Advances in Clinical and Experimental Medicine

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Advances in Clinical and Experimental Medicine

Ahead of print

doi: 10.17219/acem/154955

Publication type: meta-analysis

Language: English

License: Creative Commons Attribution 3.0 Unported (CC BY 3.0)

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Chen Z, Zhang H. A meta-analysis on the role of brain-derived neurotrophic factor in Parkinson’s disease patients [published online as ahead of print on November 18, 2022]. Adv Clin Exp Med. 2023. doi:10.17219/acem/154955

A meta-analysis on the role of brain-derived neurotrophic factor in Parkinson’s disease patients

Zhen Chen1,A,B,C,D,E,F, Hui Zhang1,A,B,C,D,E,F

1 Department of Neurology, Xuzhou Central Hospital, China


Background. Brain-derived neurotrophic factor (BDNF) is essential for the development of dopaminergic neurons in the substantia nigra.

Objectives. To investigate the level of BDNF among Parkinson’s disease (PD) subjects and the influence of depression on BDNF levels.

Materials and methods. A total of 1920 subjects were included in the analysis; of these, 1034 had PD and 886 were healthy controls. A thorough literature search up to May 2022 was conducted. The mean difference (MD) of BDNF levels and 95% confidence intervals (95% CIs) were calculated with random or fixed effects models.

Results. Compared to healthy controls, levels of BDNF were significantly lower in patients with PD (MD = −1.60, 95% CI (−2.49, −0.70), p < 0.001). Patients with PD and depression had significantly lower levels of BDNF (MD = −3.39, 95% CI (−5.55, −1.23), p = 0.002), as well as those with PD without depression (MD = −0.80, 95% CI (−1.56, −0.03), p = 0.04). However, there was no discernible change in BDNF levels (MD = −0.82, 95% CI (1.75, 0.10), p = 0.08) between the participants with PD and depression compared to the PD patients alone.

Conclusions. Compared with healthy controls, BDNF levels were significantly lower in the subjects with PD combined with depression, and PD without depression. However, there was no discernible difference in BDNF levels between subjects with PD with depression compared to those with PD without depression.

Key words: Parkinson’s disease, BDNF, depression, dopaminergic neurons, substantia nigra



Parkinson’s disease (PD) is a degenerative neurological illness. Recent research has suggested that inflammatory processes are involved in PD, which contradicts the monoamine depletion hypothesis (the traditional approach to depression).1, 2 Given this, we might speak of an inflammatory hypothesis to explain the serotonergic, noradrenergic and dopaminergic dysfunctions that are characteristic of depression.3 In addition, low-quality diets are linked to the aforementioned negative physical, mental and cognitive health effects. Many different processes, including oxidative stress, plasticity, the microbiota–gut–brain axis, and most notably, inflammatory responses, are modulated by diet, which makes it a major risk factor for chronic diseases.4 The ventrolateral cell groups (i.e., A9 or nigrostriatal pathway) in the substantia nigra are the most susceptible to damage, whereas the dorsal and medial cell groups (i.e., A10 or mesolimbic pathway) are the most resilient ones.5 It has been hypothesized that the pacemaker-like features of dopaminergic neurons, which cause frequent intracellular calcium transients are the molecular basis for the selective vulnerability of these cells. There is some evidence that A9 neurons have impaired calcium buffering, which can contribute to cellular stress and, ultimately, the disruption of cellular homeostasis. The first affected neurons are those in the olfactory bulb (anterior olfactory nucleus) and dorsal motor nucleus of the vagus (medulla), then those in the pons (locus ceruleus), and finally those in the substantia nigra (dopaminergic neurons).5 In addition, recent evidence from studies on action control conducted on healthy individuals supported a causal role of dopamine in action control, and others addressed how PD is accompanied by impairments in covert cognitive processes.6, 7 Still, other studies investigated underlying goal-directed motor functioning (e.g., action planning, conflict adaptation, motor inhibition)8, 9 and how dopaminergic medication may modulate these action control components.

The symptoms of PD can be divided into motor symptoms and non-motor symptoms (NMSs). Motor-related symptoms include muscle rigidity, tremors and changes in speech. Sensory complaints, mental abnormalities, sleep disturbances, and autonomic dysfunction are common NMSs experienced by people with PD. Non-motor symptoms can occur in the earliest stages of the disease, even before motor impairment is clinically apparent. Depression is a notable NMS that is particularly prevalent in the early stages of the disease. It has a substantial influence on the quality of life and disability.10 The loss of dopamine-producing cells and the development of Lewy bodies in the brain commonly lead to NMSs in PD, which decreases the quality of life and presents significant hurdles in disease management. The modulation of autonomic nervous system responses is crucial for behavioral regulation.11, 12 Synuclein aggregations and the denervation of the dopaminergic nigrostriatal system are thought to play major roles in the pathophysiology of PD.13, 14 Anxiety disorders respond well to antidepressants, such as selective serotonin reuptake inhibitors and serotonin noradrenaline reuptake inhibitors, because of their proposed shared neurobiological basis: alterations in prefrontal-limbic pathways15, 16 and serotonergic projections arising from the raphe nuclei.17 However, current transcranial magnetic stimulation (TMS) has pinpointed 2 separate circuit targets for symptom clusters of depression (i.e., sorrow) and anxiety (i.e., irritability). Transcranial magnetic stimulation of the dorsomedial prefrontal cortex lowers depression symptoms and alleviates anxiety symptoms.18 Depression and other non-motor symptoms, such as reduced nonverbal communication and expressivity, may present themselves early in people with PD. Depression and other NMSs may be triggered by quinolinic acid. Research has shown that the neurotoxicity of the quinolinic acid contributes to the etiology of PD.19 The uncertainty associated with PD and coronavirus disease 2019 (COVID-19) magnified each other, and the cancellation of clinical appointments and restrictions on physical activity had substantial adverse effects on the well-being of this group of individuals.20

Neuropeptides and neurohormones play an important role in cognitive, emotional, social, and arousal functions, and are biomarkers to help evaluate risk, diagnosis, disease course, and therapeutic outcomes of a disease.21 Prior research has demonstrated that the levels of A42 and tau protein in the serum of PD patients are highly variable and do not correlate with the mean scores on tests used to evaluate the severity of cognitive disorders. Therefore, A42 and tau protein in serum cannot be used as biomarkers of neurodegenerative changes in PD with cognitive impairment.22 On the other hand, patients with neurodegenerative diseases such as PD or psychiatric disorders such as depression have decreased levels of kynurenic acid.23

In adult brains, the neurotrophin known as the brain-derived neurotrophic factor (BDNF) promotes dendrite morphogenesis, synaptic plasticity, arborization, and even neurogenesis.24, 25 Brain-derived neurotrophic factor is essential for the development of dopaminergic neurons in the substantia nigra,24 which are widely dispersed in cortical and subcortical regions. Brain-derived neurotrophic factor stimulates neurite growth and supports the survival of nigral dopaminergic neurons within the substantia nigra. Therefore, blocking the expression of BDNF results in the death of adult dopaminergic neurons.26 Parkinson’s disease patients have a lower expression of BDNF in the pars compacta of the substantia nigra,27, 28, 29 reducing trophic support for dopaminergic neurons. At the same time, the remaining dopaminergic neurons in the substantia nigra produce dwindling levels of BDNF.30


The aim of the current meta-analysis is to investigate the level of BDNF among PD subjects and the influence of comorbid depressive symptoms on BDNF levels.

Materials and methods

Study design

This meta-analysis consisted of clinical research studies that were a part of the epidemiological declaration31 and had a set study protocol. For data collection and analysis, a wide variety of databases were consulted, including PubMed, Ovid, Cochrane Library, Embase, and Google Scholar.

Data collection

Data were collected from clinical trials as well as human observational research papers that were written in any language. Studies were used regardless of sample size. Articles that did not give an association measurement, such as reviews, editorials or research letters, were not included.


According to the PICOS principle, a protocol of search strategies was developed32 and defined as follows: 1) patients (P): subjects diagnosed with PD; 2) intervention/exposure (I): BDNF; 3) comparison (C): BDNF in various subject groups; 4) outcome (O): PD compared to controls, PD with depression compared to controls, PD without depression compared to controls, and PD with depression compared to PD without depression; 5) study design (S): no restriction.33

Using the keywords and associated phrases listed in Table 1 (search strategies for different databases), we conducted a complete search of the PubMed, Ovid, Cochrane Library, Embase, and Google Scholar databases up to May 2022. The titles and abstracts of the collected publications that did not link the levels of BDNF to PD were excluded from the analysis. Two authors, ZC and HZ, acted as reviewers to identify suitable studies.

Eligibility and inclusion

The following criteria had to be met for an article to be considered for the inclusion in the meta-analysis:

1. The study was either prospective, observational, randomized, or retrospective;

2. The target intervention population consisted of individuals with PD;

3. The intervention regimen of the included studies was based on plasma samples of BDNF;

4. The study examined BDNF levels in several subject categories.

Exclusion criteria were:

1. Studies that failed to identify the plasma levels of BDNF in PD patients;

2. Studies that did not focus on the impact of comparison outcomes.

Figure 1 illustrates our selection process.


Data extracted from the studies included: study- and subject-related features in a standard format; the surname of the first author; the period of the study, the year of publication; the country of the study; the design of the study; the population type recruited in the study; the total number of subjects; categories; qualitative and quantitative evaluation method; demographic data; clinical and treatment characteristics; information source; outcome evaluation; and statistical analysis.34 A single study evaluating BDNF in PD patients yielded inconsistent results, so it was isolated. Each study was assessed for bias, and the methodological quality of the chosen studies was evaluated by the 2 authors in a blinded fashion using the risk of bias tool from the Cochrane Handbook for Systematic Reviews of Interventions, v.

The Newcastle-Ottawa Scale (NOS), a quality and bias assessment tool developed specifically for observational research, was also used to evaluate the bias. The NOS examines the sample, the comparability of cases and controls, and the exposure in observational studies, with studies being assigned values between 0 and 9. Studies with a rating of 7–9 are of the highest quality and have the lowest risk of bias compared to those of lower ratings. Studies with a quality and bias risk rating from 4 to 6 are considered to have moderate quality. Each study was reviewed by the 2 authors.

Statistical analyses

The mean difference (MD) with a 95% confidence interval (95% CI) was calculated using a random or fixed effects model. All groups were analyzed using the random effects model due to high heterogeneity, whereas the use of fixed effects model required the confirmation of high similarity between the included study and a low heterogeneity (I2) level. The I2 index (determined using Reviewer Manager and expressed in forest plots), expressed as a numeric value ranging from 0 to 100, was calculated (as a percentage). Percentages ranging from 0% to 25%, 25% to 50%, 50% to 75%, and 75% to 100% indicated no, low, moderate, and high heterogeneity, respectively.36 Fixed effects models were used when the heterogeneity was low. As previously stated, the subcategory analysis was performed by stratifying the initial evaluation into result categories. The publication bias was investigated quantitatively with the Begg’s test (the publication bias was considered present if p < 0.05).37 A two-tailed test was used to calculate the p-value. The statistical analysis and graphs were created with the Reviewer Manager v. 5.3 software (The Cochrane Collaboration, Copenhagen, Denmark) and Jamovi software v. 2.3 ( using a continuous model.


Nineteen articles (out of 1765 reviewed) published between 2009 and 2022 satisfied the inclusion criteria and were included in the meta-analysis.38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 Table 2 summarizes the findings of these investigations. Ultimately, more than 1000 people had PD and 886 were healthy controls. Number of subjects in the included studies ranged from 29 to 369.

PD patients compared to controls

Fifteen studies, which included 634 subjects, reported data stratified according to PD compared to the control group (Figure 2). Parkinson’s disease was associated with significantly lower levels of BDNF compared to controls (MD = −1.60, 95% CI (−2.49, −0.70), p < 0.001), with a heterogeneity of 99%.

PD patients with depression
compared to controls

Five studies, which included 232 subjects, reported data stratified according to PD with depression (Figure 3). Parkinson’s disease with depression was associated with significantly lower levels of BDNF (MD = −3.39, 95% CI (−5.55, −1.23), p = 0.002), with a heterogeneity of 99%.

PD patients without depression
compared to controls

Five studies, which included 259 subjects, reported data stratified according to PD without depression (Figure 4). Parkinson’s disease without depression was associated with significantly lower levels of BDNF (MD = −0.80, 95% CI (−1.56, −0.03), p = 0.04), with a heterogeneity of 94%.

PD patients with depression compared to PD patients without depression

Seven studies, which included 305 subjects, reported data stratified according to PD with depression compared to PD without depression (Figure 5). Parkinson’s disease patients with depression and PD patients without depression had no statistically significant difference in BDNF levels (MD = −0.82, 95% CI (−1.75, 0.10), p = 0.08) and a heterogeneity of 95%.

Analysis of other potential

The analysis of studies with defined sampling time (morning) similarly found significantly lower BDNF levels in PD patients compared with controls (Figure 6) (MD = −1.24, 95% CI (−2.30, −0.17), p = 0.002), with a heterogeneity of 95%.

It was not possible to assess the impact of individual characteristics such as gender and ethnicity on the comparison results as data on these variables were not collected. In addition, the publication bias was found to not be statistically different for PD subjects compared with controls (p = 0.62). Similarly, the analysis of studies with defined sampling time (i.e., morning) failed to identify statistically significant bias (p = 0.61). In addition, the results of the Begg’s test for PD patients with depression, PD patients without depression, and PD patients with depression compared to PD patients without depression were p = 0.82, p = 0.99 and p = 0.77, respectively, indicating a lack of publication bias.

The risk of bias assessment was evaluated with NOS (Table 2). Twelve studies were found to have a score between 7 and 9 points, which reflects a low risk of bias. Six studies showed a moderate risk of bias, with scores ranging from 4 to 6 points. Only one study scored 3 points, reflecting a high risk of bias resulting from low quality methodology.


A total of 1920 individuals, 1034 of whom were diagnosed with PD and 886 of whom were healthy controls, were included in the current meta-analysis.38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56 Parkinson’s disease patients, both with and without depression, had lower levels of BDNF than healthy controls. Parkinson’s disease patients with depression did not have lower levels of BDNF than PD patients without depression. It is important to be cautious when interpreting the results comparing PD patients with and without depression, as these data come from relatively small sample sizes (13 out of 19) and a limited number of studies (<100).

It is critical to determine if circulating BDNF levels may be used as a surrogate for BDNF expression in the central nervous system and neurons, given the role of this factor in PD. The association between blood levels of BDNF and hippocampal BDNF is highest in mice (R2 = 0.81).37 However, whether this association applies to people remains debated. We know that BDNF is produced by glial cells, like astrocytes and microglia, as well as extra-central nervous system cell types, such as endothelium cells and peripheral blood mononuclear cells.57 Circulating BDNF appears to originate mainly in the central nervous system, given that it may cross the blood–brain barrier and that endothelial and mononuclear cells express extremely low quantities of it.58 Therefore, studying the levels of BDNF in the serum of PD patients as a surrogate for its expression in the central nervous system is now possible. Due to their inherent ability to retain proteins, platelets are the principal source of BDNF in the blood.

Patients with PD had a lower BDNF expression and more dopamine in their striatum, according to the dopamine transporter scans.59 The expression of BDNF can be affected by a wide range of factors, including the 196 A/G single nucleotide polymorphism. This 196 A/G polymorphism, which results in a Val66Met substitution, was initially discovered by Momose et al. as a possible homozygote mutation linked to an increased risk of PD.60 This mutation was confirmed to consistently downregulate the expression of BDNF61 and it was the subject of future research to determine its link to PD risk.62, 63

Reduced expression of BDNF, irrespective of nigral dopaminergic expression, alters dopaminergic outflow to the striatum and mimics the motor symptoms of PD in mice.64 In addition, synuclein, the primary component of Lewy body fibrils in people with Parkinson’s disease, inhibits BDNF’s neurotrophic action in the substantia nigra by first downregulating BDNF expression65 and then, by competitively inhibiting BDNF signaling at the receptor level.66 Exogenous BDNF lowers the loss of dopaminergic neurons in PD models employing 6-hydroxydopamine hydrobromide and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine as well as neuronal cultures, according to the majority of research.67, 68, 69, 70 Extensive data are suggesting the protective effect of BDNF on the dopaminergic substantia nigra population in PD and its downregulation in individuals with PD.71 On the flip side, the development of PD has been associated with increasing levels of BDNF in blood and cerebrospinal fluid.38, 39 Also, an important role of physical training and exercise had been recognized, since acute exercise can boost blood levels of BDNF and then improve cognitive function shortly after exercise.72 Memory enhancement is more noticeable and strongest shortly following training matched to other cognitive areas. In addition, it was shown that both dopamine replacement therapy and anti-parkinsonism medicines upregulate BDNF to a small degree.73 As noted, these findings have sparked tremendous interest in the potential for exercise-induced alterations in BDNF to arrest neurodegeneration in Parkinson’s disease.74 Several studies reveal reduced serum levels of BDNF in PD subjects.38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 75, 76, 77, 78, 79 The Val66Met polymorphisms were not identified as predictors of PD risk except for a slight increase in risk linked with the AA+AG genotype.80 Even though some research suggests that the Val66Met variant can alter the expression of BDNF in PD, a growing body of evidence suggests that acute exercise can increase the serum levels of BDNF and alleviate the symptoms of Parkinson’s disease.81 For many, the cognitive benefits of exercise can be attributed to an increase in serum BDNF.82, 83 Parikh et al. found that the BDNF regulates the striatal dopamine levels in mice, specifically affecting the balance of glutamate and the ability to adapt cognitively and executively.84

The benefits of exercise on neuroplasticity and protection from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity were lost in animals with a complete deletion or insufficient expression of BDNF.85, 86 It is possible that the alleviation of depression and motor symptoms due to continuous exercise may also be due to an increase in BDNF protein in the striatum of mice.87

One study found a paradoxical increase in serum BDNF with increased depression duration and decreased motor capacity, whereas another study found no difference in serum BDNF when considering patients’ physical capacity.88 Brain-derived neurotrophic factor levels are higher in patients with PD who have had long-term dopamine replacement therapy, according to a study by Scalzo et al.39 This suggests that the increased expression of BDNF in advanced PD is not only due to medication-induced release of the pool of BDNF.

It is hoped that nonpharmaceutical interventions, such as exercise, can reduce the symptoms of PD. Hirsch et al. found that regulated exercise could improve blood BDNF levels and decrease Rating Scale III (RS-III) scores in individuals with PD.88 These data support the efficacy of nonpharmacological methods to induce BDNF in PD. Serum BDNF rises incrementally in the early stages of PD, most likely due to a compensatory increase in the production of BDNF by the surviving dopaminergic neurons. According to Hirsch et al., exercising a few times a week can help PD patients improve their motor scores and increase their blood levels of BDNF.88 Despite the findings stating that physical training and BDNF levels increase as PD symptoms decrease, it is unclear if this is mediated by BDNF. The findings of Scalzo et al. contradict the results of this study; however, the authors do not acknowledge or explain this discrepancy.39 Furthermore, it is important to point out that the aforementioned research supports the idea that exercise can improve depressive symptoms in PD patients by promoting BDNF expression and signaling. The effects of medications must be considered when analyzing data from PD patients. Even though numerous studies have qualitatively documented the use of common medications in study groups, many of these studies have not controlled for the effect of dosage or frequency of use. For example, it is thought that increased levels of BDNF are a contributing component in treating depression with serotonin reuptake inhibitors.89 Selegiline, an inhibitor of monoamine oxidase, an agonist of the N-methyl-D-aspartate receptor, and metformin, a tricyclic antidepressant, have been shown to have neuroprotective characteristics.90, 91, 92, 93 Many studies offered only a dichotomous assessment of depression in PD patients and did not use psychological tests to establish a quantitative score.

The results of this meta-analysis indicate that BDNF levels are decreased in patients with PD and perhaps in PD patients with depression.89, 90, 91, 92, 93, 94, 95, 96, 97, 98 For these potential connections to be demonstrated and compared with other subjects in terms of the examined consequences, further research is needed. Larger and more uniform samples are required for this type of study.99, 100, 101, 102, 103 A previous meta-analysis similarly showed that BDNF had favorable advantages in treating PD and reducing PD with depression.104, 105, 106, 107, 108, 109, 110 To determine whether age and ethnicity are connected to the outcomes of our study, well-conducted randomized controlled trials are needed.


While this study may have been skewed by excluding so many trials from our meta-analysis, these studies failed to meet our rigorous inclusion criteria. Of the 19 papers analyzed, 13 had sample sizes of less than 100 people. In addition, some of the included studies did not mention the sampling time of BDNF. There is no way to tell if the results are due to gender or ethnicity, as data on these variables were not included in our study. Patients with PD were evaluated for BDNF using data from previous research, which may have been skewed due to a lack of relevant information. Uncollected variables such as the respondents’ age, gender and nutritional status may have also skewed the results.


Parkinson’s disease combined with depression, and PD patients without depression had significantly lower levels of BDNF than healthy controls. Parkinson’s disease patients with depression did not have lower levels of BDNF than PD patients without depression. In individuals with PD, acute exercise and physical training are consistently associated with increased serum BDNF and, by extension, better motor function and lower Unified Parkinson Disease Rating Scale (UPDRS) stage III scores. Our research suggests that depression, a major comorbidity in PD, and PD both have the capacity to downregulate the expression of BDNF. In addition, possible drug effects, such as antidepressants and dopamine replacement treatment, are reflected here as well.


Table 1. Search strategy for each database


Search strategy


#1 “Parkinson’s disease” (MeSH terms) OR “brain-derived neurotrophic factor” (all fields)

#2 “brain” (MeSH terms) OR “depression” (all fields)

#3 #1 AND #2


#1 “Parkinson’s disease” (all fields) OR “brain-derived neurotrophic factor” (all fields)

#2 “brain” (all fields) OR “depression” (all fields)

#3 #1 AND #2

Google Scholar

#1 “Parkinson’s disease” OR “brain-derived neurotrophic factor”

#2 “brain” OR “depression”

#3 #1 AND #2


#1 “Parkinson’s disease”/exp OR “brain-derived neurotrophic factor”

#2 “brain”/exp OR “depression”

#3 #1 AND #2

Cochrane Library

#1 “Parkinson’s disease”: ti, ab, kw; “brain-derived neurotrophic factor”: ti, ab, kw (word variations have been searched)

#2 “brain”: ti, ab, kw OR “depression”: ti, ab, kw (word variations have been searched)

#3 #1 AND #2

ti, ab, kw – terms in either title or abstract or keyword fields; exp – exploded indexing term.
Table 2. Characteristics of the selected studies included in the meta-analysis

Study and year



Parkinson’s disease





Disease duration

H&Y in PD

UPDRS part III in PD

Depression scale


Sampling time

Salehi and Mashayekhi, 200938





65.3 ±7.2


Scalzo et al., 201039





65.7 ±8.8


7.6 ±4.5


34.5 ±23.3



Ricci et al., 201040





63.7 ±8.87


8.05 ±2.41

2.7 ±0.7

16 ≤ HAM-D


Pålhagen et al., 201041





65.3 ±7.2


6.9 ±2.4

1.8 ±0.4

22.6 ±10.1


Ventriglia et al., 201342





67.6 ±8.4


16 ≤ HAM-D score



Martín de Pablos et al., 201543





63.4 ±0.9


2.16 ±1.04


Khalil et al., 201644





59.4 ±13.1


4.4 ±2.7

2.4 ±0.7

49.2 ±16.5


Wang et al., 201645





63.6 ±9.32


4.23 ±3.1

1.59 ±0.43



Siuda et al., 201746





63.3 ±10.5


8.41 ±5.8

2.7 ±0.7

19 ≤ BDI score



Wang et al., 201747





61.64 ±8.87


3.76 ±2.56

1.6 ±0.7

53 ≤ SDS score



Rocha et al., 201848





68.71 ±10.7


5.45 ±4.13

2.44 ±0.69

34.57 ±18.43



Costa et al., 201949





68 (62.5–71.5)


4.5 (3–14.25)

2.16 ±0.44

HAM-D r = −0.44



Hernández-Vara et al., 202050





63.97 ±9.59 (38–77)


1 (0.92–1.5)

1 (1–2)

16.5 (12.75–22.00)

mean HAM-D: 5.63, SD = 3.79



Quan et al., 202051





67.19 ±8.12


4.13 ±1.50

2.12 ±0.75



Chung et al., 202052





69.67 ±8.44


2.70 ±2.45

22.89 ±10.00


Shi et al., 202153





65.04 ±10.55


2 ±2.6

1.33 ±2.89



Soke et al., 202154





57.07 ±8.18


8.13 ±4.81

8.13 ±4.81



Huang et al., 202155





62.84 ±8.73


4.96 ±2.09

2.07 ±1.02

33.78 ±8.31

HAM-D: 17 (33.78 ±8.31)



Schaeffer, 202256





58 ±10


5.6 ±5.0

1.85 ±0.42

25 ±10






PD – patients with Parkinson’s disease; H&Y – Hoehn and Yahr’s motor stage; UPDRS – Unified Parkinson’s Disease Rating Scale; NOS – Newcastle-Ottawa Scale; HAM-D – Hamilton Depression Rating Scale; SD – standard deviation; BDI – Beck Depression Inventory; SDS – Self-Rating Depression Scale.


Fig. 1. Schematic diagram of the study procedure
Fig. 2. Forest plot of brain-derived neurotrophic factor (BDNF) levels in Parkinson’s disease (PD) patients compared with healthy controls
SD – standard deviation; 95% CI – 95% confidence interval; df – degrees of freedom.
Fig. 3. Forest plot of brain-derived neurotrophic factor (BDNF) levels in Parkinson’s disease (PD) patients with depression compared with healthy controls
SD – standard deviation; 95% CI – 95% confidence interval; df – degrees of freedom.
Fig. 4. Forest plot of brain-derived neurotrophic factor (BDNF) levels in Parkinson’s disease (PD) patients without depression compared with healthy controls
SD – standard deviation; 95% CI – 95% confidence interval; df – degrees of freedom.
Fig. 5. Forest plot of brain-derived neurotrophic factor (BDNF) levels in Parkinson’s disease (PD) patients with depression compared with PD patients without depression
SD – standard deviation; 95% CI – 95% confidence interval; df – degrees of freedom.
Fig. 6. Forest plot of the morning samples BDNF levels in Parkinson’s disease (PD) patients compared with healthy controls
SD – standard deviation; 95% CI – 95% confidence interval; df – degrees of freedom.

References (110)

  1. Tanaka M, Spekker E, Szabó Á, Polyák H, Vécsei L. Modelling the neurodevelopmental pathogenesis in neuropsychiatric disorders: Bioactive kynurenines and their analogues as neuroprotective agents. In celebration of 80th birthday of Professor Peter Riederer. J Neural Transm. 2022;129(5–6):627–642. doi:10.1007/s00702-022-02513-5
  2. Rosenblat JD, Cha DS, Mansur RB, McIntyre RS. Inflamed moods: A review of the interactions between inflammation and mood disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2014;53:23–34. doi:10.1016/j.pnpbp.2014.01.013
  3. Carrera-González M del P, Cantón-Habas V, Rich-Ruiz M. Aging, depression and dementia: The inflammatory process. Adv Clin Exp Med. 2022;31(5):469–473. doi:10.17219/acem/149897
  4. Hepsomali P, Coxon C. Inflammation and diet: Focus on mental and cognitive health. Adv Clin Exp Med. 2022;31(8):821–825. doi:10.17219/acem/152350
  5. Dickson DW. Neuropathology of Parkinson disease. Parkinsonism Relat Disord. 2018;46:S30–S33. doi:10.1016/j.parkreldis.2017.07.033
  6. Battaglia S, Cardellicchio P, Di Fazio C, Nazzi C, Fracasso A, Borgomaneri S. The influence of vicarious fear-learning in “infecting” reactive action inhibition. Front Behav Neurosci. 2022;16:946263. doi:10.3389/fnbeh.2022.946263
  7. Borgomaneri S, Serio G, Battaglia S. Please, don’t do it! Fifteen years of progress of non-invasive brain stimulation in action inhibition. Cortex. 2020;132:404–422. doi:10.1016/j.cortex.2020.09.002
  8. Battaglia S, Serio G, Scarpazza C, D’Ausilio A, Borgomaneri S. Frozen in (e)motion: How reactive motor inhibition is influenced by the emotional content of stimuli in healthy and psychiatric populations. Behav Res Ther. 2021;146:103963. doi:10.1016/j.brat.2021.103963
  9. Mazzoni P, Shabbott B, Cortes JC. Motor control abnormalities in Parkinson’s disease. Cold Spring Harb Perspect Med. 2012;2(6):a009282. doi:10.1101/cshperspect.a009282
  10. Cao X, Yang F, Zheng J, Wang X, Huang Q. Aberrant structure MRI in Parkinson’s disease and comorbidity with depression based on multinomial tensor regression analysis. J Pers Med. 2022;12(1):89. doi:10.3390/jpm12010089
  11. Ellena G, Battaglia S, Làdavas E. The spatial effect of fearful faces in the autonomic response. Exp Brain Res. 2020;238(9):2009–2018. doi:10.1007/s00221-020-05829-4
  12. Borgomaneri S, Vitale F, Battaglia S, Avenanti A. Early right motor cortex response to happy and fearful facial expressions: A TMS motor-evoked potential study. Brain Sci. 2021;11(9):1203. doi:10.3390/brainsci11091203
  13. Tanaka M, Szabó Á, Spekker E, Polyák H, Tóth F, Vécsei L. Mitochondrial impairment: A common motif in neuropsychiatric presentation? The link to the tryptophan–kynurenine metabolic system. Cells. 2022;11(16):2607. doi:10.3390/cells11162607
  14. Byeon H. Development of a stacking-based ensemble machine learning for detection of depression in Parkinson’s disease: Preliminary research. Biol Life Sci Forum. 2021;9:10857. doi:10.3390/ECCM-10857
  15. McTeague LM, Rosenberg BM, Lopez JW, et al. Identification of common neural circuit disruptions in emotional processing across psychiatric disorders. Am J Psychiatry. 2020;177(5):411–421. doi:10.1176/appi.ajp.2019.18111271
  16. Kovner R, Oler JA, Kalin NH. Cortico-limbic interactions mediate adaptive and maladaptive responses relevant to psychopathology. Am J Psychiatry. 2019;176(12):987–999. doi:10.1176/appi.ajp.2019.19101064
  17. An Y, Chen C, Inoue T, et al. Mirtazapine exerts an anxiolytic-like effect through activation of the median raphe nucleus-dorsal hippocampal 5-HT pathway in contextual fear conditioning in rats. Prog Neuropsychopharmacol Biol Psychiatry. 2016;70:17–23. doi:10.1016/j.pnpbp.2016.04.014
  18. Chen C. Recent advances in the study of the comorbidity of depressive and anxiety disorders. Adv Clin Exp Med. 2022;31(4):355–358. doi:10.17219/acem/147441
  19. Hestad K, Alexander J, Rootwelt H, Aaseth JO. The role of tryptophan dysmetabolism and quinolinic acid in depressive and neurodegenerative diseases. Biomolecules. 2022;12(7):998. doi:10.3390/biom12070998
  20. Holland C, Garner I, Simpson J, et al. Impacts of COVID-19 lockdowns on frailty and wellbeing in older people and those living with long-term conditions. Adv Clin Exp Med. 2021;30(11):1111–1114. doi:10.17219/acem/144135
  21. Tanaka M, Vécsei L. Editorial of Special Issue ‘Dissecting Neurological and Neuropsychiatric Diseases: Neurodegeneration and Neuroprotection.’ Int J Mol Sci. 2022;23(13):6991. doi:10.3390/ijms23136991
  22. Chojdak-Łukasiewicz J, Małodobra-Mazur M, Zimny A, Noga L, Paradowski B. Plasma tau protein and Aβ42 level as markers of cognitive impairment in patients with Parkinson’s disease. Adv Clin Exp Med. 2020;29(1):115–121. doi:10.17219/acem/112058
  23. Martos D, Tuka B, Tanaka M, Vécsei L, Telegdy G. Memory enhancement with kynurenic acid and its mechanisms in neurotransmission. Biomedicines. 2022;10(4):849. doi:10.3390/biomedicines10040849
  24. Porritt MJ, Batchelor PE, Howells DW. Inhibiting BDNF expression by antisense oligonucleotide infusion causes loss of nigral dopaminergic neurons. Exp Neurol. 2005;192(1):226–234. doi:10.1016/j.expneurol.2004.11.030
  25. Nagahara AH, Tuszynski MH. Potential therapeutic uses of BDNF in neurological and psychiatric disorders. Nat Rev Drug Discov. 2011;10(3):209–219. doi:10.1038/nrd3366
  26. Murer MG, Yan Q, Raisman-Vozari R. Brain-derived neurotrophic factor in the control human brain, and in Alzheimer’s disease and Parkinson’s disease. Prog Neurobiol. 2001;63(1):71–124. doi:10.1016/S0301-0082(00)00014-9
  27. Howells DW, Porritt MJ, Wong JYF, et al. Reduced BDNF mRNA expression in the Parkinson’s disease substantia nigra. Exp Neurol. 2000;166(1):127–135. doi:10.1006/exnr.2000.7483
  28. Mogi M, Togari A, Kondo T, et al. Brain-derived growth factor and nerve growth factor concentrations are decreased in the substantia nigra in Parkinson’s disease. Neurosci Lett. 1999;270(1):45–48. doi:10.1016/S0304-3940(99)00463-2
  29. Parain K, Murer MG, Yan Q, et al. Reduced expression of brain-derived neurotrophic factor protein in Parkinson’s disease substantia nigra. Neuroreport. 1999;10(3):557–561. doi:10.1097/00001756-199902250-00021
  30. Collier TJ, Dung Ling Z, Carvey PM, et al. Striatal trophic factor activity in aging monkeys with unilateral MPTP-induced parkinsonism. Exp Neurol. 2005;191:S60–S67. doi:10.1016/j.expneurol.2004.08.018
  31. Stroup DF. Meta-analysis of observational studies in epidemiology: A proposal for reporting. JAMA. 2000;283(15):2008. doi:10.1001/jama.283.15.2008
  32. Higgins JPT. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557–560. doi:10.1136/bmj.327.7414.557
  33. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: Explanation and elaboration. J Clin Epidemiol. 2009;62(10):e1–e34. doi:10.1016/j.jclinepi.2009.06.006
  34. Gupta A, Das A, Majumder K, et al. Obesity is independently associated with increased risk of hepatocellular cancer-related mortality: A systematic review and meta-analysis. Am J Clin Oncol. 2018;41(9):874–881. doi:10.1097/COC.0000000000000388
  35. Higgins JPT, Altman DG, Gotzsche PC, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928. doi:10.1136/bmj.d5928
  36. Sheikhbahaei S, Trahan TJ, Xiao J, et al. FDG-PET/CT and MRI for evaluation of pathologic response to neoadjuvant chemotherapy in patients with breast cancer: A meta-analysis of diagnostic accuracy studies. Oncologist. 2016;21(8):931–939. doi:10.1634/theoncologist.2015-0353
  37. Klein AB, Williamson R, Santini MA, et al. Blood BDNF concentrations reflect brain-tissue BDNF levels across species. Int J Neuropsychopharm. 2011;14(3):347–353. doi:10.1017/S1461145710000738
  38. Salehi Z, Mashayekhi F. Brain-derived neurotrophic factor concentrations in the cerebrospinal fluid of patients with Parkinson’s disease. J Clin Neurosci. 2009;16(1):90–93. doi:10.1016/j.jocn.2008.03.010
  39. Scalzo P, Kümmer A, Bretas TL, Cardoso F, Teixeira AL. Serum levels of brain-derived neurotrophic factor correlate with motor impairment in Parkinson’s disease. J Neurol. 2010;257(4):540–545. doi:10.1007/s00415-009-5357-2
  40. Ricci V, Pomponi M, Martinotti G, et al. Antidepressant treatment restores brain-derived neurotrophic factor serum levels and ameliorates motor function in Parkinson disease patients. J Clin Psychopharmacol. 2010;30(6):751–753. doi:10.1097/JCP.0b013e3181fc2ec7
  41. Pålhagen S, Qi H, Mårtensson B, Wålinder J, Granérus AK, Svenningsson P. Monoamines, BDNF, IL-6 and corticosterone in CSF in patients with Parkinson’s disease and major depression. J Neurol. 2010;257(4):524–532. doi:10.1007/s00415-009-5353-6
  42. Ventriglia M, Zanardini R, Bonomini C, et al. Serum brain-derived neurotrophic factor levels in different neurological diseases. Biomed Res Int. 2013;2013:901082. doi:10.1155/2013/901082
  43. Martín de Pablos A, García-Moreno JM, Fernández E. Does the cerebrospinal fluid reflect altered redox state but not neurotrophic support loss in Parkinson’s disease? Antioxid Redox Signal. 2015;23(11):893–898. doi:10.1089/ars.2015.6423
  44. Khalil H, Alomari MA, Khabour OF, Al-Hieshan A, Bajwa JA. Relationship of circulatory BDNF with cognitive deficits in people with Parkinson’s disease. J Neurol Sci. 2016;362:217–220. doi:10.1016/j.jns.2016.01.032
  45. Wang Y, Liu H, Zhang BS, Soares JC, Zhang XY. Low BDNF is associated with cognitive impairments in patients with Parkinson’s disease. Parkinsonism Relat Disord. 2016;29:66–71. doi:10.1016/j.parkreldis.2016.05.023
  46. Siuda J, Patalong-Ogiewa M, Żmuda W, et al. Cognitive impairment and BDNF serum levels. Neurol Neurochir Pol. 2017;51(1):24–32. doi:10.1016/j.pjnns.2016.10.001
  47. Wang Y, Liu H, Du XD, et al. Association of low serum BDNF with depression in patients with Parkinson’s disease. Parkinsonism Relat Disord. 2017;41:73–78. doi:10.1016/j.parkreldis.2017.05.012
  48. Rocha NP, Ferreira JPS, Scalzo PL, et al. Circulating levels of neurotrophic factors are unchanged in patients with Parkinson’s disease. Arq Neuropsiquiatr. 2018;76(5):310–315. doi:10.1590/0004-282x20180035
  49. Costa CM, de Oliveira GL, Fonseca ACS, Lana R de C, Polese JC, Pernambuco AP. Levels of cortisol and neurotrophic factor brain-derived in Parkinson’s disease. Neurosci Lett. 2019;708:134359. doi:10.1016/j.neulet.2019.134359
  50. Hernández-Vara J, Sáez-Francàs N, Lorenzo-Bosquet C, et al. BDNF levels and nigrostriatal degeneration in “drug naïve” Parkinson’s disease patients. An “in vivo” study using I-123-FP-CIT SPECT. Parkinsonism Relat Disord. 2020;78:31–35. doi:10.1016/j.parkreldis.2020.06.037
  51. Quan Y, Wang J, Wang S, Zhao J. Association of the plasma long non-coding RNA MEG3 with Parkinson’s disease. Front Neurol. 2020;11:532891. doi:10.3389/fneur.2020.532891
  52. Chung CC, Huang PH, Chan L, Chen JH, Chien LN, Hong CT. Plasma exosomal brain-derived neurotrophic factor correlated with the postural instability and gait disturbance-related motor symptoms in patients with Parkinson’s disease. Diagnostics. 2020;10(9):684. doi:10.3390/diagnostics10090684
  53. Shi MY, Ma CC, Chen FF, et al. Possible role of glial cell line-derived neurotrophic factor for predicting cognitive impairment in Parkinson’s disease: A case-control study. Neural Regen Res. 2021;16(5):885. doi:10.4103/1673-5374.297091
  54. Soke F, Kocer B, Fidan I, Keskinoglu P, Guclu-Gunduz A. Effects of task-oriented training combined with aerobic training on serum BDNF, GDNF, IGF-1, VEGF, TNF-α, and IL-1β levels in people with Parkinson’s disease: A randomized controlled study. Exp Gerontol. 2021;150:111384. doi:10.1016/j.exger.2021.111384
  55. Huang Y, Huang C, Zhang Q, Wu W, Sun J. Serum BDNF discriminates Parkinson’s disease patients with depression from without depression and reflect motor severity and gender differences. J Neurol. 2021;268(4):1411–1418. doi:10.1007/s00415-020-10299-3
  56. Schaeffer E, Roeben B, Granert O, et al. Effects of exergaming on hippocampal volume and brain‐derived neurotrophic factor levels in Parkinson’s disease. Eur J Neurol. 2022;29(2):441–449. doi:10.1111/ene.15165
  57. Quesseveur G, David DJ, Gaillard MC, et al. BDNF overexpression in mouse hippocampal astrocytes promotes local neurogenesis and elicits anxiolytic-like activities. Transl Psychiatry. 2013;3(4):e253. doi:10.1038/tp.2013.30
  58. Karege F, Schwald M, Cisse M. Postnatal developmental profile of brain-derived neurotrophic factor in rat brain and platelets. Neurosci Lett. 2002;328(3):261–264. doi:10.1016/S0304-3940(02)00529-3
  59. Ziebell M, Khalid U, Klein AB, et al. Striatal dopamine transporter binding correlates with serum BDNF levels in patients with striatal dopaminergic neurodegeneration. Neurobiol Aging. 2012;33(2):428.e1–428.e5. doi:10.1016/j.neurobiolaging.2010.11.010
  60. Momose Y, Murata M, Kobayashi K, et al. Association studies of multiple candidate genes for Parkinson’s disease using single nucleotide polymorphisms. Ann Neurol. 2002;51(1):133–136. doi:10.1002/ana.10079
  61. Egan MF, Kojima M, Callicott JH, et al. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell. 2003;112(2):257–269. doi:10.1016/S0092-8674(03)00035-7
  62. Dai L, Wang D, Meng H, et al. Association between the BDNF G196A and C270T polymorphisms and Parkinson’s disease: A meta-analysis. Int J Neurosci. 2013;123(10):675–683. doi:10.3109/00207454.2013.798784
  63. Dluzen DE, Anderson LI, McDermott JL, Kucera J, Walro JM. Striatal dopamine output is compromised within +/− BDNF mice. Synapse. 2002;43(2):112–117. doi:10.1002/syn.10027
  64. Yuan Y, Sun J, Zhao M, et al. Overexpression of α-synuclein downregulates BDNF expression. Cell Mol Neurobiol. 2010;30(6):939–946. doi:10.1007/s10571-010-9523-y
  65. Kang SS, Zhang Z, Liu X, et al. TrkB neurotrophic activities are blocked by α-synuclein, triggering dopaminergic cell death in Parkinson’s disease. Proc Natl Acad Sci U S A. 2017;114(40):10773–10778. doi:10.1073/pnas.1713969114
  66. Mocchetti I, Bachis A, Nosheny RL, Tanda G. Brain-derived neurotrophic factor expression in the substantia nigra does not change after lesions of dopaminergic neurons. Neurotox Res. 2007;12(2):135–143. doi:10.1007/BF03033922
  67. Goldberg NRS, Caesar J, Park A, et al. 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;5(5):791–804. doi:10.1016/j.stemcr.2015.09.008
  68. Yoshimoto Y, Lin Q, Collier TJ, Frim DM, Breakefield XO, Bohn MC. Astrocytes retrovirally transduced with BDNF elicit behavioral improvement in a rat model of Parkinson’s disease. Brain Res. 1995;691(1–2):25–36. doi:10.1016/0006-8993(95)00596-I
  69. Zhao L, He LX, Huang SN, et al. Protection of dopamine neurons by vibration training and upregulation of brain-derived neurotrophic factor in a MPTP mouse model of Parkinson’s disease. Physiol Res. 2014;63(5):649–657. doi:10.33549/physiolres.932743
  70. Ferreira RN, de Miranda AS, Rocha NP, Simoes e Silva AC, Teixeira AL, da Silva Camargos ER. Neurotrophic factors in Parkinson’s disease: What have we learned from preclinical and clinical studies? Curr Med Chem. 2018;25(31):3682–3702. doi:10.2174/0929867325666180313101536
  71. Onerup A, Angenete E, Bock D, et al. The effect of pre- and post-operative physical activity on recovery after colorectal cancer surgery (PHYSSURG-C): Study protocol for a randomised controlled trial. Trials. 2017;18(1):212. doi:10.1186/s13063-017-1949-9
  72. Okazawa H, Murata M, Watanabe M, Kamei M, Kanazawa I. Dopaminergic stimulation up-regulates the in vivo expression of brain-derived neurotrophic factor (BDNF) in the striatum. FEBS Lett. 1992;313(2):138–142. doi:10.1016/0014-5793(92)81430-T
  73. Campos C, Rocha NBF, Lattari E, Paes F, Nardi AE, Machado S. Exercise-induced neuroprotective effects on neurodegenerative diseases: The key role of trophic factors. Exp Rev Neurother. 2016;16(6):723–734. doi:10.1080/14737175.2016.1179582
  74. Angelucci F, Peppe A, Carlesimo GA, et al. A pilot study on the effect of cognitive training on BDNF serum levels in individuals with Parkinson’s disease. Front Hum Neurosci. 2015;9:130. doi:10.3389/fnhum.2015.00130
  75. Frazzitta G, Maestri R, Ghilardi MF, et al. Intensive rehabilitation increases BDNF serum levels in Parkinsonian patients: A randomized study. Neurorehabil Neural Repair. 2014;28(2):163–168. doi:10.1177/1545968313508474
  76. Khalil H, Alomari MA, Khabour O, Al-Hieshan A, Bajwa JA. The association between physical activity with cognitive function and brain-derived neurotrophic factor in people with Parkinson’s disease: A pilot study. J Aging Phys Act. 2017;25(4):646–652. doi:10.1123/japa.2016-0121
  77. Marusiak J, Żeligowska E, Mencel J, et al. Interval training-induced alleviation of rigidity and hypertonia in patients with Parkinson’s disease is accompanied by increased basal serum brain-derived neurotrophic factor. J Rehabil Med. 2015;47(4):372–375. doi:10.2340/16501977-1931
  78. Sajatovic M, Ridgel A, Walter E, et al. A randomized trial of individual versus group-format exercise and self-management in individuals with Parkinson’s disease and comorbid depression. Patient Prefer Adherence. 2017;11:965–973. doi:10.2147/PPA.S135551
  79. Zoladz JA, Majerczak J, Zeligowska E, et al. Moderate-intensity interval training increases serum brain-derived neurotrophic factor level and decreases inflammation in Parkinson’s disease patients. J Physiol Pharmacol. 2014;65(3):441–448. PMID:24930517.
  80. Lee YH, Song GG. BDNF 196 G/A and 270 C/T polymorphisms and susceptibility to Parkinson’s disease: A meta-analysis. J Mot Behav. 2014;46(1):59–66. doi:10.1080/00222895.2013.862199
  81. Phillips C. Brain-derived neurotrophic factor, depression, and physical activity: Making the neuroplastic connection. Neural Plast. 2017;2017:7260130. doi:10.1155/2017/7260130
  82. de Assis GG, de Almondes KM. Exercise-dependent BDNF as a modulatory factor for the executive processing of individuals in course of cognitive decline: A systematic review. Front Psychol. 2017;8:584. doi:10.3389/fpsyg.2017.00584
  83. Etnier JL, Labban JD, Karper WB, et al. Innovative research exploring the effects of physical activity and genetics on cognitive performance in community-based older adults. J Aging Phys Act. 2015;23(4):559–568. doi:10.1123/japa.2014-0221
  84. Parikh V, Naughton SX, Yegla B, Guzman DM. Impact of partial dopamine depletion on cognitive flexibility in BDNF heterozygous mice. Psychopharmacology. 2016;233(8):1361–1375. doi:10.1007/s00213-016-4229-6
  85. Gerecke KM, Jiao Y, Pagala V, Smeyne RJ. Exercise does not protect against MPTP-induced neurotoxicity in BDNF happloinsufficent mice. PLoS One. 2012;7(8):e43250. doi:10.1371/journal.pone.0043250
  86. Ieraci A, Madaio AI, Mallei A, Lee FS, Popoli M. Brain-derived neurotrophic factor Val66Met human polymorphism impairs the beneficial exercise-induced neurobiological changes in mice. Neuropsycho­pharmacology. 2016;41(13):3070–3079. doi:10.1038/npp.2016.120
  87. Tuon T, Valvassori SS, Dal Pont GC, et al. Physical training prevents depressive symptoms and a decrease in brain-derived neurotrophic factor in Parkinson’s disease. Brain Res Bull. 2014;108:106–112. doi:10.1016/j.brainresbull.2014.09.006
  88. Hirsch MA, van Wegen EEH, Newman MA, Heyn PC. Exercise-induced increase in brain-derived neurotrophic factor in human Parkinson’s disease: A systematic review and meta-analysis. Transl Neurodegener. 2018;7(1):7. doi:10.1186/s40035-018-0112-1
  89. Kishi T, Yoshimura R, Ikuta T, Iwata N. Brain-derived neurotrophic factor and major depressive disorder: Evidence from meta-analyses. Front Psychiatry. 2018;8:308. doi:10.3389/fpsyt.2017.00308
  90. Paumier KL, Sortwell CE, Madhavan L, et al. Chronic amitriptyline treatment attenuates nigrostriatal degeneration and significantly alters trophic support in a rat model of Parkinsonism. Neuropsychopharmacology. 2015;40(4):874–883. doi:10.1038/npp.2014.262
  91. Zhao Q, Cai D, Bai Y. Selegiline rescues gait deficits and the loss of dopaminergic neurons in a subacute MPTP mouse model of Parkinson’s disease. Int J Mol Med. 2013;32(4):883–891. doi:10.3892/ijmm.2013.1450
  92. Bustos G, Abarca J, Bustos V, et al. NMDA receptors mediate an early up-regulation of brain-derived neurotrophic factor expression in substantia nigra in a rat model of presymptomatic Parkinson’s disease. J Neurosci Res. 2009;87(10):2308–2318. doi:10.1002/jnr.22063
  93. Patil SP, Jain PD, Ghumatkar PJ, Tambe R, Sathaye S. Neuroprotective effect of metformin in MPTP-induced Parkinson’s disease in mice. Neuroscience. 2014;277:747–754. doi:10.1016/j.neuroscience.2014.07.046
  94. Elgendy MO, Hassan AH, Saeed H, Abdelrahim ME, Eldin RS. Asthmatic children and MDI verbal inhalation technique counseling. Pulm Pharmacol Ther. 2020;61:101900. doi:10.1016/j.pupt.2020.101900
  95. Osama H, Abdullah A, Gamal B, et al. Effect of honey and royal jelly against cisplatin-induced nephrotoxicity in patients with cancer. J Am Coll Nutr. 2017;36(5):342–346. doi:10.1080/07315724.2017.1292157
  96. Sayed AM, Khalaf AM, Abdelrahim MEA, Elgendy MO. Repurposing of some anti‐infective drugs for COVID‐19 treatment: A surveillance study supported by an in silico investigation. Int J Clin Pract. 2021;75(4):e13877. doi:10.1111/ijcp.13877
  97. Saeed H, Elberry AA, Eldin AS, Rabea H, Abdelrahim MEA. Effect of nebulizer designs on aerosol delivery during non-invasive mechanical ventilation: A modeling study of in vitro data. Pulm Ther. 2017;3(1):233–241. doi:10.1007/s41030-017-0033-7
  98. Saeed H, Abdelrahim ME, Rabea H, Salem HF. Impact of advanced patient counseling using a training device and smartphone application on asthma control. Respir Care. 2020;65(3):326–332. doi:10.4187/respcare.06903
  99. Madney YM, Laz NI, Elberry AA, Rabea H, Abdelrahim MEA. The influence of changing interfaces on aerosol delivery within high flow oxygen setting in adults: An in-vitro study. J Drug Deliv Sci Technol. 2020;55:101365. doi:10.1016/j.jddst.2019.101365
  100. Hassan A, Rabea H, Hussein RRS, et al. In-vitro characterization of the aerosolized dose during non-invasive automatic continuous positive airway pressure ventilation. Pulm Ther. 2016;2(1):115–126. doi:10.1007/s41030-015-0010-y
  101. Harb HS, Laz NI, Rabea H, Abdelrahim MEA. First-time handling of different inhalers by chronic obstructive lung disease patients. Exp Lung Res. 2020;46(7):258–269. doi:10.1080/01902148.2020.1789903
  102. Abdelrahim ME, Assi KH, Chrystyn H. Relative bioavailability of terbutaline to the lung following inhalation, using urinary excretion. Br J Clin Pharmacol. 2011;71(4):608–610. doi:10.1111/j.1365-2125.2010.03873.x
  103. Harb HS, Elberry AA, Rabea H, Fathy M, Abdelrahim MEA. Is Combihaler usable for aerosol delivery in single limb non-invasive mechanical ventilation? J Drug Deliv Sci Technol. 2017;40:28–34. doi:10.1016/j.jddst.2017.05.022
  104. Karimi N, Ashourizadeh H, Akbarzadeh Pasha B, et al. Blood levels of brain-derived neurotrophic factor (BDNF) in people with multiple sclerosis (MS): A systematic review and meta-analysis. Multiple Scler Relat Dis. 2022;65:103984. doi:10.1016/j.msard.2022.103984
  105. D’Souza T, Rajkumar AP. Systematic review of genetic variants associated with cognitive impairment and depressive symptoms in Parkinson’s disease. Acta Neuropsychiatr. 2020;32(1):10–22. doi:10.1017/neu.2019.28
  106. Wang Q, Liu J, Guo Y, Dong G, Zou W, Chen Z. Association between BDNF G196A (Val66Met) polymorphism and cognitive impairment in patients with Parkinson’s disease: A meta-analysis. Braz J Med Biol Res. 2019;52(8):e8443. doi:10.1590/1414-431x20198443
  107. Jiang L, Zhang H, Wang C, Ming F, Shi X, Yang M. Serum level of brain-derived neurotrophic factor in Parkinson’s disease: A meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2019;88:168–174. doi:10.1016/j.pnpbp.2018.07.010
  108. You T, Ogawa EF. Effects of meditation and mind-body exercise on brain-derived neurotrophic factor: A literature review of human experimental studies. Sports Med Health Sci. 2020;2(1):7–9. doi:10.1016/j.smhs.2020.03.001
  109. Mojtabavi H, Shaka Z, Momtazmanesh S, Ajdari A, Rezaei N. Circulating brain-derived neurotrophic factor as a potential biomarker in stroke: A systematic review and meta-analysis. J Transl Med. 2022;20(1):126. doi:10.1186/s12967-022-03312-y
  110. Rahmani F, Saghazadeh A, Rahmani M, et al. Plasma levels of brain-derived neurotrophic factor in patients with Parkinson disease: A systematic review and meta-analysis. Brain Res. 2019;1704:127–136. doi:10.1016/j.brainres.2018.10.006