovic et al. [57] did not report if the blood sample collection was obtained in the morning or later during the day. Plasma samples of BDNF were assayed by using ELISA per manufacturer instructions (Quantikine® ELISA Human BDNF Immunoassay; R&D Systems, Minneapolis, MN, USA). Frazzitta et al. [56] did not report blood sample collection time but reported that serum BDNF concentrations were evaluated in a capture ELISA according to the protocol provided by the manufacturer without including the kit manufacturer information. Marusiak et al. [62] and Zoladz et al. [61] assayed serum BDNF from morning blood samples with an ELISA Kit (Promega, Wallisellen, Switzerland) after appropriate dilution with Block and Sample solution (provided with the kit). Angelucci et al. [63] analyzed serum BDNF from blood samples that were obtained in the morning. Sandwich ELISA (R&D Systems, USA; cat. No. DY248) was used for BDNF assays according to the manufacturer’s instructions. Fontanesi [60] used morning blood samples for the BDNF assays by EDTA Western Blotting.

The main limitation of this review is the small number of papers that were available for inclusion. Although our results are based on a small number of studies, the participant characteristics were relatively homogenous in terms of years of age, Parkinson’s disease stage, years since diagnosis, and ambulatory status. The studies were also homogenous in the adoption of cycling training mode, administration of the MDS-UPDRS and the pharmacologic characteristics of the participants [57, 60‐63]. Our study is limited to the focus on one neurotrophic factor, exercise-induced changes in BDNF concentrations in human PD, and not other neurotrophic factors, which limits the generalizability to BDNF only. Although there are a number of potential opportunities for including BDNF as a clinical marker of brain health in PD [81], including outcome prediction [82], and/or development of physical exercise treatment interventions [84], further studies and methodological evaluations need to take place to standardize BDNF measurement and evaluate its usefulness as a clinical marker of brain health in PD.

The Cochrane Library Guidelines do not recommend meta-analysis when the designs of the studies are too different, if the outcomes measured are not sufficiently similar, or if there are concerns about the quality of the studies, for an average result across the studies to be meaningful (for review, see http://​www.​cochranelibrary.​com/​about/​about-cochrane-systematic-reviews.​html). Meta-analysis was a small part of the current review. We included all human studies, including non-randomized controlled studies (except case reports/single case studies as per exclusion criteria), covering the entire body of literature.

We emphasize that the small number of available studies is a limitation and further research is urgently needed to provide a realistic evaluation of the possible effects of exercise training on BDNF of PD patients. Prior international systematic reviews have evaluated effects of exercise training on BDNF and cognition (e.g., Alzheimer’s) and usually these synthesis reports also have had a small number of studies (between 6-8) [85].

We propose that strengths of the current preliminary meta-analysis and systematic review include: a) the manuscript addresses a clinically important, understudied area of neurorestorative rehabilitation research, and b) the results challenge and seek to shift current research and clinical practice paradigms by extending novel theoretical concepts of physiologic use of exercise on neuroplasticity in ageing human brain to humans living with Parkinson’s disease.