Elsevier

Brain Research

Volume 1704, 1 February 2019, Pages 127-136
Brain Research

Research report
Plasma levels of brain-derived neurotrophic factor in patients with Parkinson disease: A systematic review and meta-analysis

https://doi.org/10.1016/j.brainres.2018.10.006Get rights and content

Highlights

  • Serum BDNF is lower in Parkinson disease, regardless of co-morbid depression.

  • Parkinson and major depression robustly and equally lower serum BDNF levels.

  • Severity of motor disability and advanced age predict lower serum BDNF in Parkinson.

  • Moderate to high intensity exercise boosts BDNF in serum of Parkinsonian patients.

  • Serum BDNF paradoxically associates with poor physical capacity in early Parkinson.

Abstract

Background

Brain-derived neurotrophic factor (BDNF) is an abundant neurotrophin in the adult brain. Serum BDNF levels might be used as a proxy for its central expression. Considering conflicting reports, we aimed to answer “How do serum/CSF levels of BDNF change in patients with PD?”.

Methods

We conducted a comprehensive search in MEDLINE, EMBASE and SCOPUS databases including 12 eligible studies. Five studies compared BDNF in serum of PD patients versus healthy controls (HC) and 3 studies provided BDNF levels in sera of non-depressed and depressed PD patients (NDPD and DPD). Review Manager and Software version 3.0 were used for meta-analysis and meta-regressions. Mean difference (MD) was used for measurement of effect size.

Results

PD patients had reduced serum BDNF levels compared to HC (MD = -2.99 ng/mL). Serum BDNF was highest in DPD patients compared to HC (MD = -4.83 ng/mL), with no difference between DPD and NDPD patients in serum BDNF levels. Among co-variates that were eligible for meta-regression, age, sex, and Hoehn and Yahr (H&Y) motor stage had significant positive associations with the effect size in the difference of serum BDNF between patients and HC.

Conclusions

PD patients had reduced serum BDNF levels compared to HC, regardless of presence of co-morbid depression. PD is at least equally effective in reducing serum BDNF levels as depression. Motor progression predicts serum BDNF downregulation in PD. Acute exercise improves motor function and depressive symptoms in PD probably via BDNF upregulation. The paradoxical rise in serum BDNF in advance PD is probably compensatory in nature.

Introduction

The brain-derived neurotrophic factor (BDNF) is a ubiquitous neurotrophin, maintaining dopaminergic neuronal survival (Porritt et al., 2005), promoting synaptic plasticity, dendritic morphogenesis and arborisation (Harward et al., 2016), and even neurogenesis in adult brain (Nagahara and Tuszynski, 2011). Widely distributed in cortical and subcortical areas, BDNF is crucial for proper establishment of dopaminergic neurons population in the substantia nigra (SN) in the developing brain (Murer et al., 2001). BDNF later supports neurite outgrowth and promotes survival of nigral dopaminergic neurons within SN so that inhibition of BDNF expression results in loss of adult dopaminergic neurons (Porritt et al., 2005). BDNF expression is downregulated in the pars compacta of SN in patients with Parkinson disease (PD) (Howells et al., 2000, Mogi et al., 1999, Parain et al., 1999), depriving dopaminergic neurons from trophic support, while the remaining dopaminergic neurons in SN produce progressively lower BDNF levels (Collier et al., 2005). Lower BDNF expression disrupts dopaminergic output to the striatum, independent from nigral dopaminergic expression, reproducing the prototypic motor signs of Parkinson disease in mice (Dluzen et al., 2002). Moreover, α-synuclein, which is the main component of Lewy body fibrils in PD patients, effectively blocks neurotrophic activity of BDNF in SN, first by downregulating BDNF expression (Yuan et al., 2010), and second by competitive inhibition of BDNF signalling at receptor level (Kang et al., 2017). Although some have reported BDNF levels to be unchanged in MPTP and 6-OHDA induced nigral lesions (Mocchetti et al., 2007), most studies have a consensus that exogenous introduction of BDNF is able to mitigate dopaminergic neuronal loss in neuronal culture (Goldberg et al., 2015, Yoshimoto et al., 1995), and in 6-OHDA (Sadan et al., 2009) and in MPTP models of PD (Zhao et al., 2014).

Robust evidence has been produced on the protective role of BDNF in dopaminergic population of SN in PD and downregulation of BDNF in PD patients (Ferreira et al., 2018). In contrast, increased levels of BDNF has been found in serum and cerebrospinal fluid (CSF) along with PD progression (Salehi and Mashayekhi, 2009, Scalzo et al., 2010). At the same time a known role for exercise or physical training had been established, in that acute exercise can increase BDNF concentration in serum and thereafter improve cognitive performance immediately post-exercise, in healthy adults (Onerup et al., 2017). This effect is most strong shortly following training and is more pronounced in improving memory, compared to other cognitive domains. It was also revealed that anti-parkinsonism agents, even dopamine replacement therapy, exerted part of their effect by upregulating BDNF (Okazawa et al., 1992). These facts have raised keen interest in the role of exercise-induced changes in BDNF to combat neurodegeneration in PD (as reviewed by Campos in 2016) (Campos et al., 2016).

A search into the literature indicates several studies reporting decreased serum BDNF levels in PD (Angelucci et al., 2015, Khalil et al., 2016, Ricci et al., 2010, Rocha et al., 2018, Scalzo et al., 2010, Wang et al., 2016, Wang et al., 2017, Zoladz et al., 2014), a few reporting increased serum BDNF in PD (Siuda et al., 2017, Ventriglia et al., 2013), and some other pointing out to CSF expression of BDNF (Leverenz et al., 2011, Martin de Pablos et al., 2015, Palhagen et al., 2010, Salehi and Mashayekhi, 2009), or BDNF levels with regards to physical capacity or exercise (Frazzitta et al., 2014, Khalil et al., 2017, Marusiak et al., 2015, Sajatovic et al., 2017, Scalzo et al., 2010, Zoladz et al., 2014). Considering conflicting reports on serum levels of BDNF in PD, the current study aims to answer the question: “How do serum levels of BDNF change in patients with PD?”

Section snippets

Study selection

The study selection details are depicted in Fig. 1. Database search yielded a total number of 1665 records. Preliminary screening excluded 1315 studies based on title/abstract. Full text of the remaining 350 articles were extracted and articles were assessed based on inclusion criteria by careful reading of the abstract and when necessary full text. Thirty-two studies were selected for detailed review and corresponding authors of these articles were contacted and invited to send study group

Discussion

In the systematic review of the literature we addressed changes in serum BDNF levels in patients with parkinson disease, considering presence of comorbid depression as a relevant determining factor. Several studies have reported decreased serum BDNF levels in PD patients compared to healthy individuals (Angelucci et al., 2015, Khalil et al., 2016, Ricci et al., 2010, Rocha et al., 2018, Scalzo et al., 2010, Wang et al., 2016, Wang et al., 2017, Zoladz et al., 2014), while some others reported

Conclusion

Results of this review of literature and meta-analysis showed serum BDNF levels to be lower in PD patients compared to HCs with a large effect size. This difference was even bigger in PD patients with co-morbid depression, while there was no difference in serum BDNF between DPD and NDPD patients. Male gender, disease duration and motor score positively predicted BDNF level difference between PD and HC. The higher disease duration and H&Y motor stage, the larger was the difference between serum

Protocol and registration

Study protocol, including objectives of the review, PICO Question, inclusion and exclusion criteria – for participants, types of studies, intervention/exposure and outcome, search strategy, data collection, and methods for data synthesis/analysis, was developed according to the PRISMA guideline (Moher et al., 2009) and deposited in the PROSPERO (https://www.crd.york.ac.uk/PROSPERO/) with the registration number of 77746. The study protocol was approved by local ethics committee at the

Conflict of interests

Authors have no conflicts of interest to disclose.

Funding

Authors received no funding to perform the study.

Ethical standards

All human and animal studies have been approved by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

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