Determinants of serum brain-derived neurotrophic factor
Introduction
Brain-derived neurotrophic factor (BDNF) belongs to the neurotrophin family of growth factors and affects the survival and synaptic plasticity of neurons in the adult central nervous system (Mossner et al., 2007). BDNF binds with the TrkB tyrosine kinase receptor (Chao, 2003), which results in intracellular phosphorylation and activation of intracellular signaling cascades that lead to activation of prosurvival pathways and/or inactivation of proapoptotic signaling (Ullrich and Schlessinger, 1990). BDNF is expressed throughout the whole central nervous system (Binder and Scharfman, 2004) and significant concentrations are also found in peripheral blood (Brunoni et al., 2008, Sen et al., 2008). BDNF crosses the blood–brain barrier by a high capacity, saturable transport system (Pan et al., 1998). In animal models, cortical BDNF levels are highly correlated with peripheral serum BDNF levels (Karege et al., 2002a, Karege et al., 2002b, Sartorius et al., 2009), but evidence on the contrary has been shown as well (Elfving et al., 2010). Inconsistencies might be explained by the fact that BDNF-expression and its TrkB receptor is not specific for neuronal cells in the brain, but can also be found in endothelial cells, smooth muscles cells, endocrine cells and immune cells in peripheral tissues (Ernfors et al., 1990, Maisonpierre et al., 1990, Yamamoto and Gurney, 1990, Maisonpierre et al., 1991, Scarisbrick et al., 1993, Esteban et al., 1995, Hiltunen et al., 1996, Nemoto et al., 1998, Kerschensteiner et al., 1999, Donovan et al., 2000).
The supposed importance of neuroplasticity in both the etiology and recovery of psychiatric disorders, has led to many studies linking serum BDNF to a wide variety of psychiatric and neurodegenerative diseases (Nakazato et al., 2003, Binder and Scharfman, 2004, Azoulay et al., 2005, Yasutake et al., 2006, Hashimoto et al., 2006, Ciammola et al., 2007, Gratacos et al., 2007, Machado-Vieira et al., 2007, Ikeda et al., 2008). For proper interpretation of serum BDNF levels in humans, however, knowledge about the key determinants of serum BDNF levels are essential for adequate control of confounding factors.
As touched above, BDNF is not only considered to be a neurotrophin, but also an immunotrophin, epitheliotrophin and metabotrophin (Chaldakov et al., 2007). As of yet somatic conditions that have been correlated to BDNF mainly include cardiovascular disease or cardiovascular risk factors or disease (Ejiri et al., 2005, Fujinami et al., 2008, Hristova and Aloe, 2006, Suwa et al., 2006, Geroldi et al., 2006, Krabbe et al., 2007). For example, patients with acute coronary syndrome as well as patients with diabetes mellitus do have lower plasma levels of BDNF (Manni et al., 2005, Fujinami et al., 2008). One may thus hypothesize that BDNF is an underlying mechanism linking psychiatric and somatic illnesses. However, spurious associations may be explained due to (unknown) confounding factors, since health indicators like alcohol use, smoking and physical exercise have also been linked to BDNF (Chan et al., 2008, Montag et al., 2008, Tang et al., 2008, Currie et al., 2009, Umene-Nakano et al., 2009).
Even more basic determinants, like socio-demographic variables and sampling characteristics have not specifically been examined. Although most human studies control for sex and age effects, reported effects of sex and age are contradictory. These mixed results may be explained by small sample sizes ranging from as low as 10 (Marano et al., 2007) through a maximum of 465 participants (Ziegenhorn et al., 2007), as well as failure to control for potentially confounding factors (Shimizu et al., 2003, Lang et al., 2004, Aydemir et al., 2007, Ziegenhorn et al., 2007). Recently, it has been suggested that BDNF exerts sex-specific stress-related effects in mice (Autry et al., 2009). Nevertheless, human studies report similar serum BDNF levels in men and women (Lang et al., 2004, Laske et al., 2007, Ziegenhorn et al., 2007), with the exception of one study in which the sex differences reported could be explained by confounding depressive symptoms (Karege et al., 2002a, Karege et al., 2002b). As BDNF levels have been associated with estrogen levels (Sohrabji and Lewis, 2006) we might even expect different age-related effects in women and men around the menopausal age. Finally, the effect of sampling characteristics on serum BDNF levels have hardly been examined. The few studies available, however, do suggest a decrease of BDNF levels after long-term storage (Trajkovska et al., 2007) and a diurnal variation within individuals (Piccinni et al., 2008).
Considering the broad interest in BDNF, the many factors associated with serum BDNF levels and the conflicting results of even basic variables, it is surprising that no studies have been conducted to examine the independent effects of potential determinants of serum BDNF levels in humans.
Therefore, we conducted the present study to examine the determinants of serum BDNF in a large and well-defined cohort of people without current psychiatric or neurologic diseases. Potential determinants are based on prior literature and categorized in four blocks: sampling characteristics, socio-demographic variables, lifestyle indicators and (chronic) diseases.
Section snippets
Population
Data are from the baseline measurement of the Netherlands Study of Depression and Anxiety (NESDA). NESDA is a multi-site naturalistic cohort study aimed to describe the 8-year course and consequences of depressive and anxiety disorders and to integrate biological and research paradigms within an epidemiological approach. Recruitment took place in the general population, in general practices and in mental health organizations. The baseline sample consists of 2981 participants aged 18 through 65
Results
Throughout the manuscript β and p-values have slightly changed as a result of the exclusion of three samples below the detection limit.
Main findings
Within a large cohort of people free from psychiatric disorders and neurodegenerative diseases, we identified eight independent determinants of serum BDNF levels, i.e. time of blood withdrawal, time of storage, food intake before sampling, urbanicity, age, sex, smoking status and drinking behavior. Below we will discuss these determinants in more depth.
Sampling variables
Three sampling variables had an independent effect on serum BDNF levels in our study. First, although the overall decline was small, BDNF levels
Role of the funding source
The NESDA study infrastructure is financed by the Geestkracht program of ZonMW, the Dutch Scientific Organisation-Medical Sciences (grant nr. 10.000.1002) and by complementary funding from participating mental healthcare institutions (GGZ Buitenamstel, GGZ Drenthe, GGZ Friesland, GGZ Geestgronden, GGZ Rivierduinen, and Lentis) and Universities (Leiden University Medical Center, University Medical Center Groningen, and VU University Medical Center). BDNF measurements were financed with NWO
Conflict of interest
We affirm that the manuscript contains original work that has not been published previously and is not being considered for publication elsewhere. The study was conducted at the ‘Nijmegen University Medical Centre’, Nijmegen, the Netherlands, and all authors assert that none has any commercial or financial involvements that might present an appearance of a conflict of interest in connection with the submitted manuscript.
Acknowledgement
The authors would like to thank Robin Struijk for performing the BDNF measurements.
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