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Sun Y, Shi X, Ohm M, Korte M, Zagrebelsky M. Deciphering genetic causality between plasma BDNF and 91 circulating inflammatory proteins through bidirectional mendelian randomization. Sci Rep 2025; 15:10312. [PMID: 40133606 PMCID: PMC11937598 DOI: 10.1038/s41598-025-95546-1] [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: 09/04/2024] [Accepted: 03/21/2025] [Indexed: 03/27/2025] Open
Abstract
Prior studies reported an association between the levels of brain-derived neurotrophic factor (BDNF) circulating in the bloodstream and those of different inflammatory factors. However, their causal relationship remains unclear. Here, we performed a Mendelian randomization (MR) study to investigate the causal relationships between plasma BDNF levels and 91 circulating inflammatory proteins to shed light on the possible role of BDNF in the pathogenesis and progression of inflammation-related neurological diseases in order to distinguish correlation from possible causal effects. Data for plasma BDNF levels were derived from a genome-wide association study (GWAS) encompassing 3,301 European participants. Genetic association estimates for 91 inflammation proteins were extracted from a GWAS meta-analysis that enrolled 14,824 European participants. The primary MR analysis employed the inverse variance weighted (IVW) method and was corroborated by additional methods including MR-Egger, weighted median, weighted mode, and simple mode. Analyses of sensitivity were performed by evaluating the heterogeneity, horizontal pleiotropy, and robustness of the results. Genetic evidence indicated that elevated plasma BDNF levels possibly contribute to decreased concentrations of 13 inflammation proteins (OR: 0.951-0.977), including beta-nerve growth factor (Beta-NGF), caspase 8 (CASP-8), interleukin-15 receptor subunit alpha (IL-15RA), interleukin-17 A (IL-17 A), interleukin-17 C (IL-17 C), interleukin-2 (IL-2), interleukin-20 (IL-20), interleukin-20 receptor subunit alpha (IL-20RA), interleukin-24 (IL-24), interleukin-33 (IL-33), leukemia inhibitory factor (LIF), neurturin (NRTN), as well as neurotrophin-3 (NT-3). The associations between BDNF and IL-33 remained statistically significant after FDR correction (FDR > 0.05). Furthermore, reverse MR analysis showed that C-C motif chemokine 23 (CCL23), CUB domain-containing protein 1 (CDCP1), and NRTN is suggestive for a positive causal effect on BDNF plasma levels (OR: 1.240-1.422). Moreover, 5 proteins are likely to be associated with lower plasma levels of BDNF (OR: 0.742-0.971), including adenosine deaminase (ADA), cystatin D (CST5), interleukin-13 (IL-13), interleukin-17 A (IL-17 A), and vascular endothelial growth factor A (VEGF-A). Genetically determined plasma BDNF levels influence IL-33 and are possibly associated with 12 circulating inflammatory proteins. The data suggest that 8 inflammatory proteins exhibit either negative or protective roles to BDNF levels, respectively. Of these, 5 are negatively associated with BDNF levels, while 3 play protective roles. These findings may offer new theoretical and empirical insights into the pathogenesis and progression of inflammation-related neurological diseases.
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Affiliation(s)
- Yesheng Sun
- Division of Cellular Neurobiology, Zoological Institute, TU Braunschweig, Braunschweig, Germany
| | - Xizi Shi
- Division of Cellular Neurobiology, Zoological Institute, TU Braunschweig, Braunschweig, Germany
- Research Group Neuroinflammation and Neurodegeneration, Helmholtz Centre for Infection Research, AG NIND, Braunschweig, Germany
| | - Melanie Ohm
- Division of Cellular Neurobiology, Zoological Institute, TU Braunschweig, Braunschweig, Germany
| | - Martin Korte
- Division of Cellular Neurobiology, Zoological Institute, TU Braunschweig, Braunschweig, Germany
- Research Group Neuroinflammation and Neurodegeneration, Helmholtz Centre for Infection Research, AG NIND, Braunschweig, Germany
| | - Marta Zagrebelsky
- Division of Cellular Neurobiology, Zoological Institute, TU Braunschweig, Braunschweig, Germany.
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Calder AE, Hase A, Hasler G. Effects of psychoplastogens on blood levels of brain-derived neurotrophic factor (BDNF) in humans: a systematic review and meta-analysis. Mol Psychiatry 2025; 30:763-776. [PMID: 39613915 PMCID: PMC11753367 DOI: 10.1038/s41380-024-02830-z] [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] [Received: 03/12/2024] [Revised: 11/01/2024] [Accepted: 11/05/2024] [Indexed: 12/01/2024]
Abstract
BACKGROUND Peripheral levels of brain-derived neurotrophic factor (BDNF) are often used as a biomarker for the rapid plasticity-promoting effects of ketamine, psychedelics, and other psychoplastogens in humans. However, studies analyzing peripheral BDNF after psychoplastogen exposure show mixed results. In this meta-analysis, we aimed to test whether the rapid upregulation of neuroplasticity seen in preclinical studies is detectable using peripheral BDNF in humans. METHODS This analysis was pre-registered (PROSPERO ID: CRD42022333096) and funded by the University of Fribourg. We systematically searched PubMed, Web of Science, and PsycINFO to meta-analyze the effects of all available psychoplastogens on peripheral BDNF levels in humans, including ketamine, esketamine, LSD, psilocybin, ayahuasca, DMT, MDMA, scopolamine, and rapastinel. Risk of bias was assessed using Cochrane Risk of Bias Tools. Using meta-regressions and mixed effects models, we additionally analyzed the impact of several potential moderators. RESULTS We included 29 studies and found no evidence that psychoplastogens elevate peripheral BDNF levels in humans (SMD = 0.024, p = 0.64). This result was not affected by drug, dose, blood fraction, participant age, or psychiatric diagnoses. In general, studies with better-controlled designs and fewer missing values reported smaller effect sizes. Later measurement timepoints showed minimally larger effects on BDNF. CONCLUSION These data suggest that peripheral BDNF levels do not change after psychoplastogen administration in humans. It is possible that peripheral BDNF is not an informative marker of rapid changes in neuroplasticity, or that preclinical findings on psychoplastogens and neuroplasticity may not translate to human subjects. Limitations of this analysis include the reliability and validity of BDNF measurement and low variation in some potential moderators. More precise methods of measuring rapid changes in neuroplasticity, including neuroimaging and stimulation-based methods, are recommended for future studies attempting to translate preclinical findings to humans.
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Affiliation(s)
- Abigail E Calder
- Molecular Psychiatry Lab, Department of Medicine, University of Fribourg, Fribourg, Switzerland
| | - Adrian Hase
- Molecular Psychiatry Lab, Department of Medicine, University of Fribourg, Fribourg, Switzerland
| | - Gregor Hasler
- Molecular Psychiatry Lab, Department of Medicine, University of Fribourg, Fribourg, Switzerland.
- Fribourg Mental Health Network, Chemin du Cardinal-Journet 3, 1752, Villars-sur-Glâne, Switzerland.
- Lake Lucerne Institute, Vitznau, Switzerland.
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Wang M, Hua Y, Bai Y. A review of the application of exercise intervention on improving cognition in patients with Alzheimer's disease: mechanisms and clinical studies. Rev Neurosci 2025; 36:1-25. [PMID: 39029521 DOI: 10.1515/revneuro-2024-0046] [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: 03/29/2024] [Accepted: 07/08/2024] [Indexed: 07/21/2024]
Abstract
Alzheimer's disease (AD) is the most common form of dementia, leading to sustained cognitive decline. An increasing number of studies suggest that exercise is an effective strategy to promote the improvement of cognition in AD. Mechanisms of the benefits of exercise intervention on cognitive function may include modulation of vascular factors by affecting cardiovascular risk factors, regulating cardiorespiratory health, and enhancing cerebral blood flow. Exercise also promotes neurogenesis by stimulating neurotrophic factors, affecting neuroplasticity in the brain. Additionally, regular exercise improves the neuropathological characteristics of AD by improving mitochondrial function, and the brain redox status. More and more attention has been paid to the effect of Aβ and tau pathology as well as sleep disorders on cognitive function in persons diagnosed with AD. Besides, there are various forms of exercise intervention in cognitive improvement in patients with AD, including aerobic exercise, resistance exercise, and multi-component exercise. Consequently, the purpose of this review is to summarize the findings of the mechanisms of exercise intervention on cognitive function in patients with AD, and also discuss the application of different exercise interventions in cognitive impairment in AD to provide a theoretical basis and reference for the selection of exercise intervention in cognitive rehabilitation in AD.
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Affiliation(s)
- Man Wang
- Department of Rehabilitation Medicine, Huashan Hospital, Fudan University, No. 12 Middle Wulumuqi Road, Jing'an District, Shanghai 200040, China
- Department of Rehabilitation Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Yan Hua
- Department of Rehabilitation Medicine, Huashan Hospital, Fudan University, No. 12 Middle Wulumuqi Road, Jing'an District, Shanghai 200040, China
| | - Yulong Bai
- Department of Rehabilitation Medicine, Huashan Hospital, Fudan University, No. 12 Middle Wulumuqi Road, Jing'an District, Shanghai 200040, China
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Behrendt T, Quisilima JI, Bielitzki R, Behrens M, Glazachev OS, Brigadski T, Leßmann V, Schega L. Brain-Derived neurotrophic factor and inflammatory biomarkers are unaffected by acute and chronic intermittent hypoxic-hyperoxic exposure in geriatric patients: a randomized controlled trial. Ann Med 2024; 56:2304650. [PMID: 38253008 PMCID: PMC10810628 DOI: 10.1080/07853890.2024.2304650] [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: 07/11/2023] [Accepted: 11/24/2023] [Indexed: 01/24/2024] Open
Abstract
BACKGROUND Animal and human studies have shown that exposure to hypoxia can increase brain-derived neurotrophic factor (BDNF) protein transcription and reduce systematic inflammatory cytokine response. Therefore, the aim of this study was to investigate the acute and chronic effects of intermittent hypoxic-hyperoxic exposure (IHHE) prior to aerobic exercise on BDNF, interleukin-6 (IL-6), and C-reactive protein (CRP) blood levels in geriatric patients. PATIENTS AND METHODS Twenty-five geriatric patients (83.1 ± 5.0 yrs, 71.1 ± 10.0 kg, 1.8 ± 0.9 m) participated in a placebo-controlled, single-blinded trial and were randomly assigned to either an intervention (IG) or control group (CG) performing an aerobic cycling training (17 sessions, 20 min·session-1, 3 sessions·week-1). Prior to aerobic cycling exercise, the IG was additionally exposed to IHHE for 30 min, whereas the CG received continuous normoxic air. Blood samples were taken immediately before (pre-exercise) and 10 min (post-exercise) after the first session as well as 48 h (post-training) after the last session to determine serum (BDNFS) and plasma BDNF (BDNFP), IL-6, and CRP levels. Intervention effects were analyzed using a 2 x 2 analysis of covariance with repeated measures. Results were interpreted based on effect sizes with a medium effect considered as meaningful (ηp2 ≥ 0.06, d ≥ 0.5). RESULTS CRP was moderately higher (d = 0.51) in the CG compared to the IG at baseline. IHHE had no acute effect on BDNFS (ηp2 = 0.01), BDNFP (ηp2 < 0.01), BDNF serum/plasma-ratio (ηp2 < 0.01), IL-6 (ηp2 < 0.01), or CRP (ηp2 = 0.04). After the 6-week intervention, an interaction was found for BDNF serum/plasma-ratio (ηp2 = 0.06) but not for BDNFS (ηp2 = 0.04), BDNFP (ηp2 < 0.01), IL-6 (ηp2 < 0.01), or CRP (ηp2 < 0.01). BDNF serum/plasma-ratio increased from pre-exercise to post-training (d = 0.67) in the CG compared to the IG (d = 0.51). A main effect of time was found for BDNFP (ηp2 = 0.09) but not for BDNFS (ηp2 = 0.02). Within-group post-hoc analyses revealed a training-related reduction in BDNFP in the IG and CG by 46.1% (d = 0.73) and 24.7% (d = 0.57), respectively. CONCLUSION The addition of 30 min IHHE prior to 20 min aerobic cycling seems not to be effective to increase BDNFS and BDNFP or to reduce IL-6 and CRP levels in geriatric patients after a 6-week intervention.The study was retrospectively registered at drks.de (DRKS-ID: DRKS00025130).
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Affiliation(s)
- Tom Behrendt
- Department of Sport Science, Chair for Health and Physical Activity, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | - Jessica Ibanez Quisilima
- Department of Sport Science, Chair for Health and Physical Activity, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | - Robert Bielitzki
- Department of Sport Science, Chair for Health and Physical Activity, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | - Martin Behrens
- University of Applied Sciences for Sport and Management Potsdam, Potsdam, Germany
| | - Oleg S. Glazachev
- Department of Human Physiology, Institute of Clinical Medicine, I.M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - Tanja Brigadski
- Department of Informatics and Microsystem Technology, University of Applied Sciences Kaiserslautern, Zweibrücken, Germany
| | - Volkmar Leßmann
- Institute of Physiology, Otto-von-Guericke University Magdeburg, Medical Faculty, Magdeburg, Germany
- Center for Behavioral Brain Sciences, Magdeburg, Germany
| | - Lutz Schega
- Department of Sport Science, Chair for Health and Physical Activity, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
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Moreira P, Macedo J, Matos P, Bicker J, Fortuna A, Figueirinha A, Salgueiro L, Batista MT, Silva A, Silva S, Resende R, Branco PC, Cruz MT, Pereira CF. Effect of bioactive extracts from Eucalyptus globulus leaves in experimental models of Alzheimer's disease. Biomed Pharmacother 2024; 181:117652. [PMID: 39486370 DOI: 10.1016/j.biopha.2024.117652] [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: 08/01/2024] [Revised: 10/19/2024] [Accepted: 10/28/2024] [Indexed: 11/04/2024] Open
Abstract
Current therapies for Alzheimer's disease (AD) do not delay its progression, therefore, novel disease-modifying strategies are urgently needed. Recently, an increasing number of compounds from natural origin with protective properties against AD have been identified. Mixtures or extracts obtained from natural products containing several bioactive compounds have multifunctional properties and have drawn the attention because multiple AD pathways can be simultaneously modulated. This study evaluated the in vitro and in vivo effect of the essential oil (EO) obtained from the hydrodistillation of Eucalyptus globulus leaves, and an extract obtained from the hydrodistillation residual water (HRW). It was observed that EO and HRW have anti-inflammatory effect in brain immune cells modeling AD, namely lipopolysaccharide (LPS)- and amyloid-beta (Aβ)-stimulated microglia. In cell models that mimic AD-related neuronal dysfunction, HRW attenuated Aβ secretion and Aβ-induced mitochondrial dysfunction. Since the HRW's major components did not cross the blood-brain barrier, both EO and HRW were administered to the APP/PS1 transgenic AD mouse model by an intranasal route, which reduced cortical and hippocampal Aβ levels, and to rescue memory deficits and anxiety-like behaviors. Finally, HRW and EO were found to regulate cholesterol levels in aged mice after intranasal administration, suggesting that these extracts can reduce hypercholesterolemia and avoid risk for AD development. Overall, findings support a protective role of E. globulus extracts against AD‑like pathology and cognitive impairment highlighting the underlying mechanisms. These extracts obtained from underused forest biomass could be useful to develop nutraceutical supplements helpful to avoid AD risk and to prevent its progression.
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Affiliation(s)
- Patrícia Moreira
- CNC-Center for Neuroscience and Cell Biology, CIBB-Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra 3004-504, Portugal; Faculty of Pharmacy, University of Coimbra, Coimbra 3000-548, Portugal.
| | - Jéssica Macedo
- Faculty of Pharmacy, University of Coimbra, Coimbra 3000-548, Portugal
| | - Patrícia Matos
- Faculty of Pharmacy, University of Coimbra, Coimbra 3000-548, Portugal; LAQV, REQUIMTE, Faculty of Pharmacy, University of Coimbra, Coimbra 3000-548, Portugal; CIEPQPF, Research Center for Chemical Processes Engineering and Forest Products, Faculty of Pharmacy, University of Coimbra, Coimbra 3000-548, Portugal
| | - Joana Bicker
- Faculty of Pharmacy, University of Coimbra, Coimbra 3000-548, Portugal
| | - Ana Fortuna
- Faculty of Pharmacy, University of Coimbra, Coimbra 3000-548, Portugal
| | - Artur Figueirinha
- Faculty of Pharmacy, University of Coimbra, Coimbra 3000-548, Portugal; LAQV, REQUIMTE, Faculty of Pharmacy, University of Coimbra, Coimbra 3000-548, Portugal; CIEPQPF, Research Center for Chemical Processes Engineering and Forest Products, Faculty of Pharmacy, University of Coimbra, Coimbra 3000-548, Portugal
| | - Lígia Salgueiro
- Faculty of Pharmacy, University of Coimbra, Coimbra 3000-548, Portugal; CIEPQPF, Research Center for Chemical Processes Engineering and Forest Products, Faculty of Pharmacy, University of Coimbra, Coimbra 3000-548, Portugal
| | - Maria Teresa Batista
- CIEPQPF, Research Center for Chemical Processes Engineering and Forest Products, Faculty of Pharmacy, University of Coimbra, Coimbra 3000-548, Portugal
| | - Ana Silva
- CNC-Center for Neuroscience and Cell Biology, CIBB-Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra 3004-504, Portugal
| | - Sónia Silva
- Faculty of Pharmacy, University of Coimbra, Coimbra 3000-548, Portugal; iCBR-Coimbra Institute for Clinical and Biomedical Research, CIBB-Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra 3004-504, Portugal
| | - Rosa Resende
- CNC-Center for Neuroscience and Cell Biology, CIBB-Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra 3004-504, Portugal
| | - Pedro Costa Branco
- RAIZ-Forest and Paper Research Institute, Eixo, Aveiro 3800-783, Portugal
| | - Maria Teresa Cruz
- CNC-Center for Neuroscience and Cell Biology, CIBB-Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra 3004-504, Portugal; Faculty of Pharmacy, University of Coimbra, Coimbra 3000-548, Portugal
| | - Cláudia Fragão Pereira
- CNC-Center for Neuroscience and Cell Biology, CIBB-Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra 3004-504, Portugal; Faculty of Medicine, University of Coimbra, Coimbra 3000-548, Portugal.
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Buzas R, Ciubotaru P, Faur AC, Preda M, Ardelean M, Georgescu D, Dumitrescu P, Lighezan DF, Popa MD. Correlation of the FIB-4 Liver Biomarker Score with the Severity of Heart Failure. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:1943. [PMID: 39768827 PMCID: PMC11679668 DOI: 10.3390/medicina60121943] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 11/19/2024] [Accepted: 11/23/2024] [Indexed: 01/11/2025]
Abstract
Background and Objectives: Heart failure is associated with high morbidity and mortality and linked with several pre-existing health conditions and risk factors. Early detection and prompt management in heart failure improves patient outcomes. Liver involvement is associated with heart failure disease progression, and hence liver biomarkers and liver fibrosis may have a prognostic impact. Several blood test based markers and scoring systems estimate liver fibrosis and hence can be useful prognostic tools. Materials and Methods: We retrospectively analyzed a series of 303 patients with decompensated heart failure in a city in western Romania over a period of 6 months. Several biochemical parameters were measured, the FIB-4 score was estimated and echocardiography was performed. Results for targeted variables are presented using descriptive statistics. Patients were analyzed based on their LVEF categories. Statistical analysis was based on ANOVA one-way tests for continuous variables and Chi-square tests for categorical variables. Pairwise comparisons were performed based on Bonferroni adjusted significance tests. The correlations between FIB-4 score, LVEF and NT-pro BNP in patients with and without diabetes and hypertension were explored using Spearman's correlation coefficient. Result: Age, gender, NYHA class, death, history of (h/o) type 2 diabetes mellitus (T2DM), h/o coronary artery disease (CAD), h/o arrhythmias, sodium, potassium, creatinine, eGFR, uric acid, NT-pro BNP, left atrial volume, LDL, HDL, and TG were analyzed by LVEF categories using ANOVA one-way tests, Chi-square tests, and Bonferroni correction comparisons. We found a strong statistically significant correlation between each of NT-pro BNP, left atrial volume, LDL, and HDL with the LVEF categories. Discussion: Early detection of cardiac dysfunction leads to better management in patients with cardiovascular risk factors including diabetes and hypertension. High LDL and low HDL levels contribute to a reduction in left ventricular (LV) function. Available literature suggests the FIB-4 score as superior to other non-invasive markers of fibrosis. It utilizes the patient's age, platelet count, AST, and ALT, which can be available retrospectively, making it an easy and inexpensive tool. FIB-4 score has a few limitations. Conclusions: Our study has shown a statistically significant positive correlation between severity categories of LVEF and FIB-4 score for heart failure patients with and without diabetes, and for heart failure patients with or without hypertension. We propose the implementation of FIB-4 score as a prognostic tool for heart failure.
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Affiliation(s)
- Roxana Buzas
- 1st Medical Semiology, Internal Medicine, Department V, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania (P.C.); (D.G.)
- Center for Advanced Research in Cardiovascular Pathology and in Hemostaseology, 300041 Timisoara, Romania
| | - Paul Ciubotaru
- 1st Medical Semiology, Internal Medicine, Department V, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania (P.C.); (D.G.)
- Center for Advanced Research in Cardiovascular Pathology and in Hemostaseology, 300041 Timisoara, Romania
| | - Alexandra Corina Faur
- Department of Anatomy and Embryology, “Victor Babeș” University of Medicine and Pharmacy Timișoara, Eftimie Murgu Square, No. 2, 300041 Timișoara, Romania
| | - Marius Preda
- Second Discipline of Surgical Semiology, Department IX—Surgery—1, “Victor Babes University of Medicine and Pharmacy, 300041 Timisoara, Romania
- Second Clinic of General Surgery and Surgical Oncology, Emergency Clinical Municipal Hospital, 300079 Timisoara, Romania
- Breast Surgery Research Center, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Melania Ardelean
- 1st Medical Semiology, Internal Medicine, Department V, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania (P.C.); (D.G.)
- Center for Advanced Research in Cardiovascular Pathology and in Hemostaseology, 300041 Timisoara, Romania
| | - Doina Georgescu
- 1st Medical Semiology, Internal Medicine, Department V, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania (P.C.); (D.G.)
- Center for Advanced Research in Cardiovascular Pathology and in Hemostaseology, 300041 Timisoara, Romania
| | - Patrick Dumitrescu
- General Medicine, “Victor Babeș” University of Medicine and Pharmacy from Timișoara, Eftimie Murgu Sq. No. 2, 300041 Timișoara, Romania;
| | - Daniel Florin Lighezan
- 1st Medical Semiology, Internal Medicine, Department V, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania (P.C.); (D.G.)
- Center for Advanced Research in Cardiovascular Pathology and in Hemostaseology, 300041 Timisoara, Romania
| | - Mihaela-Diana Popa
- Department of Microbiology, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania
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Ngoc APT, Zahoor A, Kim DG, Yang SH. Using Synbiotics as a Therapy to Protect Mental Health in Alzheimer's Disease. J Microbiol Biotechnol 2024; 34:1739-1747. [PMID: 39099195 PMCID: PMC11485767 DOI: 10.4014/jmb.2403.03021] [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: 03/12/2024] [Revised: 05/29/2024] [Accepted: 06/10/2024] [Indexed: 08/06/2024]
Abstract
Alzheimer's disease (AD) is a progressive neurological disorder that represents a major cause of dementia worldwide. Its pathogenesis involves multiple pathways, including the amyloid cascade, tau protein, oxidative stress, and metal ion dysregulation. Recent studies have suggested a critical link between changes in gut microbial diversity and the disruption of the gut-brain axis in AD. Previous studies primarily explored the potential benefits of probiotics and prebiotics in managing AD. However, studies have yet to fully describe a novel promising approach involving the use of synbiotics, which include a combination of active probiotics and new-generation prebiotics. Synbiotics show potential for mitigating the onset and progression of AD, thereby offering a holistic approach to address the multifaceted nature of AD. This review article primarily aims to gain further insights into the mechanisms of AD, specifically the intricate interaction between gut bacteria and the brain via the gut-brain axis. By understanding this relationship, we can identify potential targets for intervention and therapeutic strategies to combat AD effectively. This review also discusses substantial evidence supporting the role of synbiotics as a promising AD treatment that surpasses traditional probiotic or prebiotic interventions. We find that synbiotics may be used not only to address cognitive decline but also to reduce AD-related psychological burden, thus enhancing the overall quality of life of patients with AD.
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Affiliation(s)
- Anh Pham Thi Ngoc
- Department of Biotechnology, Chonnam National University, Yeosu 59626, Republic of Korea
| | - Adil Zahoor
- Department of Biotechnology, Chonnam National University, Yeosu 59626, Republic of Korea
| | - Dong Gyun Kim
- Department of Biotechnology, Chonnam National University, Yeosu 59626, Republic of Korea
| | - Seung Hwan Yang
- Department of Biotechnology, Chonnam National University, Yeosu 59626, Republic of Korea
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Mark VW. Biomarkers and Rehabilitation for Functional Neurological Disorder. J Pers Med 2024; 14:948. [PMID: 39338202 PMCID: PMC11433361 DOI: 10.3390/jpm14090948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 08/21/2024] [Accepted: 09/02/2024] [Indexed: 09/30/2024] Open
Abstract
Functional neurological disorder, or FND, is widely misunderstood, particularly when considering recent research indicating that the illness has numerous biological markers in addition to its psychiatric disorder associations. Nonetheless, the long-held view that FND is a mental illness without a biological basis, or even a contrived (malingered) illness, remains pervasive both in current medical care and general society. This is because FND involves intermittent disability that rapidly and involuntarily alternates with improved neurological control. This has in turn caused shaming, perceived low self-efficacy, and social isolation for the patients. Until now, biomarker reviews for FND tended not to examine the features that are shared with canonical neurological disorders. This review, in contrast, examines current research on FND biomarkers, and in particular their overlap with canonical neurological disorders, along with the encouraging outcomes for numerous physical rehabilitation trials for FND. These findings support the perspective endorsed here that FND is unquestionably a neurological disorder that is also associated with many biological markers that lie outside of the central nervous system. These results suggest that FND entails multiple biological abnormalities that are widely distributed in the body. General healthcare providers would benefit their care for their patients through their improved understanding of the illness and recourses for support and treatment that are provided in this review.
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Affiliation(s)
- Victor W. Mark
- Department of Physical Medicine and Rehabilitation, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA; ; Tel.: +1-205-934-3499
- Department of Neurology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35249, USA
- Department of Psychology, College of Arts and Sciences, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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Zhang M, Hu X, Wang L. A Review of Cerebrospinal Fluid Circulation and the Pathogenesis of Congenital Hydrocephalus. Neurochem Res 2024; 49:1123-1136. [PMID: 38337135 PMCID: PMC10991002 DOI: 10.1007/s11064-024-04113-z] [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: 09/01/2023] [Revised: 01/13/2024] [Accepted: 01/20/2024] [Indexed: 02/12/2024]
Abstract
The brain's ventricles are filled with a colorless fluid known as cerebrospinal fluid (CSF). When there is an excessive accumulation of CSF in the ventricles, it can result in high intracranial pressure, ventricular enlargement, and compression of the surrounding brain tissue, leading to potential damage. This condition is referred to as hydrocephalus. Hydrocephalus is classified into two categories: congenital and acquired. Congenital hydrocephalus (CH) poses significant challenges for affected children and their families, particularly in resource-poor countries. Recognizing the psychological and economic impacts is crucial for developing interventions and support systems that can help alleviate the distress and burden faced by these families. As our understanding of CSF production and circulation improves, we are gaining clearer insights into the causes of CH. In this article, we will summarize the current knowledge regarding CSF circulation pathways and the underlying causes of CH. The main causes of CH include abnormalities in the FoxJ1 pathway of ventricular cilia, dysfunctions in the choroid plexus transporter Na+-K+-2Cl- contransporter isoform 1, developmental abnormalities in the cerebral cortex, and structural abnormalities within the brain. Understanding the causes of CH is indeed crucial for advancing research and developing effective treatment strategies. In this review, we will summarize the findings from existing studies on the causes of CH and propose potential research directions to further our understanding of this condition.
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Affiliation(s)
- Mingzhao Zhang
- Laboratory of pathology, Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing, 100850, China
| | - Xiangjun Hu
- Laboratory of pathology, Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing, 100850, China.
| | - Lifeng Wang
- Laboratory of pathology, Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing, 100850, China.
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10
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Ho K, Bodi NE, Sharma TP. Normal-Tension Glaucoma and Potential Clinical Links to Alzheimer's Disease. J Clin Med 2024; 13:1948. [PMID: 38610712 PMCID: PMC11012506 DOI: 10.3390/jcm13071948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 03/21/2024] [Accepted: 03/25/2024] [Indexed: 04/14/2024] Open
Abstract
Glaucoma is a group of optic neuropathies and the world's leading cause of irreversible blindness. Normal-tension glaucoma (NTG) is a subtype of glaucoma that is characterized by a typical pattern of peripheral retinal loss, in which the patient's intraocular pressure (IOP) is considered within the normal range (<21 mmHg). Currently, the only targetable risk factor for glaucoma is lowering IOP, and patients with NTG continue to experience visual field loss after IOP-lowering treatments. This demonstrates the need for a better understanding of the pathogenesis of NTG and underlying mechanisms leading to neurodegeneration. Recent studies have found significant connections between NTG and cerebral manifestations, suggesting NTG as a neurodegenerative disease beyond the eye. Gaining a better understanding of NTG can potentially provide new Alzheimer's Disease diagnostics capabilities. This review identifies the epidemiology, current biomarkers, altered fluid dynamics, and cerebral and ocular manifestations to examine connections and discrepancies between the mechanisms of NTG and Alzheimer's Disease.
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Affiliation(s)
- Kathleen Ho
- Eugene and Marilyn Glick Eye Institute, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN 46202, USA;
| | - Nicole E. Bodi
- Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA;
| | - Tasneem P. Sharma
- Eugene and Marilyn Glick Eye Institute, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN 46202, USA;
- Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA;
- Stark Neurosciences Research Institute, Indianapolis, IN 46202, USA
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11
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Criscuolo C, Chartampila E, Ginsberg SD, Scharfman HE. Dentate Gyrus Granule Cells Show Stability of BDNF Protein Expression in Mossy Fiber Axons with Age, and Resistance to Alzheimer's Disease Neuropathology in a Mouse Model. eNeuro 2024; 11:ENEURO.0192-23.2023. [PMID: 38164567 PMCID: PMC10913042 DOI: 10.1523/eneuro.0192-23.2023] [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: 06/02/2023] [Revised: 11/03/2023] [Accepted: 11/13/2023] [Indexed: 01/03/2024] Open
Abstract
Brain-derived neurotrophic factor (BDNF) is important in the development and maintenance of neurons and their plasticity. Hippocampal BDNF has been implicated in Alzheimer's disease (AD) because hippocampal levels in AD patients and AD animal models are often downregulated, suggesting that reduced BDNF contributes to AD. However, the location where hippocampal BDNF protein is most highly expressed, the mossy fiber (MF) axons of dentate gyrus granule cells (GCs), has been understudied, and not in controlled conditions. Therefore, we evaluated MF BDNF protein in the Tg2576 mouse model of AD. Tg2576 and wild-type (WT) mice of both sexes were examined at 2-3 months of age, when amyloid-β (Aβ) is present in neurons but plaques are absent, and 11-20 months of age, after plaque accumulation. As shown previously, WT mice exhibited high levels of MF BDNF protein. Interestingly, there was no significant decline with age in either the genotype or sex. Notably, MF BDNF protein was correlated with GC ΔFosB, a transcription factor that increases after 1-2 weeks of elevated neuronal activity. We also report the novel finding that Aβ in GCs or the GC layer was minimal even at old ages. The results indicate that MF BDNF is stable in the Tg2576 mouse, and MF BDNF may remain unchanged due to increased GC neuronal activity, since BDNF expression is well known to be activity dependent. The resistance of GCs to long-term Aβ accumulation provides an opportunity to understand how to protect vulnerable neurons from increased Aβ levels and therefore has translational implications.
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Affiliation(s)
- Chiara Criscuolo
- Center for Dementia Research, The Nathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962
- Department of Child & Adolescent Psychiatry, NewYork University Grossman School of Medicine, New York, NY 10016
| | - Elissavet Chartampila
- Center for Dementia Research, The Nathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
| | - Stephen D Ginsberg
- Center for Dementia Research, The Nathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962
- Department of Neuroscience & Physiology, NewYork University Grossman School of Medicine, New York, NY 10016
- Psychiatry, NewYork University Grossman School of Medicine, New York, NY 10016
- NYU Neuroscience Institute, NewYork University Grossman School of Medicine, New York, NY 10016
| | - Helen E Scharfman
- Center for Dementia Research, The Nathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962
- Department of Child & Adolescent Psychiatry, NewYork University Grossman School of Medicine, New York, NY 10016
- Department of Neuroscience & Physiology, NewYork University Grossman School of Medicine, New York, NY 10016
- NYU Neuroscience Institute, NewYork University Grossman School of Medicine, New York, NY 10016
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12
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Majewska A, Le L, Feidler A, Li H, Kara-Pabani K, Lamantia C, O'Banion MK. Noradrenergic signaling controls Alzheimer's disease pathology via activation of microglial β2 adrenergic receptors. RESEARCH SQUARE 2024:rs.3.rs-3976896. [PMID: 38464247 PMCID: PMC10925421 DOI: 10.21203/rs.3.rs-3976896/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/12/2024]
Abstract
Norepinephrine (NE) is a potent anti-inflammatory agent in the brain. In Alzheimer's disease (AD), the loss of NE signaling heightens neuroinflammation and exacerbates amyloid pathology. NE inhibits surveillance activity of microglia, the brain's resident immune cells, via their β2 adrenergic receptors (β2ARs). Here, we investigate the role of microglial β2AR signaling in AD pathology in the 5xFAD mouse model of AD. We found that loss of cortical NE projections preceded the degeneration of NE-producing neurons and that microglia in 5xFAD mice, especially those microglia that were associated with plaques, significantly downregulated β2AR gene expression early in amyloid pathology. Importantly, dampening microglial β2AR signaling worsened plaque load and the associated neuritic damage, while stimulating microglial β2AR signaling attenuated amyloid pathology. Our results suggest that microglial β2AR could be explored as a potential therapeutic target to modify AD pathology.
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Affiliation(s)
| | | | | | - Herman Li
- University of Rochester Medical Center
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13
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Ballestar-Tarín ML, Ibáñez-del Valle V, Mafla-España MA, Navarro-Martínez R, Cauli O. Salivary Brain-Derived Neurotrophic Factor and Cortisol Associated with Psychological Alterations in University Students. Diagnostics (Basel) 2024; 14:447. [PMID: 38396487 PMCID: PMC10887844 DOI: 10.3390/diagnostics14040447] [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: 12/21/2023] [Revised: 01/27/2024] [Accepted: 02/14/2024] [Indexed: 02/25/2024] Open
Abstract
INTRODUCTION Recent evidence reported mental health issues in university students such as anxiety and depressive symptoms and poor sleep quality. Decreased plasma brain-derived neurotrophic factor (BDNF) levels have been proposed as a biomarker of depressive symptoms, whereas cortisol levels are an index of energy mobilization and stress and have been linked to sleep quality. Given that salivary biomarkers represent an interesting new field of research, the aim of this cross-sectional study was to evaluate salivary BDNF and cortisol levels in university students to assess whether they have associations with psychological disturbances such as anxiety and depressive symptoms, sleep quality, and stress level. METHODS Salivary BDNF and cortisol levels were measured by specific immunoassays in 70 students whose mental health was also evaluated on the same day through the evaluation of anxiety and depression symptoms (Goldberg scale), sleep quality (Pittsburg Sleep Quality Index and Athens Insomnia Scale), and stress (self-perceived stress scale) and healthy lifestyle habits (alcohol consumption, smoking, regular exercise, and body mass index) were also measured. Multivariate regression analyses were performed in order to identify the strengths of associations between psychological alterations and the concentrations of BDNF, cortisol, and other variables. RESULTS Salivary BDNF levels were significantly higher in students with more depressive symptoms, whereas no significant differences were found for cortisol levels. When performing the binary logistic regression model, BDNF levels are included as a predictor variable for a high-depressive-symptoms burden (p < 0.05). Students with worse sleep quality on the Pittsburg Scale had higher cortisol levels (p < 0.05). The subdomains of sleep latency and sleep medication were those significantly associated with salivary cortisol levels in logistic regression analyses (OR = 15.150, p = 0.028). Sleep medication only appeared to be related to cortisol levels (OR = 185.142, p = 0.019). Perceived stress levels and anxiety symptoms were not associated with BDNF or cortisol levels. CONCLUSIONS BDNF could play a key role in the pathophysiology of mood-related disorders, and elevation of its peripheral levels could contribute to protecting neurons from the development of mental illness. Higher salivary cortisol levels measured in the morning are accompanied by poorer sleep quality. More research is needed, focusing on salivary biomarkers of disorders related to depressive symptoms and poor sleep quality as a potential tool for the diagnosis and prevention of mental illness.
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Affiliation(s)
- María Luisa Ballestar-Tarín
- Department of Nursing, University of Valencia, 46010 Valencia, Spain; (M.L.B.-T.); (M.A.M.-E.); (R.N.-M.)
- Nursing Care and Education Research Group in (GRIECE) GIUV 2019-456, Department of Nursing, University of Valencia, 46010 Valencia, Spain
| | - Vanessa Ibáñez-del Valle
- Department of Nursing, University of Valencia, 46010 Valencia, Spain; (M.L.B.-T.); (M.A.M.-E.); (R.N.-M.)
- Frailty Research Organized Group (FROG), University of Valencia, 46010 Valencia, Spain
| | | | - Rut Navarro-Martínez
- Department of Nursing, University of Valencia, 46010 Valencia, Spain; (M.L.B.-T.); (M.A.M.-E.); (R.N.-M.)
- Frailty Research Organized Group (FROG), University of Valencia, 46010 Valencia, Spain
- Department of Hematology, University General Hospital, 46014 Valencia, Spain
| | - Omar Cauli
- Department of Nursing, University of Valencia, 46010 Valencia, Spain; (M.L.B.-T.); (M.A.M.-E.); (R.N.-M.)
- Frailty Research Organized Group (FROG), University of Valencia, 46010 Valencia, Spain
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14
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Chowdhury MA, Collins JM, Gell DA, Perry S, Breadmore MC, Shigdar S, King AE. Isolation and Identification of the High-Affinity DNA Aptamer Target to the Brain-Derived Neurotrophic Factor (BDNF). ACS Chem Neurosci 2024; 15:346-356. [PMID: 38149631 DOI: 10.1021/acschemneuro.3c00661] [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] [Indexed: 12/28/2023] Open
Abstract
Aptamers are functional oligonucleotide ligands used for the molecular recognition of various targets. The natural characteristics of aptamers make them an excellent alternative to antibodies in diagnostics, therapeutics, and biosensing. DNA aptamers are mainly single-stranded oligonucleotides (ssDNA) that possess a definite binding to targets. However, the application of aptamers to the fields of brain health and neurodegenerative diseases has been limited to date. Herein, a DNA aptamer against the brain-derived neurotrophic factor (BDNF) protein was obtained by in vitro selection. BDNF is a potential biomarker of brain health and neurodegenerative diseases and has functions in the synaptic plasticity and survival of neurons. We identified eight aptamers that have binding affinity for BDNF from a 50-nucleotide library. Among these aptamers, NV_B12 showed the highest sensitivity and selectivity for detecting BDNF. In an aptamer-linked immobilized sorbent assay (ALISA), the NV_B12 aptamer strongly bound to BDNF protein, in a dose-dependent manner. The dissociation constant (Kd) for NV_B12 was 0.5 nM (95% CI: 0.4-0.6 nM). These findings suggest that BDNF-specific aptamers could be used as an alternative to antibodies in diagnostic and detection assays for BDNF.
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Affiliation(s)
- Md Anisuzzaman Chowdhury
- Wicking Dementia Research and Education Centre, University of Tasmania, 17 Liverpool Street, Hobart, Tasmania 7000, Australia
| | - Jessica M Collins
- Wicking Dementia Research and Education Centre, University of Tasmania, 17 Liverpool Street, Hobart, Tasmania 7000, Australia
| | - David A Gell
- Menzies Research Institute, School of Medicine, University of Tasmania, 17 Liverpool Street, Hobart, Tasmania 7000, Australia
| | - Sharn Perry
- Wicking Dementia Research and Education Centre, University of Tasmania, 17 Liverpool Street, Hobart, Tasmania 7000, Australia
| | - Michael C Breadmore
- Australian Centre for Research on Separation Science (ACROSS), School of Chemistry, University of Tasmania, Sandy Bay, Hobart, Tasmania 7001, Australia
| | - Sarah Shigdar
- School of Medicine, Faculty of Health, Deakin University, Geelong, Victoria 3220, Australia
| | - Anna E King
- Wicking Dementia Research and Education Centre, University of Tasmania, 17 Liverpool Street, Hobart, Tasmania 7000, Australia
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15
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Love RWB. Aniracetam: An Evidence-Based Model for Preventing the Accumulation of Amyloid-β Plaques in Alzheimer's Disease. J Alzheimers Dis 2024; 98:1235-1241. [PMID: 38552113 DOI: 10.3233/jad-231247] [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] [Indexed: 04/20/2024]
Abstract
Alzheimer's disease is the leading cause of dementia in the world. It affects 6 million people in the United States and 50 million people worldwide. Alzheimer's disease is characterized by the accumulation of amyloid-β plaques (Aβ), an increase in tau protein neurofibrillary tangles, and a loss of synapses. Since the 1990s, removing and reducing Aβ has been the focus of Alzheimer's treatment and prevention research. The accumulation of Aβ can lead to oxidative stress, inflammation, neurotoxicity, and eventually apoptosis. These insults impair signaling systems in the brain, potentially leading to memory loss and cognitive decline. Aniracetam is a safe, effective, cognitive-enhancing drug that improves memory in both human and animal studies. Aniracetam may prevent the production and accumulation of Aβ by increasing α-secretase activity through two distinct pathways: 1) increasing brain derived neurotrophic factor expression and 2) positively modulating metabotropic glutamate receptors. This is the first paper to propose an evidence-based model for aniracetam reducing the accumulation and production of Aβ.
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Affiliation(s)
- Robert W B Love
- Research Department, Brain Fit For Life, LLC, Lewes, DE, USA
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16
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Le L, Feidler AM, Li H, Kara-Pabani K, Lamantia C, O'Banion MK, Majewska KA. Noradrenergic signaling controls Alzheimer's disease pathology via activation of microglial β2 adrenergic receptors. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.12.01.569564. [PMID: 38106167 PMCID: PMC10723313 DOI: 10.1101/2023.12.01.569564] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2023]
Abstract
In Alzheimer's disease (AD) pathophysiology, plaque and tangle accumulation trigger an inflammatory response that mounts positive feed-back loops between inflammation and protein aggregation, aggravating neurite damage and neuronal death. One of the earliest brain regions to undergo neurodegeneration is the locus coeruleus (LC), the predominant site of norepinephrine (NE) production in the central nervous system (CNS). In animal models of AD, dampening the impact of noradrenergic signaling pathways, either through administration of beta blockers or pharmacological ablation of the LC, heightened neuroinflammation through increased levels of pro-inflammatory mediators. Since microglia are the resident immune cells of the CNS, it is reasonable to postulate that they are responsible for translating the loss of NE tone into exacerbated disease pathology. Recent findings from our lab demonstrated that noradrenergic signaling inhibits microglia dynamics via β2 adrenergic receptors (β2ARs), suggesting a potential anti-inflammatory role for microglial β2AR signaling. Thus, we hypothesize that microglial β2 adrenergic signaling is progressively impaired during AD progression, which leads to the chronic immune vigilant state of microglia that worsens disease pathology. First, we characterized changes in microglial β2AR signaling as a function of amyloid pathology. We found that LC neurons and their projections degenerate early and progressively in the 5xFAD mouse model of AD; accompanied by mild decrease in the levels of norepinephrine and its metabolite normetanephrine. Interestingly, while 5xFAD microglia, especially plaque-associated microglia, significant downregulated β2AR gene expression early in amyloid pathology, they did not lose their responsiveness to β2AR stimulation. Most importantly, we demonstrated that specific microglial β2AR deletion worsened disease pathology while chronic β2AR stimulation resulted in attenuation of amyloid pathology and associated neuritic damage, suggesting microglial β2AR might be used as potential therapeutic target to modify AD pathology.
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Affiliation(s)
- L Le
- Department of Neuroscience, Del Monte Institute for Neuroscience, University of Rochester, Rochester, NY
| | - A M Feidler
- Department of Neuroscience, Del Monte Institute for Neuroscience, University of Rochester, Rochester, NY
| | - H Li
- Medical Scientist Training Program, University of Rochester, Rochester NY
| | - K Kara-Pabani
- Department of Neuroscience, Del Monte Institute for Neuroscience, University of Rochester, Rochester, NY
| | - C Lamantia
- Department of Neuroscience, Del Monte Institute for Neuroscience, University of Rochester, Rochester, NY
| | - M K O'Banion
- Department of Neuroscience, Del Monte Institute for Neuroscience, University of Rochester, Rochester, NY
| | - K A Majewska
- Department of Neuroscience, Del Monte Institute for Neuroscience, University of Rochester, Rochester, NY
- Center for Visual Science, University of Rochester, Rochester NY
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17
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Shen R, Ardianto C, Celia C, Sidharta VM, Sasmita PK, Satriotomo I, Turana Y. Brain-derived neurotrophic factor interplay with oxidative stress: neuropathology approach in potential biomarker of Alzheimer's disease. Dement Neuropsychol 2023; 17:e20230012. [PMID: 38053647 PMCID: PMC10695442 DOI: 10.1590/1980-5764-dn-2023-0012] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 07/05/2023] [Accepted: 07/30/2023] [Indexed: 12/07/2023] Open
Abstract
The aging population poses a serious challenge concerning an increased prevalence of Alzheimer's disease (AD) and its impact on global burden, morbidity, and mortality. Oxidative stress, as a molecular hallmark that causes susceptibility in AD, interplays to other AD-related neuropathology cascades and decreases the expression of central and circulation brain-derived neurotrophic factor (BDNF), an essential neurotrophin that serves as nerve development and survival, and synaptic plasticity in AD. By its significant correlation with the molecular and clinical progression of AD, BDNF can potentially be used as an objectively accurate biomarker for AD diagnosis and progressivity follow-up in future clinical practice. This comprehensive review highlights the oxidative stress interplay with BDNF in AD neuropathology and its potential use as an AD biomarker.
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Affiliation(s)
- Robert Shen
- Atma Jaya Catholic University of Indonesia, School of Medicine and Health Sciences, Jakarta, Indonesia
| | - Christian Ardianto
- Atma Jaya Catholic University of Indonesia, School of Medicine and Health Sciences, Jakarta, Indonesia
| | - Celia Celia
- Atma Jaya Catholic University of Indonesia, School of Medicine and Health Sciences, Jakarta, Indonesia
| | - Veronika Maria Sidharta
- Atma Jaya Catholic University of Indonesia, School of Medicine and Health Sciences, Jakarta, Indonesia
| | - Poppy Kristina Sasmita
- Atma Jaya Catholic University of Indonesia, School of Medicine and Health Sciences, Jakarta, Indonesia
| | - Irawan Satriotomo
- University of Florida, Gainesville, Department of Neurology, Florida, USA
- Satriotomo Foundation, Indonesia Neuroscience Institute, Jakarta, Indonesia
| | - Yuda Turana
- Atma Jaya Catholic University of Indonesia, School of Medicine and Health Sciences, Jakarta, Indonesia
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18
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Angelucci F, Veverova K, Katonová A, Vyhnalek M, Hort J. Serum PAI-1/BDNF Ratio Is Increased in Alzheimer's Disease and Correlates with Disease Severity. ACS OMEGA 2023; 8:36025-36031. [PMID: 37810633 PMCID: PMC10552510 DOI: 10.1021/acsomega.3c04076] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 07/27/2023] [Indexed: 10/10/2023]
Abstract
We previously demonstrated that serum levels of plasminogen activator inhibitor-1 (PAI-1), which inhibits both the tissue plasminogen activator (tPA) and plasmin activity, are increased in patients with Alzheimer's disease. tPA/plasmin not only prevents the accumulation of β-amyloid in the brain but also is involved in the synthesis of the brain-derived neurotrophic factor (BDNF), a neurotrophin whose levels are reduced in Alzheimer. In the present study, we compared BDNF serum levels in Alzheimer patients with dementia to those in Alzheimer patients with amnestic mild cognitive impairment and to cognitively healthy controls. Moreover, we examined whether the PAI-1/BDNF ratio correlates with disease severity, as measured by Mini-Mental State Examination. Our results showed that BDNF serum levels are lower (13.7% less) and PAI-1 levels are higher in Alzheimer patients with dementia than in Alzheimer patients with amnestic mild cognitive impairment patients (23% more) or controls (36% more). Furthermore, the PAI-1/BDNF ratio was significantly increased in Alzheimer patients as compared to amnestic mild cognitive impairment (36.4% more) and controls (40% more). Lastly, the PAI-1/BDNF ratio negatively correlated with the Mini-Mental score. Our results suggest that increased PAI-1 levels in Alzheimer, by impairing the production of the BDNF, are implicated in disease progression. They also indicate that the PAI-1/BDNF ratio could be used as a marker of Alzheimer. In support of this hypothesis, a strong negative correlation between the PAI-1/BDNF ratio and the Mini-Mental score was observed.
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Affiliation(s)
- Francesco Angelucci
- Memory
Clinic, Department of Neurology, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague 150 06, Czech Republic
- International
Clinical Research Centre, St. Anne’s
University Hospital, Brno 602 00,Czech Republic
| | - Katerina Veverova
- Memory
Clinic, Department of Neurology, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague 150 06, Czech Republic
| | - Alžbeta Katonová
- Memory
Clinic, Department of Neurology, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague 150 06, Czech Republic
| | - Martin Vyhnalek
- Memory
Clinic, Department of Neurology, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague 150 06, Czech Republic
| | - Jakub Hort
- Memory
Clinic, Department of Neurology, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague 150 06, Czech Republic
- International
Clinical Research Centre, St. Anne’s
University Hospital, Brno 602 00,Czech Republic
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19
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Manolopoulos A, Delgado-Peraza F, Mustapic M, Pucha KA, Nogueras-Ortiz C, Daskalopoulos A, Knight DD, Leoutsakos JM, Oh ES, Lyketsos CG, Kapogiannis D. Comparative assessment of Alzheimer's disease-related biomarkers in plasma and neuron-derived extracellular vesicles: a nested case-control study. Front Mol Biosci 2023; 10:1254834. [PMID: 37828917 PMCID: PMC10565036 DOI: 10.3389/fmolb.2023.1254834] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 09/12/2023] [Indexed: 10/14/2023] Open
Abstract
Introduction: Alzheimer's disease (AD) is currently defined according to biomarkers reflecting the core underlying neuropathological processes: Aβ deposition, Tau, and neurodegeneration (ATN). The soluble phase of plasma and plasma neuron-derived extracellular vesicles (NDEVs) are increasingly being investigated as sources of biomarkers. The aim of this study was to examine the comparative biomarker potential of these two biofluids, as well as the association between respective biomarkers. Methods: We retrospectively identified three distinct diagnostic groups of 44 individuals who provided samples at baseline and at a mean of 3.1 years later; 14 were cognitively unimpaired at baseline and remained so (NRM-NRM), 13 had amnestic MCI that progressed to AD dementia (MCI-DEM) and 17 had AD dementia at both timepoints (DEM-DEM). Plasma NDEVs were isolated by immunoaffinity capture targeting the neuronal markers L1CAM, GAP43, and NLGN3. In both plasma and NDEVs, we assessed ATN biomarkers (Aβ42, Aβ40, total Tau, P181-Tau) alongside several other exploratory markers. Results: The Aβ42/Aβ40 ratio in plasma and NDEVs was lower in MCI-DEM than NRM-NRM at baseline and its levels in NDEVs decreased over time in all three groups. Similarly, plasma and NDEV-associated Aβ42 was lower in MCI-DEM compared to NRM-NRM at baseline and its levels in plasma decreased over time in DEM-DEM. For NDEV-associated proBDNF, compared to NRM-NRM, its levels were lower in MCI-DEM and DEM-DEM at baseline, and they decreased over time in the latter group. No group differences were found for other exploratory markers. NDEV-associated Aβ42/Aβ40 ratio and proBDNF achieved the highest areas under the curve (AUCs) for discriminating between diagnostic groups, while proBDNF was positively associated with Mini-Mental State Examination (MMSE) score. No associations were found between the two biofluids for any assessed marker. Discussion: The soluble phase of plasma and plasma NDEVs demonstrate distinct biomarker profiles both at a single time point and longitudinally. The lack of association between plasma and NDEV measures indicates that the two types of biofluids demonstrate distinct biomarker signatures that may be attributable to being derived through different biological processes. NDEV-associated proBDNF may be a useful biomarker for AD diagnosis and monitoring.
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Affiliation(s)
- Apostolos Manolopoulos
- Intramural Research Program, Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, MD, United States
| | - Francheska Delgado-Peraza
- Intramural Research Program, Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, MD, United States
| | - Maja Mustapic
- Intramural Research Program, Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, MD, United States
| | - Krishna Ananthu Pucha
- Intramural Research Program, Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, MD, United States
| | - Carlos Nogueras-Ortiz
- Intramural Research Program, Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, MD, United States
| | - Alexander Daskalopoulos
- Intramural Research Program, Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, MD, United States
| | - De’Larrian DeAnté Knight
- Intramural Research Program, Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, MD, United States
| | - Jeannie-Marie Leoutsakos
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, United States
- Richman Family Precision Medicine Center of Excellence in Alzheimer’s Disease, Johns Hopkins School of Medicine, Baltimore, MD, United States
| | - Esther S. Oh
- Richman Family Precision Medicine Center of Excellence in Alzheimer’s Disease, Johns Hopkins School of Medicine, Baltimore, MD, United States
- Division of Geriatric Medicine and Gerontology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, United States
| | - Constantine G. Lyketsos
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, United States
- Richman Family Precision Medicine Center of Excellence in Alzheimer’s Disease, Johns Hopkins School of Medicine, Baltimore, MD, United States
| | - Dimitrios Kapogiannis
- Intramural Research Program, Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, MD, United States
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20
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Chatanaka MK, Sohaei D, Diamandis EP, Prassas I. Beyond the amyloid hypothesis: how current research implicates autoimmunity in Alzheimer's disease pathogenesis. Crit Rev Clin Lab Sci 2023; 60:398-426. [PMID: 36941789 DOI: 10.1080/10408363.2023.2187342] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 03/01/2023] [Indexed: 03/23/2023]
Abstract
The amyloid hypothesis has so far been at the forefront of explaining the pathogenesis of Alzheimer's Disease (AD), a progressive neurodegenerative disorder that leads to cognitive decline and eventual death. Recent evidence, however, points to additional factors that contribute to the pathogenesis of this disease. These include the neurovascular hypothesis, the mitochondrial cascade hypothesis, the inflammatory hypothesis, the prion hypothesis, the mutational accumulation hypothesis, and the autoimmunity hypothesis. The purpose of this review was to briefly discuss the factors that are associated with autoimmunity in humans, including sex, the gut and lung microbiomes, age, genetics, and environmental factors. Subsequently, it was to examine the rise of autoimmune phenomena in AD, which can be instigated by a blood-brain barrier breakdown, pathogen infections, and dysfunction of the glymphatic system. Lastly, it was to discuss the various ways by which immune system dysregulation leads to AD, immunomodulating therapies, and future directions in the field of autoimmunity and neurodegeneration. A comprehensive account of the recent research done in the field was extracted from PubMed on 31 January 2022, with the keywords "Alzheimer's disease" and "autoantibodies" for the first search input, and "Alzheimer's disease" with "IgG" for the second. From the first search, 19 papers were selected, because they contained recent research on the autoantibodies found in the biofluids of patients with AD. From the second search, four papers were selected. The analysis of the literature has led to support the autoimmune hypothesis in AD. Autoantibodies were found in biofluids (serum/plasma, cerebrospinal fluid) of patients with AD with multiple methods, including ELISA, Mass Spectrometry, and microarray analysis. Through continuous research, the understanding of the synergistic effects of the various components that lead to AD will pave the way for better therapeutic methods and a deeper understanding of the disease.
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Affiliation(s)
- Miyo K Chatanaka
- Department of Laboratory and Medicine Pathobiology, University of Toronto, Toronto, Canada
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada
| | - Dorsa Sohaei
- Faculty of Medicine and Health Sciences, McGill University, Montreal, Canada
| | - Eleftherios P Diamandis
- Department of Laboratory and Medicine Pathobiology, University of Toronto, Toronto, Canada
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada
- Department of Clinical Biochemistry, University Health Network, Toronto, Canada
| | - Ioannis Prassas
- Laboratory Medicine Program, University Health Network, Toronto, Canada
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Papaliagkas V, Kalinderi K, Vareltzis P, Moraitou D, Papamitsou T, Chatzidimitriou M. CSF Biomarkers in the Early Diagnosis of Mild Cognitive Impairment and Alzheimer's Disease. Int J Mol Sci 2023; 24:ijms24108976. [PMID: 37240322 DOI: 10.3390/ijms24108976] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 05/09/2023] [Accepted: 05/16/2023] [Indexed: 05/28/2023] Open
Abstract
Alzheimer's disease (AD) is a rapidly growing disease that affects millions of people worldwide, therefore there is an urgent need for its early diagnosis and treatment. A huge amount of research studies are performed on possible accurate and reliable diagnostic biomarkers of AD. Due to its direct contact with extracellular space of the brain, cerebrospinal fluid (CSF) is the most useful biological fluid reflecting molecular events in the brain. Proteins and molecules that reflect the pathogenesis of the disease, e.g., neurodegeneration, accumulation of Abeta, hyperphosphorylation of tau protein and apoptosis may be used as biomarkers. The aim of the current manuscript is to present the most commonly used CSF biomarkers for AD as well as novel biomarkers. Three CSF biomarkers, namely total tau, phospho-tau and Abeta42, are believed to have the highest diagnostic accuracy for early AD diagnosis and the ability to predict AD development in mild cognitive impairment (MCI) patients. Moreover, other biomarkers such as soluble amyloid precursor protein (APP), apoptotic proteins, secretases and inflammatory and oxidation markers are believed to have increased future prospects.
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Affiliation(s)
- Vasileios Papaliagkas
- Department of Biomedical Sciences, School of Health Sciences, International Hellenic University, Alexandrion University Campus, 57400 Sindos, Greece
| | - Kallirhoe Kalinderi
- Laboratory of Medical Biology-Genetics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Patroklos Vareltzis
- Department of Chemical Engineering, School of Engineering, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Despoina Moraitou
- Laboratory of Psychology, School of Psychology, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Theodora Papamitsou
- Histology and Embryology Department, Faculty of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Maria Chatzidimitriou
- Department of Biomedical Sciences, School of Health Sciences, International Hellenic University, Alexandrion University Campus, 57400 Sindos, Greece
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22
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Want A, Morgan JE, Barde YA. Brain-derived neurotrophic factor measurements in mouse serum and plasma using a sensitive and specific enzyme-linked immunosorbent assay. Sci Rep 2023; 13:7740. [PMID: 37173369 PMCID: PMC10182034 DOI: 10.1038/s41598-023-34262-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 04/26/2023] [Indexed: 05/15/2023] Open
Abstract
This study is about the quantification and validation of BDNF levels in mouse serum and plasma using a sensitive immunoassay. While BDNF levels are readily detectable in human serum, the functional implications of these measurements are unclear as BDNF released from human blood platelets is the main contributor to the serum levels of BDNF. As mouse platelets do not contain BDNF, this confounding factor is absent in the mouse. Accordingly, BDNF levels in mouse serum and plasma were found to be indistinguishable at 9.92 ± 1.97 pg/mL for serum and 10.58 ± 2.43 pg/mL for plasma (p = 0.473). These levels are approximately a thousand times lower than those measured in human serum and pre-adsorption with anti-BDNF, but not with anti-NGF or anti-NT3 monoclonal antibodies, markedly reduced the BDNF signal. These results open the possibility to explore the relevance of BDNF levels as a biomarker in accessible body fluids using existing mouse models mimicking human pathological conditions.
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Affiliation(s)
- Andrew Want
- School of Optometry and Vision Sciences, Cardiff University, Cardiff, CF24 4HQ, UK
| | - James E Morgan
- School of Optometry and Vision Sciences, Cardiff University, Cardiff, CF24 4HQ, UK
| | - Yves-Alain Barde
- School of Bioscience, Cardiff University, Cardiff, CF10 3AX, UK.
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23
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Criscuolo C, Chartampila E, Ginsberg SD, Scharfman HE. Stability of dentate gyrus granule cell mossy fiber BDNF protein expression with age and resistance of granule cells to Alzheimer's disease neuropathology in a mouse model. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.07.539742. [PMID: 37214931 PMCID: PMC10197599 DOI: 10.1101/2023.05.07.539742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Abstract
The neurotrophin brain-derived neurotrophic factor (BDNF) is important in development and maintenance of neurons and their plasticity. Hippocampal BDNF has been implicated Alzheimer's disease (AD) because hippocampal levels in AD patients and AD animal models are consistently downregulated, suggesting that reduced BDNF contributes to AD. However, the location where hippocampal BDNF protein is most highly expressed, the mossy fiber (MF) axons of dentate gyrus (DG) granule cells (GCs), has been understudied, and never in controlled in vivo conditions. We examined MF BDNF protein in the Tg2576 mouse model of AD. Tg2576 and wild type (WT) mice of both sexes were examined at 2-3 months of age, when amyloid-β (Aβ) is present in neurons but plaques are absent, and 11-20 months of age, after plaque accumulation. As shown previously, WT mice exhibited high levels of MF BDNF protein. Interestingly, there was no significant decline with age in either genotype or sex. Notably, we found a correlation between MF BDNF protein and GC ΔFosB, a transcription factor that increases after 1-2 weeks of elevated neuronal activity. Remarkably, there was relatively little evidence of Aβ in GCs or the GC layer even at old ages. Results indicate MF BDNF is stable in the Tg2576 mouse, and MF BDNF may remain unchanged due to increased GC neuronal activity, since BDNF expression is well known to be activity-dependent. The resistance of GCs to long-term Aβ accumulation provides an opportunity to understand how to protect other vulnerable neurons from increased Aβ levels and therefore has translational implications.
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Affiliation(s)
- Chiara Criscuolo
- Center for Dementia Research, the Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, 10962, USA
- Department of Child & Adolescent Psychiatry, New York University Grossman School of Medicine, New York, NY, 10016, USA
| | - Elissavet Chartampila
- Center for Dementia Research, the Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, 10962, USA
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Stephen D. Ginsberg
- Center for Dementia Research, the Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, 10962, USA
- Department of Neuroscience & Physiology, New York University Grossman School of Medicine, New York, NY, 10016, USA
- Department of Psychiatry, New York University Grossman School of Medicine, New York, NY, 10016, USA
- NYU Neuroscience Institute, New York University Grossman School of Medicine, New York, NY, 10016, USA
| | - Helen E. Scharfman
- Center for Dementia Research, the Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, 10962, USA
- Department of Child & Adolescent Psychiatry, New York University Grossman School of Medicine, New York, NY, 10016, USA
- Department of Neuroscience & Physiology, New York University Grossman School of Medicine, New York, NY, 10016, USA
- NYU Neuroscience Institute, New York University Grossman School of Medicine, New York, NY, 10016, USA
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24
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Pisani A, Paciello F, Del Vecchio V, Malesci R, De Corso E, Cantone E, Fetoni AR. The Role of BDNF as a Biomarker in Cognitive and Sensory Neurodegeneration. J Pers Med 2023; 13:jpm13040652. [PMID: 37109038 PMCID: PMC10140880 DOI: 10.3390/jpm13040652] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 04/04/2023] [Accepted: 04/08/2023] [Indexed: 04/29/2023] Open
Abstract
Brain-derived neurotrophic factor (BDNF) has a crucial function in the central nervous system and in sensory structures including olfactory and auditory systems. Many studies have highlighted the protective effects of BDNF in the brain, showing how it can promote neuronal growth and survival and modulate synaptic plasticity. On the other hand, conflicting data about BDNF expression and functions in the cochlear and in olfactory structures have been reported. Several clinical and experimental research studies showed alterations in BDNF levels in neurodegenerative diseases affecting the central and peripheral nervous system, suggesting that BDNF can be a promising biomarker in most neurodegenerative conditions, including Alzheimer's disease, shearing loss, or olfactory impairment. Here, we summarize current research concerning BDNF functions in brain and in sensory domains (olfaction and hearing), focusing on the effects of the BDNF/TrkB signalling pathway activation in both physiological and pathological conditions. Finally, we review significant studies highlighting the possibility to target BDNF as a biomarker in early diagnosis of sensory and cognitive neurodegeneration, opening new opportunities to develop effective therapeutic strategies aimed to counteract neurodegeneration.
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Affiliation(s)
- Anna Pisani
- Department of Otolaryngology Head and Neck Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Fabiola Paciello
- Department of Neuroscience, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
- Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
| | - Valeria Del Vecchio
- Department of Neuroscience, Reproductive Sciences and Dentistry-Audiology Section, University of Naples Federico II, 80131 Naples, Italy
| | - Rita Malesci
- Department of Neuroscience, Reproductive Sciences and Dentistry-Audiology Section, University of Naples Federico II, 80131 Naples, Italy
| | - Eugenio De Corso
- Department of Otolaryngology Head and Neck Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
- Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
| | - Elena Cantone
- Department of Neuroscience, Reproductive Sciences and Dentistry-ENT Section, University of Naples Federico II, 80131 Naples, Italy
| | - Anna Rita Fetoni
- Department of Neuroscience, Reproductive Sciences and Dentistry-Audiology Section, University of Naples Federico II, 80131 Naples, Italy
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Nikolac Perkovic M, Borovecki F, Filipcic I, Vuic B, Milos T, Nedic Erjavec G, Konjevod M, Tudor L, Mimica N, Uzun S, Kozumplik O, Svob Strac D, Pivac N. Relationship between Brain-Derived Neurotrophic Factor and Cognitive Decline in Patients with Mild Cognitive Impairment and Dementia. Biomolecules 2023; 13:biom13030570. [PMID: 36979505 PMCID: PMC10046678 DOI: 10.3390/biom13030570] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 03/10/2023] [Accepted: 03/17/2023] [Indexed: 03/30/2023] Open
Abstract
In the last decade, increasing evidence has emerged linking alterations in the brain-derived neurotrophic factor (BDNF) expression with the development of Alzheimer's disease (AD). Because of the important role of BDNF in cognition and its association with AD pathogenesis, the aim of this study was to evaluate the potential difference in plasma BDNF concentrations between subjects with mild cognitive impairment (MCI; N = 209) and AD patients (N = 295) and to determine the possible association between BDNF plasma levels and the degree of cognitive decline in these individuals. The results showed a significantly higher (p < 0.001) concentration of plasma BDNF in subjects with AD (1.16; 0.13-21.34) compared with individuals with MCI (0.68; 0.02-19.14). The results of the present study additionally indicated a negative correlation between cognitive functions and BDNF plasma concentrations, suggesting higher BDNF levels in subjects with more pronounced cognitive decline. The correlation analysis revealed a significant negative correlation between BDNF plasma levels and both Mini-Mental State Examination (p < 0.001) and Clock Drawing test (p < 0.001) scores. In conclusion, the results of our study point towards elevated plasma BDNF levels in AD patients compared with MCI subjects, which may be due to the body's attempt to counteract the early and middle stages of neurodegeneration.
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Affiliation(s)
- Matea Nikolac Perkovic
- Laboratory for Molecular Neuropsychiatry, Division of Molecular Medicine, Ruder Boskovic Institute, 10000 Zagreb, Croatia
| | - Fran Borovecki
- Department of Neurology, University Hospital Centre Zagreb, 10000 Zagreb, Croatia
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Igor Filipcic
- Psychiatric Hospital "Sveti Ivan", 10090 Zagreb, Croatia
| | - Barbara Vuic
- Laboratory for Molecular Neuropsychiatry, Division of Molecular Medicine, Ruder Boskovic Institute, 10000 Zagreb, Croatia
| | - Tina Milos
- Laboratory for Molecular Neuropsychiatry, Division of Molecular Medicine, Ruder Boskovic Institute, 10000 Zagreb, Croatia
| | - Gordana Nedic Erjavec
- Laboratory for Molecular Neuropsychiatry, Division of Molecular Medicine, Ruder Boskovic Institute, 10000 Zagreb, Croatia
| | - Marcela Konjevod
- Laboratory for Molecular Neuropsychiatry, Division of Molecular Medicine, Ruder Boskovic Institute, 10000 Zagreb, Croatia
| | - Lucija Tudor
- Laboratory for Molecular Neuropsychiatry, Division of Molecular Medicine, Ruder Boskovic Institute, 10000 Zagreb, Croatia
| | - Ninoslav Mimica
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
- Department for Biological Psychiatry and Psychogeriatrics, University Psychiatric Hospital Vrapče, 10090 Zagreb, Croatia
| | - Suzana Uzun
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
- Department for Biological Psychiatry and Psychogeriatrics, University Psychiatric Hospital Vrapče, 10090 Zagreb, Croatia
| | - Oliver Kozumplik
- Department for Biological Psychiatry and Psychogeriatrics, University Psychiatric Hospital Vrapče, 10090 Zagreb, Croatia
| | - Dubravka Svob Strac
- Laboratory for Molecular Neuropsychiatry, Division of Molecular Medicine, Ruder Boskovic Institute, 10000 Zagreb, Croatia
| | - Nela Pivac
- Laboratory for Molecular Neuropsychiatry, Division of Molecular Medicine, Ruder Boskovic Institute, 10000 Zagreb, Croatia
- University of Applied Sciences Hrvatsko Zagorje Krapina, 49000 Krapina, Croatia
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26
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Li Y, Chen J, Yu H, Ye J, Wang C, Kong L. Serum brain-derived neurotrophic factor as diagnosis clue for Alzheimer's disease: A cross-sectional observational study in the elderly. Front Psychiatry 2023; 14:1127658. [PMID: 37009109 PMCID: PMC10060560 DOI: 10.3389/fpsyt.2023.1127658] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 02/27/2023] [Indexed: 03/18/2023] Open
Abstract
ObjectiveBrain-derived neurotrophic factor (BDNF) has not been validated as a diagnostic marker for Alzheimer's disease (AD). To provide a different perspective, this study aimed to evaluate the relationship between serum levels of mature BDNF (mBDNF) and precursor BDNF (proBDNF) in AD and to investigate whether serum BDNF levels or the ratio of mBDNF levels to proBDNF levels (M/P) could be a valuable biomarker for determining the risk of AD in elderly individuals.MethodA total of 126 subjects who met the inclusion criteria were assigned to either the AD group (n = 62) or the healthy control group (HC, n = 64) in this cross-sectional observationl study. Serum levels of mBDNF and proBDNF were measured using enzyme immunoassay kits. We analyzed the Mini-Mental State Examination (MMSE) scores from the two groups and examined the associations between AD and BDNF metabolism.ResultsThe serum concentration of proBDNF was significantly higher in ADs (4140.937 pg/ml) than in HCs (2606.943 pg/ml; p < 0.01). The MMSE significantly correlated with proBDNF (p < 0.01, r = −0.686) and M/P (p < 0.01, r = 0.595) in all subjects. To determine the risk for AD, the area under the receiver operating characteristic curve was calculated, which was 0.896 (95% confidence interval 0.844–0.949) for proBDNF and 0.901 (95% 0.850–0.953) for proBDNF and M/P combined.ConclusionWe observed a correlation between low serum proBDNF levels and higher MMSE scores in AD. The most effective diagnostic strategy was the combination of proBDNF and M/P, whereas mBDNF levels performed poorly when we evaluated the predictive model.
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Affiliation(s)
- Yuanyuan Li
- Medical Department, Qingdao University, Qingdao, China
| | - Jiao Chen
- Department of Geriatric Psychiatry, Qingdao Mental Health Center, Qingdao, Shandong, China
| | - Hui Yu
- Department of Geriatric Psychiatry, Qingdao Mental Health Center, Qingdao, Shandong, China
| | - Jiayu Ye
- School of Mental Health, Jining Medical University, Jining, Shandong, China
| | - Chunxia Wang
- Department of Geriatric Psychiatry, Qingdao Mental Health Center, Qingdao, Shandong, China
- *Correspondence: Chunxia Wang
| | - Lingli Kong
- Department of Geriatric Psychiatry, Qingdao Mental Health Center, Qingdao, Shandong, China
- Lingli Kong
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27
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Wang T, Li T, Hao S, Han Y, Cai Y. Association of plasma BDNF levels with different stages of Alzheimer's disease: a cross-sectional study. Neurol Res 2023; 45:234-240. [PMID: 36453692 DOI: 10.1080/01616412.2022.2129760] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
BACKGROUND Growing evidence shows that the expression of brain-derived neurotrophic factor (BDNF) is altered in the peripheral blood of participants with Alzheimer's disease (AD). It is unclear, however, whether altered BDNF expression is also observed in the early stages of AD. METHODS In the present study, 138 normal controls (NC), 57 participants with subjective cognitive decline (SCD), and 37 participants with amnestic mild cognitive impairment (aMCI) and AD were included. Plasma BDNF protein levels were assessed using a commercial multiplex Luminex-based kit. Patient samples were also probed for the presence of BDNF gene variant rs6265. RESULTS Pairwise comparisons between the groups showed that there was not a significant difference in BDNF levels when comparing SCD with NC and when comparing SCD with aMCI/AD, but BDNF levels in aMCI/AD samples were increased when compared with NC samples. For models differentiating clinical groups, discriminant analysis was performed by including education, APOE genotype, and BDNF levels in the model. This approach distinguishes participants with SCD (AUC = 0.630) and aMCI/AD (AUC = 0.665) from NC. CONCLUSION Our results suggest that expression of BDNF in plasma is altered at the clinical stage of AD.
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Affiliation(s)
- Ting Wang
- Department of Biobank, Xuanwu Hospital of Capital Medical University, Beijing, China.,National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital of Capital Medical University, Beijing, China
| | - Taoran Li
- Department of Neurology, Xuanwu Hospital of Capital Medical University, Beijing, China
| | - Shuwen Hao
- Department of Biobank, Xuanwu Hospital of Capital Medical University, Beijing, China.,National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital of Capital Medical University, Beijing, China
| | - Ying Han
- National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital of Capital Medical University, Beijing, China.,Department of Neurology, Xuanwu Hospital of Capital Medical University, Beijing, China.,Center of Alzheimer's Disease, Beijing Institute for Brain Disorders, Xuanwu Hospital of Capital Medical University, Beijing, China
| | - Yanning Cai
- Department of Biobank, Xuanwu Hospital of Capital Medical University, Beijing, China.,National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital of Capital Medical University, Beijing, China.,Beijing Geriatric Medical Research Center, Xuanwu Hospital of Capital Medical University, Beijing, China
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28
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Yalachkov Y, Anschütz V, Maiworm M, Jakob J, Schaller-Paule MA, Schäfer JH, Reiländer A, Friedauer L, Behrens M, Steffen F, Bittner S, Foerch C. Serum and cerebrospinal fluid BDNF concentrations are associated with neurological and cognitive improvement in multiple sclerosis: A pilot study. Mult Scler Relat Disord 2023; 71:104567. [PMID: 36805176 DOI: 10.1016/j.msard.2023.104567] [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: 01/05/2023] [Revised: 02/05/2023] [Accepted: 02/11/2023] [Indexed: 02/19/2023]
Abstract
BACKGROUND Biomarkers of disease activity have been intensively studied in multiple sclerosis (MS) but knowledge on predictors of disability improvement is limited. The aim of this pilot study was to explore whether increased brain-derived neurotrophic factor concentrations in serum and CSF (sBDNF/cBDNF) precede neurological and cognitive improvement in MS. METHODS In this pilot, monocentric prospective cohort study we collected serum/CSF samples at baseline together with EDSS (n = 36) and cognitive testing (n = 34) in patients with relapsing-remitting/primary progressive MS or clinically isolated syndrome. BDNF was assessed in serum and CSF with a single molecule array (SIMOA) HD-1 analyser (Quanterix). Twelve months later EDSS and cognitive testing were repeated. BDNF concentrations of patients with vs. without disability or cognitive improvement (disability improvement: decrease in EDSS ≥ 0.5; cognitive improvement: average z-score increase in neuropsychological performance ≥ 0.5) were compared using univariate ANOVAs adjusting for covariates. RESULTS Compared to subjects without, patients with disability improvement had higher sBDNF at baseline (q = 0.04). Subjects with cognitive improvement had higher cBDNF at baseline than those without cognitive improvement (q = 0.004). Secondary analysis demonstrated significant correlations between sBDNF and EDSS change (q = 0.036), cBDNF and average z-score change (q = 0.04) and cBDNF and number of cognitive tests with improvement (q = 0.04), while controlling for covariates. CONCLUSIONS Our findings suggest a possible role for BDNF in neurological and cognitive improvement in MS. These findings have to be confirmed in a larger sample but they already highlight the potential of BDNF as a biomarker for disability improvement and neuroplasticity in MS.
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Affiliation(s)
- Yavor Yalachkov
- Department of Neurology, University Hospital Frankfurt, Frankfurt am Main, Germany.
| | - Victoria Anschütz
- Department of Neurology, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Michelle Maiworm
- Department of Neurology, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Jasmin Jakob
- Department of Neurology, University Hospital Frankfurt, Frankfurt am Main, Germany; Department of Neurology, University Medical Center Mainz, Mainz, Germany
| | - Martin A Schaller-Paule
- Department of Neurology, University Hospital Frankfurt, Frankfurt am Main, Germany; Department of Psychiatry and Psychotherapy, University Medical Center Mainz, Mainz, Germany
| | - Jan Hendrik Schäfer
- Department of Neurology, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Annemarie Reiländer
- Department of Neurology, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Lucie Friedauer
- Department of Neurology, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Marion Behrens
- Department of Neurology, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Falk Steffen
- Department of Neurology, University Medical Center Mainz, Mainz, Germany
| | - Stefan Bittner
- Department of Neurology, University Medical Center Mainz, Mainz, Germany
| | - Christian Foerch
- Department of Neurology, University Hospital Frankfurt, Frankfurt am Main, Germany; Department of Neurology, RKH Klinikum Ludwigsburg, Ludwigsburg, Germany
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29
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Kouter K, Nikolac Perkovic M, Nedic Erjavec G, Milos T, Tudor L, Uzun S, Mimica N, Pivac N, Videtic Paska A. Difference in Methylation and Expression of Brain-Derived Neurotrophic Factor in Alzheimer's Disease and Mild Cognitive Impairment. Biomedicines 2023; 11:235. [PMID: 36830773 PMCID: PMC9953261 DOI: 10.3390/biomedicines11020235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/31/2022] [Accepted: 01/11/2023] [Indexed: 01/19/2023] Open
Abstract
Due to the increasing number of progressive dementias in the population, numerous studies are being conducted that seek to determine risk factors, biomarkers and pathological mechanisms that could help to differentiate between normal symptoms of aging, mild cognitive impairment (MCI) and dementia. The aim of this study was to investigate the possible association of levels of BDNF and COMT gene expression and methylation in peripheral blood cells with the development of Alzheimer's disease (AD). Our results revealed higher expression levels of BDNF (p < 0.001) in MCI subjects compared to individuals diagnosed with AD. However, no difference in COMT gene expression (p = 0.366) was detected. DNA methylation of the CpG islands and other sequences with potential effects on gene expression regulation revealed just one region (BDNF_9) in the BDNF gene (p = 0.078) with marginally lower levels of methylation in the AD compared to MCI subjects. Here, we show that the level of BDNF expression in the periphery is decreased in subjects with AD compared to individuals with MCI. The combined results from the gene expression analysis and DNA methylation analysis point to the potential of BDNF as a marker that could help distinguish between MCI and AD patients.
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Affiliation(s)
- Katarina Kouter
- Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, SI-1000 Ljubljana, Slovenia
| | - Matea Nikolac Perkovic
- Laboratory for Molecular Neuropsychiatry, Division of Molecular Medicine, Ruder Boskovic Institute, 10000 Zagreb, Croatia
| | - Gordana Nedic Erjavec
- Laboratory for Molecular Neuropsychiatry, Division of Molecular Medicine, Ruder Boskovic Institute, 10000 Zagreb, Croatia
| | - Tina Milos
- Laboratory for Molecular Neuropsychiatry, Division of Molecular Medicine, Ruder Boskovic Institute, 10000 Zagreb, Croatia
| | - Lucija Tudor
- Laboratory for Molecular Neuropsychiatry, Division of Molecular Medicine, Ruder Boskovic Institute, 10000 Zagreb, Croatia
| | - Suzana Uzun
- Department for Biological Psychiatry and Psychogeriatrics, University Psychiatric Hospital Vrapce, 10090 Zagreb, Croatia
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Ninoslav Mimica
- Department for Biological Psychiatry and Psychogeriatrics, University Psychiatric Hospital Vrapce, 10090 Zagreb, Croatia
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Nela Pivac
- Laboratory for Molecular Neuropsychiatry, Division of Molecular Medicine, Ruder Boskovic Institute, 10000 Zagreb, Croatia
| | - Alja Videtic Paska
- Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, SI-1000 Ljubljana, Slovenia
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Chen S, Huang W, He T, Zhang M, Jin X, Jiang L, Xu H, Chen K. Exploring the Causality Between Plasma Brain-Derived Neurotrophic Factor and Neurological Diseases: A Mendelian Randomization Study. J Alzheimers Dis 2023; 96:135-148. [PMID: 37742652 DOI: 10.3233/jad-230693] [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] [Indexed: 09/26/2023]
Abstract
BACKGROUND Brain-derived neurotrophic factor (BDNF) is a protein synthesized in the brain and widely expressed in the nervous system. Previous studies have demonstrated a controversial role of BDNF in neurological diseases. OBJECTIVE In this study, we aimed to assess the association between BDNF levels and the risk of neurological diseases by Mendelian randomization analysis. METHODS From a genome-wide association analysis of plasma proteins comprising 3,301 European participants, we isolated 25 genetic variations as instrumental variables for BDNF levels. Summary statistics data on six common neurological diseases as outcome variables. Two-sample Mendelian randomization (MR) analysis was used to assess whether plasma BDNF is causally related to neurological diseases. We also performed sensitivity analysis to ensure the robustness of the results and reverse MR to exclude potential reverse causality. RESULTS We confirmed the significant causal relationship between BDNF levels and the risk of Alzheimer's disease (AD) (OR, 0.92; 95% CI, 0.85, 0.98; p = 0.013). Other methods have also shown similar results. We infer that BDNF also reduces the risk of epilepsy (OR, 0.94; 95% CI, 0.90, 0.98; p = 0.004). In reverse MR analysis, we also found that AD can affect the level of BDNF. CONCLUSIONS Our study suggests higher plasma BDNF was associated with the reduced risk of AD. Moreover, higher plasma BDNF is a protective factor on AD and focal epilepsy. The results provide credence to the idea that BDNF may play a significant role in the development of focal epilepsy and AD.
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Affiliation(s)
- Shihao Chen
- Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Wenting Huang
- Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Tao He
- Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Mulan Zhang
- Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xing Jin
- Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | | | - Huiqin Xu
- Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Keyang Chen
- Department of Neurology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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Haque SS. Biomarkers in the diagnosis of neurodegenerative diseases. RUDN JOURNAL OF MEDICINE 2022. [DOI: 10.22363/2313-0245-2022-26-4-431-440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Biomarkers are molecules that behave as of biological states. Ideally, they should have high sensitivity, specificity, and accuracy in reflecting the total disease burden. The review discusses the current status of biomarkers used in neurological disorders. Neurodegenerative diseases are a heterogeneous group disorders characterized by progressive loss of structure and function of the central nervous system or peripheral nervous system. The review discusses the main biomarkers that have predictive value for describing clinical etiology, pathophysiology, and intervention strategies. Preciseness and reliability are one of important requirement for good biomarker. As a result of the analysis of literature data, it was revealed that beta-amyloid, total tau protein and its phosphorylated forms are the first biochemical biomarkers of neurodegenerative diseases measured in cerebrospinal fluid, but these markers are dependent upon invasive lumbar puncture and therefore it’s a cumbersome process for patients. Among the various biomarkers of neurodegenerative diseases, special attention is paid to miRNAs. MicroRNAs, important biomarkers in many disease states, including neurodegenerative disorders, make them promising candidates that may lead to identify new therapeutic targets. Conclusions. Biomarkers of neurological disease are present optimal amount in the cerebrospinal fluid but they are also present in blood at low levels. The data obtained reveal the predictive value of molecular diagnostics of neurodegenerative disorders and the need for its wider use.
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Hao Y, Xie B, Fu X, Xu R, Yang Y. New Insights into lncRNAs in Aβ Cascade Hypothesis of Alzheimer's Disease. Biomolecules 2022; 12:biom12121802. [PMID: 36551230 PMCID: PMC9775548 DOI: 10.3390/biom12121802] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 11/24/2022] [Accepted: 11/29/2022] [Indexed: 12/04/2022] Open
Abstract
Alzheimer's disease (AD) is the most common type of dementia, but its pathogenesis is not fully understood, and effective drugs to treat or reverse the progression of the disease are lacking. Long noncoding RNAs (lncRNAs) are abnormally expressed and deregulated in AD and are closely related to the occurrence and development of AD. In addition, the high tissue specificity and spatiotemporal specificity make lncRNAs particularly attractive as diagnostic biomarkers and specific therapeutic targets. Therefore, an in-depth understanding of the regulatory mechanisms of lncRNAs in AD is essential for developing new treatment strategies. In this review, we discuss the unique regulatory functions of lncRNAs in AD, ranging from Aβ production to clearance, with a focus on their interaction with critical molecules. Additionally, we highlight the advantages and challenges of using lncRNAs as biomarkers for diagnosis or therapeutic targets in AD and present future perspectives in clinical practice.
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Affiliation(s)
- Yitong Hao
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun 130021, China
| | - Bo Xie
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun 130021, China
| | - Xiaoshu Fu
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun 130021, China
| | - Rong Xu
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun 130021, China
| | - Yu Yang
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun 130021, China
- Correspondence:
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Szarowicz CA, Steece-Collier K, Caulfield ME. New Frontiers in Neurodegeneration and Regeneration Associated with Brain-Derived Neurotrophic Factor and the rs6265 Single Nucleotide Polymorphism. Int J Mol Sci 2022; 23:8011. [PMID: 35887357 PMCID: PMC9319713 DOI: 10.3390/ijms23148011] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 07/11/2022] [Accepted: 07/12/2022] [Indexed: 11/20/2022] Open
Abstract
Brain-derived neurotrophic factor is an extensively studied neurotrophin implicated in the pathology of multiple neurodegenerative and psychiatric disorders including, but not limited to, Parkinson's disease, Alzheimer's disease, Huntington's disease, traumatic brain injury, major de-pressive disorder, and schizophrenia. Here we provide a brief summary of current knowledge on the role of BDNF and the common human single nucleotide polymorphism, rs6265, in driving the pathogenesis and rehabilitation in these disorders, as well as the status of BDNF-targeted therapies. A common trend has emerged correlating low BDNF levels, either detected within the central nervous system or peripherally, to disease states, suggesting that BDNF replacement therapies may hold clinical promise. In addition, we introduce evidence for a distinct role of the BDNF pro-peptide as a biologically active ligand and the need for continuing studies on its neurological function outside of that as a molecular chaperone. Finally, we highlight the latest research describing the role of rs6265 expression in mechanisms of neurodegeneration as well as paradoxical advances in the understanding of this genetic variant in neuroregeneration. All of this is discussed in the context of personalized medicine, acknowledging there is no "one size fits all" therapy for neurodegenerative or psychiatric disorders and that continued study of the multiple BDNF isoforms and genetic variants represents an avenue for discovery ripe with therapeutic potential.
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Affiliation(s)
- Carlye A. Szarowicz
- Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA; (C.A.S.); (K.S.-C.)
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA
| | - Kathy Steece-Collier
- Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA; (C.A.S.); (K.S.-C.)
| | - Margaret E. Caulfield
- Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA; (C.A.S.); (K.S.-C.)
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Polyakova M, Mueller K, Arelin K, Lampe L, Rodriguez FS, Luck T, Kratzsch J, Hoffmann KT, Riedel-Heller S, Villringer A, Schoenknecht P, Schroeter ML. Increased Serum NSE and S100B Indicate Neuronal and Glial Alterations in Subjects Under 71 Years With Mild Neurocognitive Disorder/Mild Cognitive Impairment. Front Cell Neurosci 2022; 16:788150. [PMID: 35910248 PMCID: PMC9329528 DOI: 10.3389/fncel.2022.788150] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 05/27/2022] [Indexed: 11/13/2022] Open
Abstract
Background Mild cognitive impairment (MCI) is considered a pre-stage of different dementia syndromes. Despite diagnostic criteria refined by DSM-5 and a new term for MCI – “mild neurocognitive disorder” (mild NCD) – this diagnosis is still based on clinical criteria. Methods To link mild NCD to the underlying pathophysiology we assessed the degree of white matter hyperintensities (WMH) in the brain and peripheral biomarkers for neuronal integrity (neuron-specific enolase, NSE), plasticity (brain-derived neurotrophic factor, BDNF), and glial function (S100B) in 158 community-dwelling subjects with mild NCD and 82 healthy controls. All participants (63–79 years old) were selected from the Leipzig-population-based study of adults (LIFE). Results Serum S100B levels were increased in mild NCD in comparison to controls (p = 0.007). Serum NSE levels were also increased but remained non-significant after Bonferroni-Holm correction (p = 0.04). Furthermore, age by group interaction was significant for S100B. In an age-stratified sub-analysis, NSE and S100B were higher in younger subjects with mild NCD below 71 years of age. Some effects were inconsistent after controlling for potentially confounding factors. The discriminatory power of the two biomarkers NSE and S100B was insufficient to establish a pathologic threshold for mild NCD. In subjects with mild NCD, WMH load correlated with serum NSE levels (r = 0.20, p = 0.01), independently of age. Conclusion Our findings might indicate the presence of neuronal (NSE) and glial (S100B) injury in mild NCD. Future studies need to investigate whether younger subjects with mild NCD with increased biomarker levels are at risk of developing major NCD.
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Affiliation(s)
- Maryna Polyakova
- Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany
- Clinic for Cognitive Neurology, University of Leipzig, Leipzig, Germany
- LIFE–Leipzig Research Center for Civilization Diseases, Leipzig University, Leipzig, Germany
- University Clinic for Psychiatry and Psychotherapy, Leipzig University, Leipzig, Germany
- *Correspondence: Maryna Polyakova
| | - Karsten Mueller
- Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany
| | - Katrin Arelin
- Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany
- LIFE–Leipzig Research Center for Civilization Diseases, Leipzig University, Leipzig, Germany
| | - Leonie Lampe
- Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany
- LIFE–Leipzig Research Center for Civilization Diseases, Leipzig University, Leipzig, Germany
| | - Francisca S. Rodriguez
- LIFE–Leipzig Research Center for Civilization Diseases, Leipzig University, Leipzig, Germany
- Research Group Psychosocial Epidemiology and Public Health, German Center for Neurodegenerative Diseases (DZNE), Greifswald, Germany
| | - Tobias Luck
- LIFE–Leipzig Research Center for Civilization Diseases, Leipzig University, Leipzig, Germany
- Faculty of Applied Social Sciences, University of Applied Sciences Erfurt, Erfurt, Germany
| | - Jürgen Kratzsch
- LIFE–Leipzig Research Center for Civilization Diseases, Leipzig University, Leipzig, Germany
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Leipzig University, Leipzig, Germany
| | | | - Steffi Riedel-Heller
- LIFE–Leipzig Research Center for Civilization Diseases, Leipzig University, Leipzig, Germany
- Institute of Social Medicine, Occupational Health and Public Health (ISAP), Leipzig University, Leipzig, Germany
| | - Arno Villringer
- Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany
- LIFE–Leipzig Research Center for Civilization Diseases, Leipzig University, Leipzig, Germany
- Institute of Neuroradiology, University Clinic, Leipzig, Germany
| | - Peter Schoenknecht
- LIFE–Leipzig Research Center for Civilization Diseases, Leipzig University, Leipzig, Germany
- University Clinic for Psychiatry and Psychotherapy, Leipzig University, Leipzig, Germany
- Department of Psychiatry and Psychotherapy, University Affiliated Hospital Arnsdorf, Technical University of Dresden, Dresden, Germany
| | - Matthias L. Schroeter
- Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany
- Clinic for Cognitive Neurology, University of Leipzig, Leipzig, Germany
- LIFE–Leipzig Research Center for Civilization Diseases, Leipzig University, Leipzig, Germany
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Rauch J, Steffen JF, Muntau B, Gisbrecht J, Pörtner K, Herden C, Niller HH, Bauswein M, Rubbenstroth D, Mehlhoop U, Allartz P, Tappe D. Human Borna disease virus 1 encephalitis shows marked pro-inflammatory biomarker and tissue immunoactivation during the course of disease. Emerg Microbes Infect 2022; 11:1843-1856. [PMID: 35788177 PMCID: PMC9336484 DOI: 10.1080/22221751.2022.2098831] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Human Borna disease virus 1 (BoDV-1) encephalitis is a severe emerging disease with a very high case-fatality rate. While the clinical disease, case definitions, diagnostic algorithms and neuropathology have been described, very little is known about the immunological processes of human BoDV-1 encephalitis. Here, we analyzed serum and cerebrospinal fluid (CSF) samples from 10 patients with fatal BoDV-1 encephalitis for changes of different cytokines, chemokines, growth factors and other biomarkers over time. From one of these individuals, also autoptic formalin-fixed brain tissue was analyzed for the expression of inflammatory biomarkers by mRNA levels and immunostaining; in a further patient, only formalin-fixed brain tissue was available and examined in addition. A marked and increasing immune activation from the initial phase to the last phase of acute BoDV-1 encephalitis is shown in serum and CSF, characterized by cytokine concentration changes (IFNγ, IL-5, IL-6, IL-9, IL-10, IL-12p40, IL-13, IL-18, TGF-β1) with a predominantly pro-inflammatory pattern over time. IFNγ production was demonstrated in endothelial cells, astrocytes and microglia, IL-6 in activated microglia, and TGF-β1 in endothelial cells, activated astrocytes and microglia. This was paralleled by an increase of chemokines (CCL-2, CCL-5, CXCL-10, IL-8) to attract immune cells to the site of infection, contributing to inflammation and tissue damage. Pathologically low growth factor levels (BDNF, β-NGF, PDGF) were seen. Changed levels of arginase and sTREM further fostered the pro-inflammatory state. This dysbalanced, pro-inflammatory state likely contributes importantly to the fatal outcome of human BoDV-1 encephalitis, and might be a key target for possible treatment attempts.
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Affiliation(s)
- Jessica Rauch
- Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
| | | | - Birgit Muntau
- Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
| | - Jana Gisbrecht
- Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
| | - Kirsten Pörtner
- Robert Koch Institute, Department of Infectious Disease Epidemiology, Berlin, Germany
| | - Christiane Herden
- Institute for Veterinary Pathology, Justus-Liebig-University Gießen, Gießen, Germany
| | - Hans Helmut Niller
- Institute of Clinical Microbiology and Hygiene, Regensburg University Hospital, Regensburg, Germany
| | - Markus Bauswein
- Institute of Clinical Microbiology and Hygiene, Regensburg University Hospital, Regensburg, Germany
| | - Dennis Rubbenstroth
- Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Greifswald-Insel Riems, Germany
| | - Ute Mehlhoop
- Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
| | - Petra Allartz
- Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
| | - Dennis Tappe
- Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
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Azman KF, Zakaria R. Recent Advances on the Role of Brain-Derived Neurotrophic Factor (BDNF) in Neurodegenerative Diseases. Int J Mol Sci 2022; 23:6827. [PMID: 35743271 PMCID: PMC9224343 DOI: 10.3390/ijms23126827] [Citation(s) in RCA: 82] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Revised: 06/14/2022] [Accepted: 06/16/2022] [Indexed: 02/04/2023] Open
Abstract
Neurotrophins, such as brain-derived neurotrophic factor (BDNF), are essential for neuronal survival and growth. The signaling cascades initiated by BDNF and its receptor are the key regulators of synaptic plasticity, which plays important role in learning and memory formation. Changes in BDNF levels and signaling pathways have been identified in several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and Huntington's disease, and have been linked with the symptoms and course of these diseases. This review summarizes the current understanding of the role of BDNF in several neurodegenerative diseases, as well as the underlying molecular mechanism. The therapeutic potential of BDNF treatment is also discussed, in the hope of discovering new avenues for the treatment of neurodegenerative diseases.
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Affiliation(s)
- Khairunnuur Fairuz Azman
- Department of Physiology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia;
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St. Peter M, Brough DE, Lawrence A, Nelson-Brantley J, Huang P, Harre J, Warnecke A, Staecker H. Improving Control of Gene Therapy-Based Neurotrophin Delivery for Inner Ear Applications. Front Bioeng Biotechnol 2022; 10:892969. [PMID: 35721868 PMCID: PMC9204055 DOI: 10.3389/fbioe.2022.892969] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 04/27/2022] [Indexed: 11/13/2022] Open
Abstract
Background: Survival and integrity of the spiral ganglion is vital for hearing in background noise and for optimal functioning of cochlear implants. Numerous studies have demonstrated that supplementation of supraphysiologic levels of the neurotrophins BDNF and NT-3 by pumps or gene therapy strategies supports spiral ganglion survival. The endogenous physiological levels of growth factors within the inner ear, although difficult to determine, are likely extremely low within the normal inner ear. Thus, novel approaches for the long-term low-level delivery of neurotrophins may be advantageous. Objectives: This study aimed to evaluate the long-term effects of gene therapy-based low-level neurotrophin supplementation on spiral ganglion survival. Using an adenovirus serotype 28-derived adenovector delivery system, the herpes latency promoter, a weak, long expressing promoter system, has been used to deliver the BDNF or NTF3 genes to the inner ear after neomycin-induced ototoxic injury in mice. Results: Treatment of the adult mouse inner ear with neomycin resulted in acute and chronic changes in endogenous neurotrophic factor gene expression and led to a degeneration of spiral ganglion cells. Increased survival of spiral ganglion cells after adenoviral delivery of BDNF or NTF3 to the inner ear was observed. Expression of BDNF and NT-3 could be demonstrated in the damaged organ of Corti after gene delivery. Hearing loss due to overexpression of neurotrophins in the normal hearing ear was avoided when using this novel vector–promoter combination. Conclusion: Combining supporting cell-specific gene delivery via the adenovirus serotype 28 vector with a low-strength long expressing promoter potentially can provide long-term neurotrophin delivery to the damaged inner ear.
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Affiliation(s)
| | | | - Anna Lawrence
- Department of Otolaryngology, University of Kansas School of Medicine, Kansas City, KS, United States
| | | | - Peixin Huang
- Department of Otolaryngology, University of Kansas School of Medicine, Kansas City, KS, United States
| | - Jennifer Harre
- Department of Otolaryngology, Hannover Medical School, Hannover, Germany
| | - Athanasia Warnecke
- Department of Otolaryngology, Hannover Medical School, Hannover, Germany
| | - Hinrich Staecker
- Department of Otolaryngology, University of Kansas School of Medicine, Kansas City, KS, United States
- *Correspondence: Hinrich Staecker,
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Fernández-Rodríguez R, Álvarez-Bueno C, Martínez-Ortega IA, Martínez-Vizcaíno V, Mesas AE, Notario-Pacheco B. Immediate effect of high-intensity exercise on brain-derived neurotrophic factor in healthy young adults: A systematic review and meta-analysis. JOURNAL OF SPORT AND HEALTH SCIENCE 2022; 11:367-375. [PMID: 34481089 PMCID: PMC9189701 DOI: 10.1016/j.jshs.2021.08.004] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 06/09/2021] [Accepted: 07/20/2021] [Indexed: 06/13/2023]
Abstract
BACKGROUND Although brain-derived neurotrophic factor (BDNF) has been identified as a molecular biomarker of the neurophysiological effects induced by exercise, the acute effects of high-intensity exercise (HIE) on BDNF levels are inconclusive. This study aims to estimate the immediate effects of HIE on BDNF levels in healthy young adults. METHODS A systematic search was conducted in the MEDLINE, Scopus, Cochrane CENTRAL, and SPORTDiscuss databases up to December 2020. Randomized controlled trials (RCTs) and non-RCTs reporting pre-post changes in serum or plasma BDNF after an acute intervention of HIE compared to a control condition were included. Pooled effect sizes (p-ESs) and 95% confidence intervals (95%CIs) were calculated for RCTs using a random effects model with Stata/SE (Version 15.0; StataCorp., College Station, TX, USA). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. PROPERO registration number: CRD42020221047. RESULTS A total of 22 studies with 552 individuals (age range: 20-31 years; 59.1% male) were included. The meta-analysis included 10 RCTs that reported valid outcome data. Higher BDNF levels were observed when HIE interventions were compared with non-exercise (p-ES = 0.55, 95%CI: 0.12-0.98; I2 = 25.7%; n = 4 studies) and light-intensity exercise (p-ES = 0.78, 95%CI: 0.15-1.40; I2 = 52.4%; n = 3 studies) but not moderate-intensity exercise (p-ES = 0.93, 95%CI: -0.16 to 2.02; I2 = 88.5%; n = 4 studies) conditions. CONCLUSION In comparison to non-exercise or light-intensity exercises, an immediate increase in BDNF levels may occur when young adults perform HIE. Given the benefits obtained maximizing circulating BDNF when performing HIE and its potential effects on brain health, our findings suggest that HIE could be recommended by clinicians as a useful exercise strategy to healthy adults.
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Affiliation(s)
| | - Celia Álvarez-Bueno
- Health and Social Research Center, Universidad de Castilla-La Mancha, Cuenca 16071, Spain; Universidad Politécnica y Artística del Paraguay, Asunción 2024, Paraguay.
| | | | - Vicente Martínez-Vizcaíno
- Health and Social Research Center, Universidad de Castilla-La Mancha, Cuenca 16071, Spain; Faculty of Medicine, Universidad Autónoma de Chile, Talca 3460000, Chile
| | - Arthur Eumann Mesas
- Health and Social Research Center, Universidad de Castilla-La Mancha, Cuenca 16071, Spain; Postgraduate Program in Public Health, Universidad Estadual de Londrina, Londrina 86051-990, Brazil
| | - Blanca Notario-Pacheco
- Health and Social Research Center, Universidad de Castilla-La Mancha, Cuenca 16071, Spain
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Gao L, Zhang Y, Sterling K, Song W. Brain-derived neurotrophic factor in Alzheimer's disease and its pharmaceutical potential. Transl Neurodegener 2022; 11:4. [PMID: 35090576 PMCID: PMC8796548 DOI: 10.1186/s40035-022-00279-0] [Citation(s) in RCA: 193] [Impact Index Per Article: 64.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Accepted: 01/01/2022] [Indexed: 12/14/2022] Open
Abstract
Synaptic abnormalities are a cardinal feature of Alzheimer's disease (AD) that are known to arise as the disease progresses. A growing body of evidence suggests that pathological alterations to neuronal circuits and synapses may provide a mechanistic link between amyloid β (Aβ) and tau pathology and thus may serve as an obligatory relay of the cognitive impairment in AD. Brain-derived neurotrophic factors (BDNFs) play an important role in maintaining synaptic plasticity in learning and memory. Considering AD as a synaptic disorder, BDNF has attracted increasing attention as a potential diagnostic biomarker and a therapeutical molecule for AD. Although depletion of BDNF has been linked with Aβ accumulation, tau phosphorylation, neuroinflammation and neuronal apoptosis, the exact mechanisms underlying the effect of impaired BDNF signaling on AD are still unknown. Here, we present an overview of how BDNF genomic structure is connected to factors that regulate BDNF signaling. We then discuss the role of BDNF in AD and the potential of BDNF-targeting therapeutics for AD.
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Affiliation(s)
- Lina Gao
- Shandong Collaborative Innovation Center for Diagnosis, Treatment and Behavioral Interventions of Mental Disorders, Institute of Mental Health, College of Pharmacy, Jining Medical University, Jining, 272067, Shandong, China
- Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada
| | - Yun Zhang
- National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
| | - Keenan Sterling
- Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada
| | - Weihong Song
- Shandong Collaborative Innovation Center for Diagnosis, Treatment and Behavioral Interventions of Mental Disorders, Institute of Mental Health, College of Pharmacy, Jining Medical University, Jining, 272067, Shandong, China.
- Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada.
- National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China.
- Institute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province, School of Mental Health and The Affiliated Kangning Hospital, Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, 325001, Zhejiang, China.
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Pathak N, Vimal SK, Tandon I, Agrawal L, Hongyi C, Bhattacharyya S. Neurodegenerative Disorders of Alzheimer, Parkinsonism, Amyotrophic Lateral Sclerosis and Multiple Sclerosis: An Early Diagnostic Approach for Precision Treatment. Metab Brain Dis 2022; 37:67-104. [PMID: 34719771 DOI: 10.1007/s11011-021-00800-w] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 07/11/2021] [Indexed: 12/21/2022]
Abstract
Neurodegenerative diseases (NDs) are characterised by progressive dysfunction of synapses, neurons, glial cells and their networks. Neurodegenerative diseases can be classified according to primary clinical features (e.g., dementia, parkinsonism, or motor neuron disease), anatomic distribution of neurodegeneration (e.g., frontotemporal degenerations, extrapyramidal disorders, or spinocerebellar degenerations), or principal molecular abnormalities. The most common neurodegenerative disorders are amyloidosis, tauopathies, a-synucleinopathy, and TAR DNA-binding protein 43 (TDP-43) proteopathy. The protein abnormalities in these disorders have abnormal conformational properties along with altered cellular mechanisms, and they exhibit motor deficit, mitochondrial malfunction, dysfunctions in autophagic-lysosomal pathways, synaptic toxicity, and more emerging mechanisms such as the roles of stress granule pathways and liquid-phase transitions. Finally, for each ND, microglial cells have been reported to be implicated in neurodegeneration, in particular, because the microglial responses can shift from neuroprotective to a deleterious role. Growing experimental evidence suggests that abnormal protein conformers act as seed material for oligomerization, spreading from cell to cell through anatomically connected neuronal pathways, which may in part explain the specific anatomical patterns observed in brain autopsy sample. In this review, we mention the human pathology of select neurodegenerative disorders, focusing on how neurodegenerative disorders (i.e., Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis) represent a great healthcare problem worldwide and are becoming prevalent because of the increasing aged population. Despite many studies have focused on their etiopathology, the exact cause of these diseases is still largely unknown and until now with the only available option of symptomatic treatments. In this review, we aim to report the systematic and clinically correlated potential biomarker candidates. Although future studies are necessary for their use in early detection and progression in humans affected by NDs, the promising results obtained by several groups leads us to this idea that biomarkers could be used to design a potential therapeutic approach and preclinical clinical trials for the treatments of NDs.
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Affiliation(s)
- Nishit Pathak
- Department of Pharmaceutical Sciences and Chinese Traditional Medicine, Southwest University, Beibei, Chongqing, 400715, People's Republic of China
| | - Sunil Kumar Vimal
- Department of Pharmaceutical Sciences and Chinese Traditional Medicine, Southwest University, Beibei, Chongqing, 400715, People's Republic of China
| | - Ishi Tandon
- Amity University Jaipur, Rajasthan, Jaipur, Rajasthan, India
| | - Lokesh Agrawal
- Graduate School of Comprehensive Human Sciences, Kansei Behavioural and Brain Sciences, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki, 305-8577, Japan
| | - Cao Hongyi
- Department of Pharmaceutical Sciences and Chinese Traditional Medicine, Southwest University, Beibei, Chongqing, 400715, People's Republic of China
| | - Sanjib Bhattacharyya
- Department of Pharmaceutical Sciences and Chinese Traditional Medicine, Southwest University, Beibei, Chongqing, 400715, People's Republic of China.
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Nowroozi A, Salehi MA, Mohammadi S. Brain-derived neurotrophic factor in patients with epilepsy: A systematic review and meta-analysis. Epilepsy Res 2021; 178:106794. [PMID: 34773766 DOI: 10.1016/j.eplepsyres.2021.106794] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 09/13/2021] [Accepted: 10/15/2021] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Epilepsy affects almost 1% of people and is characterized by sudden seizures. To date, no reliable biomarker has been found to diagnose or predict the outcomes of epilepsy. Brain-derived neurotrophic factor (BDNF) levels have recently been shown to differ between patients with certain neurologic disorders and normal population, and it is unknown whether this is the case for epilepsy. In this study, we mainly aim to answer this question. METHODS We searched three databases for studies comparing BDNF levels between patients with epilepsy and controls. Quality assessment of included studies was performed using the Newcastle-Ottawa scale and statistical analyses were carried out in STATA software version 16. RESULTS Final analyses included 10 studies involving 403 patients with epilepsy. BDNF levels were statistically similar between patients and controls (standardized mean difference (SMD) = - 0.30, 95% CI = - 1.32 to 0.71, p = 0.56). When categorized by epilepsy subtype, patients with partial epilepsy showed lower BDNF measures than controls (95% CI = - 1.42 to - 0.32, p < 0.01), while the difference was not significant in patients with generalized epilepsy (95% CI = - 2.81 to 1.65, p = 0.61). Subgroup analyses indicated that BDNF was lower in patients than controls when age or sex matching was not present. Patient samples acquired in the morning also showed significantly lower BDNF levels than controls, unlike afternoon samples. Meta-regression identified no predictor for the difference in BDNF levels. CONCLUSION Generally, patients with epilepsy had BDNF levels similar to general population, although patients with partial epilepsy showed lower BDNF levels. Taking into account the sub-group analyses, further studies with higher qualities are required to evaluate the role and utility of BDNF in epilepsy.
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Affiliation(s)
- Ali Nowroozi
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| | | | - Soheil Mohammadi
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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Souza-Talarico JN, Bromberg E, Santos JLF, Freitas BS, Silva DF, Duarte YAO. Family and Community Support, Brain-Derived Neurotrophic Factor, and Cognitive Performance in Older Adults: Findings From the Health, Wellbeing and Aging Study Population-Based Cohort. Front Behav Neurosci 2021; 15:717847. [PMID: 34621159 PMCID: PMC8490800 DOI: 10.3389/fnbeh.2021.717847] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 08/27/2021] [Indexed: 11/13/2022] Open
Abstract
Background: Social networks can modulate physiological responses, protects against the detrimental consequences of prolonged stress, and enhance health outcomes. Family ties represent an essential source of social networks among older adults. However, the impact of family support on cognitive performance and the biological factors influencing that relationship is still unclear. We aimed to determine the relationship between family support, cognitive performance and BDNF levels. Methods: Cross-sectional data from three-hundred, eight-six individuals aged on average 60 years enrolled in the Health, Wellbeing and Aging Study (SABE), a population-cohort study, were assessed for family support, community support and cognitive performance. Structural and functional family support was evaluated based on family size and interactions allied to scores in the Family APGAR questionnaire. Community assistance (received or provided) assessed the community support. Cognitive performance was determined using the Mini-Mental State Examination (MMSE), verbal fluency (animals per minute) and backward digital span. Blood samples were obtained to determine BDNF levels. Results: Multivariate analysis showed that functional family support, but not structural, was associated with higher MMSE, verbal fluency and digit span scores, even controlling for potential cofounders (p < 0.001). Providing support to the community, rather than receiving support from others, was associated with better cognitive performance (p < 0.001). BDNF concentration was not associated with community support, family function, or cognitive performance. Conclusion: These findings suggest that emotional components of functional family and community support (e.g., loving and empathic relationship) may be more significant to cognitive health than size and frequency of social interactions.
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Affiliation(s)
- Juliana Nery Souza-Talarico
- College of Nursing, The University of Iowa, Iowa City, IA, United States.,School of Nursing, University of Sao Paulo, São Paulo, Brazil
| | - Elke Bromberg
- Department of Morphophysiological Sciences, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil.,National Institute of Science and Technology for Translational Medicine (INCT-TM)/Brazilian National Research Council (CNPq), Ribeirão Preto, Brazil
| | | | - Betania Souza Freitas
- Department of Morphophysiological Sciences, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil
| | | | - Yeda Aparecida Oliveira Duarte
- School of Nursing, University of Sao Paulo, São Paulo, Brazil.,Faculty of Public Health, University of Sao Paulo, São Paulo, Brazil
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Phipps CJ, Murman DL, Warren DE. Stimulating Memory: Reviewing Interventions Using Repetitive Transcranial Magnetic Stimulation to Enhance or Restore Memory Abilities. Brain Sci 2021; 11:1283. [PMID: 34679348 PMCID: PMC8533697 DOI: 10.3390/brainsci11101283] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 09/24/2021] [Accepted: 09/25/2021] [Indexed: 12/18/2022] Open
Abstract
Human memory systems are imperfect recording devices that are affected by age and disease, but recent findings suggest that the functionality of these systems may be modifiable through interventions using non-invasive brain stimulation such as repetitive transcranial magnetic stimulation (rTMS). The translational potential of these rTMS interventions is clear: memory problems are the most common cognitive complaint associated with healthy aging, while pathological conditions such as Alzheimer's disease are often associated with severe deficits in memory. Therapies to improve memory or treat memory loss could enhance independence while reducing costs for public health systems. Despite this promise, several important factors limit the generalizability and translational potential of rTMS interventions for memory. Heterogeneity of protocol design, rTMS parameters, and outcome measures present significant challenges to interpretation and reproducibility. However, recent advances in cognitive neuroscience, including rTMS approaches and recent insights regarding functional brain networks, may offer methodological tools necessary to design new interventional studies with enhanced experimental rigor, improved reproducibility, and greater likelihood of successful translation to clinical settings. In this review, we first discuss the current state of the literature on memory modulation with rTMS, then offer a commentary on developments in cognitive neuroscience that are relevant to rTMS interventions, and finally close by offering several recommendations for the design of future investigations using rTMS to modulate human memory performance.
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Affiliation(s)
| | | | - David E. Warren
- Department of Neurological Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA; (C.J.P.); (D.L.M.)
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A proposal: How to study pro-myelinating proteins in MS. Autoimmun Rev 2021; 21:102924. [PMID: 34416371 DOI: 10.1016/j.autrev.2021.102924] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 08/14/2021] [Indexed: 12/15/2022]
Abstract
Multiple sclerosis (MS) is an inflammatory and degenerative disease of the CNS. An unmet need in MS is repair i.e.,promoting endogenous regeneration and remyelination after demyelinating inflammatory injury. Remyelination is critical in neuronal preservation and the prevention of clinical progression. There is a good deal of evidence for histological repair and remyelination in MS patients. Repair is driven by several prominent endogenous pro-myelinating proteinsincluding neural cellular adhesion molecule (N-CAM) and brain derived neurotrophic factor (BDNF) among others. To follow changes during acute re-myelination in vivo in MS subjects, non conventional MRI techniques are necessary such as quantitative susceptibility mapping (QSM) that detects the release of Fe from dying oligodendroglial cells and myelin water imaging (MWI) that detects water captured within newly formed myelin. The best time to monitor changes in pro-myelinating proteins and link those changes to imaging evolution is immediately after the acute inflammatory response in MS lesions (gadolinium enhancement [Gd+]) during an intense period of remyelination. We can monitor MS subjects with new Gd + lesions with periodic imaging along with sampling of blood and CSF and determine if myelin formation is linked with increases in pro-myelinating proteins. This would lead to potential therapeutic manipulation with directly administered proteins to promote CNS re-myelination in animal models and in early clinical trials.
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Bourbeau KC, Moriarty TA, Bellovary BN, Bellissimo GF, Ducharme JB, Haeny TJ, Zuhl MN. Cardiovascular, Cellular, and Neural Adaptations to Hot Yoga versus Normal-Temperature Yoga. Int J Yoga 2021; 14:115-126. [PMID: 34188383 PMCID: PMC8191229 DOI: 10.4103/ijoy.ijoy_134_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 02/28/2021] [Accepted: 03/25/2021] [Indexed: 11/25/2022] Open
Abstract
CONTEXT Chronic heat exposure promotes cardiovascular and cellular adaptations, improving an organism's ability to tolerate subsequent stressors. Heat exposure may also promote neural adaptations and alter the neural-hormonal stress response. Hot-temperature yoga (HY) combines mind-body exercise with heat exposure. The added heat component in HY may induce cardiovascular and cellular changes, along with neural benefits and modulation of stress hormones. AIMS The purpose of the present study is to compare the cardiovascular, cellular heat shock protein 70 (HSP70), neural, and hormonal adaptations of HY versus normal-temperature yoga (NY). SETTINGS AND DESIGN Twenty-two subjects (males = 11 and females = 11, 26 ± 6 years) completed 4 weeks of NY (n = 11) or HY (n = 11, 41°C, 40% humidity). Yoga sessions were performed 3 times/week following a modified Bikram protocol. SUBJECTS AND METHODS Pre- and posttesting included (1) hemodynamic measures during a heat tolerance test and maximal aerobic fitness test; (2) neural and hormonal adaptations using serum brain-derived neurotrophic factor (BDNF) and adrenocorticotropic hormone (ACTH), along with a mental stress questionnaire; and (3) cellular adaptations (HSP70) in peripheral blood mononuclear cells (PBMCs). STATISTICAL ANALYSIS Within- and between-group Student's t-test analyses were conducted to compare pre- and post-VO2 max, perceived stress, BDNF, HSP70, and ACTH in HY and NY groups. RESULTS Maximal aerobic fitness increased in the HY group only. No evidence of heat acclimation or change in mental stress was observed. Serum BDNF significantly increased in yoga groups combined. Analysis of HSP70 suggested higher expression of HSP70 in the HY group only. CONCLUSIONS Twelve sessions of HY promoted cardiovascular fitness and cellular thermotolerance adaptations. Serum BDNF increased in response to yoga (NY + HY) and appeared to not be temperature dependent.
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Affiliation(s)
- Kelsey Christian Bourbeau
- Department of Kinesiology, University of Northern Iowa, Cedar Falls, Iowa, USA
- Department of Health, Exercise and Sports Science, University of New Mexico, Albuquerque, NM, USA
| | - Terence A Moriarty
- Department of Kinesiology, University of Northern Iowa, Cedar Falls, Iowa, USA
| | | | - Gabriella F Bellissimo
- Department of Kinesiology, State University of New York College at Cortland, Cortland, NY, USA
| | - Jeremy B Ducharme
- Department of Health, Exercise and Sports Science, University of New Mexico, Albuquerque, NM, USA
| | - Truman J Haeny
- Department of Health, Exercise and Sports Science, University of New Mexico, Albuquerque, NM, USA
| | - Micah N Zuhl
- School of Health Sciences, Central Michigan University, Mount Pleasant, Michigan, USA
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Liou KT, Garland SN, Li QS, Sadeghi K, Green J, Autuori I, Orlow I, Mao JJ. Effects of acupuncture versus cognitive behavioral therapy on brain-derived neurotrophic factor in cancer survivors with insomnia: an exploratory analysis. Acupunct Med 2021; 39:637-645. [PMID: 33752446 DOI: 10.1177/0964528421999395] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
INTRODUCTION Decreased brain-derived neurotrophic factor (BDNF) is associated with poor sleep. This study examined the effects of acupuncture versus cognitive behavioral therapy for insomnia (CBT-I) on serum BDNF and sleep outcomes in cancer survivors with insomnia. METHODS This was an exploratory analysis of a randomized clinical trial (n = 160) comparing acupuncture versus CBT-I for cancer survivors with insomnia. Interventions were delivered over 8 weeks. Outcomes were assessed at baseline and week 8. Serum BDNF was evaluated with enzyme-linked immunosorbent assay (ELISA). Sleep was evaluated with the insomnia severity index and consensus sleep diary. Pearson correlations between BDNF and sleep outcomes were calculated. Data analysis was limited to 87 survivors who provided serum samples. RESULTS Among 87 survivors, the mean age was 61.9 (SD: 11.4) years, 51.7% were women, and 24.1% were non-White. Mean serum BDNF did not significantly increase in acupuncture (n = 50) or CBT-I (n = 37) groups. When analysis was restricted to patients with low baseline BDNF (i.e. levels below the sample median of 47.1 ng/mL), the acupuncture group (n = 22) demonstrated a significant 7.2 ng/mL increase in mean serum BDNF (P = 0.03), whereas the CBT-I group (n = 21) demonstrated a non-significant 2.9 ng/mL increase (P = 0.28). Serum BDNF was not significantly correlated with sleep outcomes (all P > 0.05). CONCLUSION Among cancer survivors with insomnia and low baseline BDNF, acupuncture significantly increased serum BDNF levels; however, the clinical significance of this finding requires further investigation.Trial registration no. NCT02356575 (ClinicalTrials.gov).
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Affiliation(s)
- Kevin T Liou
- Integrative Medicine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA
| | - Sheila N Garland
- Department of Psychology, Memorial University of Newfoundland, St. John's, NL, Canada
| | - Q Susan Li
- Integrative Medicine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA
| | - Keimya Sadeghi
- Molecular Epidemiology Laboratory, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, USA
| | - Jamie Green
- Integrative Medicine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA
| | - Isidora Autuori
- Molecular Epidemiology Laboratory, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, USA
| | - Irene Orlow
- Molecular Epidemiology Laboratory, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, USA
| | - Jun J Mao
- Integrative Medicine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA
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Oraby MI, El Masry HA, Abd El Shafy SS, Abdul Galil EM. Serum level of brain-derived neurotrophic factor in patients with relapsing–remitting multiple sclerosis: a potential biomarker for disease activity. THE EGYPTIAN JOURNAL OF NEUROLOGY, PSYCHIATRY AND NEUROSURGERY 2021. [DOI: 10.1186/s41983-021-00296-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Brain-derived neurotrophic factor (BDNF) is secreted by immune cells in response to neuroimmune and inflammatory cascades as an act to prevent axonal and neuronal damage after various pathological insults. The serum level of BDNF is altered in a diversity of neurological diseases. The aim of this work was to investigate the serum level of BDNF in patients with relapsing–remitting multiple sclerosis and the relation between BDNF and disease activity and severity.
Methods
A case–control study was conducted on 90 subjects: 60 patients with relapsing–remitting multiple sclerosis (30 in relapse and 30 in remission) on different lines of medical treatment and 30 healthy volunteers as a control. Clinical, functional, and radiological evaluation was done for the patients, and all the patients and controls were subjected to assessment of the serum level of BDNF by sandwich-ELISA technique.
Results
The BDNF level was significantly higher in MS patients in relapse than in patients in remission (P value = 0.006). In the remission group, there was no significant linear correlation between different MS patients’ characteristics and BDNF level, while in the relapse group, a positive linear correlation was found between the number of T2 infratentorial lesions and BDNF level (r = 0.402, P = 0.028). There was no statistically significant difference between the BDNF level in patients administered different drugs for MS in both remission and relapse groups (P value > 0.05).
Conclusion
BDNF was significantly higher in relapsing–remitting multiple sclerosis patients in the relapse phase. Attention should be paid to the link between serum BDNF level as a neuroprotective factor and multiple sclerosis; it can be a biomarker for MS activity in the near future.
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Voigt RM, Raeisi S, Yang J, Leurgans S, Forsyth CB, Buchman AS, Bennett DA, Keshavarzian A. Systemic brain derived neurotrophic factor but not intestinal barrier integrity is associated with cognitive decline and incident Alzheimer's disease. PLoS One 2021; 16:e0240342. [PMID: 33661922 PMCID: PMC7932071 DOI: 10.1371/journal.pone.0240342] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Accepted: 02/15/2021] [Indexed: 11/19/2022] Open
Abstract
The inflammatory hypothesis posits that sustained neuroinflammation is sufficient to induce neurodegeneration and the development of Alzheimer's disease (AD) and Alzheimer's dementia. One potential source of inflammation is the intestine which harbors pro-inflammatory microorganisms capable of promoting neuroinflammation. Systemic inflammation is robustly associated with neuroinflammation as well as low levels of brain derived neurotrophic factor (BDNF) in the systemic circulation and brain. Thus, in this pilot study, we tested the hypothesis that intestinal barrier dysfunction precedes risk of death, incident AD dementia and MCI, cognitive impairment and neuropathology. Serum BDNF was associated with changes in global cognition, working memory, and perceptual speed but not risk of death, incident AD dementia, incident MCI, or neuropathology. Neither of the markers of intestinal barrier integrity examined, including lipopolysaccharide binding protein (LBP) nor intestinal fatty acid binding protein (IFABP), were associated with risk of death, incident AD dementia, incident mild cognitive impairment (MCI), change in cognition (global or domains), or neuropathology. Taken together, the data in this pilot study suggest that intestinal barrier dysfunction does not precede diagnosis of AD or MCI, changes in cognition, or brain pathology. However, since MCI and AD are related to global cognition, the findings with BDNF and the contiguous cognitive measures suggest low power with the trichotomous cognitive status measures. Future studies with larger sample sizes are necessary to further investigate the results from this pilot study.
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Affiliation(s)
- Robin M. Voigt
- Division of Digestive Diseases and Nutrition, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, United States of America
- * E-mail:
| | - Shohreh Raeisi
- Division of Digestive Diseases and Nutrition, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, United States of America
| | - Jingyun Yang
- Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, Illinois, United States of America
- Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, United States of America
| | - Sue Leurgans
- Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, Illinois, United States of America
- Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, United States of America
| | - Christopher B. Forsyth
- Division of Digestive Diseases and Nutrition, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, United States of America
| | - Aron S. Buchman
- Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, Illinois, United States of America
- Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, United States of America
| | - David A. Bennett
- Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, Illinois, United States of America
- Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, United States of America
| | - Ali Keshavarzian
- Division of Digestive Diseases and Nutrition, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, United States of America
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Ou ZYA, Byrne LM, Rodrigues FB, Tortelli R, Johnson EB, Foiani MS, Arridge M, De Vita E, Scahill RI, Heslegrave A, Zetterberg H, Wild EJ. Brain-derived neurotrophic factor in cerebrospinal fluid and plasma is not a biomarker for Huntington's disease. Sci Rep 2021; 11:3481. [PMID: 33568689 PMCID: PMC7876124 DOI: 10.1038/s41598-021-83000-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 01/18/2021] [Indexed: 11/08/2022] Open
Abstract
Brain-derived neurotrophic factor (BDNF) is implicated in the survival of striatal neurons. BDNF function is reduced in Huntington's disease (HD), possibly because mutant huntingtin impairs its cortico-striatal transport, contributing to striatal neurodegeneration. The BDNF trophic pathway is a therapeutic target, and blood BDNF has been suggested as a potential biomarker for HD, but BDNF has not been quantified in cerebrospinal fluid (CSF) in HD. We quantified BDNF in CSF and plasma in the HD-CSF cohort (20 pre-manifest and 40 manifest HD mutation carriers and 20 age and gender-matched controls) using conventional ELISAs and an ultra-sensitive immunoassay. BDNF concentration was below the limit of detection of the conventional ELISAs, raising doubt about previous CSF reports in neurodegeneration. Using the ultra-sensitive method, BDNF concentration was quantifiable in all samples but did not differ between controls and HD mutation carriers in CSF or plasma, was not associated with clinical scores or MRI brain volumetric measures, and had poor ability to discriminate controls from HD mutation carriers, and premanifest from manifest HD. We conclude that BDNF in CSF and plasma is unlikely to be a biomarker of HD progression and urge caution in interpreting studies where conventional ELISA was used to quantify CSF BDNF.
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Affiliation(s)
- Zhen-Yi Andy Ou
- UCL Huntington's Disease Centre, UCL Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK
| | - Lauren M Byrne
- UCL Huntington's Disease Centre, UCL Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK
| | - Filipe B Rodrigues
- UCL Huntington's Disease Centre, UCL Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK
| | - Rosanna Tortelli
- UCL Huntington's Disease Centre, UCL Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK
| | - Eileanoir B Johnson
- UCL Huntington's Disease Centre, UCL Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK
| | - Martha S Foiani
- UK Dementia Research Institute at UCL, London, WC1E 6BT, UK
- Department of Neurodegenerative Disease, UCL Institute of Neurology, London, WC1N 3BG, UK
| | - Marzena Arridge
- Lysholm Department of Neuroradiology, National Hospital for Neurology and Neurosurgery, London, WC1N 3BG, UK
| | - Enrico De Vita
- Lysholm Department of Neuroradiology, National Hospital for Neurology and Neurosurgery, London, WC1N 3BG, UK
- Department of Biomedical Engineering, School of Biomedical Engineering and Imaging Sciences, King's College London, London, SE1 7EH, UK
| | - Rachael I Scahill
- UCL Huntington's Disease Centre, UCL Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK
| | - Amanda Heslegrave
- UK Dementia Research Institute at UCL, London, WC1E 6BT, UK
- Department of Neurodegenerative Disease, UCL Institute of Neurology, London, WC1N 3BG, UK
| | - Henrik Zetterberg
- UK Dementia Research Institute at UCL, London, WC1E 6BT, UK
- Department of Neurodegenerative Disease, UCL Institute of Neurology, London, WC1N 3BG, UK
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, 431 80, Mölndal, Sweden
- Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, 431 80, Mölndal, Sweden
| | - Edward J Wild
- UCL Huntington's Disease Centre, UCL Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK.
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Galle S, Licher S, Milders M, Deijen JB, Scherder E, Drent M, Ikram A, van Duijn CM. Plasma Brain-Derived Neurotropic Factor Levels Are Associated with Aging and Smoking But Not with Future Dementia in the Rotterdam Study. J Alzheimers Dis 2021; 80:1139-1149. [PMID: 33646145 PMCID: PMC8150496 DOI: 10.3233/jad-200371] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/18/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND Brain-derived neurotropic factor (BDNF) plays a vital role in neuronal survival and plasticity and facilitates long-term potentiation, essential for memory. Alterations in BDNF signaling have been associated with cognitive impairment, dementia, and Alzheimer's disease. Although peripheral BDNF levels are reduced in dementia patients, it is unclear whether changes in BDNF levels precede or follow dementia onset. OBJECTIVE In the present study, we examined the association between BDNF plasma levels and dementia risk over a follow-up period of up to 16 years. METHODS Plasma BDNF levels were assessed in 758 participants of the Rotterdam Study. Dementia was assessed from baseline (1997-1999) to follow-up until January 2016. Associations of plasma BDNF and incident dementia were assessed with Cox proportional hazards models, adjusted for age and sex. Associations between plasma BDNF and lifestyle and metabolic factors are investigated using linear regression. RESULTS During a follow up of 3,286 person-years, 131 participants developed dementia, of whom 104 had Alzheimer's disease. We did not find an association between plasma BDNF and risk of dementia (adjusted hazard ratio 0.99; 95%CI 0.84-1.16). BDNF levels were positively associated with age (B = 0.003, SD = 0.001, p = 0.002), smoking (B = 0.08, SE = 0.01, p = < 0.001), and female sex (B = 0.03, SE = 0.01, p = 0.03), but not with physical activity level (B = -0.01, SE = 0.01, p = 0.06). CONCLUSION The findings suggest that peripheral BDNF levels are not associated with an increased risk of dementia.
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Affiliation(s)
- Sara Galle
- Department of Clinical, Neuro- and Developmental Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
- Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Silvan Licher
- Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Maarten Milders
- Department of Clinical, Neuro- and Developmental Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Jan Berend Deijen
- Department of Clinical, Neuro- and Developmental Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
- Hersencentrum Mental Health Institute, Amsterdam, The Netherlands
| | - Erik Scherder
- Department of Clinical, Neuro- and Developmental Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Madeleine Drent
- Department of Clinical, Neuro- and Developmental Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
- Department of Internal Medicine, Endocrinology Section, Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - Arfan Ikram
- Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Cornelia M. van Duijn
- Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands
- Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
- Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, Oxford, United Kingdom
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