Circulating brain-derived neurotrophic factor as a potential biomarker in stroke: a systematic review and meta-analysis

Beyond 13 million people are affected by stroke annually, which is among the leading causes of incapacity and mortality, placing a significant psycho-socio economic burden worldwide [1]. Through the advent of medical techniques, mortality rates following stroke have dropped remarkably, leading to higher disability-adjusted life years (DALY) [2]. Approximately 26% of patients with stroke (PwS) will face levels of dependency in their daily activities up to six months after the stroke onset [3]. However, the motor function is not the mere focus of disabilities among PwS; patients’ cognitive profile and affect are also altered by stroke [4, 5].

Acute stroke is referred to the acute onset of focal neurological findings in a vascular territory. There are two main types of stroke, following a vascular occlusion resulting in an infarct, regarded as ischemic stroke (85%), or caused by a sudden burst of a blood vessel, regarded as hemorrhagic stroke (15%). In response to this cerebrovascular event, CNS uses an ability to adapt and reorganize the damage known as “Neuroplasticity”. A group of signaling molecules known as neurotrophins play essential roles in synaptic plasticity, neurogenesis and survival regulations in neural cells [6‐8]. In particular, many studies have investigated Brain-Derived Neurotrophic Factor (BDNF) as a member of the neurotrophins family for its role in the nervous system [9‐11]. Extensive evidence demonstrated some associations between BDNF level and various neurological disorders; for instance, low concentrations of BDNF has been reported in neurodegenerative and neuropsychiatric disorders such as Alzheimer’s disease, Parkinson’s disease, depression, autism spectrum disorders, and post-traumatic stress disorder [9‐12].

Keen interest has been raised to find the relationship between the altered level of BDNF and stroke; studies hypothesize that BDNF level is correlated with the size of the stroke legion, cognitive profile, and functional outcome [13‐15]. Based on the substantial impact of stroke, a systematic review and meta-analysis are essential to address the precise association of circulating BDNF in PwS in various conditions.

Our initial database search revealed a total number of 6243 citations. We removed 2495 duplicate citations, and 3653 additional citations were excluded through title and abstract screening. We retrieved 95 articles for full-text screening, from which 29 studies were excluded for the following reasons: animal sample size, review article, duplicated articles from one same study, in vitro study, and reporting one single measure in one single study group at only one-time point. An additional number of 5 articles were removed during the data extraction because of: insufficient data despite author contact [22, 26], reporting BNGF instead of BDNF [23], unclear data from an extensive cohort study (Framingham [3]), reporting peripheral BDNF in association with another biomarker instead of pure measures [27].

Finally, a total number of 62 articles were entered into our systematic review. We could not enter 16 articles to any meta-analysis group for the following reasons; providing delta BDNF instead of exact measures [28], reporting peripheral BDNF as a proportion to the control group [29], the full text was not found. However the abstract was sufficient to extract the descriptive data [30], unsatisfactory data and irresponsive author (missing SD despite reporting the mean) [31], single study group with no comparison or specific grouping which did not fall into our meta-analysis categorizations [14, 32‐42].

With this study, we confirm that the BDNF level is significantly lower in the patients with stroke than in the healthy controls. Interestingly, it is also lower in patients with post-stroke depression compared to PwS without depression. These results are compatible with the hypothesis that a lower level of BDNF is associated with the pathogenesis of neural loss in several neuropsychiatric disorders and cognitive deficits [12, 86‐91]. Although the severity and type of stroke, either ischemic or hemorrhagic, can possibly correlate with the BDNF level as addressed by Chaturvedi et al. [82], the lack of reporting data from the included studies prohibited us from further regression analysis of these influential factors.

We assume that neural rehabilitation following a stroke measured with BDNF happens in an insignificant amount in the absence of additional intervention. Individual differences in the neural recovery have made some fluctuations in the level of BDNF days, weeks and months post-stroke, but have led to no significant differences between various time points in this meta-analysis; the overall BDNF pattern was neither increasing nor decreasing through time. This implies that stroke can lead to an irreversible decrease in the level of BDNF or the rate of neural recovery.

In addition, our analysis also confirmed a positive effect of physical training, regardless of performing exercise or routine physiotherapy or rehabilitation, on the BDNF level immediately after the intervention. In contrast, no significant effect was detected when the BDNF samples were collected after a time point from the intervention (delayed). Moreover, the analysis of the effect of rTMS on PwS showed zero effect on the circulating BDNF.

BDNF protein is a member of nerve growth factors, discovered in 1982 [92]; since then, a strong body of evidence has suggested important roles of BDNF in neurogenesis and synaptic plasticity along with suppressive effects on apoptosis in the central and peripheral nervous system. BDNF works through different signaling mechanisms by binding to its high-affinity receptor, known as tropomyosin receptor kinase B (TrkB) [90, 93]. It appears that three main cascades are involved in BDNF signaling pathways; (1) Ras/MAPK/ERK pathway; (2) IRS-1/PI3K/AKT pathway, and (3) PLC/DAG/IP3 pathway. These pathways result in the regulation of the encoding of various proteins, which are associated with different processes such as neurogenesis, synaptic plasticity, and cell survival [90, 94‐96]. All of which are essential for synaptogenesis, restoring the ability of recovery and survival after a neural insult such as stroke [97]. Circulating BDNF is detected and measured chiefly by ELISA kits; However, these kits demonstrate a reasonable difference in mean BDNF measures in the same samples; they differ in the number of mature vs pro BDNF detection. Among the existing kits, the Biosensis and Aviscera-Bioscience, measuring total BDNF and mature BDNF, respectively, are the most performant and recommended for clinical studies. Moreover, plasma samples are sensitive to preparation procedures such as room temperature and varying time needed for platelet lysis, making the pre-procedure time-consuming and leading to different reported measures with changing operators. Thus, it is advised to measure serum BDNF concentration minimally affected by extrinsic factors and about 100 folds higher than plasma levels [98].

Many studies have focused on the alternation of the peripheral BDNF level in different situations and reported BDNF changes in neurodegenerative disorders, brain insults, and psychiatric disorders [12, 89‐91, 93]. Stroke as the second leading cause of death and morbidity worldwide is investigated remarkably, specifically in regards to post-stroke recovery measures. A notable number of studies have investigated the impact of numerous modalities such as oral or intravenous medications, physical interventions, and brain stimulation on the BDNF level as an indicator of plasticity in PwS. Within medications, rtPA, antioxidants such as Saffron, statins, and Cytoflavin, have shown promising effects on increasing the BDNF level in each individual study [39, 42, 52, 61], which did not meet the meta-analysis threshold in the current research article (total number of 3 studies). Additionally, specific brain stimulation using rTMS which was assessed by 4 independent studies showed zero effect on BDNF in our meta-analysis.

In conclusion, stroke significantly affects the level of BDNF, which is positively correlated with neural plasticity and post-stroke recovery in various domains such as cognition, affect, and motor function. Our study also confirms the significantly lower levels of BDNF in patients with stroke than the healthy controls, patients with the clinical diagnosis of depression to non-depressed patients and significantly higher levels of BDNF in patients who do moderate to severe physical training. Furthermore, literature imposes different modalities to overcome the effect of BDNF reduction, from which our study confirms the short-term effect of moderate to intense exercise or rehabilitation. We believe that BDNF could be regarded as a valuable diagnostic biomarker for acute stroke and a potential screening factor to observe the effectiveness of treatment. Existing modalities lack a definite protocol by which a maximum benefit is reached. Thus, further studies should focus on addressing the exact dosage of proposed drugs such as antioxidants, antidepressants, statins and a definite intensity and duration for the physical training. Lastly, investigating the role of BDNF supplementation for severe stroke patients could be of great value.