RESUMEN
BACKGROUND: Brain-derived neurotrophic factor (BDNF) is critical for enhancing the survival and growth of neurons and modulating the synaptic plasticity. BDNF levels have been demonstrated to be changed in plasma and cerebrospinal fluid (CSF) following brain insults such as inflammation or ischemia or infection in several studies. Currently, there is no systematic review regarding BDNF levels in encephalitis or encephalopathy patients. Considering inconsistency between studies, we aimed to pool the data from existing studies to determine whether blood or CSF levels of BDNF are different in patients with encephalopathy/encephalitis. METHODS: We comprehensively searched Web of Science, PubMed, Scopus, and Embase databases to identify eligible studies. The last search occurred in December 2022. RESULTS: 12 studies met our inclusion criteria and ten studies including 283 patients and 323 healthy controls were enrolled in this meta-analysis. In comparison to controls, patients with encephalitis/encephalopathy had higher levels of BDNF in their CSF [standardized mean difference (SMD) = 1.48, 95% CI 0.18-2.77; P = 0.03)], while their blood levels of BDNF did not differ significantly [standardized mean difference (SMD) = 0.27, 95% CI = - 0.71 to 1.25; P = 0.58)]. Moreover, regarding the heterogeneity among studies reporting BDNF blood levels, we performed two subgroup analyses based on the disease etiology and the specimen (plasma and serum); none of them indicated statistically significant difference in BDNF levels between the subgroups (P = 0.41 and 0.20, respectively). CONCLUSION: Meta-analysis provides evidence that patients with encephalopathy/encephalitis have higher CSF levels of BDNF compared to controls.
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Encefalopatías , Encefalitis , Humanos , Factor Neurotrófico Derivado del Encéfalo/líquido cefalorraquídeo , Biomarcadores , EncéfaloRESUMEN
BACKGROUND: Cognitive performance may be impaired in MS even at the earliest stages of disease. We tested whether brain-derived neurotrophic factor and neurofilament light chain levels in serum and cerebrospinal fluid (CSF) samples (sNfL/cNfL/sBDNF/cBDNF) collected at the time of diagnosis are associated with cognitive performance. METHODS: We measured sNfL/cNfL/sBDNF/cBDNF using single-molecule array (Simoa) in 47 newly diagnosed patients (32 relapsing-remitting MS/6 primary progressive MS/9 clinically isolated syndrome). Partial correlations between average z-score on neuropsychological tests and sNfL/sBDNF/cNfL/cBDNF were computed after adjusting for covariates. Multivariate analysis of covariance determined the effect of cognitive status on biomarker levels. A composite measure of NfL and BDNF was submitted to similar exploratory analysis. RESULTS: Cognitive performance correlated inversely with cNfL (r=-0.451/q=0.032) and cBDNF (r=-0.406/q=0.034). Impairment in at least two different tests was linked to higher cNfL (p=0.011) and cBDNF (p=0.035) levels compared to impairment in only one test and for cNfL also compared to no impairment at all (p=0.01). Composite CSF biomarker measure accounting for both cNfL and cBDNF correlated more strongly with tests of information processing (p=0.048) and verbal learning/memory consolidation (p = 0.02) as compared to the single CSF biomarkers. CONCLUSIONS: CSF BDNF and NfL levels measured at the time of diagnosis are inversely associated with cognitive performance in MS. Our findings suggest that CSF biomarkers linked to different pathophysiological processes reflect neuropsychological impairment in the earliest stages of the disease. Combining different CSF measures might facilitate the developing of a better biomarker of cognition in MS.
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Factor Neurotrófico Derivado del Encéfalo , Cognición , Filamentos Intermedios , Esclerosis Múltiple , Biomarcadores/líquido cefalorraquídeo , Factor Neurotrófico Derivado del Encéfalo/líquido cefalorraquídeo , Humanos , Esclerosis Múltiple/líquido cefalorraquídeo , Esclerosis Múltiple/diagnósticoRESUMEN
INTRODUCTION: Previous studies have demonstrated that cytokines, transforming growth factor (TGF-ß1), and brain-derived neurotrophic factor (BDNF) can impact the intensity of pain in rodents. However, the roles of cytokines, TGF-ß1 and BDNF in humans with chronic pain in osteoarthritis remains unclear, and no comparison between plasma and central cerebral spinal fluid (CSF) has been conducted. METHODS: Patients with osteoarthritis who were scheduled to receive spinal anesthesia were enrolled. The intensity of pain was evaluated with a visual analogue scale (VAS). In addition, patients with genitourinary system (GU) diseases and without obvious pain (VAS 0-1) were included as a comparison (control) group. The levels of TGF-ß1, BDNF, tumor necrosis factor-α (TNF-α), and interleukin (IL)-8 within the CSF and plasma were collected and evaluated before surgery. RESULTS: The plasma and CSF TGF-ß1 levels were significantly lower in the osteoarthritis patients with pain (VAS ≥ 3) than in the GU control patients. Downregulation of plasma BDNF was also found in osteoarthritis patients with pain. The Spearman correlation analysis showed that the VAS pain scores were significantly negatively correlated with the levels of TGF-ß1 in the CSF of patients with osteoarthritis. However, there was no significant correlations between the pain scores and the levels of BDNF, TNF-α, and IL-8 in either the CSF or plasma. CONCLUSIONS: TGF-ß1 but not BDNF, TNF-α, or IL-8 may be an important biological indicator in the CSF of osteoarthritis patients with chronic pain.
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Biomarcadores/análisis , Dolor Crónico/patología , Osteoartritis/patología , Factor de Crecimiento Transformador beta1/sangre , Anciano , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Factor Neurotrófico Derivado del Encéfalo/sangre , Factor Neurotrófico Derivado del Encéfalo/líquido cefalorraquídeo , Dolor Crónico/complicaciones , Femenino , Humanos , Interleucina-8/sangre , Interleucina-8/líquido cefalorraquídeo , Masculino , Persona de Mediana Edad , Osteoartritis/complicaciones , Índice de Severidad de la Enfermedad , Factor de Crecimiento Transformador beta1/líquido cefalorraquídeo , Enfermedades Urogenitales/complicaciones , Enfermedades Urogenitales/patologíaRESUMEN
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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Factor Neurotrófico Derivado del Encéfalo/sangre , Factor Neurotrófico Derivado del Encéfalo/líquido cefalorraquídeo , Enfermedad de Huntington/sangre , Enfermedad de Huntington/líquido cefalorraquídeo , Adulto , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Estudios de Cohortes , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Inmunoensayo , Masculino , Persona de Mediana EdadRESUMEN
To evaluate changes in concentrations of selected biomarkers, neurotrophic factors, and growth factors in the cerebrospinal fluid during pregnancy. A prospective observational study was conducted in 32 pregnant women undergoing gynecological and obstetrical surgery under spinal anesthesia in a university hospital. Beta-amyloid(1-42) and beta-amyloid(1-40) peptides, brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor, and vascular endothelial growth factor were analyzed in cerebrospinal fluid using an enzyme-linked immunosorbent assay. Eight women in second trimester pregnancy who underwent spinal anesthesia for gynecological or obstetrical surgery were compared with 24 matched women in third trimester pregnancies. CSF concentrations of beta-amyloid(1-42) were significantly higher in third trimester pregnancies (p = 0.025). During third trimester, the beta-amyloid ratio correlated with the vascular endothelial growth factor (rs = 0.657; p = 0.008). Higher concentrations of beta-amyloid(1-42) in cerebrospinal fluid of third trimester pregnancies and correlations between the beta-amyloid ratio and the vascular endothelial growth factor support the hypothesis that beta-amyloid peptides are involved in complex adaptive brain alterations during pregnancy.
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Péptidos beta-Amiloides/líquido cefalorraquídeo , Fragmentos de Péptidos/líquido cefalorraquídeo , Embarazo/líquido cefalorraquídeo , Biomarcadores , Factor Neurotrófico Derivado del Encéfalo/líquido cefalorraquídeo , Femenino , Factor Neurotrófico Derivado de la Línea Celular Glial/líquido cefalorraquídeo , Humanos , Segundo Trimestre del Embarazo , Estudios Prospectivos , Factor A de Crecimiento Endotelial Vascular/líquido cefalorraquídeoRESUMEN
This study examined the effects of systemic administration of the TrkB receptor antagonist (ANA-12) during induction of morphine dependence on the severity of physical and psychological dependence and the cerebrospinal fluid (CSF) BDNF levels in morphine-dependent and withdrawn rats. Rats became morphine-dependent by increasing daily doses of morphine for 7 days, along with ANA-12 injection. Then, rats were tested for the severity of physical dependence on morphine (spontaneous withdrawal signs), anxiety-like (the elevated plus maze), depressive-like (sucrose preference test) behaviors after spontaneous morphine withdrawal. Also, the CSF BDNF levels were assessed 2 h after the last dose of morphine and day 13 after morphine withdrawal in morphine-dependent and withdrawn rats. We found that the morphine withdrawal signs were significantly higher in morphine dependent rats receiving ANA-12 on days of 5-7 after morphine withdrawal, also ANA-12 exacerbated overall dependence severity. While, the percentage of time spent in the open arms and sucrose preference were higher in morphine-dependent rats receiving ANA-12 than morphine-dependent rats receiving saline. Also, the ANA-12 injection decreased the CSF BDNF levels following morphine dependence, while increased it after morphine withdrawal. We conclude that the ANA-12 exacerbated the severity of physical morphine dependence but attenuated the anxiety/depressive-like behaviors in morphine-dependent and withdrawn rats. Also, ANA-12 injection was able to reverse the changes in the CSF BDNF levels. Therefore, ANA-12 is not more likely to complete treatment for opiate addiction.
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Azepinas/farmacología , Benzamidas/farmacología , Factor Neurotrófico Derivado del Encéfalo/líquido cefalorraquídeo , Dependencia Psicológica , Dependencia de Morfina/metabolismo , Receptor trkB/antagonistas & inhibidores , Síndrome de Abstinencia a Sustancias/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Masculino , Dependencia de Morfina/líquido cefalorraquídeo , Dependencia de Morfina/diagnóstico , Ratas , Ratas Wistar , Índice de Severidad de la Enfermedad , Síndrome de Abstinencia a Sustancias/líquido cefalorraquídeoRESUMEN
This paper aims to investigate the possible roles of a set of neurotrophic factors (brain-derived neurotrophic factor-BDNF, nerve growth factor-NGF) and neuropeptides (neuropeptide Y-NPY, and galanin) in children with active epileptogenesis. The cerebrospinal fluid (CSF) levels of BDNF, NPY, NGF and galanin were measured with enzyme-linked immunosorbent assays in epileptic children (n = 73) and controls (n = 64). There were no significant alterations in the CSF levels of BDNF, NPY and NGF in epileptic children with active clinical seizures compared with the levels of controls. However profoundly depressed galanin levels were found in infants with epileptic encephalopathy (mean ± SD:0.63 ± 0.19 pg/ml) and significantly increased galanin levels were measured in children with drug resistant epilepsy during the period of status epilepticus (mean ± SD: 6.92 ± 1.19, pg/ml pg/ml) compared with the levels of controls. Depressed levels of galanin might reflect a defective anti-epileptogenic effect of galanin in infants with epileptic encephalopathy. On the contrary, increased CSF levels of galanin might be a result of anti-epileptogenic effects of this peptide in epileptic children with status epilepticus.
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Factor Neurotrófico Derivado del Encéfalo/líquido cefalorraquídeo , Epilepsia/líquido cefalorraquídeo , Galanina/líquido cefalorraquídeo , Factor de Crecimiento Nervioso/líquido cefalorraquídeo , Neuropéptido Y/líquido cefalorraquídeo , Animales , Niño , Femenino , Humanos , Lactante , Masculino , Estado Epiléptico/líquido cefalorraquídeoRESUMEN
OBJECTIVE: Preclinical evidence suggests a role for brain-derived neurotrophic factor (BDNF) in the mode of action of electroconvulsive therapy (ECT). Clinical data regarding BDNF levels in serum or plasma are more inconsistent. We measured BDNF levels from the cerebrospinal fluid (CSF) in patients with major depression before and shortly after a course of ECT. METHODS: Cerebrospinal fluid and serum BDNF levels were determined using commercially available enzyme-linked immunosorbent assay (ELISA) kits. RESULTS: We included 9 patients with a severe depressive episode within a major depressive disorder into the study. The CSF BDNF concentrations at baseline were lower compared with those CSF BDNF levels after the complete ECT treatment (P = 0.042), whereas no such a constellation was found for serum BDNF. No associations between the BDNF levels and the amount of individual ECT sessions or the reduction of the depressive symptoms were found. CONCLUSIONS: For the first time, it has been shown that CSF BDNF concentrations increase during a course of ECT in patients with a severe unipolar depressive episode, which is in line with the neurotrophin hypothesis as a mode of action of ECT, although it was not possible to demonstrate either a dose-effect relation or a relationship with the actual antidepressant effects in our small sample. Major limitation is the small sample size.
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Factor Neurotrófico Derivado del Encéfalo/líquido cefalorraquídeo , Trastorno Depresivo Mayor/terapia , Terapia Electroconvulsiva , Adulto , Anciano , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Factor Neurotrófico Derivado del Encéfalo/sangre , Femenino , Alemania , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Amyotrophic lateral sclerosis (ALS) remains a fatal disease with limited therapeutic options. Signaling via neurotrophins (NTs), neuroinflammation, and certain micro-RNAs are believed to play essential role in ALS pathogenesis. Lineage-negative stem/progenitor cells (Lin-) were obtained from bone marrow of 18 ALS patients and administered intrathecally. Clinical assessment was performed using ALS Functional Rating Scale (FRSr) and Norris scale. Protein concentrations were measured in plasma and cerebrospinal fluid (CSF) by multiplex fluorescent bead-based immunoassay. Gene expression in nucleated blood cells was assessed using gene microarray technique. Finally, miRNA expression was analyzed using qPCR in CSF and plasma samples. We observed a significant decrease of C-reactive protein (CRP) concentration in plasma on the seventh day from the application of cells. Gene array results revealed decreased expression of gene sets responsible for neutrophil activation. Further analysis revealed moderate negative correlation between CRP level in CSF and clinical outcome. Brain-derived neurotrophic factor (BDNF) concentrations in both plasma and CSF significantly correlated with the favorable clinical outcome. On a micro-RNA level, we observed significant increase of miR-16-5p expression one week after transplantation in both body fluids and significant increase of miR-206 expression in plasma. Administration of Lin- cells may decrease inflammatory response and prevent neurodegeneration. However, these issues require further investigations.
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Esclerosis Amiotrófica Lateral/terapia , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Proteína C-Reactiva/metabolismo , MicroARNs/sangre , MicroARNs/genética , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/inmunología , Factor Neurotrófico Derivado del Encéfalo/sangre , Factor Neurotrófico Derivado del Encéfalo/líquido cefalorraquídeo , Proteína C-Reactiva/líquido cefalorraquídeo , Linaje de la Célula , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Humanos , Inmunidad Humoral , Inyecciones Espinales , MicroARNs/líquido cefalorraquídeo , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Trasplante de Células MadreRESUMEN
BACKGROUND: Neurotrophins, especially brain-derived neurotrophic factor (BDNF) have gained significant therapeutic interest particularly in neurologic and psychiatric disorders and they have been found in human breast milk of mothers who suffered from adverse outcomes in pregnancy. This study tested the hypothesis that oral administration of BDNF/GDNF (glial cell line-derived neurotrophic factor) can exert a biological effect in a rat model of severe neuropathology induced by olfactory bulbectomy (OBX), which exhibits dysregulation of BDNF signaling and impaired blood-brain barrier. METHODS: Adult male albino Sprague-Dawley rats underwent the OBX surgery and separate groups of OBX and sham-operated controls received one oral dose of vehicle, BDNF (0.005 mg/kg), GDNF (0.03 mg/kg) or their combination. One week after neurotrophin dosing the rats were sacrificed and BDNF level was assessed by ELISA in the blood serum and cerebrospinal fluid. RESULTS: A significant decrease of serum BDNF level was found in the OBX model. This alteration was normalized by all types of treatment BDNF, GDNF, or their combination. No influence of sham surgery or treatment was observed in the control rats. BDNF levels in cerebrospinal fluid were below detection limit. CONCLUSION: This study indicates that oral administration of neurotrophins is able to exert a biological effect in the OBX model. There is a number of potential mechanisms, which remain to be elucidated.
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Barrera Hematoencefálica/metabolismo , Encefalopatías/sangre , Factor Neurotrófico Derivado del Encéfalo/sangre , Factores de Crecimiento Nervioso/sangre , Administración Oral , Animales , Transporte Biológico , Barrera Hematoencefálica/efectos de los fármacos , Factor Neurotrófico Derivado del Encéfalo/administración & dosificación , Factor Neurotrófico Derivado del Encéfalo/líquido cefalorraquídeo , Modelos Animales de Enfermedad , Masculino , Factores de Crecimiento Nervioso/administración & dosificación , Factores de Crecimiento Nervioso/líquido cefalorraquídeo , Bulbo Olfatorio/cirugía , Prueba de Estudio Conceptual , Ratas Sprague-Dawley , Proteínas RecombinantesRESUMEN
Most growth factors are synthesized as precursors and biologically active forms are generated by proteolytic cleavage of the pro-domain. However, the biological functions of pro-domains are ill-defined. New roles were recently reported for the pro-domain of brain-derived neurotrophic factor (BDNF), a well-known growth factor in the brain. Interestingly, the pro-domain of BDNF (BDNF pro-peptide) is localized at presynaptic termini, where it facilitates long-term depression (LTD) in hippocampal slices, implicating it as a novel synaptic modulator. BDNF binds its pro-peptide with high affinity in a pH-dependent manner and when bound to BDNF, the BDNF pro-peptide cannot facilitate hippocampal LTD, representing a new mechanism of regulation. The BDNF pro-peptide is present in human cerebrospinal fluid (CSF) and levels were significantly lower in patients with major depressive disorder (MDD) than in controls. Notably, male MDD patients exhibit significantly lower levels of CSF pro-peptide than females. These findings demonstrate that the BDNF pro-peptide is a biologically important synaptic modulator and is associated with MDD, particularly in males.
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Factor Neurotrófico Derivado del Encéfalo/metabolismo , Trastorno Depresivo Mayor/metabolismo , Hipocampo/metabolismo , Depresión Sináptica a Largo Plazo/fisiología , Neurotransmisores/metabolismo , Terminales Presinápticos/metabolismo , Animales , Factor Neurotrófico Derivado del Encéfalo/líquido cefalorraquídeo , Femenino , Humanos , Masculino , Ratones , Precursores de Proteínas/líquido cefalorraquídeo , Precursores de Proteínas/metabolismo , Ratas , Transmisión SinápticaRESUMEN
The role of brain-derived neurotrophic factor (BDNF) and its related molecules has been extensively studied in the context of psychiatric disorders. In the present study, we focused on the newly identified BDNF pro-peptide, which is generated together with mature BDNF by proteolytic processing of their precursor, proBDNF. Here, we report, for the first time, that BDNF pro-peptide is present in human cerebrospinal fluid (CSF) and quantifiable by western blotting. We measured CSF BDNF pro-peptide levels in 27 patients with schizophrenia, 18 patients with major depressive disorder (MDD), and 27 healthy controls matched for age, sex, and ethnicity (Japanese). The ratio of the BDNF pro-peptide level to the total protein level in MDD patients was significantly lower than that in controls (Kruskal-Wallis with Dunn's multiple comparisons test; pâ¯=â¯0.046). When men and women were examined separately, males with MDD had a significantly lower BDNF pro-peptide/protein ratio than male controls (pâ¯=â¯0.047); this difference was not found in female subjects. The ratio tended to be lower in male schizophrenia patients (pâ¯=â¯0.10). Although we tried to measure the levels of mature BDNF in CSF, they were below the limit of detection of the ELISA and multiple analyte profiling technology. Taken together, the results suggest that reduced CSF BDNF pro-peptide levels are associated with MDD, particularly in males. Further studies involving a larger sample size are warranted.
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Factor Neurotrófico Derivado del Encéfalo/líquido cefalorraquídeo , Trastorno Depresivo Mayor/líquido cefalorraquídeo , Esquizofrenia/líquido cefalorraquídeo , Adulto , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Deep brain stimulation (DBS) of the medial forebrain bundle (MFB) displays a promising antidepressant effects in patients with treatment-refractory depression; however, a clear consensus on underlying mechanisms is still enigmatic. Herein, we investigated the effects of MFB-DBS on anhedonic-like behavior using the Froot Loops® consumption in a chronic unpredictable mild stress (CUS) model of depression, biochemical estimation of peripheral and central inflammatory cytokines, stress hormone, and brain-derived neurotrophic factor (BDNF). Seven days of MFB-DBS significantly reversed the 42-day CUS-generated anhedonic-like phenotype (p < 0.02) indicated by an increase in Froot Loops® consumption. Gross locomotor activity and body weight remained unaffected across the different groups. A dramatic augmentation of adrenocorticotropic hormone levels was seen in the plasma and cerebrospinal fluid (CSF) samples of CUS rats, which significantly reduced following MFB-DBS treatment. However, C-reactive protein levels were found to be unaffected. Interestingly, decreased levels of BDNF in the CUS animals were augmented in the plasma, CSF, and hippocampus following MFB-DBS, but remained unaltered in the nucleus accumbens (NAc). While multiplex assay revealed no change in the neuronal levels of inflammatory cytokines including IL-1α, IL-4, IL-10, IL-12, IL-13, and IL-17 in the neuroanatomical framework of the hippocampus and NAc, increased levels of IL-1ß, IL-2, IL-5, IL-6, IL-7, IL-18, TNF-α, and INF-γ were seen in these brain structures after CUS and were differentially modulated in the presence of MFB stimulation. Here, we show that there is dysregulation of BDNF and neuroimmune mediators in a stress-driven chronic depression model, and that chronic MFB-DBS has the potential to undo these aberrations.
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Anhedonia , Conducta Animal , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Citocinas/metabolismo , Estimulación Encefálica Profunda , Depresión/complicaciones , Mediadores de Inflamación/metabolismo , Haz Prosencefálico Medial/patología , Hormona Adrenocorticotrópica/sangre , Hormona Adrenocorticotrópica/líquido cefalorraquídeo , Animales , Factor Neurotrófico Derivado del Encéfalo/sangre , Factor Neurotrófico Derivado del Encéfalo/líquido cefalorraquídeo , Proteína C-Reactiva/líquido cefalorraquídeo , Proteína C-Reactiva/metabolismo , Depresión/sangre , Depresión/líquido cefalorraquídeo , Depresión/fisiopatología , Modelos Animales de Enfermedad , Conducta Alimentaria , Hipocampo/metabolismo , Masculino , Actividad Motora , Núcleo Accumbens/metabolismo , Ratas Wistar , Estrés Psicológico/sangre , Estrés Psicológico/líquido cefalorraquídeo , Estrés Psicológico/complicaciones , Estrés Psicológico/fisiopatologíaRESUMEN
OBJECTIVE: Previous studies suggest that the brain-derived neurotrophic factor (BDNF) Val66Met (rs6265) polymorphism may influence symptom onset in Alzheimer's disease (AD). Our recent cross-sectional findings suggest that Met66 may influence clinical expression in dominantly inherited AD (DIAD) through its effects on tau. However, it remains unclear whether carriage of Met66 in DIAD results in faster increases in cerebrospinal fluid (CSF) tau and ptau181 , and whether these increases are associated with accelerated brain volume loss and memory decline. METHODS: A total of 211 subjects (101 mutation noncarriers, 110 mutation carriers), who were cognitively normal, as defined by a Clinical Dementia Rating global score of 0, completed assessments of cognitive function, neuroimaging, and CSF sampling over 3.5 years as part of the Dominantly Inherited Alzheimer's Network. RESULTS: In mutation carriers, Met66 carriers showed faster memory decline (4×), hippocampal volume loss (16×), and CSF tau and ptau181 increases (6×) than Val66 homozygotes. BDNF did not influence rates of cortical ß-amyloid accumulation or change in CSF Aß42 levels in mutation carriers. In mutation noncarriers, BDNF genotype had no effect on change in cognition, brain volume, cortical ß-amyloid accumulation, or change in any CSF measures of tau, ptau181 , and CSF Aß42 . INTERPRETATION: As in sporadic AD, the deleterious effects of ß-amyloid on cognitive function, brain volume loss, and CSF tau in DIAD mutation carriers are less in Val66 homozygotes. The BDNF Val66Met polymorphism should be considered as a potential moderator of clinical trial outcomes in current treatment and prevention trials in DIAD and sporadic AD. Ann Neurol 2018;84:424-435.
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Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Factor Neurotrófico Derivado del Encéfalo/líquido cefalorraquídeo , Encéfalo/metabolismo , Proteínas tau/líquido cefalorraquídeo , Adulto , Anciano , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Cognición/fisiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/líquido cefalorraquídeo , Fragmentos de Péptidos/metabolismo , Proteínas tau/metabolismoRESUMEN
Accumulating evidence suggest that aberrations of neurotrophic factors are involved in the etiology and pathogenesis of Alzheimer's disease (AD), but clinical data were inconsistent. Therefore, a meta-analysis on neurotrophic factor levels in AD is necessary. We performed a systematic review of blood, CSF, and post-mortem brain neurotrophic factor levels in patients with AD compared with controls and quantitatively summarized the clinical data in blood and CSF with a meta-analytical technique. A systematic search of PubMed and Web of Science identified 98 articles in this study (with samples more than 9000). Random effects meta-analysis demonstrated that peripheral blood BDNF levels were significantly decreased in AD patients compared with controls. However, blood NGF, IGF, and VEGF did not show significant differences between cases and controls. In CSF, random effects meta-analysis showed significantly deceased BDNF and increased NGF levels in patients with AD, whereas IGF and VEGF did not show significant differences between the AD group and control group. In addition, 23 post-mortem studies were included in the systematic review. Although data from post-mortem brains were not always consistent across studies, most studies suggested decreased BDNF and increased (pro)NGF levels in hippocampus and neocortex of patients with AD. These results provide strong clinical evidence that AD is accompanied by an aberrant neurotrophin profile, and future investigations into neurotrophins as biomarkers (especially CSF BDNF and NGF) and therapeutic targets for AD may be warranted.
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Enfermedad de Alzheimer/sangre , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Encéfalo/metabolismo , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/patología , Autopsia , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Biomarcadores/metabolismo , Factor Neurotrófico Derivado del Encéfalo/sangre , Factor Neurotrófico Derivado del Encéfalo/líquido cefalorraquídeo , HumanosRESUMEN
Until now, it is impossible to identify a fatal traumatic brain injury (TBI) before post-mortem radiological investigations or an autopsy take place. It would be preferable to have an additional diagnostic tool such as post-mortem biochemistry to get greater insight into the pathological pathways and survival times after sustaining TBI. Cerebrospinal fluid (CSF) and serum samples of 84 autopsy cases were collected from forensic autopsies with post-mortem intervals (PMI) of up to 148 h. The cases were categorized into a fatal TBI case group (n = 42) and non-TBI controls (n = 42). The values of glial fibrillary acidic protein (GFAP), brain-derived neurotrophic factor (BDNF), and neutrophil gelatinase-associated lipocalin (NGAL) were analyzed by means of quantitative chemiluminescent multiplex immunoassays. The main results indicate that the usage of liquid samples with good macroscopic quality is more relevant for meaningful biomarker analyses than the length of the PMI. All three proteins were shown to differentiate TBI fatalities from the controls in CSF. In serum, only GFAP could be shown to be able to identify TBI cases. This study is the first approach to measure the three proteins together in CSF and serum in autopsy cases. Determined threshold values may differentiate between fatal TBI and control cases. The presented results emphasize the possible use of post-mortem biochemistry as a supplemental tool in everyday forensic routine.
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Líquidos Corporales/química , Química Encefálica , Lesiones Traumáticas del Encéfalo/sangre , Lesiones Traumáticas del Encéfalo/líquido cefalorraquídeo , Proteínas del Tejido Nervioso/sangre , Proteínas del Tejido Nervioso/líquido cefalorraquídeo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Autopsia , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Lesiones Traumáticas del Encéfalo/diagnóstico , Factor Neurotrófico Derivado del Encéfalo/sangre , Factor Neurotrófico Derivado del Encéfalo/líquido cefalorraquídeo , Estudios de Casos y Controles , Causas de Muerte , Femenino , Patologia Forense , Proteína Ácida Fibrilar de la Glía/sangre , Proteína Ácida Fibrilar de la Glía/líquido cefalorraquídeo , Humanos , Lipocalina 2/sangre , Lipocalina 2/líquido cefalorraquídeo , Masculino , Persona de Mediana Edad , Cambios Post Mortem , Análisis de Supervivencia , Adulto JovenRESUMEN
Midbrain dopamine neuronal loss and neuroinflammation are two phenomena that are associated with brain senescence. Neurotrophic factor changes and oxidative stress could subserve these phenomena. Aging-related brain changes can be well monitored through the cerebrospinal fluid (CSF). The objective was to analyze neurotrophic and oxidative parameters that could be related to midbrain dopamine neuronal loss or brain inflammation in the CSF of elderly subjects: 1) levels of the dopaminotrophic factors BDNF, GDNF, persephin, and neurturin, 2) levels of the proinflammatory factors TGFß1 and TGFß2; 3) activity of main antioxidant enzymes (catalases, glutathione-peroxidase, glutathione-reductase, glutathione-S-transferases, peroxirredoxins, and superoxide-dismutases), 4) ferritin content, antioxidant protein which reduces reactive free iron, and 5) antioxidant potential of the cerebrospinal fluid. ELISA and PAO tests were used. Subjects were also evaluated clinically, and the group of old subjects with mild cognitive impairment was studied separately. The findings indicate that normal elderly CSF is devoid of changes in either dopaminotrophic or proinflammatory factors. The antioxidant efficacy is slightly reduced with normal aging, through a reduction of glutathione-S-transferase activity in people older than 74â¯years (pâ¯<â¯0.05). However old people with mild cognitive impairment show reduced BDNF levels, and stronger signs of oxidative stress such as low antioxidant potential and glutathione-S-transferase activity (pâ¯<â¯0.05). To sum up, the present study demonstrates that, in CSF of normal senescence, dopaminotrophic factors and proinflammatory TGF-family ligands are not affected, and antioxidant efficacy is slightly reduced. CSF of elderly subjects with mild cognitive impairment shows more oxidative and trophic changes that are characterized by reduction of BDNF content, glutathione-S-transferase activity, and antioxidant potential.
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Envejecimiento/metabolismo , Factor Neurotrófico Derivado del Encéfalo/líquido cefalorraquídeo , Dopamina/metabolismo , Glutatión Transferasa/líquido cefalorraquídeo , Mesencéfalo/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antioxidantes/metabolismo , Disfunción Cognitiva/líquido cefalorraquídeo , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de Crecimiento Nervioso/líquido cefalorraquídeo , Estrés Oxidativo , Adulto JovenRESUMEN
Over the last decade, finding a reliable biomarker for the early detection of schizophrenia (Scz) has been a topic of interest. The main goal of the current review is to provide a comprehensive view of the brain, blood, cerebrospinal fluid (CSF), and serum biomarkers of Scz disease. Imaging studies have demonstrated that the volumes of the corpus callosum, thalamus, hippocampal formation, subiculum, parahippocampal gyrus, superior temporal gyrus, prefrontal and orbitofrontal cortices, and amygdala-hippocampal complex were reduced in patients diagnosed with Scz. It has been revealed that the levels of interleukin 1ß (IL-1ß), IL-6, IL-8, and TNF-α were increased in patients with Scz. Decreased mRNA levels of brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB), neurotrophin-3 (NT-3), nerve growth factor (NGF), and vascular endothelial growth factor (VEGF) genes have also been reported in Scz patients. Genes with known strong relationships with this disease include BDNF, catechol-O-methyltransferase (COMT), regulator of G-protein signaling 4 (RGS4), dystrobrevin-binding protein 1 (DTNBP1), neuregulin 1 (NRG1), Reelin (RELN), Selenium-binding protein 1 (SELENBP1), glutamic acid decarboxylase 67 (GAD 67), and disrupted in schizophrenia 1 (DISC1). The levels of dopamine, tyrosine hydroxylase (TH), serotonin or 5-hydroxytryptamine (5-HT) receptor 1A and B (5-HTR1A and 5-HTR1B), and 5-HT1B were significantly increased in Scz patients, while the levels of gamma-aminobutyric acid (GABA), 5-HT transporter (5-HTT), and 5-HT receptor 2A (5-HTR2A) were decreased. The increased levels of SELENBP1 and Glycogen synthase kinase 3 subunit α (GSK3α) genes in contrast with reduced levels of B-cell translocation gene 1 (BTG1), human leukocyte antigen DRB1 (HLA-DRB1), heterogeneous nuclear ribonucleoprotein A3 (HNRPA3), and serine/arginine-rich splicing factor 1 (SFRS1) genes have also been reported. This review covers various dysregulation of neurotransmitters and also highlights the strengths and weaknesses of studies attempting to identify candidate biomarkers.
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Encéfalo/metabolismo , Esquizofrenia/sangre , Esquizofrenia/líquido cefalorraquídeo , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Biomarcadores/metabolismo , Factor Neurotrófico Derivado del Encéfalo/sangre , Factor Neurotrófico Derivado del Encéfalo/líquido cefalorraquídeo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Catecol O-Metiltransferasa/sangre , Catecol O-Metiltransferasa/líquido cefalorraquídeo , Catecol O-Metiltransferasa/metabolismo , Moléculas de Adhesión Celular Neuronal/sangre , Moléculas de Adhesión Celular Neuronal/líquido cefalorraquídeo , Moléculas de Adhesión Celular Neuronal/metabolismo , Disbindina/sangre , Disbindina/líquido cefalorraquídeo , Disbindina/metabolismo , Proteínas de la Matriz Extracelular/sangre , Proteínas de la Matriz Extracelular/líquido cefalorraquídeo , Proteínas de la Matriz Extracelular/metabolismo , Humanos , Factores de Crecimiento Nervioso/sangre , Factores de Crecimiento Nervioso/líquido cefalorraquídeo , Factores de Crecimiento Nervioso/metabolismo , Proteínas del Tejido Nervioso/sangre , Proteínas del Tejido Nervioso/líquido cefalorraquídeo , Proteínas del Tejido Nervioso/metabolismo , Neurotrofina 3 , Corteza Prefrontal/metabolismo , Proteína Reelina , Esquizofrenia/diagnóstico por imagen , Serina Endopeptidasas/sangre , Serina Endopeptidasas/líquido cefalorraquídeo , Serina Endopeptidasas/metabolismo , Factor A de Crecimiento Endotelial VascularRESUMEN
BACKGROUND: An imbalance in the excitatory/inhibitory systems in the pain networks may explain the persistent chronic pain after hallux valgus surgery. Thus, to contra-regulate this dysfunction, the use of transcranial direct current stimulation (tDCS) becomes attractive. OBJECTIVE: We tested the hypothesis that two preoperative active(a)-tDCS sessions compared with sham(s)-tDCS could improve the postoperative pain [as indexed by Visual Analogue Scale (VAS) at rest and during walking (primary outcomes)]. To assess their effect on the change in the Numerical Pain Scale (NPS0-10) during Conditioned Pain Modulation (CPM-task), disability related to pain (DRP) and analgesic consumption (secondary outcomes). Also, we assessed if the brain derived neurotrophic factor (BDNF) in the cerebral spinal fluid (CSF) after tDCS could predict the intervention's effect on the DRP. METHODS: It is a prospective, double blind, sham-controlled, randomized single center, 40 women (18-70 years-old) who had undergone hallux valgus surgery were randomized to receive two sessions (20 minutes each) of anodal a-tDCS or s-tDCS on the primary motor cortex at night and in the morning before the surgery. To assess the DRP was used the Brazilian Profile of Chronic Pain: Screen (B-PCP:S). RESULTS: A-tDCS group showed lower scores on VAS at rest and during walking (P<0.001). At rest, the difference between groups was 2.13cm (95%CI = 1.59 to 2.68) while during walking was 1.67cm (95%CI = 1.05 to 2.28). A-tDCS, when compared to s-tDCS reduced analgesic doses in 73.25% (P<0.001), produced a greater reduction in B-PCP:S (mean difference of 9.41 points, 95%CI = 0.63 to 18.21) and higher function of descending pain modulatory system (DPMS) during CPM-task. CONCLUSION: A-tDCS improves postoperative pain, the DRP and the function of DPMS. Also, the CSF BDNF after a-tDCS predicted the improvement in the DRP. In overall, these findings suggest that a-tDCS effects may be mediated by top-down regulatory mechanisms associated with the inhibitory cortical control. TRIAL REGISTRATION: ClinicalTrials.gov NCT02360462.
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Hallux Valgus/cirugía , Plasticidad Neuronal , Dolor Postoperatorio/terapia , Cuidados Preoperatorios , Estimulación Transcraneal de Corriente Directa , Adulto , Factor Neurotrófico Derivado del Encéfalo/líquido cefalorraquídeo , Dolor Crónico , Método Doble Ciego , Femenino , Humanos , Persona de Mediana Edad , Dolor Postoperatorio/metabolismo , Estudios ProspectivosRESUMEN
Brain autopsy and biomarker studies indicate that the pathology of Alzheimer's disease (AD) is initiated at least 10-20 years before clinical symptoms. This provides a window of opportunity to initiate preventive treatment. However, this emphasizes the necessity for biomarkers that identify individuals at risk for developing AD later in life. In this cross-sectional study, originating from three epidemiologic studies in Sweden (n=1428), the objective was to examine whether amyloid pathology, as determined by low cerebrospinal fluid (CSF) concentration of the 42 amino acid form of ß-amyloid (Aß42), is associated with biomarker evidence of other pathological changes in cognitively healthy elderly. A total of 129 patients were included and CSF levels of Aß42, total tau, tau phosphorylated at threonine 181 (p-tau), neurogranin, VILIP-1, VEGF, FABP3, Aß40, neurofilament light, MBP, orexin A, BDNF and YKL-40 were measured. Among these healthy elderly, 35.6% (N=46) had CSF Aß42 levels below 530 pg ml-1. These individuals displayed significantly higher CSF concentrations of t-tau (P<0.001), p-tau (181) (P<0.001), neurogranin (P=0.009) and FABP3 (P=0.044) compared with amyloid-negative individuals. Our study indicates that there is a subpopulation among healthy older individuals who have amyloid pathology along with signs of ongoing neuronal and synaptic degeneration, as well as tangle pathology. Previous studies have demonstrated that increase in CSF tau and p-tau is a specific sign of AD progression that occurs downstream of the deposition of Aß. On the basis of this, our data suggest that these subjects are at risk for developing AD. We also confirm the association between APOE É4 and amyloid pathology in healthy older individuals.