Research reportPlasma levels of brain-derived neurotrophic factor in patients with Parkinson disease: A systematic review and meta-analysis
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.
References (79)
Striatal 6-OHDA lesion in mice: Investigating early neurochemical changes underlying Parkinson's disease
Behav. Brain Res.
(2010)Striatal trophic factor activity in aging monkeys with unilateral MPTP-induced parkinsonism
Exp. Neurol.
(2005)The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function
Cell
(2003)Dose-and gender-specific effects of resistance training on circulating levels of brain derived neurotrophic factor (BDNF) in community-dwelling older adults
Exp. Gerontol.
(2015)Neural Stem Cells Rescue Cognitive and Motor Dysfunction in a Transgenic Model of Dementia with Lewy Bodies through a BDNF-Dependent Mechanism
Stem Cell Rep.
(2015)Reduced BDNF mRNA expression in the Parkinson's disease substantia nigra
Exp. Neurol.
(2000)- et al.
Postnatal developmental profile of brain-derived neurotrophic factor in rat brain and platelets
Neurosci. Lett.
(2002) Relationship of circulatory BDNF with cognitive deficits in people with Parkinson's disease
J. Neurol. Sci.
(2016)Cerebrospinal fluid biomarkers and cognitive performance in non-demented patients with Parkinson's disease
Parkinsonism Relat. Disord.
(2011)Brain-derived growth factor and nerve growth factor concentrations are decreased in the substantia nigra in Parkinson's disease
Neurosci. Lett.
(1999)