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Cited by 750Nerve injury and regenerationNeuroinflammation and Neurodegeneration MechanismsTryptophan and brain disorders

Brain-Derived Neurotrophic Factor in Brain Disorders: Focus on Neuroinflammation

Open access
Lima Giacobbo, Bruno, Doorduin, Janine, Klein, Hans C., Dierckx, Rudi A. J. O., Bromberg, Elke, de Vries, Erik F. J.·2019·Molecular Neurobiology
DOI 10.1007/s12035-018-1283-6PMC PMC6476855
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Abstract

Brain-derived neurotrophic factor (BDNF) is one of the most studied neurotrophins in the healthy and diseased brain. As a result, there is a large body of evidence that associates BDNF with neuronal maintenance, neuronal survival, plasticity, and neurotransmitter regulation. Patients with psychiatric and neurodegenerative disorders often have reduced BDNF concentrations in their blood and brain. A current hypothesis suggests that these abnormal BDNF levels might be due to the chronic inflammatory state of the brain in certain disorders, as neuroinflammation is known to affect several BDNF-related signaling pathways. Activation of glia cells can induce an increase in the levels of pro- and antiinflammatory cytokines and reactive oxygen species, which can lead to the modulation of neuronal function and neurotoxicity observed in several brain pathologies. Understanding how neuroinflammation is involved in disorders of the brain, especially in the disease onset and progression, can be crucial for the development of new strategies of treatment. Despite the increasing evidence for the involvement of BDNF and neuroinflammation in brain disorders, there is scarce evidence that addresses the interaction between the neurotrophin and neuroinflammation in psychiatric and neurodegenerative diseases. This review focuses on the effect of acute and chronic inflammation on BDNF levels in the most common psychiatric and neurodegenerative disorders and aims to shed some light on the possible biological mechanisms that may influence this effect. In addition, this review will address the effect of behavior and pharmacological interventions on BDNF levels in these disorders.

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review summarizes evidence linking brain-derived neurotrophic factor (BDNF) to psychiatric and neurodegenerative disorders, with a focus on how neuroinflammation may alter BDNF signaling. It concludes that BDNF is commonly reduced in many brain pathologies, but whether these changes are causal or consequential remains unresolved.

Key findings

  • BDNF is involved in neuronal maintenance, survival, plasticity, and neurotransmitter regulation; many psychiatric and neurodegenerative disorders show reduced BDNF in blood and brain, though epilepsy is an exception with increased BDNF expression in hippocampus and cortex.
  • Neuroinflammation may modulate BDNF through pro-inflammatory cytokines and NF-κB signaling; chronic stress and inflammatory challenges can reduce Bdnf mRNA in plasticity-related brain regions, and some studies report that cytokines such as IL-1β downregulate BDNF expression.
  • Around 90% of blood BDNF is stored in platelets, and in animal models mature BDNF concentration can be ten times higher than pro-BDNF; however, it remains unclear whether serum BDNF reflects brain BDNF levels.
  • Clinical examples include: about one-third of MDD patients show no symptom change with common antidepressants; more than 50% of substantia nigra neurons are estimated lost before PD clinical symptoms appear; and 30% of epilepsy patients show little to no response to common antiepileptic drugs.

Methods

  • Narrative review of preclinical and clinical literature on BDNF in brain disorders, including major depressive disorder, bipolar disorder, schizophrenia, Alzheimer’s disease, Parkinson’s disease, epilepsy, aging, and therapeutic/lifestyle interventions.
  • Synthesizes findings from animal models, postmortem human studies, serum/plasma measurements, PET imaging, and pharmacological or behavioral intervention studies.
  • No primary data collection, systematic search strategy, or meta-analysis is described in the paper.

Limitations

  • The paper states that there is scarce evidence directly addressing the interaction between BDNF and neuroinflammation in psychiatric and neurodegenerative diseases, and that the exact regulatory mechanisms are not yet clear.
  • The paper states that there is no conclusive evidence distinguishing whether changes in BDNF levels are causative or a consequence of disease onset, and that discrepancies between brain and plasma BDNF alterations need further elucidation.
  • The paper notes that animal models cannot properly reproduce complex human disorders and usually mimic only part of the symptoms, with low predictive validity; evident from the text, this is a narrative review without a described systematic search or quality appraisal.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1007/s12035-018-1283-6

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 179 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    In humans, BDNF is known to be a useful biomarker for several psychiatric disorders.

    “In humans, BDNF is known to be a useful biomarker for several psychiatric disorders [54].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54] Chen S, Jiang H, Liu Y et al (2017) Combined serum levels of multiple proteins in tPA-BDNF pathway may aid the diagnosis of five mental disorders. Sci Rep 7:6871. https://doi.org/10.1038/s41598-017-06832-6 source

      Not checked in the free run.

  • Premisecitation

    BDNF single nucleotide polymorphism (val66met) is associated with the severity of depression in patients.

    “BDNF single nucleotide polymorphism (val66met), however, is associated with the severity of depression in patients [64].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [64] Hosang GM, Shiles C, Tansey KE et al (2014) Interaction between stress and the BDNFVal66Met polymorphism in depression: a systematic review and meta-analysis. BMC Med 12:7. https://doi.org/10.1186/1741-7015-12-7 source

      Not checked in the free run.

  • Premisecitation

    Patients with psychiatric and neurodegenerative disorders often have reduced BDNF concentrations in their blood and brain.

    “Patients with psychiatric and neurodegenerative disorders often have reduced BDNF concentrations in their blood and brain.”
    • Also stated in: § BDNF Expression and Function · plain
      “Many brain pathologies cause reduction of BDNF protein levels both in the brain and serum of patients [19–22].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [19] Jiang H, Chen S, Li C et al (2017) The serum protein levels of the tPA-BDNF pathway are implicated in depression and antidepressant treatment. Transl Psychiatry 7:e1079. https://doi.org/10.1038/tp.2017.43 source

      Not checked in the free run.

    • cites [20] Borba EM, Duarte JA, Bristot G et al (2016) Brain-derived neurotrophic factor serum levels and hippocampal volume in mild cognitive impairment and dementia due to Alzheimer disease. Dement Geriatr Cogn Dis Extra 91:559–567. https://doi.org/10.1159/000450601 source

      Not checked in the free run.

    • cites [21] Galvez-Contreras AY, Campos-Ordonez T, Lopez-Virgen V et al (2016) Growth factors as clinical biomarkers of prognosis and diagnosis in psychiatric disorders. Cytokine Growth Factor Rev. https://doi.org/10.1016/j.cytogfr.2016.08.004 source

      Not checked in the free run.

    • cites [22] Autry AE, Monteggia LM (2012) Brain-derived neurotrophic factor and neuropsychiatric disorders. Pharmacol Rev 64:238–258. https://doi.org/10.1124/pr.111.005108 source

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  • Premisecitation

    NF-κB is closely involved in the innate and adaptive immune response in several psychiatric and neurodegenerative diseases.

    “NF-κB is closely involved in the innate and adaptive immune response in several psychiatric and neurodegenerative diseases [27].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Tilstra JS, Clauson CL, Niedernhofer LJ, Robbins PD (2011) NF-κB in aging and disease. Aging Dis 2:449–465

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  • Interpretationreasoning

    The role of BDNF in neuroinflammation is strongly related to its ability to induce-and being induced by-NF-κB.

    “Thus, the role of BDNF in neuroinflammation is strongly related to its ability to induce—and being induced by—NF-κB.”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 14
  • May combine two claims. 44

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    There is scarce evidence that addresses the interaction between BDNF and neuroinflammation in psychiatric and neurodegenerative diseases.

    “Despite the increasing evidence for the involvement of BDNF and neuroinflammation in brain disorders, there is scarce evidence that addresses the interaction between the neurotrophin and neuroinflammation in psychiatric and neurodegenerative diseases.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    Activation of glia cells can induce an increase in the levels of pro- and antiinflammatory cytokines and reactive oxygen species, which can lead to the modulation of neuronal function and neurotoxicity observed in several brain pathologies.

    “Activation of glia cells can induce an increase in the levels of pro- and antiinflammatory cytokines and reactive oxygen species, which can lead to the modulation of neuronal function and neurotoxicity observed in several brain pathologies.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    External stimuli (e.g., stress, trauma, infection) can submit the aged brain more easily into a state of mild chronic neuroinflammation, making the brain more prone to apoptotic signaling.

    “As a result, external stimuli (e.g., stress, trauma, infection) can submit the aged brain more easily into a state of mild chronic neuroinflammation, making the brain more prone to apoptotic signaling [40].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Niraula A, Sheridan JF, Godbout JP (2017) Microglia priming with aging and stress. Neuropsychopharmacology 42:318–333. https://doi.org/10.1038/npp.2016.185 source

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  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Neuroinflammation is known to affect several BDNF-related signaling pathways.

    “as neuroinflammation is known to affect several BDNF-related signaling pathways.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Chronic stress can lead to the activation of pro-inflammatory microglia, releasing cytokines and pro-inflammatory substances, and recruitment of peripheral immune cells to the brain, thus creating the inflammatory environment that is characteristic for many brain pathologies.

    “Chronic stress can lead to the activation of pro-inflammatory microglia, releasing cytokines and pro-inflammatory substances, and recruitment of peripheral immune cells to the brain, thus creating the inflammatory environment that is characteristic for many brain pathologies.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Both mature BDNF and pro-BDNF can be secreted and bind to the low affinity p75 neurotrophin receptor (p75NTR), which causes activation of the apoptosis cascade.

    “Both mature BDNF and pro-BDNF can be secreted and bind to the low affinity p75 neurotrophin receptor (p75NTR), which causes activation of the apoptosis cascade [6, 7].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [6] Barker PA (2009) Whither proBDNF? Nat Neurosci 12:105–106. https://doi.org/10.1038/nn0209-105 source

      Not checked in the free run.

    • cites [7] Lu B, Pang PT, Woo NH (2005) The yin and yang of neurotrophin action. Nat Rev Neurosci 6:603–614. https://doi.org/10.1038/nrn1726 source

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    Premisecitation

    One of the main factors of inflammatory activation is the nuclear factor-kappa B (NF-κB), a transcription factor that induces the expression of several pro- and antiapoptotic genes, including Bdnf.

    “One of the main factors of inflammatory activation is the nuclear factor-kappa B (NF-κB), a transcription factor that induces the expression of several pro- and antiapoptotic genes, including Bdnf [26].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Marini AM, Jiang X, Wu X et al (2004) Role of brain-derived neurotrophic factor and NF-kappaB in neuronal plasticity and survival: from genes to phenotype. Restor Neurol Neurosci 22:121–130

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both MDD patients and animal models of depression show a remarkable reduction in serum BDNF levels.

    “Both MDD patients [57–59] and animal models of depression [60, 61] show a remarkable reduction in serum BDNF levels.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [57] Gonul AS, Akdeniz F, Taneli F et al (2005) Effect of treatment on serum brain-derived neurotrophic factor levels in depressed patients. Eur Arch Psychiatry Clin Neurosci 255:381–386. https://doi.org/10.1007/s00406-005-0578-6 source

      Not checked in the free run.

    • cites [58] Karege F, Perret G, Bondolfi G et al (2002) Decreased serum brain-derived neurotrophic factor levels in major depressed patients. Psychiatry Res 109:143–148. https://doi.org/10.1016/S0165-1781(02)00005-7 source

      Not checked in the free run.

    • cites [59] Shimizu E, Hashimoto K, Okamura N et al (2003) Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants. Biol Psychiatry 54:70–75. https://doi.org/10.1016/S0006-3223(03)00181-1 source

      Not checked in the free run.

    • cites [60] Chen Q, Luo Y, Kuang S et al (2017) Cyclooxygenase-2 signalling pathway in the cortex is involved in the pathophysiological mechanisms in the rat model of depression. Sci Rep 7:488. https://doi.org/10.1038/s41598-017-00609-7 source

      Not checked in the free run.

    • cites [61] Larsen MH, Mikkelsen JD, Hay-Schmidt A, Sandi C (2010) Regulation of brain-derived neurotrophic factor (BDNF) in the chronic unpredictable stress rat model and the effects of chronic antidepressant treatment. J Psychiatr Res 44:808–816. https://doi.org/10.1016/j.jpsychires.2010.01.005 source

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    Premisecitation

    Heterozygous BDNF mice show increased weight gain, aggressiveness, anxiety, and contextual memory impairment and therefore have been suggested as an animal model for mood disorders.

    “Heterozygous BDNF mice show increased weight gain, aggressiveness, anxiety, and contextual memory impairment and therefore have been suggested as an animal model for mood disorders [55].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] Lindholm JSO, Castrén E (2014) Mice with altered BDNF signaling as models for mood disorders and antidepressant effects. Front Behav Neurosci 8:143. https://doi.org/10.3389/fnbeh.2014.00143 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Bdnf gene expression is strongly regulated by a wide array of endogenous and exogenous stimuli (e.g., stress, physical activity, brain injury, diet).

    “Bdnf gene expression is strongly regulated by a wide array of endogenous and exogenous stimuli (e.g., stress, physical activity, brain injury, diet).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Cleaved, mature BDNF binds to its high-affinity receptor tyrosine kinase B (TrkB), activating several signaling cascades, including the Ras-mitogen-activated protein kinase (MAPK), the phosphatidylinositol-3-kinase (PI3K), and the phospholipase Cγ (PLC-γ) pathway.

    “On the other hand, cleaved, mature BDNF binds to its high-affinity receptor tyrosine kinase B (TrkB), activating several signaling cascades, including the Ras-mitogen-activated protein kinase (MAPK), the phosphatidylinositol-3-kinase (PI3K), and the phospholipase Cγ (PLC-γ) pathway.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    Brain pathologies are usually associated with a downregulation of BDNF release, resulting in reduced BDNF levels in the brain and in blood.

    “Brain pathologies are usually associated with a downregulation of BDNF release, resulting in reduced BDNF levels in the brain and in blood.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationnone given

    There is still a gap in our understanding of the physiological mechanisms that lead to changes in BDNF levels under pathological conditions.

    “However, there is still a gap in our understanding of the physiological mechanisms that lead to changes in BDNF levels under pathological conditions.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    BDNF plays a role in maintaining brain function by inducing survival signaling and neuroplasticity.

    “It is known that BDNF plays a role in maintaining brain function by inducing survival signaling and neuroplasticity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In the brain, BDNF is involved in plasticity, neuronal survival, formation of new synapses, dendritic branching, and modulation of excitatory and inhibitory neurotransmitter profiles.

    “In the brain, BDNF is involved in plasticity, neuronal survival, formation of new synapses, dendritic branching, and modulation of excitatory and inhibitory neurotransmitter profiles [11, 12].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [11] Edelmann E, Lessmann V, Brigadski T (2014) Pre- and postsynaptic twists in BDNF secretion and action in synaptic plasticity. Neuropharmacology 76(Pt C):610–627. https://doi.org/10.1016/j.neuropharm.2013.05.043 source

      Not checked in the free run.

    • cites [12] Panja D, Bramham CR (2014) BDNF mechanisms in late LTP formation: a synthesis and breakdown. Neuropharmacology 76(Pt C):664–676. https://doi.org/10.1016/j.neuropharm.2013.06.024 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Around 90% of the BDNF in blood is stored within platelets.

    “Around 90% of the BDNF in blood is stored within platelets [18].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Fujimura H, Altar CA, Chen R et al (2002) Brain-derived neurotrophic factor is stored in human platelets and released by agonist stimulation. Thromb Haemost 87:728–734. https://doi.org/10.1016/j.bbi.2008.05.010 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Studies have shown that activation of p75NTR increases apoptotic and inflammatory signaling in neurons and glial cells by activation of c-Jun N-terminal kinases (JNK) and NF-κB expression, respectively.

    “Studies have shown that activation of p75NTR increases apoptotic and inflammatory signaling in neurons and glial cells by activation of c-Jun N-terminal kinases (JNK) and NF-κB expression, respectively [32, 33].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [32] Hempstead BL (2002) The many faces of p75NTR. Curr Opin Neurobiol 12:260–267. https://doi.org/10.1016/S0959-4388(02)00321-5 source

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    • cites [33] Chao MV (2003) Neurotrophins and their receptors: a convergence point for many signalling pathways. Nat Rev Neurosci 4:299–309. https://doi.org/10.1038/nrn1078 source

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    Premisecitation

    Successful antidepressant treatment is usually associated with an increase in BDNF levels in serum and plasma, whereas treatment failure is associated with a lack of response of plasma BDNF levels.

    “Successful antidepressant treatment is usually associated with an increase in BDNF levels in serum and plasma [65, 66], whereas treatment failure is associated with a lack of response of plasma BDNF levels.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [65] Björkholm C, Monteggia LM (2016) BDNF—a key transducer of antidepressant effects. Neuropharmacology 102:72–79. https://doi.org/10.1016/j.neuropharm.2015.10.034 source

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    • cites [66] Molendijk ML, Bus BAA, Spinhoven P et al (2011) Serum levels of brain-derived neurotrophic factor in major depressive disorder: state–trait issues, clinical features and pharmacological treatment. Mol Psychiatry 16:1088–1095. https://doi.org/10.1038/mp.2010.98 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisereasoning

    BDNF has been suggested as a candidate biomarker of pathological conditions, and therapy efficacy, as most of current treatments are accompanied by a significant change in blood BDNF levels.

    “BDNF has been suggested as a candidate biomarker of pathological conditions, and therapy efficacy, as most of current treatments are accompanied by a significant change in blood BDNF levels.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Neuroinflammation could be the key factor for the decrease of Bdnf gene expression in schizophrenic patients, as pro-inflammatory cytokines increase methylation of Bdnf gene, leading to a decrease of CREB binding to the specific Bdnf site.

    “Neuroinflammation could be the key factor for the decrease of Bdnf gene expression in schizophrenic patients, as pro-inflammatory cytokines increase methylation of Bdnf gene, leading to a decrease of CREB binding to the specific Bdnf site.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    BDNF seems an important player in the pathophysiology and might be a biomarker for monitoring treatment response in depression.

    “Thus, BDNF seems an important player in the pathophysiology and might be a biomarker for monitoring treatment response in depression [65, 67].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [65] Björkholm C, Monteggia LM (2016) BDNF—a key transducer of antidepressant effects. Neuropharmacology 102:72–79. https://doi.org/10.1016/j.neuropharm.2015.10.034 source

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    • cites [67] Castrén E, Rantamäki T (2010) The role of BDNF and its receptors in depression and antidepressant drug action: reactivation of developmental plasticity. Dev. Neurobiol. 70:289–297 source

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  • May combine two claims.

    Premisecitation

    Treatment with antidepressants can result in an antiinflammatory response throughout the brain, mitigating the inflammatory unbalance to homeostatic levels and normalizing BDNF concentrations.

    “Interestingly, treatment with antidepressants can result in an antiinflammatory response throughout the brain, mitigating the inflammatory unbalance to homeostatic levels and normalizing BDNF concentrations [83, 84].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [83] Dahl J, Ormstad H, Aass HCD et al (2014) The plasma levels of various cytokines are increased during ongoing depression and are reduced to normal levels after recovery. Psychoneuroendocrinology 45:77–86. https://doi.org/10.1016/j.psyneuen.2014.03.019 source

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    • cites [84] Hannestad J, DellaGioia N, Bloch M (2011) The effect of antidepressant medication treatment on serum levels of inflammatory cytokines: a meta-analysis. Neuropsychopharmacology 36:2452–2459. https://doi.org/10.1038/npp.2011.132 source

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    Premisecitation

    Patients treated with IFN-α were shown to have decreased serum BDNF levels in combination with increased protein levels of the cytokines IL-1 and IL-2.

    “Patients treated with IFN-α were shown to have decreased serum BDNF levels in combination with increased protein levels of the cytokines IL-1 and IL-2 [81, 82].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [81] Lotrich FE, Albusaysi S, Ferrell RE (2013) Brain-derived Neurotrophic factor serum levels and genotype: association with depression during interferon-alpha treatment. Neuropsychopharmacology 38:985–995. https://doi.org/10.1038/npp.2012.263 source

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    • cites [82] Kenis G, Prickaerts J, van Os J et al (2011) Depressive symptoms following interferon-α therapy: mediated by immune-induced reductions in brain-derived neurotrophic factor? Int J Neuropsychopharmacol 14:247–253. https://doi.org/10.1017/S1461145710000830 source

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  • May combine two claims.

    Premisecitation

    Serum BDNF levels in schizophrenic patients decrease with age but were independent of the dosage of medication.

    “Serum BDNF levels in schizophrenic patients decrease with age but were independent of the dosage of medication [110].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [110] Green MJ, Matheson SL, Shepherd A et al (2011) Brain-derived neurotrophic factor levels in schizophrenia: a systematic review with meta-analysis. Mol Psychiatry 16:960–972. https://doi.org/10.1038/mp.2010.88 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    It is known that schizophrenia patients have upregulated genes for inflammatory cytokines, and downregulated Bdnf gene transcription.

    “It is known that schizophrenia patients have upregulated genes for inflammatory cytokines [122, 123], and downregulated Bdnf gene transcription [124, 125].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [122] Sabunciyan S, Maher B, Bahn S et al (2015) Association of DNA methylation with acute mania and inflammatory markers. PLoS One 10:e0132001. https://doi.org/10.1371/journal.pone.0132001 source

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    • cites [123] Van Den Oord EJCG, Clark SL, Xie LY et al (2016) A whole methylome CpG-SNP association study of psychosis in blood and brain tissue. Schizophr Bull 42:1018–1026. https://doi.org/10.1093/schbul/sbv182 source

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    • cites [124] Mill J, Tang T, Kaminsky Z et al (2008) Epigenomic profiling reveals DNA-methylation changes associated with major psychosis. Am J Hum Genet 82:696–711. https://doi.org/10.1016/j.ajhg.2008.01.008 source

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    • cites [125] Kordi-Tamandani DM, Sahranavard R, Torkamanzehi A (2012) DNA methylation and expression profiles of the brain-derived neurotrophic factor (BDNF) and dopamine transporter (DAT1) genes in patients with schizophrenia. Mol Biol Rep 39:1–5 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Treatment of BD patients with lithium or valproate inhibits PKC upregulation, normalizing its level to that of euthymic subjects, and increases BDNF levels.

    “Treatment of BD patients with lithium or valproate inhibits PKC upregulation, normalizing its level to that of euthymic subjects, and increases BDNF levels [105].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [105] Zarate CA, Manji HK (2009) Protein kinase C inhibitors: rationale for use and potential in the treatment of bipolar disorder. CNS Drugs 23:569–582 source

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  • May combine two claims.

    Interpretationreasoning

    These preclinical and clinical findings show that long-term exposure to stress or inflammation leads to a decrease in BDNF levels, reducing the capacity of the neurons to cope with further challenges (i.e., neuronal plasticity), and ultimately leading to a decreased function and neuronal death.

    “These preclinical and clinical findings show that long-term exposure to stress or inflammation leads to a decrease in BDNF levels, reducing the capacity of the neurons to cope with further challenges (i.e., neuronal plasticity), and ultimately leading to a decreased function and neuronal death.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Two recent meta-analyses have shown that serum and plasma levels of BDNF in BD patients during depressive and manic episodes are decreased, but no difference in BDNF levels between BD patients in an euthymic episode and healthy controls was found.

    “Two recent meta-analyses have shown that serum and plasma levels of BDNF in BD patients during depressive and manic episodes are decreased, but no difference in BDNF levels between BD patients in an euthymic episode and healthy controls was found [88, 89].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [88] Fernandes BS, Molendijk ML, Köhler CA et al (2015) Peripheral brain-derived neurotrophic factor (BDNF) as a biomarker in bipolar disorder: a meta-analysis of 52 studies. BMC Med 13:289. https://doi.org/10.1186/s12916-015-0529-7 source

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    • cites [89] Munkholm K, Vinberg M, Kessing LV (2016) Peripheral blood brain-derived neurotrophic factor in bipolar disorder: a comprehensive systematic review and meta-analysis. Mol Psychiatry 21:216–228. https://doi.org/10.1038/mp.2015.54 source

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    Premisecitation

    Wang and colleagues have found an association for serum BDNF levels, but not for IL-1β or IL-6.

    “while Wang and colleagues have found an association for serum BDNF levels, but not for IL-1β or IL-6 [98].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [98] Wang T-Y, Lee S-Y, Chen S-L et al (2016) Comparing clinical responses and the biomarkers of BDNF and cytokines between subthreshold bipolar disorder and bipolar II disorder. Sci Rep 6:27431. https://doi.org/10.1038/srep27431 source

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    Premisecitation

    These triggers can induce inflammatory changes that are associated with reduced neurotransmitter signaling, increased oxidative stress, and reduced synaptic branching.

    “These triggers can induce inflammatory changes that are associated with reduced neurotransmitter signaling, increased oxidative stress, and reduced synaptic branching [118].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [118] Khandaker GM, Cousins L, Deakin J et al (2015) Inflammation and immunity in schizophrenia: implications for pathophysiology and treatment. Lancet Psychiatry 2:258–270. https://doi.org/10.1016/S2215-0366(14)00122-9 source

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    Premisecitation

    Diagnosis of neurodegenerative diseases is usually based on subjective cognitive tests in combination with neuroimaging, but the current techniques are not able to successfully diagnose these diseases in their earlier stages, when the pathology is already present but does not cause symptoms yet.

    “Diagnosis of neurodegenerative diseases is usually based on subjective cognitive tests in combination with neuroimaging [131–133], but the current techniques are not able to successfully diagnose these diseases in their earlier stages, when the pathology is already present but does not cause symptoms yet.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [131] Barthel H, Schroeter ML, Hoffmann KT, Sabri O (2015) PET/MR in dementia and other neurodegenerative diseases. Semin Nucl Med 45:224–233 source

      Not checked in the free run.

    • cites [132] Agrawal M, Biswas A (2015) Molecular diagnostics of neurodegenerative disorders. Front Mol Biosci 2. https://doi.org/10.3389/fmolb.2015.00054 source

      Not checked in the free run.

    • cites [133] Zhu L, Ploessl K, Kung HF (2014) PET/SPECT imaging agents for neurodegenerative diseases. Chem Soc Rev 43:6683–6691. https://doi.org/10.1039/C3CS60430F source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In humans, early- and late-onset Alzheimer's disease show increased pro-inflammatory cytokines and decreased serum BDNF, with no correlation between pro-inflammatory and neurotrophin results in both studies.

    “In humans, two studies have shown an increase in pro-inflammatory cytokines and a decrease in BDNF levels in the serum of early- and late-onset AD, although there was no correlation with pro-inflammatory and neurotrophin results in both studies [141, 156].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [141] Gezen-Ak D, Dursun E, Hanağası H et al (2013) BDNF, TNFα, HSP90, CFH, and IL-10 serum levels in patients with early or late onset Alzheimer’s disease or mild cognitive impairment. J Alzheimer’s Dis 37:185–195. https://doi.org/10.3233/JAD-130497 source

      Not checked in the free run.

    • cites [156] Dursun E, Gezen-Ak D, Hanağası H et al (2015) The interleukin 1 alpha, interleukin 1 beta, interleukin 6 and alpha-2-macroglobulin serum levels in patients with early or late onset Alzheimer’s disease, mild cognitive impairment or Parkinson’s disease. J Neuroimmunol 283:50–57. https://doi.org/10.1016/j.jneuroim.2015.04.014 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Attempts to discover new biomarkers for the diagnosis of early stages of the disease are ongoing.

    “Attempts to discover new biomarkers for the diagnosis of early stages of the disease are ongoing [134–136].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [134] Jové M, Portero-Otín M, Naudí A et al (2014) Metabolomics of human brain aging and age-related neurodegenerative diseases. J Neuropathol Exp Neurol 73:640–657. https://doi.org/10.1097/NEN.0000000000000091 source

      Not checked in the free run.

    • cites [135] Olsson B, Lautner R, Andreasson U et al (2016) CSF and blood biomarkers for the diagnosis of Alzheimer’s disease: a systematic review and meta-analysis. Lancet Neurol 15:673–684 source

      Not checked in the free run.

    • cites [136] Parnetti L, Castrioto A, Chiasserini D et al (2013) Cerebrospinal fluid biomarkers in Parkinson disease. Nat Rev Neurol 9:131–140. https://doi.org/10.1038/nrneurol.2013.10 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In Alzheimer's disease, disease-related changes decrease BDNF axonal transport, reducing BDNF availability in the synaptic cleft and diminishing signaling through TrkB receptors.

    “These changes decrease BDNF axonal transport, resulting in reduced availability of BDNF within the synaptic cleft and consequently diminished signaling through TrkB receptors [137, 138].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [137] Gan KJ, Silverman MA (2015) Dendritic and axonal mechanisms of Ca2+ elevation impair BDNF transport in a oligomer-treated hippocampal neurons. Mol Biol Cell 26:1058–1071. https://doi.org/10.1091/mbc.E14-12-1612 source

      Not checked in the free run.

    • cites [138] Tejeda GS, Díaz-Guerra M (2017) Integral characterization of defective BDNF/TrkB Signalling in neurological and psychiatric disorders leads the way to new therapies. Int J Mol Sci 18:268. https://doi.org/10.3390/ijms18020268 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Aggregated α-synuclein can induce an acute, local neuroinflammatory process in Parkinson's disease-associated brain structures, which suppresses BDNF expression and reduces BDNF protein levels.

    “Aggregated α-synuclein can induce an acute, local neuroinflammatory process in PD-associated brain structures, which suppresses BDNF expression and reduces BDNF protein levels.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    BDNF levels are reduced in plasma of patients with mild cognitive impairment and Alzheimer's disease.

    “BDNF levels are also reduced in plasma of patients with mild cognitive impairment (MCI) [140] and AD [141].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [140] Levada OA, Cherednichenko NV, Trailin AV, Troyan AS (2016) Plasma brain-derived neurotrophic factor as a biomarker for the main types of mild neurocognitive disorders and treatment efficacy: a preliminary study. Dis Markers 2016:4095723. https://doi.org/10.1155/2016/4095723 source

      Not checked in the free run.

    • cites [141] Gezen-Ak D, Dursun E, Hanağası H et al (2013) BDNF, TNFα, HSP90, CFH, and IL-10 serum levels in patients with early or late onset Alzheimer’s disease or mild cognitive impairment. J Alzheimer’s Dis 37:185–195. https://doi.org/10.3233/JAD-130497 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    In Alzheimer's disease, upregulated pro-inflammatory cytokines are expected to decrease BDNF levels in cognition-related brain structures, leading to decreased survival signaling and neuronal death.

    “As these cytokines are upregulated in AD, a decrease of BDNF levels is expected to occur in such brain structures, leading to a decrease in survival signaling and, consequently, neuronal death.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Serum BDNF levels are increased in Parkinson's disease patients, especially in moderate to severe stages of the disease.

    “some reports describe that the BDNF levels in serum are increased in PD patients, especially in moderate to severe stages of the disease [167, 168].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [167] Ventriglia M, Zanardini R, Bonomini C et al (2013) Serum brain-derived neurotrophic factor levels in different neurological diseases. Biomed Res Int 2013:901082. https://doi.org/10.1155/2013/901082 source

      Not checked in the free run.

    • cites [168] Scalzo P, Kümmer A, Bretas TL et al (2010) Serum levels of brain-derived neurotrophic factor correlate with motor impairment in Parkinson’s disease. J Neurol 257:540–545. https://doi.org/10.1007/s00415-009-5357-2 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In rats injected with Aβ in the hippocampus, BDNF decreases and TNF-α, IL-6, and caspase-3 protein levels increase 3 weeks after intracerebroventricular injection.

    “Prakash shows that rats injected with Aβ in the hippocampus have a remarkable decrease in BDNF and increased TNF-α, IL-6, and caspase-3 protein levels 3 weeks after intracerebroventricular injection.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [154] Prakash A, Kumar A (2014) Role of nuclear receptor on regulation of BDNF and neuroinflammation in hippocampus of β-amyloid animal model of Alzheimer’s disease. Neurotox Res 25:335–347. https://doi.org/10.1007/s12640-013-9437-9 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inflammatory challenges are associated with risk for development of dementia-related symptoms, with increased pro-inflammatory cytokine levels.

    “Some studies have reported inflammatory challenges as an associated risk factor for the development of dementia-related symptoms, as they show increased pro-inflammatory cytokines levels [147, 148].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [147] Iwashyna TJ, Ely EW, Smith DM, Langa KM (2010) Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA 304:1787. https://doi.org/10.1001/jama.2010.1553 source

      Not checked in the free run.

    • cites [148] Holmes C, Cunningham C, Zotova E et al (2009) Systemic inflammation and disease progression in Alzheimer disease. Neurology 73:768–774. https://doi.org/10.1212/WNL.0b013e3181b6bb95 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    After Aβ1-42 injection, pro-inflammatory cytokines increase and anti-inflammatory cytokines and BDNF protein levels and gene expression decrease.

    “Another study confirmed the increase in pro-inflammatory cytokines and reduced antiinflammatory cytokines and BDNF protein levels and gene expression after Aβ1–42 injection [155].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [155] Chen J-H, Ke K-F, Lu J-H et al (2015) Protection of TGF-β1 against neuroinflammation and neurodegeneration in Aβ1-42-induced Alzheimer’s disease model rats. PLoS One 10:e0116549. https://doi.org/10.1371/journal.pone.0116549 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In Alzheimer's disease patients, higher serum BDNF concentrations are associated with less cognitive decline after 1 year, and this effect is more pronounced in more severe disease stages.

    “AD patients with higher serum concentrations of BDNF showed less cognitive decline after 1 year; this effect was more pronounced in the more severe stages of the disease [142, 143].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [142] Laske C, Stellos K, Hoffmann N et al (2011) Higher BDNF serum levels predict slower cognitive decline in Alzheimer’s disease patients. Int J Neuropsychopharmacol 14:399–404. https://doi.org/10.1017/S1461145710001008 source

      Not checked in the free run.

    • cites [143] Buchman AS, Yu L, Boyle PA et al (2016) Higher brain BDNF gene expression is associated with slower cognitive decline in older adults. Neurology 86:735–741. https://doi.org/10.1212/WNL.0000000000002387 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation

    Overexpression of BDNF may lead to an inflammatory response mediated by NF-κB, leading to astrocyte activation, increased production of cytokines and neurotoxic reactive oxygen species, and local recruitment of activated microglia.

    “It is possible that overexpression of BDNF leads to an inflammatory response mediated by NF-κB, leading to astrocyte activation, increased production of cytokines and neurotoxic reactive oxygen species, and local recruitment of activated microglia [193].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [193] Mattson MP, Camandola S (2001) NF-κB in neuronal plasticity and neurodegenerative disorders. J Clin Invest 107:247–254 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In healthy conditions, BDNF signaling induces activation of transcription factor NF-κB, which in turn induces de novo expression of the Bdnf gene.

    “In healthy conditions, BDNF signaling induces the activation of transcription factor NF-κB, which in turn induces de novo expression of the Bdnf gene [26, 192].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [26] Marini AM, Jiang X, Wu X et al (2004) Role of brain-derived neurotrophic factor and NF-kappaB in neuronal plasticity and survival: from genes to phenotype. Restor Neurol Neurosci 22:121–130

      Not checked in the free run.

    • cites [192] Kairisalo M, Korhonen L, Sepp M et al (2009) NF-κB-dependent regulation of brain-derived neurotrophic factor in hippocampal neurons by X-linked inhibitor of apoptosis protein. Eur J Neurosci 30:958–966. https://doi.org/10.1111/j.1460-9568.2009.06898.x source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In animal models, seizures are associated with increased activation of microglia, especially the M1 subtype, and increased release of pro-inflammatory mediators.

    “Studies in animal models have reported that seizures are associated with increased activation of microglia, especially of the M1 subtype [189], and an increased release of pro-inflammatory mediators [190, 191].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [189] Benson MJ, Manzanero S, Borges K (2015) Complex alterations in microglial M1/M2 markers during the development of epilepsy in two mouse models. Epilepsia 56:895–905. https://doi.org/10.1111/epi.12960 source

      Not checked in the free run.

    • cites [190] Lehtimäki KA, Peltola J, Koskikallio E et al (2003) Expression of cytokines and cytokine receptors in the rat brain after kainic acid-induced seizures. Brain Res Mol Brain Res 110:253–260 source

      Not checked in the free run.

    • cites [191] Zheng H, Zhu W, Zhao H et al (2009) Kainic acid-activated microglia mediate increased excitability of rat hippocampal neurons in vitro and in vivo: crucial role of interleukin-1beta. Neuroimmunomodulation 17:31–38. https://doi.org/10.1159/000243083 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In epilepsy, chronic seizures lead to excitotoxicity and neuronal apoptosis with associated gliosis.

    “In epilepsy, chronic seizures lead to excitotoxicity and neuronal apoptosis with associated gliosis [188].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [188] Vezzani A, French J, Bartfai T, Baram TZ (2011) The role of inflammation in epilepsy. Nat Rev Neurol 7:31–40. https://doi.org/10.1038/nrneurol.2010.178 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Dietary restriction or addition of supplementary substances such as omega-3 fatty acids or resveratrol can induce an increase in BDNF levels and reduce cognitive impairment in animal models.

    “dietary restriction (i.e., the maintenance of a balanced diet) or addition of supplementary substances (e.g., omega-3 fatty acids; resveratrol) can induce an increase in BDNF levels and reduce cognitive impairment in animal models [224–226].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [224] Duan W, Lee J, Guo Z, Mattson MP (2001) Dietary restriction stimulates BDNF production in the brain and thereby protects neurons against excitotoxic injury. J Mol Neurosci 16:1–12. https://doi.org/10.1385/JMN:16:1:1 source

      Not checked in the free run.

    • cites [225] Duan W, Guo Z, Jiang H et al (2003) Dietary restriction normalizes glucose metabolism and BDNF levels, slows disease progression, and increases survival in huntingtin mutant mice. Proc Natl Acad Sci U S A 100:2911–2916. https://doi.org/10.1073/pnas.0536856100\r0536856100 source

      Not checked in the free run.

    • cites [226] Wu A, Ying Z, Gomez-Pinilla F (2004) Dietary omega-3 fatty acids normalize BDNF levels, reduce oxidative damage, and counteract learning disability after traumatic brain injury in rats. J Neurotrauma 21:1457–1467. https://doi.org/10.1089/neu.2004.21.1457 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Exercise can act as an inductor of neuronal plasticity, neurogenesis, and neuronal survival.

    “Thus, exercise can act as an inductor of neuronal plasticity, neurogenesis and neuronal survival [208, 209].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [208] Huang T, Larsen KT, Ried-Larsen M et al (2014) The effects of physical activity and exercise on brain-derived neurotrophic factor in healthy humans: a review. Scand J Med Sci Sports 24:1–10. https://doi.org/10.1111/sms.12069 source

      Not checked in the free run.

    • cites [209] Zoladz JA, Pilc A (2010) The effect of physical activity on the brain derived neurotrophic factor: from animal to human studies. J Physiol Pharmacol 61:533–541. https://doi.org/10.1523/JNEUROSCI.6251-09.2010 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Physical activity, cognitive stimulation, and a balanced diet can stimulate BDNF expression in humans and animals.

    “Several studies on both humans and animals show that physical activity, cognitive stimulation, and a balanced diet can stimulate BDNF expression [204–207].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [204] Del Arco A, Segovia G, de Blas M et al (2011) Prefrontal cortex, caloric restriction and stress during aging: studies on dopamine and acetylcholine release, BDNF and working memory. Behav Brain Res 216:136–145. https://doi.org/10.1016/j.bbr.2010.07.024 source

      Not checked in the free run.

    • cites [205] Vaynman S, Ying Z, Gomez-Pinilla F (2004) Hippocampal BDNF mediates the efficacy of exercise on synaptic plasticity and cognition. Eur J Neurosci 20:2580–2590. https://doi.org/10.1111/j.1460-9568.2004.03720.x source

      Not checked in the free run.

    • cites [206] Vedovelli K, Silveira E, Velho E et al (2011) Effects of increased opportunity for physical exercise and learning experiences on recognition memory and brain-derived neurotrophic factor levels in brain and serum of rats. Neuroscience 199:284–291. https://doi.org/10.1016/j.neuroscience.2011.08.012 source

      Not checked in the free run.

    • cites [207] Farmer J, Zhao X, van Praag H et al (2004) Effects of voluntary exercise on synaptic plasticity and gene expression in the dentate gyrus of adult male Sprague-Dawley rats in vivo. Neuroscience 124:71–79. https://doi.org/10.1016/j.neuroscience.2003.09.029 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Environmental and physiological stimuli such as physical activity, social interactions, and sensory and cognitive stimuli are powerful modifiers of neurotrophin levels, including BDNF levels, and have been shown to alleviate symptoms of brain pathologies in both humans and animal models.

    “Environmental and physiological stimuli, such as physical activity, social interactions, and sensory and cognitive stimuli, are powerful modifiers of neurotrophin levels, including BDNF levels, and have been shown to alleviate symptoms of brain pathologies in both humans and animal models.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: BDNF levels are activity-dependent and change under positive and negative behavioral and environmental stimuli.

  • May combine two claims.

    Interpretationreasoning

    At seizure onset, there is an increase in BDNF-mediated glutamate signaling, contributing to systemic neuronal imbalance.

    “there is also an increase in BDNF-mediated glutamate signaling, contributing to the systemic neuronal imbalance.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    Both neuroinflammation and altered BDNF expression are common phenomena in many brain disorders.

    “Both neuroinflammation and altered BDNF expression are common phenomena in many brain disorders.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Neuroinflammation is regulated by factors that are also involved in modulation of BDNF expression.
52 of 52

  • The authors state this as an assumption.

    Lithium and valproate inhibit glycogen synthase kinase 3 (GSK-3) and sodium channel function, respectively.

    “The most common assumption is that lithium and valproate can inhibit glycogen synthase kinase 3 (GSK-3) and sodium channel function, respectively [102].”

  • The paper relies on this without support.

    BDNF is involved in several processes that are essential for the optimal functioning of the brain.

    “BDNF is involved in several processes that are essential for the optimal functioning of the brain.”

  • The paper relies on this without support.

    Increased hyper-phosphorylated tau impairs anterograde transport of BDNF to the axon, further decreasing BDNF signaling in the synaptic cleft.

    “Moreover, increase in hyper-phosphorylated tau impairs anterograde transport of BDNF to the axon, further decreasing BDNF signaling in the synaptic cleft.”

  • The paper relies on this without support.

    BDNF levels are activity-dependent and change under positive and negative behavioral and environmental stimuli.

    “BDNF levels are activity-dependent, which means that the expression of BDNF changes under positive (e.g., physical activity, cognitive enhancement) and negative (e.g., obesity, sedentarism) behavioral and environmental stimuli.”

  • The paper relies on this without support.

    Neuroinflammation is regulated by factors that are also involved in modulation of BDNF expression.

    “Neuroinflammation is regulated by factors that are also involved in modulation of BDNF expression.”

  • The paper relies on this without support.

    Discrepancies between brain and plasma BDNF alterations have been observed.

    “discrepancies between brain and plasma BDNF alterations have been observed”

  • The paper relies on this without support.

    Plasma BDNF can be reliably assayed, and samples are easily collected.

    “Plasma BDNF can be reliably assayed, and samples are easily collected”
7 of 7

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • A cited bipolar-disorder study is identified as an MDD study

    Minor

    The text presents Patas and colleagues' study as an analysis of BD patients, but its cited title identifies the studied condition as major depressive disorder.

  • Mouse study cited as human postmortem evidence

    Minor

    The statement cites reference 171 for postmortem evidence in humans, but that reference is explicitly a study of a mouse model.

  • Platelet explanation reverses the cited study's finding

    Minor

    The text says Karege and colleagues found that the reduced serum BDNF was not related to platelet release. The cited study's title instead says it probably resulted from lowered platelet BDNF release.

3 of 3

The citation lists haven’t been fetched yet

References 231 · Cited by 750

Authors
Lima Giacobbo, B., Doorduin, J., Klein, H. C., Dierckx, R. A. J. O., Bromberg, E., & de Vries, E. F. J.
Affiliations
  • University Medical Center Groningen (NL)
  • Pontifícia Universidade Católica do Rio Grande do Sul (BR)
ORCID
Venue
Molecular Neurobiology
Publisher
Springer Science and Business Media LLC
Published
2018-08-17
Volume
56
Issue
5
Pages
3295-3312
ISSN
  • 0893-7648 (ISSN-L)
  • 1559-1182
DOI
10.1007/s12035-018-1283-6
PMC
PMC6476855
OpenAlex
W2886207958
Cited by
750
References
231
Citations by year
2026: 64 · 2025: 106 · 2024: 126 · 2023: 122 · 2022: 132 · 2021: 114 · 2020: 63 · 2019: 23
FWCI
6.48
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Neurobiology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by)
Funders
University Medical Center Groningen
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Keywords
brain-derived neurotrophic factor, neuroinflammation, neurotrophins, mental illness, neurodegenerative diseases, glial activation, cytokines, reactive oxygen species, neurotoxicity, neuroplasticity, neurotrophin signaling, behavior, pharmacological interventions
MeSH terms
Aging, Animals, Brain, Brain Diseases, Humans, Inflammation, Models, Biological, Brain-Derived Neurotrophic Factor

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