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Hampel H, Caruso G, Nisticò R, Piccioni G, Mercuri NB, Giorgi FS, Ferrarelli F, Lemercier P, Caraci F, Lista S, Vergallo A. Biological Mechanism-based Neurology and Psychiatry: A BACE1/2 and Downstream Pathway Model. Curr Neuropharmacol 2023; 21:31-53. [PMID: 34852743 PMCID: PMC10193755 DOI: 10.2174/1570159x19666211201095701] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 11/26/2021] [Accepted: 11/28/2021] [Indexed: 02/04/2023] Open
Abstract
In oncology, comprehensive omics and functional enrichment studies have led to an extensive profiling of (epi)genetic and neurobiological alterations that can be mapped onto a single tumor's clinical phenotype and divergent clinical phenotypes expressing common pathophysiological pathways. Consequently, molecular pathway-based therapeutic interventions for different cancer typologies, namely tumor type- and site-agnostic treatments, have been developed, encouraging the real-world implementation of a paradigm shift in medicine. Given the breakthrough nature of the new-generation translational research and drug development in oncology, there is an increasing rationale to transfertilize this blueprint to other medical fields, including psychiatry and neurology. In order to illustrate the emerging paradigm shift in neuroscience, we provide a state-of-the-art review of translational studies on the β-site amyloid precursor protein cleaving enzyme (BACE) and its most studied downstream effector, neuregulin, which are molecular orchestrators of distinct biological pathways involved in several neurological and psychiatric diseases. This body of data aligns with the evidence of a shared genetic/biological architecture among Alzheimer's disease, schizoaffective disorder, and autism spectrum disorders. To facilitate a forward-looking discussion about a potential first step towards the adoption of biological pathway-based, clinical symptom-agnostic, categorization models in clinical neurology and psychiatry for precision medicine solutions, we engage in a speculative intellectual exercise gravitating around BACE-related science, which is used as a paradigmatic case here. We draw a perspective whereby pathway-based therapeutic strategies could be catalyzed by highthroughput techniques embedded in systems-scaled biology, neuroscience, and pharmacology approaches that will help overcome the constraints of traditional descriptive clinical symptom and syndrome-focused constructs in neurology and psychiatry.
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Affiliation(s)
- Harald Hampel
- Sorbonne University, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Boulevard de l'hôpital, Paris, France
| | | | - Robert Nisticò
- Laboratory of Pharmacology of Synaptic Plasticity, EBRI Rita Levi-Montalcini Foundation, Rome, Italy
- School of Pharmacy, University of Rome “Tor Vergata”, Rome, Italy
| | - Gaia Piccioni
- Laboratory of Pharmacology of Synaptic Plasticity, EBRI Rita Levi-Montalcini Foundation, Rome, Italy
- Department of Physiology and Pharmacology “V.Erspamer”, Sapienza University of Rome, Rome, Italy
| | - Nicola B. Mercuri
- Department of Systems Medicine, University of Rome “Tor Vergata”, Rome, Italy
- IRCCS Santa Lucia Foundation, Rome, Italy
| | - Filippo Sean Giorgi
- Department of Translational Research and of New Surgical and Medical Technologies, University of Pisa, Pisa, Italy
| | - Fabio Ferrarelli
- Department of Psychiatry, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA
| | - Pablo Lemercier
- Sorbonne University, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Boulevard de l'hôpital, Paris, France
| | - Filippo Caraci
- Oasi Research Institute-IRCCS, Troina, Italy
- Department of Drug Sciences, University of Catania, Catania, Italy
| | - Simone Lista
- Sorbonne University, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Boulevard de l'hôpital, Paris, France
- Memory Resources and Research Center (CMRR), Neurology Department, Gui de Chauliac University Hospital, Montpellier, France
| | - Andrea Vergallo
- Sorbonne University, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Boulevard de l'hôpital, Paris, France
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Candidate metabolic biomarkers for schizophrenia in CNS and periphery: Do any possible associations exist? Schizophr Res 2020; 226:95-110. [PMID: 30935700 DOI: 10.1016/j.schres.2019.03.009] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Revised: 03/08/2019] [Accepted: 03/11/2019] [Indexed: 02/07/2023]
Abstract
Due to the limitations of analytical techniques and the complicity of schizophrenia, nowadays it is still a challenge to diagnose and stratify schizophrenia patients accurately. Many attempts have been made to identify and validate available biomarkers for schizophrenia from CSF and/or peripheral blood in clinical studies with consideration to disease stages, antipsychotic effects and even gender differences. However, conflicting results handicap the validation and application of biomarkers for schizophrenia. In view of availability and feasibility, peripheral biomarkers have superior advantages over biomarkers in CNS. Meanwhile, schizophrenia is considered to be a devastating neuropsychiatric disease mainly taking place in CNS featured by widespread defects in multiple metabolic pathways whose dynamic interactions, until recently, have been difficult to difficult to investigate. Evidence for these alterations has been collected piecemeal, limiting the potential to inform our understanding of the interactions among relevant biochemical pathways. Taken these points together, it will be interesting to investigate possible associations of biomarkers between CNS and periphery. Numerous studies have suggested putative correlations within peripheral and CNS systems especially for dopaminergic and glutamatergic metabolic biomarkers. In addition, it has been demonstrated that blood concentrations of BDNF protein can also reflect its changes in the nervous system. In turn, BDNF also interacts with glutamatergic, dopaminergic and serotonergic systems. Therefore, this review will summarize metabolic biomarkers identified both in the CNS (brain tissues and CSF) and peripheral blood. Further, more attentions will be paid to discussing possible physical and functional associations between CNS and periphery, especially with respect to BDNF.
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Linnemann C, Lang UE. Pathways Connecting Late-Life Depression and Dementia. Front Pharmacol 2020; 11:279. [PMID: 32231570 PMCID: PMC7083108 DOI: 10.3389/fphar.2020.00279] [Citation(s) in RCA: 102] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Accepted: 02/26/2020] [Indexed: 12/12/2022] Open
Abstract
Late-life depression is associated with significant cognitive impairment. Meta-analyses showed that depression is associated with an increased risk for Alzheimer’s disease (AD) and it might be an etiological factor for AD. Since late-life depression is often connected with cognitive impairment and dementia is usually associated with depressive symptoms, a simple diagnostic approach to distinguish between the disorders is challenging. Several overlapping pathophysiological substrates might explain the comorbidity of both syndromes. Firstly, a stress syndrome, i.e., elevated cortisol levels, has been observed in up to 70% of depressed patients and also in AD pathology. Stress conditions can cause hippocampal neuronal damage as well as cognitive impairment. Secondly, the development of a depression and dementia after the onset of vascular diseases, the profile of cerebrovascular risk factors in both disorders and the impairments depending on the location of cerebrovascular lesions, speak in favor of a vascular hypothesis as a common factor for both disorders. Thirdly, neuroinflammatory processes play a key role in the etiology of depression as well as in dementia. Increased activation of microglia, changes in Transforming-Growth-Factor beta1 (TGF-beta1) signaling, production of pro-inflammatory cytokines as well as reduction of anti-inflammatory molecules are examples of common pathways impaired in dementia and depression. Fourthly, the neurotrophin BDNF is highly expressed in the central nervous system, especially in the hippocampus, where it plays a key role in the proliferation, differentiation and the maintenance of neuronal integrity throughout lifespan. It has been associated not only with antidepressant properties but also a reduction of cognitive impairment and therefore could be involved also in AD. Another etiologic factor is amyloid accumulation, as plasma amyloid beta-42 independently predicts both late-onset depression and AD. Higher plasma amyloid beta-42 predicts the development of late onset depression and conversion to possible AD. However, clinical trials with antibodies against beta amyloid recently failed, i.e., Solanezumab, Aducanumab, and Crenezumab. An overproduction of amyloid-beta might simply reflect a form of synaptic plasticity to compensate for neuronal dysfunction in different kind of neurological and psychiatric diseases of multiple etiologies. The tau hypothesis, sex/gender specific differences, epigenetics and the gut microbiota-brain axis imply other potential common pathways connecting late-life depression and dementia. In conclusion, different potential pathophysiological links between dementia and depression highlight several specific synergistic and multifaceted treatment possibilities, depending on the individual risk profile of the patient.
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Affiliation(s)
- Christoph Linnemann
- University of Basel, Universitäre Psychiatrische Kliniken (UPK), Basel, Switzerland
| | - Undine E Lang
- University of Basel, Universitäre Psychiatrische Kliniken (UPK), Basel, Switzerland
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Zou Z, Qiu J, Huang Y, Wang J, Min W, Zhou B. The BDNF Val66Met gene polymorphism is associated with increased alexithymic and anticipatory anxiety in patients with panic disorder. PSYCHOL HEALTH MED 2018; 24:505-511. [PMID: 30269521 DOI: 10.1080/13548506.2018.1516890] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
A large body of evidence indicates that patients with panic disorder(PD) report more obvious alexithymia, and previous studies suggest genetic factors may be play an important role in alexithymia. This study aims to examine the association between the Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and alexithymia, and then to evaluate the association of the BDNFVal66Met polymorphism with PD risk. 223 patients with PD and 218 healthy controls were enrolled in the study. The Toronto Alexithymia Scale (TAS-20), and Panic Disorder Severity Scale (PDSS) were administered to all subjects. And genotyping of the BDNF Val 66Met polymorphism was evaluated. Our results showed that both PD patients and normal controls with the BDNF Met/Met genotype had significantly higher total and difficulty describing feelings(DDF) subdimension scores on the TAS-20 than those with the Val/Val genotype.The patients with the BDNF Met/Met genotype were more severity of anticipatory anxiety than patients with Val/Val genotype.
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Affiliation(s)
- Zhili Zou
- a Department of Psychosomatic , Sichuan Provincial People's Hospital , Chengdu , Sichuan , China
| | - Jian Qiu
- a Department of Psychosomatic , Sichuan Provincial People's Hospital , Chengdu , Sichuan , China
| | - Yulan Huang
- a Department of Psychosomatic , Sichuan Provincial People's Hospital , Chengdu , Sichuan , China
| | - Jinyu Wang
- a Department of Psychosomatic , Sichuan Provincial People's Hospital , Chengdu , Sichuan , China
| | - Wenjiao Min
- a Department of Psychosomatic , Sichuan Provincial People's Hospital , Chengdu , Sichuan , China
| | - Bo Zhou
- a Department of Psychosomatic , Sichuan Provincial People's Hospital , Chengdu , Sichuan , China
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Shibata A, Hanatani A, Izumi Y, Kitada R, Iwata S, Yoshiyama M. Serum brain-derived neurotrophic factor level and exercise tolerance complement each other in predicting the prognosis of patients with heart failure. Heart Vessels 2018; 33:1325-1333. [PMID: 29700574 DOI: 10.1007/s00380-018-1174-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Accepted: 04/20/2018] [Indexed: 12/20/2022]
Abstract
Brain-derived neurotropic factor (BDNF) is a myokine that plays a key role in regulating survival, growth, and maintenance of neurons. We investigated whether the serum BDNF level at discharge could predict the prognosis in patients with heart failure (HF). Furthermore, we aimed to examine the relationship between this myokine and exercise tolerance. We prospectively enrolled 94 patients who were hospitalized for worsening HF and had cardiac rehabilitation. At discharge, the serum BDNF level of all patients was measured using a commercial ELISA kit and they underwent a cardiopulmonary exercise test to measure peak oxygen uptake (peak VO2). Correlation was not observed between BDNF and peak VO2. Kaplan-Meier analysis demonstrated that cardiac death or rehospitalization owing to worsening HF was significantly higher in the low BDNF group (p = 0.023). The combination of peak VO2 and BDNF levels led to the identification of subgroups with significantly different probabilities of events (p = 0.005). In particular, in the low BDNF and low peak VO2 group, the frequency of rehospitalization within half a year after discharge was much higher than that in other groups. Multivariate analysis found BDNF as an independent factor of adverse events (hazard ratio 0.956; 95% confidence interval 0.911-0.999; p = 0.046). The serum BDNF level at discharge may be a useful biomarker of the prognosis in patients with HF. Furthermore, combining BDNF and peak VO2 may be useful for predicting early cardiac events.
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Affiliation(s)
- Atsushi Shibata
- Department of Cardiovascular Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan
| | - Akihisa Hanatani
- Department of Cardiovascular Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan.
| | - Yasukatsu Izumi
- Department of Internal Medicine, Takaishikamo Hospital, Osaka, Japan
| | - Ryoko Kitada
- Department of Cardiovascular Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan
| | - Shinichi Iwata
- Department of Cardiovascular Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan
| | - Minoru Yoshiyama
- Department of Cardiovascular Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan
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Brain‐derived neutrophic factor in adolescents smoking waterpipe: The Irbid TRY. Int J Dev Neurosci 2018; 67:14-18. [DOI: 10.1016/j.ijdevneu.2018.03.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Revised: 03/09/2018] [Accepted: 03/11/2018] [Indexed: 12/11/2022] Open
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Coskunoglu A, Orenay-Boyacioglu S, Deveci A, Bayam M, Onur E, Onan A, Cam FS. Evidence of associations between brain-derived neurotrophic factor (BDNF) serum levels and gene polymorphisms with tinnitus. Noise Health 2017; 19:140-148. [PMID: 28615544 PMCID: PMC5501024 DOI: 10.4103/nah.nah_74_16] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
BACKGROUND Brain-derived neurotrophic factor (BDNF) gene polymorphisms are associated with abnormalities in regulation of BDNF secretion. Studies also linked BDNF polymorphisms with changes in brainstem auditory-evoked response test results. Furthermore, BDNF levels are reduced in tinnitus, psychiatric disorders, depression, dysthymic disorder that may be associated with stress, conversion disorder, and suicide attempts due to crises of life. For this purpose, we investigated whether there is any role of BDNF changes in the pathophysiology of tinnitus. MATERIALS AND METHODS In this study, we examined the possible effects of BDNF variants in individuals diagnosed with tinnitus for more than 3 months. Fifty-two tinnitus subjects between the ages of 18 and 55, and 42 years healthy control subjects in the same age group, who were free of any otorhinolaryngology and systemic disease, were selected for examination. The intensity of tinnitus and depression was measured using the tinnitus handicap inventory, and the differential diagnosis of psychiatric diagnoses made using the Structured Clinical Interview for Fourth Edition of Mental Disorders. BDNF gene polymorphism was analyzed in the genomic deoxyribonucleic acid (DNA) samples extracted from the venous blood, and the serum levels of BDNF were measured. One-way analysis of variance and Chi-squared tests were applied. RESULTS Serum BDNF level was found lower in the tinnitus patients than controls, and it appeared that there is no correlation between BDNF gene polymorphism and tinnitus. CONCLUSIONS This study suggests neurotrophic factors such as BDNF may have a role in tinnitus etiology. Future studies with larger sample size may be required to further confirm our results.
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Affiliation(s)
- Aysun Coskunoglu
- Department of Medical Genetics, Faculty of Medicine, Celal Bayar University, Manisa, Turkey
| | - Seda Orenay-Boyacioglu
- Department of Medical Genetics, Faculty of Medicine, Adnan Menderes University, Efeler, Aydin, Turkey
| | - Artuner Deveci
- Department of Psychiatry, Faculty of Medicine, Celal Bayar University, Manisa, Turkey
| | - Mustafa Bayam
- Department of Otorhinolaryngology, Faculty of Medicine, Celal Bayar University, Manisa, Turkey
| | - Ece Onur
- Department of Medical Biochemistry, Faculty of Medicine, Celal Bayar University, Manisa, Turkey
| | - Arzu Onan
- Department of Medical Biochemistry, Faculty of Medicine, Celal Bayar University, Manisa, Turkey
| | - Fethi S. Cam
- Department of Medical Genetics, Faculty of Medicine, Celal Bayar University, Manisa, Turkey
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Deutschenbaur L, Beck J, Kiyhankhadiv A, Mühlhauser M, Borgwardt S, Walter M, Hasler G, Sollberger D, Lang UE. Role of calcium, glutamate and NMDA in major depression and therapeutic application. Prog Neuropsychopharmacol Biol Psychiatry 2016; 64:325-33. [PMID: 25747801 DOI: 10.1016/j.pnpbp.2015.02.015] [Citation(s) in RCA: 108] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2014] [Revised: 01/04/2015] [Accepted: 02/20/2015] [Indexed: 01/17/2023]
Abstract
Major depression is a common, recurrent mental illness that affects millions of people worldwide. Recently, a unique fast neuroprotective and antidepressant treatment effect has been observed by ketamine, which acts via the glutamatergic system. Hence, a steady accumulation of evidence supporting a role for the excitatory amino acid neurotransmitter (EAA) glutamate in the treatment of depression has been observed in the last years. Emerging evidence indicates that N-methyl-D-aspartate (NMDA), group 1 metabotropic glutamate receptor antagonists and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) agonists have antidepressant properties. Indeed, treatment with NMDA receptor antagonists has shown the ability to sprout new synaptic connections and reverse stress-induced neuronal changes. Based on glutamatergic signaling, a number of therapeutic drugs might gain interest in the future. Several compounds such as ketamine, memantine, amantadine, tianeptine, pioglitazone, riluzole, lamotrigine, AZD6765, magnesium, zinc, guanosine, adenosine aniracetam, traxoprodil (CP-101,606), MK-0657, GLYX-13, NRX-1047, Ro25-6981, LY392098, LY341495, D-cycloserine, D-serine, dextromethorphan, sarcosine, scopolamine, pomaglumetad methionil, LY2140023, LY404039, MGS0039, MPEP, 1-aminocyclopropanecarboxylic acid, all of which target this system, have already been brought up, some of them recently. Drugs targeting the glutamatergic system might open up a promising new territory for the development of drugs to meet the needs of patients with major depression.
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Affiliation(s)
- Lorenz Deutschenbaur
- Department of Psychiatry and Psychotherapy (UPK), University Hospital of Basel, Basel, Switzerland
| | - Johannes Beck
- Department of Psychiatry and Psychotherapy (UPK), University Hospital of Basel, Basel, Switzerland
| | - Anna Kiyhankhadiv
- Department of Psychiatry and Psychotherapy (UPK), University Hospital of Basel, Basel, Switzerland
| | - Markus Mühlhauser
- Department of Psychiatry and Psychotherapy (UPK), University Hospital of Basel, Basel, Switzerland
| | - Stefan Borgwardt
- Department of Psychiatry and Psychotherapy (UPK), University Hospital of Basel, Basel, Switzerland
| | - Marc Walter
- Department of Psychiatry and Psychotherapy (UPK), University Hospital of Basel, Basel, Switzerland
| | - Gregor Hasler
- Department of Psychiatry and Psychotherapy (UPK), University Hospital of Basel, Basel, Switzerland
| | - Daniel Sollberger
- Department of Psychiatry and Psychotherapy (UPK), University Hospital of Basel, Basel, Switzerland
| | - Undine E Lang
- Department of Psychiatry and Psychotherapy (UPK), University Hospital of Basel, Basel, Switzerland.
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Leibrock C, Hierlmeier M, Lang UE, Lang F. Subtle Impact of Akt1 and Akt3 on Exploratory Behavior in Gene Targeted Mice. ZEITSCHRIFT FUR PSYCHOLOGIE-JOURNAL OF PSYCHOLOGY 2015. [DOI: 10.1027/2151-2604/a000218] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Abstract. The present study explored the impact of Akt1 and Akt3 on behavior. Akt1 (akt1-/-) and Akt3 (akt3-/-) knockout mice were compared to wild type (wt) mice. The akt1-/- mice, akt3-/- mice, and wt mice were similar in most parameters of the open-field test. However, the distance traveled in the center area was slightly but significantly less in akt3-/- mice than in wt mice. In the light/dark transition test akt1-/- mice had significantly lower values than wt mice and akt3-/- mice for distance traveled, number of rearings, rearing time in the light area, as well as time spent and distance traveled in the entrance area. They were significantly different from akt3-/- mice in the distance traveled, visits, number of rearings, rearing time in the light area, as well as time spent, distance traveled, number of rearings, and rearing time in the entrance area. In the O-maze the time spent, and the visits to open arms, as well as the number of protected and unprotected headdips were significantly less in akt1-/- mice than in wt mice, whereas the time spent in closed arms was significantly more in akt1-/- mice than in wt mice. Protected and unprotected headdips were significantly less in akt3-/- mice than in wt mice. In closed area, akt3-/- mice traveled a significantly larger distance at larger average speed than akt1-/- mice. No differences were observed between akt1-/- mice, akt3-/- mice and wt-type mice in the time of floating during the forced swimming test. In conclusion, akt1-/- mice and less so akt3-/ mice display subtle changes in behavior.
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Affiliation(s)
| | | | - Undine E. Lang
- Department of Psychiatry, University of Basel, Switzerland
| | - Florian Lang
- Department of Physiology I, University of Tuebingen, Germany
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Park YM, Lee BH, Um TH, Kim S. Serum BDNF levels in relation to illness severity, suicide attempts, and central serotonin activity in patients with major depressive disorder: a pilot study. PLoS One 2014; 9:e91061. [PMID: 24663244 PMCID: PMC3963843 DOI: 10.1371/journal.pone.0091061] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2013] [Accepted: 02/08/2014] [Indexed: 11/18/2022] Open
Abstract
The aim of this study was to test the hypothesis that serum levels of brain-derived neurotrophic factor (BDNF) are correlated with the loudness dependence of auditory evoked potentials (LDAEP). The question of whether there is a difference in BDNF levels between depressive patients according to their illness severity, history of suicide attempts, and central serotonin activity was also addressed. A sample of 51 patients who met the criteria for major depressive disorder following diagnosis using axis I of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders – text revision comprised the study subjects. The patients were stratified into two subgroups based on their illness severity, history of suicide attempts, and their LDAEP values. The LDAEP was evaluated by measuring the auditory event-related potentials, and serum BDNF was measured using blood sampling before beginning medication with serotonergic agents. There was no difference in serum BDNF levels between the two patient subgroups. The subgroup with moderate-to-severe depression (n = 16) was reanalyzed after stratifying it into two subgroups according to LDAEP and BDNF values (dichotomized at the medians into low and high). The high-LDAEP subgroup had higher serum BDNF levels and total Barratt Impulsiveness Scale score than the low-LDAEP subgroup (p = 0.03 and 0.036, respectively). Serum BDNF levels were positively correlated with LDAEP and total Beck Hopelessness Scale (BHS) score (r = 0.56, p = 0.025, and r = 0.59, p = 0.016, respectively). The high-BDNF subgroup had a higher LDAEP and total BHS score than the low-BDNF subgroup (p = 0.046 and p = 0.011, respectively). This is the first study to demonstrate a relationship between the BDNF level and LDAEP in Asian depressive patients. Intriguingly, the high-BDNF subgroup (divided according to illness severity) exhibited a more severe psychopathology on some psychometric rating scales, a finding that conflicts with previous results.
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Affiliation(s)
- Young-Min Park
- Department of Psychiatry, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Republic of Korea
- * E-mail:
| | - Bun-Hee Lee
- Department of Psychiatry, Gangnam Eulji Hospital, Eulji University, Seoul, Republic of Korea
| | - Tae Hyun Um
- Department of Laboratory Medicine, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Republic of Korea
| | - Sollip Kim
- Department of Laboratory Medicine, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Republic of Korea
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Penadés R, Catalán R, López-Vílchez I, Arias B, González-Rodríguez A, Galán AM, Gastó C. Brain-derived neurotrophic factor as a potential biomarker of cognitive recovery in schizophrenia. World J Psychiatry 2013; 3:93-102. [DOI: 10.5498/wjp.v3.i4.93] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2013] [Revised: 08/10/2013] [Accepted: 11/03/2013] [Indexed: 02/05/2023] Open
Abstract
Brain-derived neurotrophic factor (BDNF) has been proposed as a biomarker of schizophrenia and, more specifically, as a biomarker of cognitive recovery. Evidence collected in this review indicates that BDNF is relevant in the pathophysiology of schizophrenia and could play a role as a marker of clinical response. BDNF has been shown to play a positive role as a marker in antipsychotic treatment, and it has been demonstrated that typical antipsychotics decrease BDNF levels while atypical antipsychotics maintain or increase serum BDNF levels. Furthermore, BDNF levels have been associated with severe cognitive impairments in patients with schizophrenia. Consequently, BDNF has been proposed as a candidate target of strategies to aid the cognitive recovery process. There is some evidence suggesting that BDNF could be mediating neurobiological processes underlying cognitive recovery. Thus, serum BDNF levels seem to be involved in some synaptic plasticity and neurotransmission processes. Additionally, serum BDNF levels significantly increased in schizophrenia subjects after neuroplasticity-based cognitive training. If positive replications of those findings are published in the future then serum BDNF levels could be definitely postulated as a peripheral biomarker for the effects of intensive cognitive training or any sort of cognitive recovery in schizophrenia. All in all, the current consideration of BDNF as a biomarker of cognitive recovery in schizophrenia is promising but still premature.
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12
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Park YM, Lee SH, Lee HJ, Kang SG, Min JA, Chae JH. Association between BDNF gene polymorphisms and serotonergic activity using loudness dependence of auditory evoked potentials in healthy subjects. PLoS One 2013; 8:e60340. [PMID: 23593198 PMCID: PMC3621878 DOI: 10.1371/journal.pone.0060340] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2012] [Accepted: 02/25/2013] [Indexed: 11/18/2022] Open
Abstract
It has been proposed that the loudness dependence of auditory evoked potentials (LDAEP) would be a reliable indicator of central serotonin system activity in humans. Serotonin levels and turnover are also increased by brain-derived neurotrophic factor (BDNF). The aim of the present study was to determine whether there is an association between genetic polymorphisms of BDNF and the LDAEP in healthy Korean young adults. The cohort comprised 211 mentally and physically healthy subjects, all of whom were nonsmokers (111 males, 100 females; age: 20∼32 years). To avoid hormonal effects, the LDAEP was measured during days 2–5 after the beginning of menstruation for female subjects. In addition, BDNF polymorphisms (rs6265, rs2030324, and rs1491850) were genotyped. The strength of the LDAEP differed significantly among the BDNF genotype groups. Furthermore, the distribution of genotypic frequencies differed significantly between subjects with high and low LDAEPs. In particular, subjects with the Val/Met (A/G) genotype for rs6265, the T/T genotype for rs2030324, or the C/C genotype for rs1491850 had a higher LDAEP, indicating lower central serotonergic activity. A low LDAEP was more prevalent than a high LDAEP among those with the C-T haplotype (C genotype for rs2030424 and T genotype for rs1491850). Our results concur with previous findings on BDNF polymorphisms and serotonergic drug responses in psychiatric disorder patients. The present results suggest the possibility that BDNF polymorphisms and LDAEP patterns can predict altered serotonergic activity.
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Affiliation(s)
- Young-Min Park
- Department of Psychiatry, Inje University, Ilsan Paik Hospital, Goyang, Republic of Korea
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Nurjono M, Lee J, Chong SA. A Review of Brain-derived Neurotrophic Factor as a Candidate Biomarker in Schizophrenia. CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE 2012; 10:61-70. [PMID: 23431036 PMCID: PMC3569148 DOI: 10.9758/cpn.2012.10.2.61] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/15/2012] [Accepted: 04/26/2012] [Indexed: 12/21/2022]
Abstract
Brain-derived neurotrophic factor (BDNF), a neurotrophin known to be responsible for development, regeneration, survival and maintenance of neurons has been implicated in the pathophysiology of schizophrenia. This review seeks to complement previous reviews on biological roles of BDNF and summarizes evidence on the involvement of BDNF in the pathophysiology of schizophrenia with an emphasis on clinical relevance. The expressions of BDNF were altered in patients with schizophrenia and were found to be correlated with psychotic symptomatology. Antipsychotics appeared to have differential effects on expression of BDNF but did not restore BDNF expression of patients with schizophrenia to normal levels. In addition, evidence suggests that BDNF is involved in the major neurotransmitter systems and is associated with disruptions in brain structure, neurodevelopmental process, cognitive function, metabolic and immune systems commonly associated with schizophrenia. Besides that, BDNF has been demonstrated to be tightly regulated with estrogen which has also been previously implicated in schizophrenia. Evidence gathered in this review confirms the relevance of BDNF in the pathophysiology of schizophrenia and the potential utility of BDNF as a suitable biomarker for diagnostic and prognostic purposes for disease outcome and other co-morbidities. However, further investigations are warranted to examine the specificity of BDNF in schizophrenia compared to other neurodegenerative disorders and other neuropsychiatric illness. Longitudinal prospective studies will also be of added advantage for evaluation of prognostic utility of BDNF in schizophrenia.
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Affiliation(s)
- Milawaty Nurjono
- Research Division, Institute of Mental Health/Woodbridge Hospital, Singapore
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Simmons JG, Nathan PJ, Berger G, Allen NB. Chronic modulation of serotonergic neurotransmission with sertraline attenuates the loudness dependence of the auditory evoked potential in healthy participants. Psychopharmacology (Berl) 2011; 217:101-10. [PMID: 21465243 DOI: 10.1007/s00213-011-2265-9] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2011] [Accepted: 03/11/2011] [Indexed: 11/24/2022]
Abstract
RATIONALE The loudness dependence of the auditory evoked potential (LDAEP) has been reported to be an effective non-invasive measure of central serotonergic neurotransmission. However, acute manipulations of the serotonergic system in humans and animals have yielded inconsistent findings. OBJECTIVES In this study, we examined the chronic effect of serotonergic manipulation using the selective serotonin reuptake inhibitor, sertraline, on the LDAEP. In addition, we examined the influence of 5-HTTLPR genotype and individual differences in plasma drug concentrations on the LDAEP. METHODS The study utilised a double-blind, placebo-controlled, between-group design in which 40 (24 female) healthy adults (M age = 22.0 years, SE = 0.7) were tested following placebo or sertraline for an average of 24 days. The LDAEP was assessed 6 h post-final dose, and changes in the slope of amplitude of the N1/P2 across intensities (60, 70, 80, 90, 100 dB) were examined at Cz. RESULTS The sertraline group had a significantly smaller LDAEP than the placebo group [F(1,38) = 5.97, p = 0.02]. Drug plasma levels did not correlate with the LDAEP in the sertraline group, and there was no influence of 5-HTTLPR genotype. CONCLUSIONS We show for the first time that chronically modulating serotonin neurotransmission alters the LDAEP in healthy adults, consistent with extant literature indicating a moderating role of serotonin on this neurophysiological biomarker. The findings from this study together with previous studies suggest that the LDAEP may be a more sensitive marker of long-term or chronic rather than acute changes in the serotonin system.
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Affiliation(s)
- Julian G Simmons
- Orygen Youth Health Research Centre, Locked Bag 10, Parkville, Victoria 3052, Australia
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Lee IH, Yang YK, Chen PS, Huang HC, Yeh TL, Lu RB, Chiu NT, Yao WJ, Lin SH. Loudness dependence of auditory evoked potentials (LDAEP) correlates with the availability of dopamine transporters and serotonin transporters in healthy volunteers-a two isotopes SPECT study. Psychopharmacology (Berl) 2011; 214:617-24. [PMID: 21072504 DOI: 10.1007/s00213-010-2064-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2010] [Accepted: 10/18/2010] [Indexed: 11/27/2022]
Abstract
RATIONALE AND OBJECTIVE Although loudness dependence of auditory evoked potentials (LDAEPs) had been suggested as a noninvasive measure of central serotonin functions, recent studies suggest that LDAEP may be modulated by multiple neuromodulatory systems, such as dopamine. Here, we explore the relationship between LDAEP and dopamine and serotonin in the level of monoamine transporter availability. METHODS Forty-nine healthy volunteers received LDAEP and single-photon emission computed tomography (SPECT) using [(99m)Tc] TRODAT and [(123)I] ADAM to approximate the availability of dopamine transporters (DATs) and serotonin transporters (SERTs). RESULTS LDAEP was found to be positively associated with DAT, after adjusting for age and gender, and the log-transformed slope of loudness dependence at Cz was negatively associated with SERT. CONCLUSION Our findings provide further evidence for the possible involvement of dopamine and serotonins in the genesis of LDAEP.
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Affiliation(s)
- I Hui Lee
- Department of Psychiatry, National Cheng Kung University Hospital, 138 Sheng Li Road, Tainan, 70428, Taiwan, Republic of China.
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Nederhof E, Bouma EMC, Riese H, Laceulle OM, Ormel J, Oldehinkel AJ. Evidence for plasticity genotypes in a gene-gene-environment interaction: the TRAILS study. GENES BRAIN AND BEHAVIOR 2010; 9:968-73. [PMID: 20738408 DOI: 10.1111/j.1601-183x.2010.00637.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- E Nederhof
- Interdisciplinary Center for Psychiatric Epidemiology, Department of Psychiatry and Unit of Genetic Epidemiology & Bioinformatics, Department of Epidemiology (HR), University Medical Center Groningen, University of Groningen, The Netherlands.
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Juckel G, Schumacher C, Giegling I, Assion HJ, Mavrogiorgou P, Pogarell O, Mulert C, Hegerl U, Norra C, Rujescu D. Serotonergic functioning as measured by the loudness dependence of auditory evoked potentials is related to a haplotype in the brain-derived neurotrophic factor (BDNF) gene. J Psychiatr Res 2010; 44:541-6. [PMID: 20004415 DOI: 10.1016/j.jpsychires.2009.11.006] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2009] [Revised: 10/28/2009] [Accepted: 11/05/2009] [Indexed: 11/30/2022]
Abstract
OBJECTIVES The serotonergic system plays an important pathophysiological role in various psychiatric disorders. Brain-derived neurotrophic factor (BDNF) is involved in the differentiation and survival of serotonergic neurons. A previous study showed that low serum BDNF levels were associated with strong loudness dependence of auditory evoked potentials (LDAEP) as a reflection of low central serotonergic activity. To evaluate the genetic basis of this relationship, we studied whether the LDAEP is correlated with genetic variants within the BDNF gene. METHODS Ninety five healthy subjects (41 males, 54 females) received electrophysiological recording of LDAEP and blood drawing for BDNF genotyping. Three BDNF markers (including the single nucleotide polymorphism rs6265(Val66Met)) were analyzed. RESULTS Haplotype analysis revealed stronger LDAEP values in carriers of the G(Val)-C-T [rs6265(Val66Met)-rs2030324-rs1491850] haplotype within the BDNF gene in comparison to other haplotype carriers. These findings were demonstrated for the LDAEP of both left and right primary auditory cortices as well as for the vertex electrode (Cz). CONCLUSION Subjects with the BDNF haplotype G(Val)-C-T seem to be characterized by low serotonergic activity as well as possibly by low serum BDNF levels. These findings need replication in independent samples.
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Affiliation(s)
- Georg Juckel
- Department of Psychiatry, Ruhr University, 44791 Bochum, Germany.
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18
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Peripheral brain-derived neurotrophic factor (BDNF) as a biomarker for affective disorders? Int J Neuropsychopharmacol 2010; 13:1-4. [PMID: 19995480 DOI: 10.1017/s1461145709991039] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
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Immunosuppression Using the Mammalian Target of Rapamycin (mTOR) Inhibitor Everolimus: Pilot Study Shows Significant Cognitive and Affective Improvement. Transplant Proc 2009; 41:4285-8. [DOI: 10.1016/j.transproceed.2009.08.050] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2009] [Accepted: 08/17/2009] [Indexed: 11/19/2022]
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Lang UE, Hellweg R, Gallinat J, Bajbouj M. Acute prefrontal cortex transcranial magnetic stimulation in healthy volunteers: no effects on brain-derived neurotrophic factor (BDNF) concentrations in serum. J Affect Disord 2008; 107:255-8. [PMID: 17825920 DOI: 10.1016/j.jad.2007.08.008] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2007] [Revised: 08/13/2007] [Accepted: 08/13/2007] [Indexed: 01/19/2023]
Abstract
BACKGROUND Transcranial magnetic stimulation (TMS) of the dorsolateral prefrontal cortex is a brain stimulation technique widely used to treat depression. BDNF serum concentrations have been shown to be decreased in patients with major depressive disorder and can be upregulated by several antidepressive treatment strategies including repetitive TMS. METHODS In this study we were interested whether acute TMS evolves effects on serum BDNF concentrations in 42 healthy volunteers. RESULTS Mean BDNF serum concentration in 19 male and 23 female volunteers was 10.70+/-3.6 ng/ml (n=42) at baseline, and 10.76+/-3.9 ng/ml (n=42) after TMS treatment. BDNF serum levels did not change after acute TMS (n=42, Z=-0.44, p=0.965). BDNF serum concentrations at baseline did not differ between male (n=19, 10.05+/-2.6 ng/ml) and female (n=23, 11.25+/-4.27 ng/ml) participants of the study (n=42, Z=-0.91, p=0.363). CONCLUSIONS Our result suggests that TMS does not change BDNF serum concentrations immediately in healthy human volunteers.
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Affiliation(s)
- Undine E Lang
- Department of Psychiatry and Psychotherapy, Charité-University Medicine Berlin, Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany.
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Gallinat J, Bauer M, Heinz A. Genes and Neuroimaging: Advances in Psychiatric Research. NEURODEGENER DIS 2008; 5:277-85. [DOI: 10.1159/000135612] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
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Ziegenhorn AA, Schulte-Herbrüggen O, Danker-Hopfe H, Malbranc M, Hartung HD, Anders D, Lang UE, Steinhagen-Thiessen E, Schaub RT, Hellweg R. Serum neurotrophins—A study on the time course and influencing factors in a large old age sample. Neurobiol Aging 2007; 28:1436-45. [PMID: 16879899 DOI: 10.1016/j.neurobiolaging.2006.06.011] [Citation(s) in RCA: 222] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2006] [Accepted: 06/13/2006] [Indexed: 12/15/2022]
Abstract
The neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are important mediators of brain and neuronal development, the maintenance of homeostatic conditions in the adult nervous system, and the complex interplay of central and peripheral physiological and pathophysiological factors. To date there are few studies examining blood concentrations of neurotrophic factors in large samples of healthy and diseased individuals and no published study specifically addresses peripheral BDNF and NGF levels in late life. Using improved highly sensitive and specific fluorometric two-site enzyme-linked immunosorbent assays we examined BDNF (n=465) and NGF (n=175) serum levels in a large cohort of elderly individuals (age range: 70-103 years). Neither BDNF nor NGF serum levels proved to be normally distributed, indicating that previously published studies with small sample sizes using parametric testing may be misleading. A significant correlation was found between BDNF and platelet count (r=0.344, p<0.01), age and BDNF protein (r=-0.101, p=0.029) and BDNF and NGF serum levels (r=0.152, p=0.04). No other major influencing factors were found including gender, depression, and dementia.
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Affiliation(s)
- Andreas A Ziegenhorn
- Department of Psychiatry, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Eschenallee 3, 14050 Berlin, Germany
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Lang UE, Hellweg R, Seifert F, Schubert F, Gallinat J. Correlation between serum brain-derived neurotrophic factor level and an in vivo marker of cortical integrity. Biol Psychiatry 2007; 62:530-5. [PMID: 17560556 DOI: 10.1016/j.biopsych.2007.01.002] [Citation(s) in RCA: 123] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2006] [Revised: 01/03/2007] [Accepted: 01/03/2007] [Indexed: 01/13/2023]
Abstract
BACKGROUND Brain-derived neurotrophic factor (BDNF) signaling at synapses improves synaptic strengthening associated with learning and memory. In the present study we hypothesized that serum BDNF concentration is associated with in vivo level of cerebral N-acetylaspartate (NAA), a well established marker of neuronal integrity. METHODS In 36 healthy subjects BDNF serum concentration and absolute concentration of NAA together with other metabolites were measured by proton magnetic resonance spectroscopy (1H-MRS) in regions with high BDNF levels (anterior cingulate cortex [ACC], left hippocampus). Relationship between BDNF concentration and brain metabolites was studied in linear regression analysis with BDNF concentration as dependent variable and metabolite concentrations, age, and gender as predictor variables. RESULTS The BDNF serum concentrations were positively associated with the concentrations of NAA (T = 2.193, p = .037) and total choline (T = 1.997, p = .055; trend) but not total creatine or glutamate in the ACC. No significant association was observed between BDNF serum concentration and absolute metabolite concentrations in the hippocampus. CONCLUSIONS The preliminary data might indicate that BDNF serum concentration reflects some aspects of neuronal plasticity as indicated by its association with NAA level in the cerebral cortex. The results would be in line with the notion that BDNF plays a central role in the regulation of neuronal survival and differentiation in the human brain.
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Affiliation(s)
- Undine E Lang
- Department of Psychiatry and Psychotherapy, Charité-University Medicine Berlin, Campus Mitte, Berlin, Germany
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Lang UE, Sander T, Lohoff FW, Hellweg R, Bajbouj M, Winterer G, Gallinat J. Association of the met66 allele of brain-derived neurotrophic factor (BDNF) with smoking. Psychopharmacology (Berl) 2007; 190:433-9. [PMID: 17186223 DOI: 10.1007/s00213-006-0647-1] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2006] [Accepted: 11/07/2006] [Indexed: 10/23/2022]
Abstract
RATIONALE It has been suggested that a susceptibility locus near the gene encoding the brain-derived neurotrophic factor (BDNF) contributes to individual differences in human addiction vulnerability. BDNF modulates several behaviors that are associated with addictive drugs, and upregulation of BDNF was found to be associated with several drugs of abuse such as amphetamine, cocaine, and nicotine. In this study, we addressed the question if a common BDNF missense variation (Val66Met) influences the risk for smoking behavior in otherwise healthy human volunteers. MATERIALS AND METHODS In total, 320 healthy unrelated volunteers (155 male, 165 female, mean age: 38.4 +/- 14.1 years) consisting of 43.3% never smokers, 20.9% former smokers, and 35.6% current smokers were investigated. RESULTS The frequency of both Met/Met genotype and Met allele was significantly increased in current and in former smokers when compared to never smokers (chi (2) = 10.856, df = 2, p = 0.004 and chi (2) = 4.350, df = 1, p = 0.045, respectively). CONCLUSIONS Our results suggest that humans who carry the Met allele of the BDNF missense polymorphism might be more vulnerable to initiate and also maintain smoking.
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Affiliation(s)
- Undine E Lang
- Department of Psychiatry and Psychotherapy, University of Dresden, Fetscherstr 74, 01307, Dresden, Germany.
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Gallinat J, Lang UE, Jacobsen LK, Bajbouj M, Kalus P, von Haebler D, Seifert F, Schubert F. Abnormal hippocampal neurochemistry in smokers: evidence from proton magnetic resonance spectroscopy at 3 T. J Clin Psychopharmacol 2007; 27:80-4. [PMID: 17224719 DOI: 10.1097/jcp.0b013e31802dffde] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVE In animals, nicotine, the primary psychoactive constituent of tobacco smoke, reduces neurogenesis and increases cell loss in both hippocampus and cortex. Accordingly, tobacco smoking has been linked to reduced performance on cognitive paradigms requiring attention and working memory in humans. However, few prior studies have tested for evidence of structural brain alterations in human tobacco smokers. In this study, proton magnetic resonance spectroscopy was used to assess the effects of chronic smoking on neuronal integrity of the hippocampus and anterior cingulate cortex (ACC). METHODS Absolute concentrations of N-acetylaspartate, total choline (tCho), and total creatine were measured in the left hippocampus and ACC in 13 chronic tobacco smokers and 13 nonsmokers matched for age, sex, and education. RESULTS The N-acetylaspartate concentration was significantly reduced in smokers relative to nonsmokers in the left hippocampus but not in the ACC. There were no group differences in the tCho and total creatine concentrations in either voxel. However, ACC tCho concentration was positively correlated with magnitude of lifetime exposure to tobacco smoke (pack-years). CONCLUSION The results are consistent with prior observations of hippocampal neuronal damage in rodents receiving nicotine and working memory deficits in human tobacco smokers. The positive relationship between tCho and lifetime tobacco exposure suggests that a component of tobacco smoke, presumably nicotine, may increase cortical membrane turnover or modify cell density. Together, these results add to growing evidence that nicotine exerts neurotoxic effects in human brain, although an a priori nature of the findings cannot be ruled out.
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Affiliation(s)
- Jürgen Gallinat
- Klinik für Psychiatrie und Psychotherapie, Charité Universitätsmedizin, Campus Mitte (PUK Charité SHK), Berlin, Germany.
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Gallinat J, Meisenzahl E, Jacobsen LK, Kalus P, Bierbrauer J, Kienast T, Witthaus H, Leopold K, Seifert F, Schubert F, Staedtgen M. Smoking and structural brain deficits: a volumetric MR investigation. Eur J Neurosci 2007; 24:1744-50. [PMID: 17004938 DOI: 10.1111/j.1460-9568.2006.05050.x] [Citation(s) in RCA: 260] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Growing evidence from animal studies indicates brain-damaging properties of nicotine exposure. Investigations in humans found a wide range of functional cerebral effects of nicotine and cigarette smoking, but studies focusing on brain damage are sparse. In 22 smokers and 23 never-smokers possible differences of the cerebral structures were investigated using magnetic resonance imaging and voxel-based morphometry. Significantly smaller grey matter volume and lower grey matter density (P = 0.05, corrected) were observed in the frontal regions (anterior cingulate, prefrontal and orbitofrontal cortex), the occipital lobe and the temporal lobe including parahippocampal gyrus, in smokers than in never-smokers. Group differences of either grey matter volume or grey matter density were also found in the thalamus, cerebellum and substantia nigra, among other regions. Smokers did not show greater volumes than never-smokers in any cerebral region. Magnitude of lifetime exposure to tobacco smoke (pack-years) was inversely correlated with volume of frontal and temporal lobes and cerebellum (P = 0.001, uncorrected). The data indicate structural deficits of several cortical and subcortical regions in smokers relative to never-smokers. The topographic profile of the group differences show some similarities to brain networks known to mediate drug reinforcement, attention and working memory processing. The present findings may explain in part the frequently reported cognitive dysfunctions in chronic cigarette consumers.
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Affiliation(s)
- Jürgen Gallinat
- Clinic for Psychiatry and Psychotherapy, Charité University Medicine, St Hedwig Krankenhaus, Turmstrasse 21, 10559 Berlin, Germany.
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Hensch T, Wargelius HL, Herold U, Lesch KP, Oreland L, Brocke B. Further evidence for an association of 5-HTTLPR with intensity dependence of auditory-evoked potentials. Neuropsychopharmacology 2006; 31:2047-54. [PMID: 16421513 DOI: 10.1038/sj.npp.1301020] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Intensity dependence of auditory-evoked potentials (IAEP) has been suggested as an indicator of central serotonergic neurotransmission. Two recent studies investigated a possible association of IAEP with a functional polymorphism in the transcriptional control region of the serotonin transporter gene (5-HTTLPR) that has a short (s) and a long (l) variant. Although both studies found an association between 5-HTTLPR and IAEP, Gallinat et al found l/l individuals to exhibit lower IAEP, whereas Strobel et al observed stronger IAEP in l/l individuals. These conflicting results require further evaluation and more attention needs to be paid to variables that are known to be confounded with the effects of IAEP and 5-HTTLPR. Using a paradigm comparable to Strobel et al, the present study analyzes the effect of 5-HTTLPR on IAEP in a healthy male student sample (N=91; age=23 years, SD=1.9) that was homogenous for most significant confounding variables. A stronger IAEP was shown in l/l individuals, irrespective of the method of IAEP parametrization. This also held at retest after 3 weeks in a subsample (N=18). Given the successful replication of Strobel et al, several possible reasons for conflicting results with regard to Gallinat et al are discussed. It is argued that the most significant difference between Gallinat et al on the one hand, and Strobel et al and this study on the other, is that different intensity ranges are used which impact IAEP. Therefore, this study encourages further analysis of dose dependence of results.
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Affiliation(s)
- Tilman Hensch
- Department of Psychology, Dresden University of Technology, Dresden, Germany.
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Kirchheiner J, Lang U, Stamm T, Sander T, Gallinat J. Association of CYP2D6 genotypes and personality traits in healthy individuals. J Clin Psychopharmacol 2006; 26:440-2. [PMID: 16855473 DOI: 10.1097/01.jcp.0000229484.52955.22] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Nathan PJ, O'Neill B, Croft RJ. Is the loudness dependence of the auditory evoked potential a sensitive and selective in vivo marker of central serotonergic function? Neuropsychopharmacology 2005; 30:1584-5; author reply 1586-7. [PMID: 16178075 DOI: 10.1038/sj.npp.1300775] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Lang UE, Hellweg R, Kalus P, Bajbouj M, Lenzen KP, Sander T, Kunz D, Gallinat J. Association of a functional BDNF polymorphism and anxiety-related personality traits. Psychopharmacology (Berl) 2005; 180:95-9. [PMID: 15918078 DOI: 10.1007/s00213-004-2137-7] [Citation(s) in RCA: 204] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2004] [Accepted: 11/18/2004] [Indexed: 10/25/2022]
Abstract
RATIONALE Converging lines of evidence point to brain-derived neurotrophic factor (BDNF) as a factor in the pathophysiology of depression. Recently, it was shown that the Val allele of the BDNF Val66Met substitution polymorphism showed a significant association with higher mean neuroticism scores of the NEO-Five Factor Inventory (NEO-FFI) in healthy subjects, and previous studies suggested the Val allele to be increased in bipolar disorder families. The association to anxiety-related traits has not been investigated so far. METHODS We tested a total of 343 unrelated subjects of German descent (171 male, 172 female, age: 39.0+/-14.6 years) who were carefully screened for psychiatric health. The self-ratable State-Trait Anxiety Inventory (STAI), which allows anxiety to be quantified as a comparatively stable personality trait, and the NEO-Five Factor Inventory (NEO-FFI) was applied. RESULTS In the trait-related anxiety score, a significant (F=3.2, df=2, p<0.042) effect of the genotype was observed with higher levels of trait anxiety in Val/Val (35.0+/-7.4) compared to Val/Met (33.4+/-6.5) and Met/Met (32.0+/-4.6) genotypes. The NEO neuroticism scores were also higher in Val/Val (29.5+/-7.0) than in Val/Met (28.4+/-6.5) or Met/Met (26.8+/-5.8) genotype, but not at a significant rate. CONCLUSIONS Our findings support the hypothesis that anxiety- and depression-related personality traits are associated with the BDNF polymorphism although the explained variance is low.
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Affiliation(s)
- Undine E Lang
- Department of Neurology, University of Tuebingen, Hoppe-Seyler-Str. 3, 72076 Tuebingen, Germany
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Gallinat J, Ströhle A, Lang UE, Bajbouj M, Kalus P, Montag C, Seifert F, Wernicke C, Rommelspacher H, Rinneberg H, Schubert F. Association of human hippocampal neurochemistry, serotonin transporter genetic variation, and anxiety. Neuroimage 2005; 26:123-31. [PMID: 15862212 DOI: 10.1016/j.neuroimage.2005.01.001] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2004] [Revised: 12/19/2004] [Accepted: 01/08/2005] [Indexed: 12/01/2022] Open
Abstract
The impact of the serotonin transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR) on anxiety-related behavior and related cerebral activation has facilitated the understanding of neurobiological mechanisms of anxiety. However, the influence of the 5-HTTLPR genotype on hippocampal neuronal development and neurochemistry, which is relevant to anxiety behavior, has not been investigated. In 38 healthy subjects, absolute concentrations of N-acetylaspartate (NAA) were measured as a main surrogate parameter for hippocampal neurochemistry on a 3-T scanner. A significantly lower hippocampal NAA concentration in s allele carriers was observed as compared to l/l genotype. Other metabolites (choline, creatine + phosphocreatine, glutamate) were unaffected by genotype. The hippocampal NAA concentration was negatively correlated with trait anxiety scores (STAI). Metabolites measured in the anterior cingulate cortex (reference region) were not associated with genotype. The results are in accordance with the recently reported relationship between hippocampal neuronal development and anxiety behavior in adult animals and show an association between human limbic neurochemistry and genetically driven serotonergic neurotransmission relevant to anxiety.
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Affiliation(s)
- Jürgen Gallinat
- Clinic for Psychiatry and Psychotherapy, Charité University Medicine, Berlin, Germany.
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