|
1
|
Yaseen AA, Alzoubi KH, Al-Sawalha N, Khabour OF, Jarab A, Ali S, Salim S, Eissenberg T. The impact of electronic cigarette aerosol exposure on spatial memory formation: Modulation by orally administered vitamin E. Neurotoxicology 2024; 105:263-271. [PMID: 39488233 DOI: 10.1016/j.neuro.2024.10.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2024] [Revised: 10/19/2024] [Accepted: 10/30/2024] [Indexed: 11/04/2024]
Abstract
The use of electronic cigarettes (ECIGs) has grown exponentially among young adolescents. Tobacco smoking, in general and ECIG use in particular, has been linked to disruption of the oxidative system, resulting in organ damage. The current investigation intends to evaluate if orally administered Vitamin E (VitE) can protect from learning and cognitive impairment induced by ECIG aerosol exposure in a rat model. This effect was determined by studying behavioral and molecular targets for potential learning and memory impairment. Adult Wistar rats were assigned to the following groups (N= 12/group): Control, ECIG, VitE, and VitE+ECIG. The animals in the groups ECIG and VitE+ECIG were exposed to ECIG aerosol (1 hr/day, 6 days/week) for four weeks. The control group and VitE group were exposed to fresh air. At the same time, the VitE group and VitE+ECIG group were given Vitamin E 100 mg/kg/ day via gavage for the same period as the exposure. The control group and ECIG group were given the vehicle via gavage. Behavioral assessment was performed using the Radial Arm Water Maze. In addition, molecular measures (BDNF, SOD, GPx, GSH, and GSSG), were measured in rats' hippocampal tissues. The results showed that VitE prevented ECIG aerosol exposure-induced impairment of spatial short-term and long-term memory formation (p<0.05), decreased BDNF, and activities/levels of GPx, SOD, and GSH (p<0.05). Moreover, VitE protected against GSSG levels increases (p<0.05) associated with ECIG aerosol exposure. In summary, exposure to ECIGs resulted in spatial memory impairments, which could be mitigated by orally administered vitamin E.
Collapse
Affiliation(s)
- Aiman A Yaseen
- Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan
| | - Karem H Alzoubi
- Department of Pharmacy Practice and Pharmacotherapeutics, University of Sharjah, Sharjah, United Arab Emirates; Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan.
| | - Nour Al-Sawalha
- Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan
| | - Omar F Khabour
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, Jordan University of Science and Technology, Irbid, Jordan
| | - Anan Jarab
- College of Pharmacy, Al Ain University, Abu Dhabi, United Arab Emirates; AAU Health and Biomedical Research Center, Al Ain University, Abu Dhabi, United Arab Emirates; Department of Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan
| | - Shirin Ali
- Research Institute of Medical & Health Sciences (RIMHS), University of Sharjah, Sharjah, United Arab Emirates
| | - Samina Salim
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, USA
| | - Thomas Eissenberg
- Department of Psychology, Virginia Commonwealth University, Richmond, VA, USA; Center for the Study of Tobacco Products, Virginia Commonwealth University, Richmond, VA, USA
| |
Collapse
|
|
2
|
Gold WA, Percy AK, Neul JL, Cobb SR, Pozzo-Miller L, Issar JK, Ben-Zeev B, Vignoli A, Kaufmann WE. Rett syndrome. Nat Rev Dis Primers 2024; 10:84. [PMID: 39511247 DOI: 10.1038/s41572-024-00568-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/02/2024] [Indexed: 11/15/2024]
Abstract
Rett syndrome (RTT) is a severe, progressive, neurodevelopmental disorder, which affects predominantly females. In most cases, RTT is associated with pathogenic variants in MECP2. MeCP2, the protein product of MECP2, is known to regulate gene expression and is highly expressed in the brain. RTT is characterized by developmental regression of spoken language and hand use that, with hand stereotypies and impaired ambulation, constitute the four core diagnostic features. Affected individuals may present multiple other neurological impairments and comorbidities, such as seizures, breathing irregularities, anxiety and constipation. Studies employing neuroimaging, neuropathology, neurochemistry and animal models show reductions in brain size and global decreases in neuronal size, as well as alterations in multiple neurotransmitter systems. Management of RTT is mainly focused on preventing the progression of symptoms, currently improved by guidelines based on natural history studies. Animal and cellular models of MeCP2 deficiency have helped in understanding the pathophysiology of RTT and guided the development of trofinetide, an IGF1-related compound, which is an approved drug for RTT, as well as of other drugs and gene therapies currently under investigation.
Collapse
Affiliation(s)
- Wendy A Gold
- Molecular Neurobiology Research Laboratory, Kids Research and Kids Neuroscience Centre, The Children's Hospital at Westmead, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
- Children's Medical Research Institute, Faculty of Medicine and Health, University of Sydney, Westmead, New South Wales, Australia
| | - Alan K Percy
- Department of Pediatrics (Neurology), University of Alabama at Birmingham, Birmingham, AL, USA
| | - Jeffrey L Neul
- Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Stuart R Cobb
- Simons Initiative for the Developing Brain, Centre for Discovery Brain Sciences, University of Edinburgh Medical School, Edinburgh, UK
| | - Lucas Pozzo-Miller
- Department of Pediatrics & Human Development, College of Human Medicine, Michigan State University, Grand Rapids, MI, USA
| | - Jasmeen K Issar
- Molecular Neurobiology Research Laboratory, Kids Research and Kids Neuroscience Centre, The Children's Hospital at Westmead, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
| | - Bruria Ben-Zeev
- Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel
- Tel Aviv University School of Medicine, Tel Aviv, Israel
| | - Aglaia Vignoli
- Childhood and Adolescence Neurology & Psychiatry Unit, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
- Department of Health Sciences, University of Milan, Milan, Italy
| | - Walter E Kaufmann
- Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
| |
Collapse
|
|
3
|
Hayat MR, Umair M, Ikhtiar H, Wazir S, Palwasha A, Shah M. The Relationship Between Brain-Derived Neurotrophic Factor and Serotonin in Major Depressive and Bipolar Disorders: A Cross-Sectional Analysis. Cureus 2024; 16:e70728. [PMID: 39493096 PMCID: PMC11530576 DOI: 10.7759/cureus.70728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/02/2024] [Indexed: 11/05/2024] Open
Abstract
Background Mood disorders like major depressive disorder (MDD) and bipolar disorder (BD) involve complex interactions between brain-derived neurotrophic factor (BDNF) and serotonin. While extensive research has explored these factors individually, their combined effects and interactions in these disorders are less understood. This study uniquely addresses this gap by examining how BDNF and serotonin interact and relate to mood disorder severity, providing new insights into their joint role in MDD and BD. Objectives The objective of this study was to examine the correlation between serum BDNF and plasma serotonin levels and to assess how these correlations relate to the severity of symptoms and overall disease severity in MDD and BD. Methodology This cross-sectional study, conducted at the Khyber Medical University, Peshawar, from January to September 2023, examined the correlation between BDNF and serotonin in individuals with MDD and BD. Participants (n = 63) aged 18-65 were recruited based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, excluding those with neurological disorders, substance abuse, or severe medical illness. A control group of 21 healthy individuals was matched by age and gender. Data collection involved demographic details, clinical history, and comorbid diagnoses assessed using the Mini International Neuropsychiatric Interview (MINI). Mood disorder severity was measured using the Hamilton Depression Rating Scale (HAM-D) for MDD and the Young Mania Rating Scale (YMRS) for BD, along with additional assessments (Beck Depression Inventory, Global Assessment of Functioning). Serum BDNF and serotonin levels were analyzed using enzyme-linked immunosorbent assay (ELISA) kits. Statistical analyses included t-tests, Mann-Whitney U tests, Pearson correlations, and subgroup analyses to assess relationships between biomarkers, mood disorder severity, and influencing factors. Results BDNF levels were found to be 20.1 ± 5.3 ng/mL in MDD, 18.5 ± 4.7 ng/mL in BD, and 25.9 ± 6.2 ng/mL in controls. Serotonin levels were 45.8 ± 12.6 ng/mL in MDD, 43.2 ± 11.4 ng/mL in BD, and 52.1 ± 14.3 ng/mL in controls. In the MDD group, significant negative correlations were observed between BDNF levels and mood disorder severity (r = -0.32, p = 0.045), whereas serotonin levels did not show significant correlations (r = -0.21, p = 0.23). In the BD group, BDNF levels also showed a significant negative correlation with manic symptoms (r = -0.28, p = 0.048), but serotonin levels showed no significant correlation. Subgroup analyses revealed that participants under 40 years had higher BDNF levels (22.8 ± 5.6 ng/mL) compared to those aged 40 and above (19.7 ± 4.3 ng/mL). Females showed higher BDNF levels (24.5 ± 6.3 ng/mL) than males (19.3 ± 3.8 ng/mL). Participants not on medication had higher BDNF levels (23.6 ± 5.1 ng/mL) compared to those on medication (17.9 ± 4.2 ng/mL). Those without comorbidities also had higher BDNF levels (23.8 ± 5.9 ng/mL) than those with comorbidities (18.2 ± 4.5 ng/mL), while serotonin levels varied similarly across these subgroups. Conclusion Lower BDNF levels are associated with mood disorders and symptom severity, indicating their potential as a biomarker.
Collapse
Affiliation(s)
- Mian Rohail Hayat
- Department of Psychiatry, Mardan Medical Complex, Medical Teaching Institution (MTI), Mardan, PAK
| | - Muhammad Umair
- Department of Physiology, Gomal Medical College, Medical Teaching Institution (MTI), Dera Ismail Khan, PAK
| | - Hina Ikhtiar
- Department of Biochemistry, Kabir Medical College, Gandhara University, Peshawar, PAK
| | - Shandana Wazir
- Department of Anatomy, Bacha Khan Medical College, Mardan, PAK
| | - Ameena Palwasha
- Department of Physiology, Jinnah Medical College, Peshawar, PAK
| | - Maheen Shah
- Department of Physiology, Abbottabad International Medical Institute, Abbottabad, PAK
| |
Collapse
|
|
4
|
Cramer SC, Parodi L, Moslemi Z, Braun R, Aldridge C, Shahbaba B, Rosand J, Holman EA. Genetic Variation and Stroke Recovery: The STRONG Study. Stroke 2024; 55:2094-2102. [PMID: 38979623 PMCID: PMC11262965 DOI: 10.1161/strokeaha.124.047643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Accepted: 06/12/2024] [Indexed: 07/10/2024]
Abstract
BACKGROUND Genetic association studies can reveal biology and treatment targets but have received limited attention for stroke recovery. STRONG (Stroke, Stress, Rehabilitation, and Genetics) was a prospective, longitudinal (1-year), genetic study in adults with stroke at 28 US stroke centers. The primary aim was to examine the association that candidate genetic variants have with (1) motor/functional outcomes and (2) stress-related outcomes. METHODS For motor/functional end points, 3 candidate gene variants (ApoE ε4, BDNF [brain-derived neurotrophic factor], and a dopamine polygenic score) were analyzed for associations with change in grip strength (3 months-baseline), function (3-month Stroke Impact Scale-Activities of Daily Living), mood (3-month Patient Health Questionnaire-8), and cognition (12-month telephone-Montreal Cognitive Assessment). For stress-related outcomes, 7 variants (serotonin transporter gene-linked promoter region, ACE [angiotensin-converting enzyme], oxytocin receptor, FKBP5 [FKBP prolyl isomerase 5], FAAH [fatty acid amide hydrolase], BDNF, and COMT [catechol-O-methyltransferase]) were assessed for associations with posttraumatic stress disorder ([PTSD]; PTSD Primary Care Scale) and depression (Patient Health Questionnaire-8) at 6 and 12 months; stress-related genes were examined as a function of poststroke stress level. Statistical models (linear, negative binomial, or Poisson regression) were based on response variable distribution; all included stroke severity, age, sex, and ancestry as covariates. Stroke subtype was explored secondarily. Data were Holm-Bonferroni corrected. A secondary replication analysis tested whether the rs1842681 polymorphism (identified in the GISCOME study [Genetics of Ischaemic Stroke Functional Outcome]) was related to 3-month modified Rankin Scale score in STRONG. RESULTS The 763 enrollees were 63.1±14.9 (mean±SD) years of age, with a median initial National Institutes of Health Stroke Scale score of 4 (interquartile range, 2-9); outcome data were available in n=515 at 3 months, n=500 at 6 months, and n=489 at 12 months. At 1 year poststroke, the rs6265 (BDNF) variant was associated with poorer cognition (0.9-point lower telephone-Montreal Cognitive Assessment score, P=1×10-5). For stress-related outcomes, rs4291 (ACE) and rs324420 (FAAH) were risk factors linking increased poststroke stress with higher 1-year depression and PTSD symptoms (P<0.05), while rs4680 (COMT) linked poststroke stress with lower 1-year depression and PTSD. Findings were unchanged when considering stroke subtype. STRONG replicated GISCOME: rs1842681 was associated with lower 3-month modified Rankin Scale score (P=3.2×10-5). CONCLUSIONS This study identified genetic associations with cognitive function, depression, and PTSD 1 year poststroke. Genetic susceptibility to PTSD and depressive symptoms varied according to the amount of poststroke stress, underscoring the critical role of lived experiences in recovery. Together, the results suggest that genetic association studies provide insights into the biology of stroke recovery in humans.
Collapse
Affiliation(s)
- Steven C. Cramer
- Dept. Neurology, UCLA; California Rehabilitation Institute; Los Angeles, CA
| | - Livia Parodi
- Dept. Neurology, Center for Genomic Medicine, McCance Center for Brain Health, MGH; Boston, MA
| | | | | | - Chad Aldridge
- Dept. Neurology, Univ. Virginia; Charlottesville, VA
| | | | - Jonathan Rosand
- Dept. Neurology, Center for Genomic Medicine, McCance Center for Brain Health, MGH; Boston, MA
| | - E. Alison Holman
- Sue & Bill Gross School of Nursing and Dept. Psychological Science; UC, Irvine; Irvine, CA
| |
Collapse
|
|
5
|
Carnwath TP, Demel SL, Prestigiacomo CJ. Genetics of ischemic stroke functional outcome. J Neurol 2024; 271:2345-2369. [PMID: 38502340 PMCID: PMC11055934 DOI: 10.1007/s00415-024-12263-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 02/14/2024] [Accepted: 02/15/2024] [Indexed: 03/21/2024]
Abstract
Ischemic stroke, which accounts for 87% of cerebrovascular accidents, is responsible for massive global burden both in terms of economic cost and personal hardship. Many stroke survivors face long-term disability-a phenotype associated with an increasing number of genetic variants. While clinical variables such as stroke severity greatly impact recovery, genetic polymorphisms linked to functional outcome may offer physicians a unique opportunity to deliver personalized care based on their patient's genetic makeup, leading to improved outcomes. A comprehensive catalogue of the variants at play is required for such an approach. In this review, we compile and describe the polymorphisms associated with outcome scores such as modified Rankin Scale and Barthel Index. Our search identified 74 known genetic polymorphisms spread across 48 features associated with various poststroke disability metrics. The known variants span diverse biological systems and are related to inflammation, vascular homeostasis, growth factors, metabolism, the p53 regulatory pathway, and mitochondrial variation. Understanding how these variants influence functional outcome may be helpful in maximizing poststroke recovery.
Collapse
Affiliation(s)
- Troy P Carnwath
- University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA.
| | - Stacie L Demel
- Department of Neurology, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA
| | - Charles J Prestigiacomo
- Department of Neurosurgery, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA
| |
Collapse
|
|
6
|
Koyya P, Manthari RK, Pandrangi SL. Brain-Derived Neurotrophic Factor - The Protective Agent Against Neurological Disorders. CNS & NEUROLOGICAL DISORDERS DRUG TARGETS 2024; 23:353-366. [PMID: 37287291 PMCID: PMC11348470 DOI: 10.2174/1871527322666230607110617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 05/19/2023] [Accepted: 05/29/2023] [Indexed: 06/09/2023]
Abstract
The burden of neurological illnesses on global health is significant. Our perception of the molecular and biological mechanisms underlying intellectual processing and behavior has significantly advanced over the last few decades, laying the groundwork for potential therapies for various neurodegenerative diseases. A growing body of literature reveals that most neurodegenerative diseases could be due to the gradual failure of neurons in the brain's neocortex, hippocampus, and various subcortical areas. Research on various experimental models has uncovered several gene components to understand the pathogenesis of neurodegenerative disorders. One among them is the brain-derived neurotrophic factor (BDNF), which performs several vital functions, enhancing synaptic plasticity and assisting in the emergence of long-term thoughts. The pathophysiology of some neurodegenerative diseases, including Alzheimer's, Parkinson's, Schizophrenia, and Huntington's, has been linked to BDNF. According to numerous research, high levels of BDNF are connected to a lower risk of developing a neurodegenerative disease. As a result, we want to concentrate on BDNF in this article and outline its protective role against neurological disorders.
Collapse
Affiliation(s)
- Prathyusha Koyya
- Department of Biotechnology, GITAM School of Science, Gandhi Institute of Technology and Management (Deemed to be University), Visakhapatnam-530045, Andhra Pradesh, India
| | - Ram Kumar Manthari
- Department of Biotechnology, GITAM School of Science, Gandhi Institute of Technology and Management (Deemed to be University), Visakhapatnam-530045, Andhra Pradesh, India
| | - Santhi Latha Pandrangi
- Department of Biochemistry and Bioinformatics, GITAM School of Science, Gandhi Institute of Technology and Management (Deemed to be University), Visakhapatnam-530045, Andhra Pradesh, India
| |
Collapse
|
|
7
|
Tomás AM, Bento-Torres NVO, Jardim NYV, Moraes PM, da Costa VO, Modesto AC, Khayat AS, Bento-Torres J, Picanço-Diniz CW. Risk Polymorphisms of FNDC5, BDNF, and NTRK2 and Poor Education Interact and Aggravate Age-Related Cognitive Decline. Int J Mol Sci 2023; 24:17210. [PMID: 38139046 PMCID: PMC10743741 DOI: 10.3390/ijms242417210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 11/07/2023] [Accepted: 11/17/2023] [Indexed: 12/24/2023] Open
Abstract
Cognitive abilities tend to decline with aging, with variation between individuals, and many studies seek to identify genetic biomarkers that more accurately anticipate risks related to pathological aging. We investigated the influence of BDNF, NTRK2, and FNDC5 single nucleotide polymorphisms (SNPs) on the cognitive performance of young and older adults with contrasting educational backgrounds. We addressed three questions: (1) Is education associated with reduced age-related cognitive decline? (2) Does the presence of SNPs explain the variation in cognitive performance observed late in life? (3) Is education differentially associated with cognition based on the presence of BDNF, NTRK2, or FNDC5 polymorphisms? We measured the cognitive functions of young and older participants, with lower and higher education, using specific and sensitive tests of the Cambridge Automated Neuropsychological Test Assessment Battery. A three-way ANOVA revealed that SNPs were associated with differential performances in executive functions, episodic memory, sustained attention, mental and motor response speed, and visual recognition memory and that higher educational levels improved the affected cognitive functions. The results revealed that distinct SNPs affect cognition late in life differentially, suggesting their utility as potential biomarkers and emphasizing the importance of cognitive stimulation that advanced education early in life provides.
Collapse
Affiliation(s)
- Alessandra Mendonça Tomás
- Neurodegeneration and Infection Research Laboratory, Institute of Biological Science, João de Barros Barreto University Hospital, Federal University of Pará, Belém 66073-000, Brazil; (A.M.T.); (N.Y.V.J.); (P.M.M.); (V.O.d.C.); (J.B.-T.); (C.W.P.-D.)
- Department of Physical Education, Federal University of Pará Application School, Belém 66095-780, Brazil
| | - Natáli Valim Oliver Bento-Torres
- Neurodegeneration and Infection Research Laboratory, Institute of Biological Science, João de Barros Barreto University Hospital, Federal University of Pará, Belém 66073-000, Brazil; (A.M.T.); (N.Y.V.J.); (P.M.M.); (V.O.d.C.); (J.B.-T.); (C.W.P.-D.)
- Graduate Program in Human Movement Sciences, Federal University of Pará, Belém 66095-780, Brazil
| | - Naina Yuki Vieira Jardim
- Neurodegeneration and Infection Research Laboratory, Institute of Biological Science, João de Barros Barreto University Hospital, Federal University of Pará, Belém 66073-000, Brazil; (A.M.T.); (N.Y.V.J.); (P.M.M.); (V.O.d.C.); (J.B.-T.); (C.W.P.-D.)
- Graduate Program in Neuroscience and Cell Biology, Federal University of Pará, Belém 66050-160, Brazil
| | - Patrícia Martins Moraes
- Neurodegeneration and Infection Research Laboratory, Institute of Biological Science, João de Barros Barreto University Hospital, Federal University of Pará, Belém 66073-000, Brazil; (A.M.T.); (N.Y.V.J.); (P.M.M.); (V.O.d.C.); (J.B.-T.); (C.W.P.-D.)
- Graduate Program in Human Movement Sciences, Federal University of Pará, Belém 66095-780, Brazil
| | - Victor Oliveira da Costa
- Neurodegeneration and Infection Research Laboratory, Institute of Biological Science, João de Barros Barreto University Hospital, Federal University of Pará, Belém 66073-000, Brazil; (A.M.T.); (N.Y.V.J.); (P.M.M.); (V.O.d.C.); (J.B.-T.); (C.W.P.-D.)
- Graduate Program in Neuroscience and Cell Biology, Federal University of Pará, Belém 66050-160, Brazil
| | - Antônio Conde Modesto
- Oncology Research Center (NPO), Graduate Program in Oncology and Medical Sciences, Federal University of Pará, Belém 66073-000, Brazil; (A.C.M.); (A.S.K.)
| | - André Salim Khayat
- Oncology Research Center (NPO), Graduate Program in Oncology and Medical Sciences, Federal University of Pará, Belém 66073-000, Brazil; (A.C.M.); (A.S.K.)
| | - João Bento-Torres
- Neurodegeneration and Infection Research Laboratory, Institute of Biological Science, João de Barros Barreto University Hospital, Federal University of Pará, Belém 66073-000, Brazil; (A.M.T.); (N.Y.V.J.); (P.M.M.); (V.O.d.C.); (J.B.-T.); (C.W.P.-D.)
- Graduate Program in Human Movement Sciences, Federal University of Pará, Belém 66095-780, Brazil
| | - Cristovam Wanderley Picanço-Diniz
- Neurodegeneration and Infection Research Laboratory, Institute of Biological Science, João de Barros Barreto University Hospital, Federal University of Pará, Belém 66073-000, Brazil; (A.M.T.); (N.Y.V.J.); (P.M.M.); (V.O.d.C.); (J.B.-T.); (C.W.P.-D.)
- Graduate Program in Neuroscience and Cell Biology, Federal University of Pará, Belém 66050-160, Brazil
- Oncology Research Center (NPO), Graduate Program in Oncology and Medical Sciences, Federal University of Pará, Belém 66073-000, Brazil; (A.C.M.); (A.S.K.)
| |
Collapse
|
|
8
|
Olié E, Lengvenyte A, Courtet P. [How can ketamine be used to manage suicidal risk?]. Biol Aujourdhui 2023; 217:157-160. [PMID: 38018943 DOI: 10.1051/jbio/2023029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Indexed: 11/30/2023]
Abstract
In France, suicidal behaviors remain a major public health issue. Depressed patients with suicidal ideation have more severe depressive symptoms, a more unfavorable disease course, and a greater number of suicide attempts than patients without suicidal ideation. Unfortunately, conventional antidepressants tend to be less effective in patients with suicidal tendencies than in those without. Nevertheless, promising advancements have emerged with the use of ketamine, which has shown significant and rapid efficacy in reducing the intensity of suicidal ideation in depressed patients within the first 72 h after its administration. Several mechanisms are potentially involved: (1) reduction of anhedonia. It has been demonstrated that ketamine reduces both anhedonia and suicidal ideation. In depressed patients, the reduction of anhedonia observed 2 h after ketamine administration is associated with metabolic changes in the anterior cingulate cortex involved in suicidal ideation; (2) activation of neuroplasticity cascades. The reduction in suicidal ideation within 24 h following ketamine administration is correlated with changes in plasma BDNF levels and is modulated by the Val66Met functional polymorphism of the BDNF gene. Moreover, preclinical and clinical studies have shown that ketamine induces functional and connectivity changes in the prefrontal and anterior cingulate regions, which are strongly implicated in suicidal behaviors; (3) reduction of inflammation. It is now widely accepted that suicidal behaviors are associated with low-grade inflammation, and with elevated quinolinic acid and reduced kynurenic acid levels. Interestingly, predictors of a reduction in suicidal ideation after ketamine infusion include initial severity of suicidal thoughts and depression, as well as baseline blood levels of kynurenic acid; (4) involvement of the opioidergic system. Post-mortem studies have indicated alterations in the opioidergic system related to suicidal behaviors. A recent study suggested that the antisuicidal effect of ketamine may depend on this system because naltrexone, an antagonist of mu opioid receptors, abolished the typical antidepressant effect and reduction in suicidal ideation observed following ketamine administration. In conclusion, ketamine exhibits promising potential in mitigating suicidal ideation - its effects are specific, rapid, albeit temporary. The suggested mechanisms driving its efficacy are multifaceted. Nevertheless, it is yet to be determined whether ketamine administration can effectively prevent suicidal behaviors.
Collapse
Affiliation(s)
- Emilie Olié
- Département Urgences et Post-Urgences Psychiatriques, CHU Lapeyronie, Hôpital Lapeyronie, 371 avenue du Doyen Gaston Giraud, 34295 Montpellier Cedex 5, France
| | - Aisté Lengvenyte
- Département Urgences et Post-Urgences Psychiatriques, CHU Lapeyronie, Hôpital Lapeyronie, 371 avenue du Doyen Gaston Giraud, 34295 Montpellier Cedex 5, France
| | - Philippe Courtet
- Département Urgences et Post-Urgences Psychiatriques, CHU Lapeyronie, Hôpital Lapeyronie, 371 avenue du Doyen Gaston Giraud, 34295 Montpellier Cedex 5, France
| |
Collapse
|
|
9
|
Lacroix A, Ramoz N, Girard M, Plansont B, Poupon D, Gorwood P, Nubukpo P. BDNF CpG methylation and serum levels covary during alcohol withdrawal in patients with alcohol use disorder: A pilot study. World J Biol Psychiatry 2023; 24:854-859. [PMID: 37526632 DOI: 10.1080/15622975.2023.2242924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 07/04/2023] [Accepted: 07/27/2023] [Indexed: 08/02/2023]
Abstract
OBJECTIVES Brain-derived neurotrophic factor (BDNF) levels vary in various conditions including alcohol use disorder (AUD). We aimed to identify drivers of these variations. METHODS Twelve patients with AUD were assessed at hospitalisation for alcohol withdrawal and four months later. We looked for associations between the change in serum BDNF levels and (1) length of abstinence, (2) anxiety (Hamilton Anxiety Scale) and depression (Beck-Depression Inventory), (3) one functional BDNF genotype (rs6265) and (4) methylation levels of 12 CpG sites within the BDNF gene (located in exons I, IV and IX). RESULTS While abstinence remained, serum BDNF level increased. This increase correlated with the variation of methylation levels of the BDNF gene, and more specifically of exon I. We found no significant effect of length of abstinence, rs6265, depression or anxiety on serum BDNF level. CONCLUSIONS Epigenetic regulation of the BDNF gene may be involved in variations of BDNF blood level associated with alcohol abstinence.
Collapse
Affiliation(s)
- Aurélie Lacroix
- Unité de Recherche et d'Innovation, Fédération de la recherche et de l'innovation, Centre Hospitalier Esquirol, Limoges, France
- Inserm U1094, IRD U270, Univ. Limoges, CHU Limoges, EpiMaCT - Epidemiology of Chronic Diseases in Tropical Zone, Institute of Epidemiology and Tropical Neurology, OmegaHealth, Limoges, France
| | - Nicolas Ramoz
- Université Paris Cité, INSERM, U1266 (Institute of Psychiatry and Neuroscience of Paris), Paris, France
| | - Murielle Girard
- Unité de Recherche et d'Innovation, Fédération de la recherche et de l'innovation, Centre Hospitalier Esquirol, Limoges, France
- Inserm U1094, IRD U270, Univ. Limoges, CHU Limoges, EpiMaCT - Epidemiology of Chronic Diseases in Tropical Zone, Institute of Epidemiology and Tropical Neurology, OmegaHealth, Limoges, France
| | - Brigitte Plansont
- Unité de Recherche et d'Innovation, Fédération de la recherche et de l'innovation, Centre Hospitalier Esquirol, Limoges, France
| | - Daphnée Poupon
- Clinique des Maladies Mentales et de l'Encéphale (CMME), Sainte-Anne Hospital, GHU Paris Psychiatrie et Neurosciences, Paris, France
| | - Philip Gorwood
- Université Paris Cité, INSERM, U1266 (Institute of Psychiatry and Neuroscience of Paris), Paris, France
- Clinique des Maladies Mentales et de l'Encéphale (CMME), Sainte-Anne Hospital, GHU Paris Psychiatrie et Neurosciences, Paris, France
| | - Philippe Nubukpo
- Unité de Recherche et d'Innovation, Fédération de la recherche et de l'innovation, Centre Hospitalier Esquirol, Limoges, France
- Inserm U1094, IRD U270, Univ. Limoges, CHU Limoges, EpiMaCT - Epidemiology of Chronic Diseases in Tropical Zone, Institute of Epidemiology and Tropical Neurology, OmegaHealth, Limoges, France
- Pôle Universitaire d'Addictologie, Centre Hospitalier Esquirol, Limoges, France
| |
Collapse
|
|
10
|
De Felice G, Luciano M, Boiano A, Colangelo G, Catapano P, Della Rocca B, Lapadula MV, Piegari E, Toni C, Fiorillo A. Can Brain-Derived Neurotrophic Factor Be Considered a Biomarker for Bipolar Disorder? An Analysis of the Current Evidence. Brain Sci 2023; 13:1221. [PMID: 37626577 PMCID: PMC10452328 DOI: 10.3390/brainsci13081221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 08/15/2023] [Accepted: 08/17/2023] [Indexed: 08/27/2023] Open
Abstract
Brain-derived neurotrophic factor (BDNF) plays a key role in brain development, contributing to neuronal survival and neuroplasticity. Previous works have found that BDNF is involved in several neurological or psychiatric diseases. In this review, we aimed to collect all available data on BDNF and bipolar disorder (BD) and assess if BDNF could be considered a biomarker for BD. We searched the most relevant medical databases and included studies reporting original data on BDNF circulating levels or Val66Met polymorphism. Only articles including a direct comparison with healthy controls (HC) and patients diagnosed with BD according to international classification systems were included. Of the 2430 identified articles, 29 were included in the present review. Results of the present review show a reduction in BDNF circulating levels during acute phases of BD compared to HC, which increase after effective therapy of the disorders. The Val66Met polymorphism was related to features usually associated with worse outcomes. High heterogeneity has been observed regarding sample size, clinical differences of included patients, and data analysis approaches, reducing comparisons among studies. Although more studies are needed, BDNF seems to be a promising biomarker for BD.
Collapse
Affiliation(s)
| | - Mario Luciano
- Department of Psychiatry, University of Campania Luigi Vanvitelli, 80138 Naples, Italy; (G.D.F.); (A.B.); (G.C.); (P.C.); (B.D.R.); (M.V.L.); (E.P.); (C.T.); (A.F.)
| | | | | | | | | | | | | | | | | |
Collapse
|
|
11
|
Treble-Barna A, Heinsberg LW, Stec Z, Breazeale S, Davis TS, Kesbhat AA, Chattopadhyay A, VonVille HM, Ketchum AM, Yeates KO, Kochanek PM, Weeks DE, Conley YP. Brain-derived neurotrophic factor (BDNF) epigenomic modifications and brain-related phenotypes in humans: A systematic review. Neurosci Biobehav Rev 2023; 147:105078. [PMID: 36764636 PMCID: PMC10164361 DOI: 10.1016/j.neubiorev.2023.105078] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 01/17/2023] [Accepted: 02/04/2023] [Indexed: 02/11/2023]
Abstract
Epigenomic modifications of the brain-derived neurotrophic factor (BDNF) gene have been postulated to underlie the pathogenesis of neurodevelopmental, psychiatric, and neurological conditions. This systematic review summarizes current evidence investigating the association of BDNF epigenomic modifications (DNA methylation, non-coding RNA, histone modifications) with brain-related phenotypes in humans. A novel contribution is our creation of an open access web-based application, the BDNF DNA Methylation Map, to interactively visualize specific positions of CpG sites investigated across all studies for which relevant data were available. Our literature search of four databases through September 27, 2021 returned 1701 articles, of which 153 met inclusion criteria. Our review revealed exceptional heterogeneity in methodological approaches, hindering the identification of clear patterns of robust and/or replicated results. We summarize key findings and provide recommendations for future epigenomic research. The existing literature appears to remain in its infancy and requires additional rigorous research to fulfill its potential to explain BDNF-linked risk for brain-related conditions and improve our understanding of the molecular mechanisms underlying their pathogenesis.
Collapse
Affiliation(s)
- Amery Treble-Barna
- Department of Physical Medicine & Rehabilitation, School of Medicine, University of Pittsburgh, PA 15261, USA.
| | - Lacey W Heinsberg
- Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA.
| | - Zachary Stec
- Department of Physical Medicine & Rehabilitation, School of Medicine, University of Pittsburgh, PA 15261, USA.
| | - Stephen Breazeale
- Department of Health and Human Development, School of Nursing, University of Pittsburgh, Pittsburgh, PA 15261, USA.
| | - Tara S Davis
- Department of Health Promotion and Development, School of Nursing, University of Pittsburgh, PA 15261, USA.
| | | | - Ansuman Chattopadhyay
- Molecular Biology Information Service, Health Sciences Library System, University of Pittsburgh, USA
| | - Helena M VonVille
- Health Sciences Library System, University of Pittsburgh, PA 15261, USA.
| | - Andrea M Ketchum
- Emeritus Health Sciences Library System, University of Pittsburgh, Pittsburgh, PA 15261, USA.
| | - Keith Owen Yeates
- Department of Psychology, Alberta Children's Hospital Research Institute and Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N1N4, Canada.
| | - Patrick M Kochanek
- Safar Center for Resuscitation Research, Department of Critical Care Medicine, School of Medicine, University of Pittsburgh, PA 15261, USA.
| | - Daniel E Weeks
- Department of Human Genetics and Department of Biostatistics, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA.
| | - Yvette P Conley
- Department of Human Genetics, School of Nursing, University of Pittsburgh, Pittsburgh, PA 15261, USA.
| |
Collapse
|
|
12
|
Treble-Barna A, Wade SL, Pilipenko V, Martin LJ, Yeates KO, Taylor HG, Kurowski BG. Brain-derived neurotrophic factor Val66Met and neuropsychological functioning after early childhood traumatic brain injury. J Int Neuropsychol Soc 2023; 29:246-256. [PMID: 35465864 PMCID: PMC9592678 DOI: 10.1017/s1355617722000194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
OBJECTIVE The present study examined the differential effect of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism on neuropsychological functioning in children with traumatic brain injury (TBI) relative to orthopedic injury (OI). METHODS Participants were drawn from a prospective, longitudinal study of children who sustained a TBI (n = 69) or OI (n = 72) between 3 and 7 years of age. Children completed a battery of neuropsychological measures targeting attention, memory, and executive functions at four timepoints spanning the immediate post-acute period to 18 months post-injury. Children also completed a comparable age-appropriate battery of measures approximately 7 years post-injury. Parents rated children's dysexecutive behaviors at all timepoints. RESULTS Longitudinal mixed models revealed a significant allele status × injury group interaction with a medium effect size for verbal fluency. Cross-sectional models at 7 years post-injury revealed non-significant but medium effect sizes for the allele status x injury group interaction for fluid reasoning and immediate and delayed verbal memory. Post hoc stratified analyses revealed a consistent pattern of poorer neuropsychological functioning in Met carriers relative to Val/Val homozygotes in the TBI group, with small effect sizes; the opposite trend or no appreciable effect was observed in the OI group. CONCLUSIONS The results suggest a differential effect of the BDNF Val66Met polymorphism on verbal fluency, and possibly fluid reasoning and immediate and delayed verbal memory, in children with early TBI relative to OI. The Met allele-associated with reduced activity-dependent secretion of BDNF-may confer risk for poorer neuropsychological functioning in children with TBI.
Collapse
Affiliation(s)
- Amery Treble-Barna
- Assistant Professor, Department of Physical Medicine & Rehabilitation, University of Pittsburgh School of Medicine, 3471 Fifth Avenue, KAU-910, Pittsburgh, PA 15213
| | - Shari L. Wade
- Professor, Division of Physical Medicine & Rehabilitation, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, 3333 Burnet Avenue, Cincinnati, OH 45229
| | - Valentina Pilipenko
- Biostatistician, Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229
| | - Lisa J. Martin
- Professor, Division of Human Genetics, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center and the University of Cincinnati School of Medicine. 3333 Burnett Av, MLC 4012, Cincinnati OH 45229
| | - Keith Owen Yeates
- Professor, Department of Psychology, University of Calgary, 2500 University Dr NW, Calgary, AB, T2N1N4 Canada
| | - H. Gerry Taylor
- Professor, Abigail Wexner Research Institute at Nationwide Children’s Hospital, and Department of Pediatrics, The Ohio State University, 700 Children’s Drive, Columbus, OH, 43205
| | - Brad G. Kurowski
- Associate Professor, Division of Pediatric Rehabilitation Medicine, Cincinnati Children’s Hospital Medical Center, Departments of Pediatrics and Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 3333 Burnett Av, MLC 4009, Cincinnati OH 45229
| |
Collapse
|
|
13
|
Singh S, Fereshetyan K, Shorter S, Paliokha R, Dremencov E, Yenkoyan K, Ovsepian SV. Brain-derived neurotrophic factor (BDNF) in perinatal depression: Side show or pivotal factor? Drug Discov Today 2023; 28:103467. [PMID: 36528281 DOI: 10.1016/j.drudis.2022.103467] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 12/03/2022] [Accepted: 12/09/2022] [Indexed: 12/15/2022]
Abstract
Perinatal depression is the most common psychiatric complication of pregnancy, with its detrimental effects on maternal and infant health widely underrated. There is a pressing need for specific molecular biomarkers, with pregnancy-related decline in brain-derived neurotrophic factor (BDNF) in the blood and downregulation of TrkB receptor in the brain reported in clinical and preclinical studies. In this review, we explore the emerging role of BDNF in reproductive biology and discuss evidence suggesting its deficiency as a risk factor for perinatal depression. With the increasing evidence for restoration of serum BDNF levels by antidepressant therapy, the strengthening association of perinatal depression with deficiency of BDNF supports its potential as a surrogate endpoint for preclinical and clinical studies.
Collapse
Affiliation(s)
- Saumya Singh
- Faculty of Science and Engineering, University of Greenwich London, Chatham Maritime, Kent ME4 4TB, UK
| | - Katarine Fereshetyan
- Neuroscience Laboratory, Cobrain Center, Yerevan State Medical University of M. Heratsi, 0025, Yerevan, Armenia
| | - Susan Shorter
- Faculty of Science and Engineering, University of Greenwich London, Chatham Maritime, Kent ME4 4TB, UK
| | - Ruslan Paliokha
- Centre of Biosciences, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Eliyahu Dremencov
- Centre of Biosciences, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Konstantin Yenkoyan
- Neuroscience Laboratory, Cobrain Center, Yerevan State Medical University of M. Heratsi, 0025, Yerevan, Armenia
| | - Saak V Ovsepian
- Faculty of Science and Engineering, University of Greenwich London, Chatham Maritime, Kent ME4 4TB, UK.
| |
Collapse
|
|
14
|
Wang M, Yang X, Yu J, Zhu J, Kim HD, Cruz A. Effects of Physical Activity on Inhibitory Function in Children with Attention Deficit Hyperactivity Disorder: A Systematic Review and Meta-Analysis. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2023; 20:1032. [PMID: 36673793 PMCID: PMC9859519 DOI: 10.3390/ijerph20021032] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Revised: 12/29/2022] [Accepted: 01/04/2023] [Indexed: 06/17/2023]
Abstract
This systematic review and meta-analysis aimed to systematically evaluate the effect of physical activity (PA) on inhibitory function in children with ADHD. Experimental studies on the effect of PA on the inhibitory function of children with ADHD were retrieved. The data were obtained from PubMed, The Cochrane Library, Web of Science, EBSCO (MEDLINE, APA Psyclnfo, ERIC), Embase, Scopus, and ProQuest. The search period was from the date of inception of the respective databases to 4 May 2022, and Reviewer Manager software (version 5.3) was used for analysis. Eleven articles and 713 samples were included in the meta-analysis. Results revealed that PA can significantly improve the inhibitory function of children with ADHD (SMD = 0.78, 95% CI: 0.45−1.10, p < 0.001). Subgroup analysis showed that the effectiveness of PA as an intervention in improving the inhibitory function of children with ADHD was moderated by the frequency, intensity, duration, type, and length of intervention. Based on the findings, PA can effectively improve interference suppression inhibitory function in children with ADHD. Longitudinal open-skill exercise for 60 min or more, two times/week has the best effect on improving inhibitory function in children with ADHD.
Collapse
Affiliation(s)
- Meng Wang
- Department of Physical Education, Keimyung University, Daegu 42601, Republic of Korea
| | - Xinyue Yang
- College of Sports Science, Shenyang Normal University, Shenyang 110034, China
| | - Jing Yu
- College of Sports Science, Shenyang Normal University, Shenyang 110034, China
| | - Jian Zhu
- Department of Physical Education, Zhongyuan University of Technology, Zhengzhou 450007, China
| | - Hyun-Duck Kim
- Department of Sport Marketing, Keimyung University, Daegu 42601, Republic of Korea
| | - Angelita Cruz
- Department of Physical Education, Keimyung University, Daegu 42601, Republic of Korea
| |
Collapse
|
|
15
|
The BDNF Val66Met Polymorphism Does Not Increase Susceptibility to Activity-Based Anorexia in Rats. BIOLOGY 2022; 11:biology11050623. [PMID: 35625351 PMCID: PMC9138045 DOI: 10.3390/biology11050623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Revised: 04/13/2022] [Accepted: 04/17/2022] [Indexed: 11/18/2022]
Abstract
Simple Summary Genetic animal models are a valuable tool for understanding how human pathologies develop. The type of animal model chosen is important for uncovering effects specific to certain behaviours and neurobiological functions. A polymorphism in the brain-derived neurotrophic factor (BDNF) has been linked with various clinical conditions in human subjects and with mouse models of anorectic behaviour. This study investigated for the first time the role of the BDNF Val66Met allelic substitution in a rat model of anorexia nervosa (AN), known as activity-based anorexia (ABA). Contrary to reports of altered BDNF signaling in patients with AN and increased anorectic behaviour in a mouse model containing the same allelic variation, it showed that 66Met did not alter susceptibility to weight loss or aspects of energy balance, including feeding and exercise in the rat model. It highlights the need to consider species–specific differences when evaluating animal models of human pathologies. Abstract Brain-derived neurotrophic factor (BDNF) is abundantly expressed in brain regions involved in both homeostatic and hedonic feeding, and it circulates at reduced levels in patients with anorexia nervosa (AN). A single nucleotide polymorphism in the gene encoding for BDNF (Val66Met) has been associated with worse outcomes in patients with AN, and it is shown to promote anorectic behaviour in a mouse model of caloric restriction paired with social isolation stress. Previous animal models of the Val66Met polymorphism have been in mice because of the greater ease in modification of the mouse genome, however, the most widely-accepted animal model of AN, known as activity-based anorexia (ABA), is most commonly conducted in rats. Here, we examine ABA outcomes in a novel rat model of the BDNF Val66Met allelic variation (Val68Met), and we investigate the role of this polymorphism in feeding, food choice and sucrose preference, and energy expenditure. We demonstrate that the BDNF Val68Met polymorphism does not influence susceptibility to ABA or any aspect of feeding behaviour. The discrepancy between these results and previous reports in mice may relate to species–specific differences in stress reactivity.
Collapse
|
|
16
|
Kostelnik C, Lucki I, Choi KH, Browne CA. Translational relevance of fear conditioning in rodent models of mild traumatic brain injury. Neurosci Biobehav Rev 2021; 127:365-376. [PMID: 33961927 DOI: 10.1016/j.neubiorev.2021.04.037] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 04/12/2021] [Accepted: 04/29/2021] [Indexed: 01/19/2023]
Abstract
Mild traumatic brain injury (mTBI) increases the risk of posttraumatic stress disorder (PTSD) in military populations. Utilizing translationally relevant animal models is imperative for establishing a platform to delineate neurobehavioral deficits common to clinical PTSD that emerge in the months to years following mTBI. Such platforms are required to facilitate preclinical development of novel therapeutics. First, this mini review provides an overview of the incidence of PTSD following mTBI in military service members. Secondly, the translational relevance of fear conditioning paradigms used in conjunction with mTBI in preclinical studies is evaluated. Next, this review addresses an important gap in the current preclinical literature; while incubation of fear has been studied in other areas of research, there are relatively few studies pertaining to the enhancement of cued and contextual fear memory over time following mTBI. Incubation of fear paradigms in conjunction with mTBI are proposed as a novel behavioral approach to advance this critical area of research. Lastly, this review discusses potential neurobiological substrates implicated in altered fear memory post mTBI.
Collapse
Affiliation(s)
- Claire Kostelnik
- Neuroscience Program, Uniformed Services University, Bethesda MD 20814, United States
| | - Irwin Lucki
- Neuroscience Program, Uniformed Services University, Bethesda MD 20814, United States; Department of Pharmacology & Molecular Therapeutics, Uniformed Services University, Bethesda MD 20814, United States; Department of Psychiatry, Uniformed Services University, Bethesda MD 20814, United States
| | - Kwang H Choi
- Neuroscience Program, Uniformed Services University, Bethesda MD 20814, United States; Department of Psychiatry, Uniformed Services University, Bethesda MD 20814, United States.
| | - Caroline A Browne
- Neuroscience Program, Uniformed Services University, Bethesda MD 20814, United States; Department of Pharmacology & Molecular Therapeutics, Uniformed Services University, Bethesda MD 20814, United States.
| |
Collapse
|
|
17
|
Martens L, Herrmann L, Colic L, Li M, Richter A, Behnisch G, Stork O, Seidenbecher C, Schott BH, Walter M. Met carriers of the BDNF Val66Met polymorphism show reduced Glx/NAA in the pregenual ACC in two independent cohorts. Sci Rep 2021; 11:6742. [PMID: 33762638 PMCID: PMC7990923 DOI: 10.1038/s41598-021-86220-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Accepted: 03/02/2021] [Indexed: 12/17/2022] Open
Abstract
The Met allele of the Val66Met SNP of the BDNF gene (rs6265) is associated with impaired activity-dependent release of brain-derived neurotrophic factor (BDNF), resulting in reduced synaptic plasticity, impaired glutamatergic neurotransmission, and morphological changes. While previous work has demonstrated Val66Met effects on magnetic resonance spectroscopy (MRS) markers of either glutamatergic metabolism (Glx) or neuronal integrity (NAA), no study has investigated Val66Met effects on these related processes simultaneously. As these metabolites share a metabolic pathway, the Glx/NAA ratio may be a more sensitive marker of changes associated with the Val66Met SNP. This ratio is increased in psychiatric disorders linked to decreased functioning in the anterior cingulate cortex (ACC). In this study, we investigated the correlation of the Val66Met polymorphism of the BDNF gene with Glx/NAA in the pregenual anterior cingulate cortex (pgACC) using MRS at 3 Tesla (T) (n = 30, all males) and 7 T (n = 98, 40 females). In both cohorts, Met carriers had lower Glx/NAA compared to Val homozygotes. Follow-up analyses using absolute quantification revealed that the Met carriers do not show decreased pgACC glutamate or glutamine levels, but instead show increased NAA compared to the Val homozygotes. This finding may in part explain conflicting evidence for Val66Met as a risk factor for developing psychiatric illnesses.
Collapse
Affiliation(s)
- Louise Martens
- University Department of Psychiatry and Psychotherapy, Tübingen, Germany.,Graduate Training Center, IMPRS, Tübingen, Germany.,Max Planck Institute for Biological Cybernetics, Tübingen, Germany
| | - Luisa Herrmann
- University Department of Psychiatry and Psychotherapy, Tübingen, Germany.,Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany
| | - Lejla Colic
- Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany.,Clinical Affective Neuroscience Laboratory, Magdeburg, Germany.,Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA
| | - Meng Li
- Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany.,Clinical Affective Neuroscience Laboratory, Magdeburg, Germany
| | - Anni Richter
- Leibniz Institute for Neurobiology, Magdeburg, Germany
| | | | - Oliver Stork
- Department of Genetics & Molecular Neurobiology, Institute of Biology, Otto-Von-Guericke-University, Magdeburg, Germany.,Center for Behavioral Brain Sciences, Magdeburg, Germany
| | - Constanze Seidenbecher
- Leibniz Institute for Neurobiology, Magdeburg, Germany.,Center for Behavioral Brain Sciences, Magdeburg, Germany
| | - Björn H Schott
- Leibniz Institute for Neurobiology, Magdeburg, Germany.,Center for Behavioral Brain Sciences, Magdeburg, Germany.,Department of Psychiatry and Psychotherapy, University Medicine Göttingen, Göttingen, Germany.,German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany
| | - Martin Walter
- University Department of Psychiatry and Psychotherapy, Tübingen, Germany. .,Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany. .,Clinical Affective Neuroscience Laboratory, Magdeburg, Germany.
| |
Collapse
|
|
18
|
de Las Heras B, Rodrigues L, Cristini J, Weiss M, Prats-Puig A, Roig M. Does the Brain-Derived Neurotrophic Factor Val66Met Polymorphism Modulate the Effects of Physical Activity and Exercise on Cognition? Neuroscientist 2020; 28:69-86. [PMID: 33300425 DOI: 10.1177/1073858420975712] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The Val66Met is a polymorphism of the brain-derived neurotrophic factor (BDNF) gene that encodes a substitution of a valine (Val) to methionine (Met) amino acid. Carrying this polymorphism reduces the activity-dependent secretion of the BDNF protein, which can potentially affect brain plasticity and cognition. We reviewed the biology of Val66Met and surveyed 26 studies (11,417 participants) that examined the role of this polymorphism in moderating the cognitive response to physical activity (PA) and exercise. Nine observational studies confirmed a moderating effect of Val66Met on the cognitive response to PA but differences between Val and Met carriers were inconsistent and only significant in some cognitive domains. Only five interventional studies found a moderating effect of Val66Met on the cognitive response to exercise, which was also inconsistent in its direction. Two studies showed a superior cognitive response in Val carriers and three studies showed a better response in Met carriers. These results do not support a general and consistent effect of Val66Met in moderating the cognitive response to PA or exercise. Both Val and Met carriers can improve specific aspects of cognition by increasing PA and engaging in exercise. Causes for discrepancies among studies, effect moderators, and future directions are discussed.
Collapse
Affiliation(s)
- Bernat de Las Heras
- Memory and Motor Rehabilitation Laboratory (MEMORY-LAB), Feil and Oberfeld Research Centre, Jewish Rehabilitation Hospital, Montreal Center for Interdisciplinary Research in Rehabilitation (CRIR), Laval, Quebec, Canada.,School of Physical and Occupational Therapy, Faculty of Medicine, McGill University, Montreal, Quebec, Canada
| | - Lynden Rodrigues
- Memory and Motor Rehabilitation Laboratory (MEMORY-LAB), Feil and Oberfeld Research Centre, Jewish Rehabilitation Hospital, Montreal Center for Interdisciplinary Research in Rehabilitation (CRIR), Laval, Quebec, Canada.,School of Physical and Occupational Therapy, Faculty of Medicine, McGill University, Montreal, Quebec, Canada
| | - Jacopo Cristini
- Memory and Motor Rehabilitation Laboratory (MEMORY-LAB), Feil and Oberfeld Research Centre, Jewish Rehabilitation Hospital, Montreal Center for Interdisciplinary Research in Rehabilitation (CRIR), Laval, Quebec, Canada.,School of Physical and Occupational Therapy, Faculty of Medicine, McGill University, Montreal, Quebec, Canada
| | - Maxana Weiss
- Memory and Motor Rehabilitation Laboratory (MEMORY-LAB), Feil and Oberfeld Research Centre, Jewish Rehabilitation Hospital, Montreal Center for Interdisciplinary Research in Rehabilitation (CRIR), Laval, Quebec, Canada.,School of Physical and Occupational Therapy, Faculty of Medicine, McGill University, Montreal, Quebec, Canada
| | - Anna Prats-Puig
- University School of Health and Sport (EUSES), University of Girona, Girona, Catalunya, Spain
| | - Marc Roig
- Memory and Motor Rehabilitation Laboratory (MEMORY-LAB), Feil and Oberfeld Research Centre, Jewish Rehabilitation Hospital, Montreal Center for Interdisciplinary Research in Rehabilitation (CRIR), Laval, Quebec, Canada.,School of Physical and Occupational Therapy, Faculty of Medicine, McGill University, Montreal, Quebec, Canada
| |
Collapse
|
|
19
|
Treble-Barna A, Pilipenko V, Wade SL, Jegga AG, Yeates KO, Taylor HG, Martin LJ, Kurowski BG. Cumulative Influence of Inflammatory Response Genetic Variation on Long-Term Neurobehavioral Outcomes after Pediatric Traumatic Brain Injury Relative to Orthopedic Injury: An Exploratory Polygenic Risk Score. J Neurotrauma 2020; 37:1491-1503. [PMID: 32024452 PMCID: PMC7307697 DOI: 10.1089/neu.2019.6866] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The addition of genetic factors to prognostic models of neurobehavioral recovery following pediatric traumatic brain injury (TBI) may account for unexplained heterogeneity in outcomes. The present study examined the cumulative influence of candidate genes involved in the inflammatory response on long-term neurobehavioral recovery in children with early childhood TBI relative to children with orthopedic injuries (OI). Participants were drawn from a prospective, longitudinal study evaluating outcomes of children who sustained TBI (n = 67) or OI (n = 68) between the ages of 3 and 7 years. Parents completed ratings of child executive function and behavior at an average of 6.8 years after injury. Exploratory unweighted and weighted polygenic risk scores (PRS) were constructed from single nucleotide polymorphisms (SNPs) across candidate inflammatory response genes (i.e., angiotensin converting enzyme [ACE], brain-derived neurotrophic factor [BDNF], interleukin-1 receptor antagonist [IL1RN], and 5'-ectonucleotidase [NT5E]) that showed nominal (p ≤ 0.20) associations with outcomes in the TBI group. Linear regression models tested the PRS × injury group (TBI vs. OI) interaction term and post-hoc analyses examined the effect of PRS within each injury group. Higher inflammatory response PRS were associated with more executive dysfunction and behavior problems in children with TBI but not in children with OI. The cumulative influence of inflammatory response genes as measured by PRS explained additional variance in long-term neurobehavioral outcomes, over and above well-established predictors and single candidate SNPs tested individually. The results suggest that some of the unexplained heterogeneity in long-term neurobehavioral outcomes following pediatric TBI may be attributable to a child's genetic predisposition to a greater or lesser inflammatory response to TBI.
Collapse
Affiliation(s)
- Amery Treble-Barna
- Department of Physical Medicine and Rehabilitation, University of Pittsburgh School of Medicine, Pittsburgh, Pennslvania, USA
| | - Valentina Pilipenko
- Division of Human Genetics, Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Shari L. Wade
- Division of Pediatric Rehabilitation Medicine, Children's Hospital Medical Center, Cincinnati, Ohio, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Anil G. Jegga
- Division of Biomedical Informatics, Children's Hospital Medical Center, Cincinnati, Ohio, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Keith Owen Yeates
- Department of Psychology, Alberta Children's Hospital Research Institute, and Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
| | - H. Gerry Taylor
- Abigail Wexner Research Institute at Nationwide Children's Hospital, and Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA
| | - Lisa J. Martin
- Division of Human Genetics, Children's Hospital Medical Center, Cincinnati, Ohio, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Brad G. Kurowski
- Division of Pediatric Rehabilitation Medicine, Children's Hospital Medical Center, Cincinnati, Ohio, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
- Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| |
Collapse
|
|
20
|
Ghosh M, Ali A, Joshi S, Srivastava AS, Tapadia MG. SLC1A3 C3590T but not BDNF G196A is a predisposition factor for stress as well as depression, in an adolescent eastern Indian population. BMC MEDICAL GENETICS 2020; 21:53. [PMID: 32171272 PMCID: PMC7071583 DOI: 10.1186/s12881-020-0993-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Accepted: 03/04/2020] [Indexed: 01/19/2023]
Abstract
Background Adolescence is a distinctive stage of various changes and is noted as peak age for onset of many psychiatric disorders, especially linked to stress and depression. Several genetic variations are being increasingly known to be linked with stress and depression. The polymorphisms in two such genes, the BDNF and SLC1A3, have been reported to be linked with either depression/stress or with suicidal behaviour. These genes have not been validated in Indian population, and therefore there is a need to investigate these genes in Indian population. The present study was undertaken to test whether the known polymorphisms SLC1A3 C3590T, SLC1A3 C869G and BDNF G196A are associated or not with stress or depression in an eastern Indian population. Methods A case-control association study was performed with 108 cases having variable levels of stress and depression and 205 matched controls. Detection of stress and depression was done by using standard instruments as PSS and CES-D, respectively and demographic profile was obtained for each individual on the basis of personal data sheet. Genotyping for the selected polymorphisms was performed by PCR followed by restriction digestion. Results The SNP SLC1A3 C3590T was found to be associated with stress and depression (p = 0.0042, OR = 2.072). Therefore, the T allele increases the risk by more than two folds for stress and depression in the present population. The other allele of SLC1A3, G869C, as well as BDNF G196A were not associated with stress or depression in the population studied. Conclusion SLC1A3 C3590T is a predisposition factor for stress and depression in an eastern Indian population, whereas SLC1A3 G869C and BDNF G196A were not found to be a risk factor. Therefore, presence of T allele of SLC1A3 C3590T, may predict the development of stress and depression in an individual. This may also help in the understanding of pathophysiology of the disease. However, these findings warrant a wider study in Indian populations and would be of significance in understanding the predisposition of stress and depression in this population.
Collapse
Affiliation(s)
- Madhumita Ghosh
- Cytogenetics Laboratory, Department of Zoology, Banaras Hindu University, Varanasi, 221005, India
| | - Akhtar Ali
- Centre for Genetic Disorders, Faculty of Science, Banaras Hindu University, Varanasi, 221005, India
| | - Shobhna Joshi
- Department of Psychology, Faculty of Arts, Banaras Hindu University, Varanasi, 221005, India
| | - Adya Shankar Srivastava
- Department of Psychiatry, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221005, India
| | - Madhu G Tapadia
- Cytogenetics Laboratory, Department of Zoology, Banaras Hindu University, Varanasi, 221005, India.
| |
Collapse
|
|
21
|
Salivary gland low-intensity pulsed ultrasound (LIPUS) stimulation as a potential treatment for various BDNF-implicated neuropsychiatric disorders. Med Hypotheses 2020; 137:109560. [PMID: 31945655 DOI: 10.1016/j.mehy.2020.109560] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 12/27/2019] [Accepted: 01/08/2020] [Indexed: 11/23/2022]
|
|
22
|
Penadés R, Bosia M, Catalán R, Spangaro M, García-Rizo C, Amoretti S, Bioque M, Bernardo M. The role of genetics in cognitive remediation in schizophrenia: A systematic review. SCHIZOPHRENIA RESEARCH-COGNITION 2019; 19:100146. [PMID: 31832337 PMCID: PMC6889757 DOI: 10.1016/j.scog.2019.100146] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Revised: 04/08/2019] [Accepted: 04/17/2019] [Indexed: 12/12/2022]
Abstract
The role of genetics in cognitive remediation therapies in schizophrenia has not been completely understood yet. Different genes involved in neurotrophic, dopaminergic and serotonin systems have reported to influence cognitive functioning in schizophrenia. These genetic factors could also be contributing to the variability in responsiveness to cognitive treatments. No comprehensive synthesis of the literature of the role of genetics in the context of cognitive remediation has been conducted until now. We aimed to systematically review the published works through three electronic database searches: PubMed, Scopus, and the Cochrane Library. Eligible studies revealed a rising interest in the field although the number of published studies was rather small (n = 10). Eventually, promising results showing a relationship between some phenotypic variations based on different polymorphisms and different levels of responsivity to cognitive remediation therapies have been described although results are still inconclusive. In case those findings will be replicated, they could be guiding future research and informing clinical decision-making in the next future.
Collapse
Affiliation(s)
- Rafael Penadés
- Barcelona Clinic Schizophrenia Unit, Hospital Clinic Barcelona, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Spain
| | - Marta Bosia
- Department of Clinical Neurosciences, IRCCS San Raffaele Scientific Institute, School of Medicine, Vita-Salute San Raffaele University, Milan, Italy
| | - Rosa Catalán
- Barcelona Clinic Schizophrenia Unit, Hospital Clinic Barcelona, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Spain
| | - Marco Spangaro
- Department of Clinical Neurosciences, IRCCS San Raffaele Scientific Institute, School of Medicine, Vita-Salute San Raffaele University, Milan, Italy
| | - Clemente García-Rizo
- Barcelona Clinic Schizophrenia Unit, Hospital Clinic Barcelona, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Spain
| | - Silvia Amoretti
- Barcelona Clinic Schizophrenia Unit, Hospital Clinic Barcelona, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Spain
| | - Miquel Bioque
- Barcelona Clinic Schizophrenia Unit, Hospital Clinic Barcelona, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Spain
| | - Miquel Bernardo
- Barcelona Clinic Schizophrenia Unit, Hospital Clinic Barcelona, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Spain
| |
Collapse
|
|
23
|
Tsai SJ. Preventive potential of low intensity pulsed ultrasound for chronic traumatic encephalopathy after repetitive head collisions in contact sports. Med Hypotheses 2019; 134:109422. [PMID: 31654885 DOI: 10.1016/j.mehy.2019.109422] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Revised: 09/29/2019] [Accepted: 10/09/2019] [Indexed: 01/25/2023]
Abstract
Chronic traumatic encephalopathy (CTE), a disease process well-recognized in boxers, American football players and military personnel, is a progressive neurodegenerative disease caused by repetitive blows to the head. Subjects with CTE can have a wide range of emotional, cognitive and physical symptoms. The cognitive group patients had a significantly higher probability of developing dementia in later years. Currently, there are no disease modifying regimen for CTE. Timely intervention of head blow could diminish the development of CTE. Low-intensity pulsed ultrasound (LIPUS) is a common adjunct used to promote bone healing for fresh fracture. Recent reports suggest that LIPUS can noninvasively modulate the cortical function and have neuroprotective effect in various animal models of traumatic brain injury, stroke, Alzheimer's disease and major depressive disorder. The multifunctional mechanisms of LIPUS neuroprotective effect include several trophic factor stimulations, anti-inflammatory properties and reduction of brain edema. From the above evidence, LIPUS intervention could be a strategy for the prevention of the clinical CTE sequelae of repetitive head blows. We hypothesized that due to its neuroprotective effects, the non-invasive and easy-to-use method of LIPUS brain stimulation could have a preventive effect on players who have head blows during the match. The development of a time sensitive protocol, resembling the therapeutic algorithm for traumatic brain injury, would potentially prevent the development of subsequent CTE adverse outcome. Further long-term longitudinal studies of LIPUS stimulation are warranted to verify the prevention efficacy of this intervention for CTE.
Collapse
Affiliation(s)
- Shih-Jen Tsai
- Department of Psychiatry, Taipei Veterans General Hospital, Taiwan; Division of Psychiatry, School of Medicine, National Yang-Ming University, Taiwan; Brain Research Center, National Yang-Ming University, Taiwan.
| |
Collapse
|
|
24
|
Antisuicidal effect, BDNF Val66Met polymorphism, and low-dose ketamine infusion: Reanalysis of adjunctive ketamine study of Taiwanese patients with treatment-resistant depression (AKSTP-TRD). J Affect Disord 2019; 251:162-169. [PMID: 30925267 DOI: 10.1016/j.jad.2019.03.075] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2019] [Revised: 03/19/2019] [Accepted: 03/21/2019] [Indexed: 01/12/2023]
Abstract
BACKGROUND Growing evidence suggests a rapid antisuicidal effect of low-dose ketamine infusion in Caucasian patients with treatment-resistant depression (TRD). However, the antisuicidal effects of ketamine on Taiwanese patients with TRD remains unknown. METHODS Seventy-one patients with TRD were randomly classified into three treatment groups: 0.5 mg/kg ketamine, 0.2 mg/kg ketamine, or normal saline (placebo) infusion. The Hamilton Depression Rating Scale (HAMD) and Montgomery-Åsberg Depression Rating Scale (MADRS) were applied prior to initiation of test infusions, at 40, 80, 120, and 240 min postinfusion, and sequentially on Days 2, 3, 4, 5, 6, 7, and 14 after ketamine or placebo infusion. Item 3 (suicide) of the HAMD and item 10 (suicidal thoughts) of the MADRS were extracted for generalized estimating equation (GEE) model analyses to investigate the antisuicidal effects of ketamine infusion. Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism was genotyped. RESULTS The GEE model revealed significant group (p = 0.007) and time (p = 0.004) effects on suicidal symptoms over times (prior to infusion to day 14 postinfusion). The group that received 0.5 mg/kg ketamine infusion exhibited a significantly lower score in item 3 of the HAMD and item 10 of the MADRS compared with the groups that received 0.2 mg/kg ketamine or placebo infusion. Among those carrying any Val allele of BDNF, both 0.5 and 0.2 mg/kg ketamine infusions were effective in reducing suicidal thoughts; however, among those with Met/Met of BDNF, only 0.5 mg/kg ketamine infusion was effective in reducing suicidal thoughts. DISCUSSION A single low-dose ketamine infusion was effective in reducing suicidal ideation among Taiwanese patients with TRD. BDNF Val66Met polymorphism may play a crucial role in the antisuicidal effects of ketamine infusion.
Collapse
|
|
25
|
Kirli U, Binbay T, Drukker M, Elbi H, Kayahan B, Gökçelli DK, Özkınay F, Onay H, Alptekin K, van Os J. Is BDNF-Val66Met polymorphism associated with psychotic experiences and psychotic disorder outcome? Evidence from a 6 years prospective population-based cohort study. Am J Med Genet B Neuropsychiatr Genet 2019; 180:113-121. [PMID: 29785763 DOI: 10.1002/ajmg.b.32641] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2018] [Revised: 04/05/2018] [Accepted: 04/23/2018] [Indexed: 12/19/2022]
Abstract
There is little research on genetic risk for the extended psychosis phenotype ranging from psychotic experiences (PEs) to psychotic disorders (PDs). In this general population-based prospective cohort study, the longitudinal associations between BDNF-Val66Met polymorphism and the different levels of the extended psychosis phenotype were investigated. Addresses were contacted in a multistage clustered probability sampling frame covering 11 districts and 302 neighborhoods at baseline (n = 4011). A nested case-control study (n = 366) recruited individuals with PEs and PDs as well as individuals with no psychotic symptoms. In this subgroup, blood sampling for genetic analysis and assessment of environmental exposures were carried out, followed by clinical re-appraisal at follow-up 6 years later (n = 254). The BDNF-Val66Met polymorphism was significantly associated with the extended psychosis phenotype. The pattern of the association was that the BDNF-Val66Met polymorphism impacted in a dose-response but extra-linear fashion, with stronger impact at the PD end of the extended psychosis phenotype. Associations were still significant after adjusting for sociodemographic factors and environmental exposures including life events, childhood adversity, socioeconomic status, urbanicity, and cannabis use. The BDNF-Val66Met polymorphism may index susceptibility to expression of psychosis along a spectrum.
Collapse
Affiliation(s)
- Umut Kirli
- Department of Psychiatry, Van Education and Research Hospital, Van, Turkey.,School for Mental Health and Neuroscience (MHeNS), Department of Psychiatry and Psychology, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Tolga Binbay
- Faculty of Medicine, Department of Psychiatry, Dokuz Eylül University, Izmir, Turkey
| | - Marjan Drukker
- School for Mental Health and Neuroscience (MHeNS), Department of Psychiatry and Psychology, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Hayriye Elbi
- Faculty of Medicine, Department of Psychiatry, Ege University, Izmir, Turkey
| | - Bülent Kayahan
- Faculty of Medicine, Department of Psychiatry, Ege University, Izmir, Turkey
| | | | - Ferda Özkınay
- Faculty of Medicine, Department of Medical Genetics, Ege University, Izmir, Turkey
| | - Hüseyin Onay
- Faculty of Medicine, Department of Medical Genetics, Ege University, Izmir, Turkey
| | - Köksal Alptekin
- Faculty of Medicine, Department of Psychiatry, Dokuz Eylül University, Izmir, Turkey
| | - Jim van Os
- School for Mental Health and Neuroscience (MHeNS), Department of Psychiatry and Psychology, Maastricht University Medical Centre, Maastricht, The Netherlands.,Department of Psychosis Studies, Institute of Psychiatry, King's College, King's Health Partners, London, United Kingdom.,Department of Psychiatry, Brain Centre Rudolf Magnus, Utrecht University Medical Centre, Utrecht, The Netherlands
| |
Collapse
|
|
26
|
Xia H, Du X, Yin G, Zhang Y, Li X, Cai J, Huang X, Ning Y, Soares JC, Wu F, Zhang XY. Effects of smoking on cognition and BDNF levels in a male Chinese population: relationship with BDNF Val66Met polymorphism. Sci Rep 2019; 9:217. [PMID: 30659208 PMCID: PMC6338731 DOI: 10.1038/s41598-018-36419-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Accepted: 11/14/2018] [Indexed: 01/17/2023] Open
Abstract
Recent studies demonstrate that brain-derived neurotrophic factor (BDNF) might be associated with nicotine addiction, and circulating BDNF is a biomarker of memory and general cognitive function. Moreover, studies suggest that a functional polymorphism of the BDNF Val66Met may mediate hippocampal-dependent cognitive functions. We aimed to explore the relationships between smoking, cognitive performance and BDNF in a normal Chinese Han population. We recruited 628 male healthy subjects, inducing 322 smokers and 306 nonsmokers, and genotyped them the BDNF Val66Met polymorphism. Of these, we assessed 114 smokers and 98 nonsmokers on the repeatable battery for the assessment of neuropsychological status (RBANS), and 103 smokers and 89 nonsmokers on serum BDNF levels. Smokers scored lower than the nonsmokers on RBANS total score (p = 0.002), immediate memory (p = 0.003) and delayed memory (p = 0.021). BDNF levels among the smokers who were Val allele carriers were correlated with the degree of cognitive impairments, especially attention, as well as with the carbon monoxide concentrations. Our findings suggest that smoking is associated with cognitive impairment in a male Chinese Han population. The association between higher BDNF levels and cognitive impairment, mainly attention in smokers appears to be dependent on the BDNF Val66Met polymorphism.
Collapse
Affiliation(s)
- Haisen Xia
- Hefei Fourth People's Hospital, Anhui Mental Health Center, Hefei, China
| | - Xiangdong Du
- Suzhou Psychiatric Hospital, The Affiliated Guangji Hospital of Soochow University, Jiangsu, China
| | - Guangzhong Yin
- Suzhou Psychiatric Hospital, The Affiliated Guangji Hospital of Soochow University, Jiangsu, China
| | - Yingyang Zhang
- Suzhou Psychiatric Hospital, The Affiliated Guangji Hospital of Soochow University, Jiangsu, China
| | - Xiaosi Li
- Hefei Fourth People's Hospital, Anhui Mental Health Center, Hefei, China
| | - Junyi Cai
- The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, China
| | - Xingbing Huang
- The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, China
| | - Yuping Ning
- The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, China
| | - Jair C Soares
- Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Fengchun Wu
- The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, China.
| | - Xiang Yang Zhang
- Institute of Psychology, Chinese Academy of Sciences, Beijing, China.
| |
Collapse
|
|
27
|
Tsai SJ, Lin E, Kuo PH, Liu YL, Yang A. A gene–gene interaction between the vascular endothelial growth factor a and brain-derived neurotrophic factor genes is associated with psychological distress in the Taiwanese population. TAIWANESE JOURNAL OF PSYCHIATRY 2019. [DOI: 10.4103/tpsy.tpsy_30_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
|
|
28
|
Tsai SJ, Lin E, Kuo PH, Liu YL, Yang A. A gene-based analysis of variants in the Brain-derived Neurotrophic Factor gene with psychological distress in a Taiwanese population. TAIWANESE JOURNAL OF PSYCHIATRY 2019. [DOI: 10.4103/tpsy.tpsy_6_19] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
|
|
29
|
Low I, Kuo PC, Tsai CL, Liu YH, Lin MW, Chao HT, Chen YS, Hsieh JC, Chen LF. Interactions of BDNF Val66Met Polymorphism and Menstrual Pain on Brain Complexity. Front Neurosci 2018; 12:826. [PMID: 30524221 PMCID: PMC6256283 DOI: 10.3389/fnins.2018.00826] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2018] [Accepted: 10/23/2018] [Indexed: 12/28/2022] Open
Abstract
The irregularity and uncertainty of neurophysiologic signals across different time scales can be regarded as neural complexity, which is related to the adaptability of the nervous system and the information processing between neurons. We recently reported general loss of brain complexity, as measured by multiscale sample entropy (MSE), at pain-related regions in females with primary dysmenorrhea (PDM). However, it is unclear whether this loss of brain complexity is associated with inter-subject genetic variations. Brain-derived neurotrophic factor (BDNF) is a widely expressed neurotrophin in the brain and is crucial to neural plasticity. The BDNF Val66Met single-nucleotide polymorphism (SNP) is associated with mood, stress, and pain conditions. Therefore, we aimed to examine the interactions of BDNF Val66Met polymorphism and long-term menstrual pain experience on brain complexity. We genotyped BDNF Val66Met SNP in 80 PDM females (20 Val/Val, 31 Val/Met, 29 Met/Met) and 76 healthy female controls (25 Val/Val, 36 Val/Met, 15 Met/Met). MSE analysis was applied to neural source activity estimated from resting-state magnetoencephalography (MEG) signals during pain-free state. We found that brain complexity alterations were associated with the interactions of BDNF Val66Met polymorphism and menstrual pain experience. In healthy female controls, Met carriers (Val/Met and Met/Met) demonstrated lower brain complexity than Val/Val homozygotes in extensive brain regions, suggesting a possible protective role of Val/Val homozygosity in brain complexity. However, after experiencing long-term menstrual pain, the complexity differences between different genotypes in healthy controls were greatly diminished in PDM females, especially in the limbic system, including the hippocampus and amygdala. Our results suggest that pain experience preponderantly affects the effect of BDNF Val66Met polymorphism on brain complexity. The results of the present study also highlight the potential utilization of resting-state brain complexity for the development of new therapeutic strategies in patients with chronic pain.
Collapse
Affiliation(s)
- Intan Low
- Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan.,Integrated Brain Research Unit, Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Po-Chih Kuo
- Institute of Statistical Science, Academia Sinica, Taipei, Taiwan
| | - Cheng-Lin Tsai
- Institute of Biomedical Informatics, National Yang-Ming University, Taipei, Taiwan
| | - Yu-Hsiang Liu
- Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan
| | - Ming-Wei Lin
- Institute of Public Health, National Yang-Ming University, Taipei, Taiwan
| | - Hsiang-Tai Chao
- Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yong-Sheng Chen
- Department of Computer Science, National Chiao Tung University, Hsinchu, Taiwan.,Center for Emergent Functional Matter Science, National Chiao Tung University, Hsinchu, Taiwan
| | - Jen-Chuen Hsieh
- Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan.,Integrated Brain Research Unit, Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan.,Brain Research Center, National Yang-Ming University, Taipei, Taiwan
| | - Li-Fen Chen
- Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan.,Integrated Brain Research Unit, Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan.,Institute of Biomedical Informatics, National Yang-Ming University, Taipei, Taiwan.,Brain Research Center, National Yang-Ming University, Taipei, Taiwan
| |
Collapse
|
|
30
|
Kuban KCK, Heeren T, O'Shea TM, Joseph RM, Fichorova RN, Douglass L, Jara H, Frazier JA, Hirtz D, Taylor HG, Rollins JV, Paneth N. Among Children Born Extremely Preterm a Higher Level of Circulating Neurotrophins Is Associated with Lower Risk of Cognitive Impairment at School Age. J Pediatr 2018; 201:40-48.e4. [PMID: 30029870 PMCID: PMC6684153 DOI: 10.1016/j.jpeds.2018.05.021] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Revised: 04/23/2018] [Accepted: 05/11/2018] [Indexed: 12/15/2022]
Abstract
OBJECTIVES To test the hypothesis that higher blood levels of neurotrophic proteins (proteins that support neuronal survival and function) in the first 2 weeks of life are associated with a lower risk of cognitive impairment at 10 years. STUDY DESIGN We evaluated 812 10-year-old children with neonatal blood specimens enrolled in the multicenter prospective Extremely Low Gestational Age Newborn Study, assessing 22 blood proteins collected on 3 days over the first 2 weeks of life. Using latent profile analysis, we derived a cognitive function level based on standardized cognitive and executive function tests. We defined high exposure as the top quartile neurotrophic protein blood level on ≥2 days either for ≥4 proteins or for a specific cluster of neurotrophic proteins (defined by latent class analysis). Multinomial logistic regression analyzed associations between high exposures and cognitive impairment. RESULTS Controlling for the effects of inflammatory proteins, persistently elevated blood levels of ≥4 neurotrophic proteins were associated with reduced risk of moderate (OR, 0.35; 95% CI, 0.18-0.67) and severe cognitive impairment (OR, 0.22; 95% CI, 0.09-0.53). Children with a cluster of elevated proteins including angiopoietin 1, brain-derived neurotrophic factor, and regulated upon activation, normal T-cell expressed, and secreted had a reduced risk of adverse cognitive outcomes (OR range, 0.31-0.6). The risk for moderate to severe cognitive impairment was least with 0-1 inflammatory and >4 neurotrophic proteins. CONCLUSIONS Persisting elevations of circulating neurotrophic proteins during the first 2 weeks of life are associated with lowered risk of impaired cognition at 10 years of age, controlling for increases in inflammatory proteins.
Collapse
Affiliation(s)
- Karl C K Kuban
- Department of Pediatrics, Division of Pediatric Neurology, Boston Medical Center, Boston, MA.
| | - Timothy Heeren
- Department of Biostatistics, Boston University School of Public Health, Boston, MA
| | - T Michael O'Shea
- Department of Pediatrics, Division of Neonatal-Perinatal Medicine, University of North Carolina, Chapel Hill, NC
| | - Robert M Joseph
- Department of Anatomy and Neuroanatomy, Boston University School of Medicine, Boston, MA
| | - Raina N Fichorova
- Laboratory of Genital Tract Biology, Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Laurie Douglass
- Department of Pediatrics, Division of Pediatric Neurology, Boston Medical Center, Boston, MA
| | - Hernan Jara
- Department of Radiology, Boston University School of Medicine, Boston, MA
| | - Jean A Frazier
- Department of Psychiatry, Eunice Kennedy Shriver Center, UMASS Medical School/ University of Massachusetts Memorial Health Care, Worcester, MA
| | - Deborah Hirtz
- National Institute of Neurological Disorders and Stroke, Bethesda, MD
| | - H Gerry Taylor
- Department of Pediatrics, Case Western Reserve University, Cleveland, OH
| | - Julie Vanier Rollins
- Department of Pediatrics, Division of Neonatal-Perinatal Medicine, University of North Carolina, Chapel Hill, NC
| | - Nigel Paneth
- Department of Epidemiology and Biostatistics and Pediatrics & Human Development, Michigan State University, East Lansing, MI
| |
Collapse
|
|
31
|
Davydova JD, Litvinov SS, Enikeeva RF, Malykh SB, Khusnutdinova EK. Recent advances in genetics of aggressive behavior. Vavilovskii Zhurnal Genet Selektsii 2018. [DOI: 10.18699/vj18.415] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
One of the most important problems of modern neurobiology and medicine is an understanding of the mechanisms of normal and pathological behavior of a person. Aggressive behavior is an integral part of the human psyche. However, environmental risk factors, mental illness and somatic diseases can lead to increased aggression to be the biological basis of antisocial behavior in a human society. An important role in development of aggressive behavior belongs to the hereditary factors that may be linked to abnormal functioning of neurotransmitter systems in the brain yet the underlying genetic mechanisms remain unclear, which is due to a large number of single nucleotide polymorphisms, insertions and deletions in the structure of genes that encode the components of the neurotransmitter systems. The most studied candidate genes for aggressive behavior are serotonergic (TPH1, TPH2, HTR2A, SLC6A4) and dopaminergic (DRD4, SLC6A3) system genes, as well as the serotonin or catecholamine metabolizing enzyme genes (COMT, MAOA). In addition, there is evidence that the hypothalamic-pituitary system genes (OXT, OXTR, AVPR1A, AVPR1B), the sex hormone receptors genes (ER1, AR), neurotrophin (BDNF) and neuronal apoptosis genes (CASP3, BAX) may also be involved in development of aggressive behavior. The results of Genome-Wide Association Studies (GWAS) have demonstrated that FYN, LRRTM4, NTM, CDH13, DYRK1A and other genes are involved in regulation of aggressive behavior. These and other evidence suggest that genetic predisposition to aggressive behavior may be a very complex process.
Collapse
Affiliation(s)
- J. D. Davydova
- Institute of Biochemistry and Genetics, Ufa Federal Research Centre of RAS
| | - S. S. Litvinov
- Institute of Biochemistry and Genetics, Ufa Federal Research Centre of RAS
| | - R. F. Enikeeva
- Institute of Biochemistry and Genetics, Ufa Federal Research Centre of RAS
| | - S. B. Malykh
- Psychological Institute, Russian Academy of Education
| | - E. K. Khusnutdinova
- Institute of Biochemistry and Genetics, Ufa Federal Research Centre of RAS; Department of Genetics and Fundamental Medicine, Bashkir State University
| |
Collapse
|
|
32
|
Balkaya M, Cho S. Genetics of stroke recovery: BDNF val66met polymorphism in stroke recovery and its interaction with aging. Neurobiol Dis 2018; 126:36-46. [PMID: 30118755 DOI: 10.1016/j.nbd.2018.08.009] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Revised: 07/24/2018] [Accepted: 08/13/2018] [Indexed: 12/13/2022] Open
Abstract
Stroke leads to long term sensory, motor and cognitive impairments. Most patients experience some degree of spontaneous recovery which is mostly incomplete and varying greatly among individuals. The variation in recovery outcomes has been attributed to numerous factors including lesion size, corticospinal tract integrity, age, gender and race. It is well accepted that genetics play a crucial role in stroke incidence and accumulating evidence suggests that it is also a significant determinant in recovery. Among the number of genes and variations implicated in stroke recovery the val66met single nucleotide polymorphism (SNP) in the BDNF gene influences post-stroke plasticity in the most significant ways. Val66met is the most well characterized BDNF SNP and is common (40-50 % in Asian and 25-32% in Caucasian populations) in humans. It reduces activity-dependent BDNF release, dampens cortical plasticity and is implicated in numerous diseases. Earlier studies on the effects of val66met on stroke outcome and recovery presented primarily a maladaptive role. Novel findings however indicate a much more intricate interaction between val66met and stroke recovery which appears to be influenced by lesion location, post-stroke stage and age. This review will focus on the role of BDNF and val66met SNP in relation to stroke recovery and try to identify potential pathophysiologic mechanisms involved. The effects of age on val66met associated alterations in plasticity and potential consequences in terms of stroke are also discussed.
Collapse
Affiliation(s)
- Mustafa Balkaya
- Burke-Cornell Medical Research Institute, 785 Mamaroneck Ave, White Plains, NY 10605, USA; Feil Family Brain and Mind Research Institute, Weill Cornell Medicine at Burke Medical Research Institute, 785 Mamaroneck Ave, White Plains, NY 10605, USA
| | - Sunghee Cho
- Burke-Cornell Medical Research Institute, 785 Mamaroneck Ave, White Plains, NY 10605, USA; Feil Family Brain and Mind Research Institute, Weill Cornell Medicine at Burke Medical Research Institute, 785 Mamaroneck Ave, White Plains, NY 10605, USA.
| |
Collapse
|
|
33
|
Tsai SJ. Critical Issues in BDNF Val66Met Genetic Studies of Neuropsychiatric Disorders. Front Mol Neurosci 2018; 11:156. [PMID: 29867348 PMCID: PMC5962780 DOI: 10.3389/fnmol.2018.00156] [Citation(s) in RCA: 91] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Accepted: 04/24/2018] [Indexed: 12/20/2022] Open
Abstract
Neurotrophins have been implicated in the pathophysiology of many neuropsychiatric diseases. Brain-derived neurotrophic factor (BDNF) is the most abundant and widely distributed neurotrophin in the brain. Its Val66Met polymorphism (refSNP Cluster Report: rs6265) is a common and functional single-nucleotide polymorphism (SNP) affecting the activity-dependent release of BDNF. BDNF Val66Met transgenic mice have been generated, which may provide further insight into the functional impact of this polymorphism in the brain. Considering the important role of BDNF in brain function, more than 1,100 genetic studies have investigated this polymorphism in the past 15 years. Although these studies have reported some encouraging positive findings initially, most of the findings cannot be replicated in following studies. These inconsistencies in BDNF Val66Met genetic studies may be attributed to many factors such as age, sex, environmental factors, ethnicity, genetic model used for analysis, and gene–gene interaction, which are discussed in this review. We also discuss the results of recent studies that have reported the novel functions of this polymorphism. Because many BDNF polymorphisms and non-genetic factors have been implicated in the complex traits of neuropsychiatric diseases, the conventional genetic association-based method is limited to address these complex interactions. Future studies should apply data mining and machine learning techniques to determine the genetic role of BDNF in neuropsychiatric diseases.
Collapse
Affiliation(s)
- Shih-Jen Tsai
- Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan.,School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan
| |
Collapse
|
|
34
|
Gene-based analysis of genes related to neurotrophic pathway suggests association of BDNF and VEGFA with antidepressant treatment-response in depressed patients. Sci Rep 2018; 8:6983. [PMID: 29725086 PMCID: PMC5934385 DOI: 10.1038/s41598-018-25529-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Accepted: 04/23/2018] [Indexed: 11/25/2022] Open
Abstract
It is well established that brain-derived neurotrophic factor (BDNF) signaling pathway plays a key role in the pathophysiology of major depressive disorder (MDD) and in therapeutic mechanisms of antidepressants. We aim to identify genetic vairiants related to MDD susceptibility and antidepressant therapeutic response by using gene-based association analysis with genes related to the neurotrophic pathway. The present study investigated the role of genetic variants in the 10 neurotrophic-related genes (BDNF, NGFR, NTRK2, MTOR, VEGFA, S100A10, SERPINE1, ARHGAP33, GSK3B, CREB1) in MDD susceptibility through a case-control (455 MDD patients and 2,998 healthy controls) study and in antidepressant efficacy (n = 455). Measures of antidepressant therapeutic efficacy were evaluated using the 21-item Hamilton Rating Scale for Depression. Our single-marker and gene-based analyses with ten genes related to the neurotrophic pathway identified 6 polymorphisms that reached a significant level (p-value < 5.0 × 10−3) in both meta- and mega-analyses in antidepressant therapeutic response. One polymorphism was mapped to BDNF and 5 other polymorphisms were mapped to VEGFA. For case-control association study, we found that all of these reported polymorphisms and genes did not reach a suggestive level. The present study supported a role of BDNF and VEGFA variants in MDD therapeutic response.
Collapse
|
|
35
|
Leviton A, Allred EN, Fichorova RN, O'Shea TM, Fordham LA, Kuban KKC, Dammann O. Circulating biomarkers in extremely preterm infants associated with ultrasound indicators of brain damage. Eur J Paediatr Neurol 2018; 22:440-450. [PMID: 29429901 PMCID: PMC5899659 DOI: 10.1016/j.ejpn.2018.01.018] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Revised: 12/09/2017] [Accepted: 01/20/2018] [Indexed: 02/06/2023]
Abstract
AIM To assess to what extent the blood concentrations of proteins with neurotrophic and angiogenic properties measured during the first postnatal month convey information about the risk of sonographically-identified brain damage among very preterm newborns. METHODS Study participants were 1219 children who had a cranial ultrasound scan during their stay in the intensive care nursery and blood specimens collected on 2 separate days at least a week apart during the first postnatal month. Concentrations of selected proteins in blood spots were measured with electrochemiluminescence or with a multiplex immunobead assay and the risks of cranial ultrasound images associated with top-quartile concentrations were assessed. RESULTS High concentrations of multiple inflammation-related proteins during the first 2 postnatal weeks were associated with increased risk of ventriculomegaly, while high concentrations of just 3 inflammation-related proteins were associated with increased risk of an echolucent/hypoechoic lesion (IL-6, IL-8, ICAM-1), especially on day 7. Concomitant high concentrations of IL6R and bFGF appeared to modulate the increased risks of ventriculomegaly and an echolucent lesion associated with inflammation. More commonly high concentrations of putative protectors/repair-enhancers did not appear to diminish these increased risks. CONCLUSION Our findings provide support for the hypothesis that endogenous proteins are capable of either protecting the brain against damage and/or enhancing repair of damage.
Collapse
Affiliation(s)
- Alan Leviton
- Boston Children's Hospital, and Harvard Medical School, Boston, MA, USA.
| | | | - Raina N Fichorova
- Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | | | | | - Karl K C Kuban
- Boston Medical Center and Boston University School of Medicine, Boston, MA, USA
| | - Olaf Dammann
- Tufts University School of Medicine, Boston, MA, USA
| |
Collapse
|
|
36
|
Tudor L, Konjevod M, Nikolac Perkovic M, Svob Strac D, Nedic Erjavec G, Uzun S, Kozumplik O, Sagud M, Kovacic Petrovic Z, Pivac N. Genetic Variants of the Brain-Derived Neurotrophic Factor and Metabolic Indices in Veterans With Posttraumatic Stress Disorder. Front Psychiatry 2018; 9:637. [PMID: 30542302 PMCID: PMC6277864 DOI: 10.3389/fpsyt.2018.00637] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Accepted: 11/08/2018] [Indexed: 12/12/2022] Open
Abstract
Posttraumatic stress disorder (PTSD) is a trauma and stressor related disorder that may develop after exposure to an event that involved the actual or possible threat of death, violence or serious injury. Its molecular underpinning is still not clear. Brain-derived neurotrophic factor (BDNF) modulates neuronal processes such as the response to stress, but also weight control, energy and glucose homeostasis. Plasma BDNF levels and a functional BDNF Val66Met (rs6265) polymorphism were reported to be associated with PTSD, as well as with increased body mass index (BMI) and dyslipidaemia in healthy subjects and patients with cardio-metabolic diseases, but these results are controversial. The other frequently studied BDNF polymorphism, C270T (rs56164415), has been associated with the development of different neuropsychiatric symptoms/disorders. As far as we are aware, there are no data on the association of BDNF Val66Met and C270T polymorphisms with metabolic indices in PTSD. Due to high rates of obesity and dyslipidaemia in PTSD, the aim of this study was to elucidate the association of BDNF Val66Met and C270T polymorphisms with BMI and lipid levels in veterans with PTSD. We hypothesized that BDNF variants contribute to susceptibility to metabolic disturbances in PTSD. The study included 333 Caucasian males with combat related PTSD, diagnosed according to DSM-5 criteria. Genotyping of the BDNF Val66Met and C270T polymorphisms was performed using the real-time PCR method. Results were analyzed using hierarchical multiple linear regression and the Mann-Whitney test, with p-value corrected to 0.005. The results showed that BDNF Val66Met and BDNF C270T polymorphisms were not significantly associated with BMI, total cholesterol, LDL-cholesterol, HDL-cholesterol or triglycerides. Although the BDNF C270T polymorphism was nominally associated only with HDL-cholesterol in veterans with PTSD, this significance disappeared after controlling for the effect of age. Namely, slightly higher plasma HDL values in T allele carriers, compared to CC homozygotes, were associated with differences in age. Our results, controlled for the critical covariates, revealed that BDNF Val66Met and C270T were not significantly associated with metabolic indices in veterans with PTSD and that these genetic variants do not contribute to susceptibility to metabolic disturbances in PTSD.
Collapse
Affiliation(s)
- Lucija Tudor
- Laboratory for Molecular Neuropsychiatry, Division of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia
| | - Marcela Konjevod
- Laboratory for Molecular Neuropsychiatry, Division of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia
| | - Matea Nikolac Perkovic
- Laboratory for Molecular Neuropsychiatry, Division of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia
| | - Dubravka Svob Strac
- Laboratory for Molecular Neuropsychiatry, Division of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia
| | - Gordana Nedic Erjavec
- Laboratory for Molecular Neuropsychiatry, Division of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia
| | - Suzana Uzun
- Department of Biological Psychiatry and Psychogeriatry, University Psychiatric Hospital Vrapce, Zagreb, Croatia.,Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia
| | - Oliver Kozumplik
- Department of Biological Psychiatry and Psychogeriatry, University Psychiatric Hospital Vrapce, Zagreb, Croatia.,Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia
| | - Marina Sagud
- School of Medicine, University of Zagreb, Zagreb, Croatia.,Department of Psychiatry, University Hospital Centre Zagreb, Zagreb, Croatia
| | - Zrnka Kovacic Petrovic
- Department of Biological Psychiatry and Psychogeriatry, University Psychiatric Hospital Vrapce, Zagreb, Croatia.,Department of Psychopharmacology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Nela Pivac
- Laboratory for Molecular Neuropsychiatry, Division of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia
| |
Collapse
|
|
37
|
Effects of crack cocaine addiction and stress-related genes on peripheral BDNF levels. J Psychiatr Res 2017; 90:78-85. [PMID: 28237884 DOI: 10.1016/j.jpsychires.2017.02.011] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2016] [Revised: 12/21/2016] [Accepted: 02/09/2017] [Indexed: 12/21/2022]
Abstract
This study examined the effects of glucocorticoid receptor (NR3C1), corticotropin-releasing hormone receptor 1 (CRHR1), and brain-derived neurotrophic factor (BDNF) genes on susceptibility to crack cocaine addiction and BDNF levels. Crack addicted patients who sought treatment (n = 280) and non-addicted individuals (n = 241) were assessed. Three SNPs in NR3C1 (rs6198, rs41423247, and rs10052957), three in CRHR1 (rs12944712, rs110402, and rs878886), and one in BDNF (rs6265) were genotyped. No significant effect was seen in the case-control analyses. Crack cocaine addicted patients showed significantly lower serum BDNF levels. Significant effects were observed for NR3C1 rs41423247 and rs10052957. These effects were restricted to non-addicted individuals and they were supported by significant gene-by-disease status interactions. For CRHR1, all SNPs were associated with BDNF levels. Although there were significant effects only in the analysis restricted to non-addicted individuals, the lack of significant results in the gene-by-disease status interaction analyses suggest a general effect on BDNF levels. The haplotype analyses presented the same effect seen in the single marker analyses. This study suggests that SNPs in the NR3C1 and CRHR1 genes may influence BDNF levels, but this effect is blunted in the context of crack cocaine addiction. Therefore, our data may be interpreted in light of several studies showing pronounced effects of crack cocaine on BDNF levels. Since peripheral BDNF is a biomarker for several psychiatric phenotypes, our results may be useful in interpreting previous associations between stress-related SNPs, drug addiction, and depression.
Collapse
|
|
38
|
Leviton A, Allred EN, Yamamoto H, Fichorova RN, Kuban K, O'Shea TM, Dammann O. Antecedents and correlates of blood concentrations of neurotrophic growth factors in very preterm newborns. Cytokine 2017; 94:21-28. [PMID: 28396037 PMCID: PMC5464409 DOI: 10.1016/j.cyto.2017.03.012] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Revised: 01/18/2017] [Accepted: 03/31/2017] [Indexed: 11/16/2022]
Abstract
AIM To identify the antecedents and very early correlates of low concentrations of neurotrophic growth factors in the blood of extremely preterm newborns during the first postnatal month. METHODS Using an immunobead assay, we measured the concentrations of neurotrophin 4 (NT4), brain-derived neurotrophic factor (BDNF), and basic fibroblast growth factor (bFGF) in blood spots collected on postnatal days 1 (N=1062), 7 (N=1087), 14 (N=989), 21 (N=940) and 28 (N=880) from infants born before the 28th week of gestation. We then sought the correlates of measurements in the top and bottom quartiles for gestational age and day the specimen was collected. RESULTS The concentrations of 2 neurotrophic proteins, NT4 and BDNF, were low among children delivered for medical (maternal or fetal) indications, and among those who were growth restricted. Children who had top quartile concentrations of NT4, BDNF, and bFGF tended to have elevated concentrations of inflammation-related proteins that day. This pattern persisted for much of the first postnatal month. CONCLUSIONS Delivery for medical indications and fetal growth restriction are associated with a relative paucity of NT4 and BDNF concentrations during the first 24 h after very preterm birth. Elevated blood concentrations of NT4, BDNF, and bFGF tended to co-occur with indicators of systemic inflammation on the same day.
Collapse
Affiliation(s)
- Alan Leviton
- Boston Children's Hospital, and Harvard Medical School, Boston, MA, United States.
| | - Elizabeth N Allred
- Boston Children's Hospital, and Harvard Medical School, Boston, MA, United States
| | | | - Raina N Fichorova
- Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States
| | - Karl Kuban
- Boston Medical Center and Boston University, Boston, MA, United States
| | | | - Olaf Dammann
- Tufts University School of Medicine, Boston, MA, United States; Hannover Medical School, Hannover, Germany
| |
Collapse
|
|
39
|
Perez-Rodriguez MM, New AS, Goldstein KE, Rosell D, Yuan Q, Zhou Z, Hodgkinson C, Goldman D, Siever LJ, Hazlett EA. Brain-derived neurotrophic factor Val66Met genotype modulates amygdala habituation. Psychiatry Res 2017; 263:85-92. [PMID: 28371657 PMCID: PMC5856456 DOI: 10.1016/j.pscychresns.2017.03.008] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2016] [Revised: 02/04/2017] [Accepted: 03/20/2017] [Indexed: 12/14/2022]
Abstract
A deficit in amygdala habituation to repeated emotional stimuli may be an endophenotype of disorders characterized by emotion dysregulation, such as borderline personality disorder (BPD). Amygdala reactivity to emotional stimuli is genetically modulated by brain-derived neurotrophic factor (BDNF) variants. Whether amygdala habituation itself is also modulated by BDNF genotypes remains unknown. We used imaging-genetics to examine the effect of BDNF Val66Met genotypes on amygdala habituation to repeated emotional stimuli. We used functional magnetic resonance imaging (fMRI) in 57 subjects (19 BPD patients, 18 patients with schizotypal personality disorder [SPD] and 20 healthy controls [HC]) during a task involving viewing of unpleasant, neutral, and pleasant pictures, each presented twice to measure habituation. Amygdala responses across genotypes (Val66Met SNP Met allele-carriers vs. Non-Met carriers) and diagnoses (HC, BPD, SPD) were examined with ANOVA. The BDNF 66Met allele was significantly associated with a deficit in amygdala habituation, particularly for emotional pictures. The association of the 66Met allele with a deficit in habituation to unpleasant emotional pictures remained significant in the subsample of BPD patients. Using imaging-genetics, we found preliminary evidence that deficient amygdala habituation may be modulated by BDNF genotype.
Collapse
Affiliation(s)
- M Mercedes Perez-Rodriguez
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Mental Illness Research Education and Clinical Center, James J. Peters Veterans Affairs Medical Center, Bronx, NY 10468, USA; CIBERSAM, Autonoma University, Fundacion Jimenez Diaz and Ramon y Cajal Hospital, Madrid, Spain.
| | - Antonia S New
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Mental Illness Research Education and Clinical Center, James J. Peters Veterans Affairs Medical Center, Bronx, NY 10468, USA
| | - Kim E Goldstein
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Daniel Rosell
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Mental Illness Research Education and Clinical Center, James J. Peters Veterans Affairs Medical Center, Bronx, NY 10468, USA
| | - Qiaoping Yuan
- Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892-9412, USA
| | - Zhifeng Zhou
- Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892-9412, USA
| | - Colin Hodgkinson
- Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892-9412, USA
| | - David Goldman
- Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892-9412, USA
| | - Larry J Siever
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Mental Illness Research Education and Clinical Center, James J. Peters Veterans Affairs Medical Center, Bronx, NY 10468, USA
| | - Erin A Hazlett
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Mental Illness Research Education and Clinical Center, James J. Peters Veterans Affairs Medical Center, Bronx, NY 10468, USA
| |
Collapse
|
|
40
|
Notaras MJ, Hill RA, Gogos JA, van den Buuse M. BDNF Val66Met Genotype Interacts With a History of Simulated Stress Exposure to Regulate Sensorimotor Gating and Startle Reactivity. Schizophr Bull 2017; 43:665-672. [PMID: 27262112 PMCID: PMC5464110 DOI: 10.1093/schbul/sbw077] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Reduced expression of Brain-Derived Neurotrophic Factor (BDNF) has been implicated in the pathophysiology of schizophrenia. The BDNF Val66Met polymorphism, which results in deficient activity-dependent secretion of BDNF, is associated with clinical features of schizophrenia. We investigated the effect of this polymorphism on Prepulse Inhibition (PPI), a translational model of sensorimotor gating which is disrupted in schizophrenia. We utilized humanized BDNFVal66Met (hBDNFVal66Met) mice which have been modified to carry the Val66Met polymorphism, as well as express humanized BDNF in vivo. We also studied the long-term effect of chronic corticosterone (CORT) exposure in these animals as a model of history of stress. PPI was assessed at 30ms and 100ms interstimulus intervals (ISI). Analysis of PPI at the commonly used 100ms ISI identified that, irrespective of CORT treatment, the hBDNFVal/Met genotype was associated with significantly reduced PPI. In contrast, PPI was not different between hBDNFMet/Met and hBDNFVal/Val genotype mice. At the 30ms ISI, CORT treatment selectively disrupted sensorimotor gating of hBDNFVal/Met heterozygote mice but not hBDNFVal/Val or hBDNFMet/Met mice. Analysis of startle reactivity revealed that chronic CORT reduced startle reactivity of hBDNFVal/Val male mice by 51%. However, this was independent of the effect of CORT on PPI. In summary, we provide evidence of a distinct BDNFVal66Met heterozygote-specific phenotype using the sensorimotor gating endophenotype of schizophrenia. These data have important implications for clinical studies where, if possible, the BDNFVal/Met heterozygote genotype should be distinguished from the BDNFMet/Met genotype.
Collapse
Affiliation(s)
- Michael J. Notaras
- Behavioural Neuroscience Laboratory, Florey Institute of Neuroscience and Mental Health, Melbourne, Australia;,Psychoneuroendocrinology Laboratory, Florey Institute of Neuroscience and Mental Health, Melbourne, Australia
| | - Rachel A. Hill
- Psychoneuroendocrinology Laboratory, Florey Institute of Neuroscience and Mental Health, Melbourne, Australia
| | - Joseph A. Gogos
- Departments of Biophysics and Neuroscience, Columbia University, New York, NY
| | - Maarten van den Buuse
- Behavioural Neuroscience Laboratory, Florey Institute of Neuroscience and Mental Health, Melbourne, Australia;,School of Psychology and Public Health, La Trobe University, Melbourne, Australia;,The College of Public Health, Medical and Veterinary Sciences, James Cook University, Queensland, Australia
| |
Collapse
|
|
41
|
Tsai SJ. Role of neurotrophic factors in attention deficit hyperactivity disorder. Cytokine Growth Factor Rev 2017; 34:35-41. [DOI: 10.1016/j.cytogfr.2016.11.003] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2016] [Revised: 11/15/2016] [Accepted: 11/25/2016] [Indexed: 12/20/2022]
|
|
42
|
BDNF concentrations and daily fluctuations differ among ADHD children and respond differently to methylphenidate with no relationship with depressive symptomatology. Psychopharmacology (Berl) 2017; 234:267-279. [PMID: 27807606 DOI: 10.1007/s00213-016-4460-1] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2016] [Accepted: 10/06/2016] [Indexed: 01/09/2023]
Abstract
RATIONALE Brain-derived neurotrophic factor (BDNF) enhances the growth and maintenance of several monoamine neuronal systems, serves as a neurotransmitter modulator and participates in the mechanisms of neuronal plasticity. Therefore, BDNF is a good candidate for interventions in the pathogenesis and/or treatment response of attention deficit hyperactivity disorder (ADHD). OBJECTIVE We quantified the basal concentration and daily fluctuation of serum BDNF, as well as changes after methylphenidate treatment. METHOD A total of 148 children, 4-5 years old, were classified into groups as follows: ADHD group (n = 107, DSM-IV-TR criteria) and a control group (CG, n = 41). Blood samples were drawn at 2000 and 0900 hours from both groups, and after 4.63 ± 2.3 months of treatment, blood was drawn only from the ADHD group for BDNF measurements. Factorial analysis was performed (Stata software, version 12.0). RESULTS Morning BDNF (36.36 ± 11.62 ng/ml) in the CG was very similar to that in the predominantly inattentive children (PAD), although the evening concentration in the CG was higher (CG 31.78 ± 11.92 vs PAD 26.41 ± 11.55 ng/ml). The hyperactive-impulsive group, including patients with comorbid conduct disorder (PHI/CD), had lower concentrations. Methylphenidate (MPH) did not modify the concentration or the absence of daily BDNF fluctuations in the PHI/CD children; however, MPH induced a significant decrease in BDNF in PAD and basal day/night fluctuations disappeared in this ADHD subtype. This profile was not altered by the presence of depressive symptoms. CONCLUSIONS Our data support a reduction in BDNF in untreated ADHD due to the lower concentrations in PHI/CD children, which is similar to other psychopathologic and cognitive disorders. MPH decreased BDNF only in the PAD group, which might indicate that BDNF is not directly implicated in the methylphenidate-induced amelioration of the neuropsychological and organic immaturity of ADHD patients.
Collapse
|
|
43
|
Rogaeva E, Schmitt-Ulms G. Does BDNF Val66Met contribute to preclinical Alzheimer's disease? Brain 2016; 139:2586-2589. [PMID: 27671028 DOI: 10.1093/brain/aww201] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Affiliation(s)
- Ekaterina Rogaeva
- Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario M5T 2S8, Canada Department of Medicine, University of Toronto, Ontario, Canada
| | - Gerold Schmitt-Ulms
- Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario M5T 2S8, Canada Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada
| |
Collapse
|
|
44
|
Narayanan V, Veeramuthu V, Ahmad-Annuar A, Ramli N, Waran V, Chinna K, Bondi MW, Delano-Wood L, Ganesan D. Missense Mutation of Brain Derived Neurotrophic Factor (BDNF) Alters Neurocognitive Performance in Patients with Mild Traumatic Brain Injury: A Longitudinal Study. PLoS One 2016; 11:e0158838. [PMID: 27438599 PMCID: PMC4954696 DOI: 10.1371/journal.pone.0158838] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2016] [Accepted: 06/22/2016] [Indexed: 01/13/2023] Open
Abstract
The predictability of neurocognitive outcomes in patients with traumatic brain injury is not straightforward. The extent and nature of recovery in patients with mild traumatic brain injury (mTBI) are usually heterogeneous and not substantially explained by the commonly known demographic and injury-related prognostic factors despite having sustained similar injuries or injury severity. Hence, this study evaluated the effects and association of the Brain Derived Neurotrophic Factor (BDNF) missense mutations in relation to neurocognitive performance among patients with mTBI. 48 patients with mTBI were prospectively recruited and MRI scans of the brain were performed within an average 10.1 (SD 4.2) hours post trauma with assessment of their neuropsychological performance post full Glasgow Coma Scale (GCS) recovery. Neurocognitive assessments were repeated again at 6 months follow-up. The paired t-test, Cohen's d effect size and repeated measure ANOVA were performed to delineate statistically significant differences between the groups [wildtype G allele (Val homozygotes) vs. minor A allele (Met carriers)] and their neuropsychological performance across the time point (T1 = baseline/ admission vs. T2 = 6th month follow-up). Minor A allele carriers in this study generally performed more poorly on neuropsychological testing in comparison wildtype G allele group at both time points. Significant mean differences were observed among the wildtype group in the domains of memory (M = -11.44, SD = 10.0, p = .01, d = 1.22), executive function (M = -11.56, SD = 11.7, p = .02, d = 1.05) and overall performance (M = -6.89 SD = 5.3, p = .00, d = 1.39), while the minor A allele carriers showed significant mean differences in the domains of attention (M = -11.0, SD = 13.1, p = .00, d = .86) and overall cognitive performance (M = -5.25, SD = 8.1, p = .01, d = .66).The minor A allele carriers in comparison to the wildtype G allele group, showed considerably lower scores at admission and remained impaired in most domains across the timepoints, although delayed signs of recovery were noted to be significant in the domains attention and overall cognition. In conclusion, the current study has demonstrated the role of the BDNF rs6265 Val66Met polymorphism in influencing specific neurocognitive outcomes in patients with mTBI. Findings were more detrimentally profound among Met allele carriers.
Collapse
Affiliation(s)
- Vairavan Narayanan
- Division of Neurosurgery, Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Wilayah Persekutuan, Malaysia
- * E-mail: (VN); (VV)
| | - Vigneswaran Veeramuthu
- Division of Neurosurgery, Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Wilayah Persekutuan, Malaysia
- * E-mail: (VN); (VV)
| | - Azlina Ahmad-Annuar
- Department of Molecular Medicine, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Wilayah Persekutuan, Malaysia
| | - Norlisah Ramli
- University Malaya Research Imaging Centre, University of Malaya, Kuala Lumpur, Wilayah Persekutuan, Malaysia
| | - Vicknes Waran
- Division of Neurosurgery, Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Wilayah Persekutuan, Malaysia
| | - Karuthan Chinna
- Julius Centre University Malaya, Department of Social and Preventive Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Mark William Bondi
- VA San Diego Healthcare System, San Diego, California, United States of America
- University of California San Diego, Department of Psychiatry, San Diego, California, United States of America
| | - Lisa Delano-Wood
- VA San Diego Healthcare System, San Diego, California, United States of America
- University of California San Diego, Department of Psychiatry, San Diego, California, United States of America
| | - Dharmendra Ganesan
- Division of Neurosurgery, Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Wilayah Persekutuan, Malaysia
| |
Collapse
|
|
45
|
Fries GR, Li Q, McAlpin B, Rein T, Walss-Bass C, Soares JC, Quevedo J. The role of DNA methylation in the pathophysiology and treatment of bipolar disorder. Neurosci Biobehav Rev 2016; 68:474-488. [PMID: 27328785 DOI: 10.1016/j.neubiorev.2016.06.010] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Revised: 06/03/2016] [Accepted: 06/12/2016] [Indexed: 12/31/2022]
Abstract
Bipolar disorder (BD) is a multifactorial illness thought to result from an interaction between genetic susceptibility and environmental stimuli. Epigenetic mechanisms, including DNA methylation, can modulate gene expression in response to the environment, and therefore might account for part of the heritability reported for BD. This paper aims to review evidence of the potential role of DNA methylation in the pathophysiology and treatment of BD. In summary, several studies suggest that alterations in DNA methylation may play an important role in the dysregulation of gene expression in BD, and some actually suggest their potential use as biomarkers to improve diagnosis, prognosis, and assessment of response to treatment. This is also supported by reports of alterations in the levels of DNA methyltransferases in patients and in the mechanism of action of classical mood stabilizers. In this sense, targeting specific alterations in DNA methylation represents exciting new treatment possibilities for BD, and the 'plastic' characteristic of DNA methylation accounts for a promising possibility of restoring environment-induced modifications in patients.
Collapse
Affiliation(s)
- Gabriel R Fries
- Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas Health Science Center at Houston (UTHealth), 1941 East Rd, 77054, Houston, TX, USA.
| | - Qiongzhen Li
- Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas Health Science Center at Houston (UTHealth), 1941 East Rd, 77054, Houston, TX, USA
| | - Blake McAlpin
- Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas Health Science Center at Houston (UTHealth), 1941 East Rd, 77054, Houston, TX, USA
| | - Theo Rein
- Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Kraepelinstraße 2-10, 80804, Munich, Germany
| | - Consuelo Walss-Bass
- Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas Health Science Center at Houston (UTHealth), 1941 East Rd, 77054, Houston, TX, USA; Neuroscience Graduate Program, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA
| | - Jair C Soares
- Center of Excellence on Mood Disorders, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA
| | - Joao Quevedo
- Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas Health Science Center at Houston (UTHealth), 1941 East Rd, 77054, Houston, TX, USA; Center of Excellence on Mood Disorders, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA; Neuroscience Graduate Program, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA; Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil
| |
Collapse
|
|
46
|
Li Y, Ma Q, Dasgupta C, Halavi S, Hartman RE, Xiao D, Zhang L. Inhibition of DNA Methylation in the Developing Rat Brain Disrupts Sexually Dimorphic Neurobehavioral Phenotypes in Adulthood. Mol Neurobiol 2016; 54:3988-3999. [PMID: 27311770 DOI: 10.1007/s12035-016-9957-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Accepted: 06/06/2016] [Indexed: 10/21/2022]
Abstract
Accumulating evidence indicates a critical implication of DNA methylation in the brain development. We aim to determine whether the disruption of DNA methylation patterns in the developing brain adversely affects neurobehavioral phenotypes later in life in a sex-dependent manner. 5-Aza-2'-deoxycytidine (5-Aza), a DNA methylation inhibitor, was administered in newborn rats from postnatal day 1 to 3. Neurobehavioral outcomes were analyzed at 3 months of age. 5-Aza treatment significantly inhibited DNA methyltransferase activity and decreased global DNA methylation levels in neonatal rat brains, resulting in asymmetric growth restriction with the increased brain to body weight ratio in both male and female rats at 14 days and 3 months of age. Compared with the saline control, 5-Aza treatment significantly improved performance of male rats on the rotarod test, and 5-Aza-treated female rats demonstrated less anxiety, less depression-like behaviors, and enhanced spatial learning performance. Of importance, neonatal 5-Aza treatment eliminated the sexually dimorphic differences in several neurobehavioral tests in adult rats. In addition, 5-Aza treatment decreased promoter methylation of brain-derived neurotrophic factor (BDNF) gene and significantly increased BDNF mRNA and protein abundance in the prefrontal cortex and hippocampus of female rats in a sex-dependent manner. Thus, brain DNA methylation appears to be essential for sexual differentiations of the brain and neurobehavioral functions. Inhibition of DNA methylation in the developing brain of early life induces aberrant neurobehavioral profiles and disrupts sexually dimorphic neurobehavioral phenotypes in adulthood, of which altered BDNF signaling pathway may be an important mediator.
Collapse
Affiliation(s)
- Yong Li
- Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, 92350, USA
| | - Qingyi Ma
- Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, 92350, USA
| | - Chiranjib Dasgupta
- Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, 92350, USA
| | - Shina Halavi
- Department of Psychology, Loma Linda University, Loma Linda, CA, 92354, USA
| | - Richard E Hartman
- Department of Psychology, Loma Linda University, Loma Linda, CA, 92354, USA
| | - Daliao Xiao
- Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, 92350, USA
| | - Lubo Zhang
- Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, 92350, USA.
| |
Collapse
|
|
47
|
Perceval G, Flöel A, Meinzer M. Can transcranial direct current stimulation counteract age-associated functional impairment? Neurosci Biobehav Rev 2016; 65:157-72. [DOI: 10.1016/j.neubiorev.2016.03.028] [Citation(s) in RCA: 69] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2015] [Revised: 02/05/2016] [Accepted: 03/14/2016] [Indexed: 12/21/2022]
|
|
48
|
Fanaei H, Khayat S, Kasaeian A, Javadimehr M. Effect of curcumin on serum brain-derived neurotrophic factor levels in women with premenstrual syndrome: A randomized, double-blind, placebo-controlled trial. Neuropeptides 2016; 56:25-31. [PMID: 26608718 DOI: 10.1016/j.npep.2015.11.003] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Revised: 11/10/2015] [Accepted: 11/10/2015] [Indexed: 12/21/2022]
Abstract
Premenstrual syndrome (PMS) is a variety of physical, mental, and behavioral symptoms that start during the late luteal phase of the menstrual cycle, and the symptoms disappear after the onset of menses. Serum brain-derived neurotrophic factor (BDNF) levels during luteal phase in women associated with PMS have more alterations than women not suffering from PMS. In this regard, altered luteal BDNF levels in women with PMS might play a role in a set of psychological and somatic symptoms of the PMS. Studies of last decade revealed neuroprotective effects of curcumin and its ability to increase BDNF levels. In the present study, we evaluated the effect of curcumin on serum BDNF level and PMS symptoms severity in women with PMS. Present study is a Randomized, Double-Blinded, Placebo-Controlled Clinical Trial. Curcumin treatment was given for three successive menstrual cycles and each cycle ran 10 days. After having identified persons with PMS, participants were randomly allocated into placebo (n=35) and curcumin (n=35) groups. Each sample in placebo and curcumin groups received two capsules daily for seven days before menstruation and for three days after menstruation for three successive menstrual cycles. Participants noted the severity of the symptoms mentioned in the daily record questionnaire. Self-report was used to determine menstrual cycle phase of participants. At the fourth day of each menstrual cycle venous blood samples were collected for BDNF measurement by ELISA method. Before intervention, BDNF levels and mean scores of PMS symptoms (mood, behavioral and physical symptoms) between two groups showed no significant differences. But in curcumin group first, second and third cycles after interventions BDNF levels were significantly higher and mean scores of PMS symptoms were significantly less than placebo group. Based on our results part of these beneficial effects of curcumin may be mediated through enhancing serum BDNF levels in women with PMS.
Collapse
Affiliation(s)
- Hamed Fanaei
- Pregnancy Health Research Center, Zahedan University of Medical Sciences, Zahedan, Iran; Department of Physiology, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Samira Khayat
- Department of Midwifery and Reproductive Health, School of Nursing and Midwifery, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Reproductive Health, School of Nursing and Midwifery, Tehran University of Medical Sciences, Tehran, Iran.
| | - Amir Kasaeian
- Hematology-Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran; Non-communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran; Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Mani Javadimehr
- School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran
| |
Collapse
|
|
49
|
Hashimoto T, Fukui K, Takeuchi H, Yokota S, Kikuchi Y, Tomita H, Taki Y, Kawashima R. Effects of the BDNF Val66Met Polymorphism on Gray Matter Volume in Typically Developing Children and Adolescents. Cereb Cortex 2016; 26:1795-803. [PMID: 26830347 PMCID: PMC4785961 DOI: 10.1093/cercor/bhw020] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
The Val66Met polymorphism of brain-derived neurotrophic factor (BDNF) is associated with psychiatric disorders and regional gray matter volume (rGMV) in adults. However, the relationship between BDNF and rGMV in children has not been clarified. In this 3-year cross-sectional/longitudinal (2 time points) study, we investigated the effects of BDNF genotypes on rGMV in 185 healthy Japanese children aged 5.7-18.4 using magnetic resonance imaging (MRI) and voxel-based morphometry (VBM) analyses. We found that the volume of the right cuneus in Met homozygotes (Met/Met) was greater than in Val homozygotes (Val/Val) in both exams, and the left insula and left ventromedial prefrontal cortex volumes were greater in Val homozygotes versus Met homozygotes in Exam l. In addition, Met homozygous subjects exhibited higher processing speed in intelligence indices than Val homozygotes and Val/Met heterozygotes at both time points. Longitudinal analysis showed that the left temporoparietal junction volume of Val/Met heterozygotes increased more substantially over the 3-year study period than in Val homozygotes, and age-related changes were observed for the Val/Met genotype. Our findings suggest that the presence of 2 Met alleles may have a positive effect on rGMV at the developmental stages analyzed in this study.
Collapse
Affiliation(s)
| | - Kento Fukui
- Department of Nuclear Medicine and Radiology, Division of Medical Neuroimaging Analysis, Institute Development, Aging and Cancer
| | | | | | - Yoshie Kikuchi
- Department of Disaster Psychiatry, International Research Institute of Disaster Science
| | - Hiroaki Tomita
- Department of Disaster Psychiatry, International Research Institute of Disaster Science
| | - Yasuyuki Taki
- Division of Developmental Cognitive Neuroscience Department of Nuclear Medicine and Radiology, Division of Medical Neuroimaging Analysis, Institute Development, Aging and Cancer Department of Community Medical Supports, Tohoku Medical Megabank Organization, Tohoku University, 980-8575 Sendai, Japan
| | | |
Collapse
|
|
50
|
Ceballos N, Sharma S. Risk and Resilience: The Role of Brain-derived Neurotrophic Factor in Alcohol Use Disorder. AIMS Neurosci 2016. [DOI: 10.3934/neuroscience.2016.4.398] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
|