RESUMO
BACKGROUND: Auraptene (AUR) and naringenin (NAR) are citrus-derived phytochemicals that influence several biological mechanisms associated with cognitive decline, including neuronal damage, oxidative stress and inflammation. Clinical evidence of the efficacy of a nutraceutical with the potential to enhance cognitive function in cohorts at risk of cognitive decline would be of great value from a preventive perspective. The primary aim of this study is to determine the cognitive effects of a 36-week treatment with citrus peel extract standardized in levels of AUR and NAR in older adults experiencing subjective cognitive decline (SCD). The secondary aim is to determine the effects of these phytochemicals on blood-based biomarkers indicative of neuronal damage, oxidative stress, and inflammation. METHODS: Eighty older persons with SCD will be recruited and randomly assigned to receive the active treatment (400 mg of citrus peel extract containing 0.1 mg of AUR and 3 mg of NAR) or the placebo at a 1:1 ratio for 36 weeks. The primary endpoint is a change in the Repeatable Battery for the Assessment of Neuropsychological Status score from baseline to weeks 18 and 36. Other cognitive outcomes will include changes in verbal and nonverbal memory, attention, executive and visuospatial functions. Blood samples will be collected from a consecutive subsample of 60 participants. The secondary endpoint is a change in interleukin-8 levels over the 36-week period. Other biological outcomes include changes in markers of neuronal damage, oxidative stress, and pro- and anti-inflammatory cytokines. CONCLUSION: This study will evaluate whether an intervention with citrus peel extract standardized in levels of AUR and NAR has cognitive and biological effects in older adults with SCD, facilitating the establishment of nutrition intervention in people at risk of cognitive decline. TRIAL REGISTRATION: The trial is registered with the United States National Library of Medicine at the National Institutes of Health Registry of Clinical Trials under the code NCT04744922 on February 9th, 2021 ( https://www. CLINICALTRIALS: gov/ct2/show/NCT04744922 ).
Assuntos
Citrus , Disfunção Cognitiva , Anti-Inflamatórios , Biomarcadores , Cognição , Disfunção Cognitiva/tratamento farmacológico , Humanos , Inflamação/tratamento farmacológico , Interleucina-8/farmacologia , Interleucina-8/uso terapêutico , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêuticoRESUMO
BACKGROUND: Sports-related concussion (SRC) is a subset of mild traumatic brain injuries occurring in contact sports. Most people recover spontaneously, but in retired professional players, the risk for neurodegenerative diseases is increased. A biomarker, such as neurofilament light chains (NfL), would help to address this issue and demonstrate sports' safety. Assessing NfL in professional soccer players may be the best way to investigate if repetitive head-impact exposure in the typical lower and asymptomatic range is harmful. OBJECTIVE: To evaluate whether the NfL in serum is a sensitive biomarker to detect mild brain injury in professional soccer players. METHODS: Thirty-six soccer players belonging to a professional Italian team underwent serum NfL assessment using ultrasensitive single-molecule array technology. Sixteen healthy nonathletic controls were also enrolled. Differences between groups and changes over time, considering pre-season vs. season, were considered. RESULTS: Serum NfL concentrations were comparable in the soccer professional players (median [interquartile range], 6.44 pg/mL [4.60-8.27] and controls (6.50 pg/mL [5.26-7.04]), with a median difference of - 0.06 pg/mL (95% CI -1.36 to 1.18), p = 0.957. No significant differences according to players' role (goalkeeper, defender, midfielder or forward) or according to timing of sampling (pre-season vs. season) were found. CONCLUSIONS: These results suggest that professional soccer, even when played at the highest level of competition, may be considered safe. Future studies assessing serum NfL levels after soccer-related concussions should be carried out, to evaluate their usefulness as a return-to-play marker avoiding second impact syndrome.
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Concussão Encefálica , Futebol , Esportes , Biomarcadores , Concussão Encefálica/diagnóstico , Humanos , Filamentos Intermediários , Futebol/lesõesRESUMO
Dysfunctions in the endo-lysosomal system have been hypothesized to underlie neurodegeneration in major neurocognitive disorders due to Alzheimer's disease (AD), Frontotemporal Lobar Degeneration (FTLD), and Lewy body disease (DLB). The aim of this study is to investigate whether these diseases share genetic variability in the endo-lysosomal pathway. In AD, DLB, and FTLD patients and in controls (948 subjects), we performed a targeted sequencing of the top 50 genes belonging to the endo-lysosomal pathway. Genetic analyses revealed (i) four previously reported disease-associated variants in the SORL1 (p.N1246K, p.N371T, p.D2065V) and DNAJC6 genes (p.M133L) in AD, FTLD, and DLB, extending the previous knowledge attesting SORL1 and DNAJC6 as AD- and PD-related genes, respectively; (ii) three predicted null variants in AD patients in the SORL1 (p.R985X in early onset familial AD, p.R1207X) and PPT1 (p.R48X in early onset familial AD) genes, where loss of function is a known disease mechanism. A single variant and gene burden analysis revealed some nominally significant results of potential interest for SORL1 and DNAJC6 genes. Our data highlight that genes controlling key endo-lysosomal processes (i.e., protein sorting/transport, clathrin-coated vesicle uncoating, lysosomal enzymatic activity regulation) might be involved in AD, FTLD and DLB pathogenesis, thus suggesting an etiological link behind these diseases.
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Doença de Alzheimer/metabolismo , Degeneração Lobar Frontotemporal/metabolismo , Predisposição Genética para Doença , Proteínas de Choque Térmico HSP40/genética , Proteínas Relacionadas a Receptor de LDL/genética , Doença por Corpos de Lewy/metabolismo , Proteínas de Membrana Transportadoras/genética , Polimorfismo de Nucleotídeo Único , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Feminino , Degeneração Lobar Frontotemporal/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Doença por Corpos de Lewy/genética , Lisossomos/metabolismo , Masculino , Pessoa de Meia-Idade , Análise de Sequência de DNARESUMO
The molecular underpinnings associated to first episode psychosis (FEP) remains to be elucidated, but compelling evidence supported an association of FEP with blood alterations in biomarkers related to immune system, growth factors and metabolism regulators. Many of these studies have not been already confirmed in larger samples or have not considered the FEP diagnostic subgroups. In order to identify biochemical signatures of FEP, the serum levels of the growth factors BDNF and VEGF, the immune regulators IL-1RA, IL-6, IL-10 and IL-17, RANTES/CCL5, MIP-1b/CCL4, IL-8 and the metabolic regulators C-peptide, ghrelin, GIP, GLP-1, glucagon, insulin, leptin, PAI-1, resistin and visfatin were analysed in 260 subjects collected in the GET UP project. The results indicated an increase of MIP-1b/CCL4, VEGF, IL-6 and PAI-1, while IL-17, ghrelin, glucagon and GLP-1 were decreased in the whole sample of FEP patients (pâ¯<â¯0.01 for all markers except for PAI-1 pâ¯<â¯0.05). No differences were evidenced for these markers among the diagnostic groups that constitute the FEP sample, whereas IL-8 is increased only in patients with a diagnosis of affective psychosis. The principal component analysis (PCA) and variable importance analysis (VIA) indicated that MIP-1b/CCL4, ghrelin, glucagon, VEGF and GLP-1 were the variables mostly altered in FEP patients. On the contrary, none of the analysed markers nor a combination of them can discriminate between FEP diagnostic subgroups. These data evidence a profile of immune and metabolic alterations in FEP patients, providing new information on the molecular mechanism associated to the psychosis onset for the development of preventive strategies and innovative treatment targets.
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Transtornos Psicóticos/imunologia , Transtornos Psicóticos/metabolismo , Adulto , Antipsicóticos , Biomarcadores/sangue , Quimiocina CCL4 , Quimiocinas/análise , Citocinas/análise , Feminino , Grelina , Glucagon , Peptídeo 1 Semelhante ao Glucagon , Humanos , Insulina , Interleucina-17 , Interleucina-6 , Leptina , Masculino , Inibidor 1 de Ativador de Plasminogênio , Fator A de Crescimento do Endotélio Vascular , Adulto JovemRESUMO
BACKGROUND/AIMS: Recent findings suggest an involvement of insulin-like growth factor-1 (IGF-1) in the pathogenesis of many psychiatric disorders; however, there is a lack of data regarding IGF-1 in patients with obsessive-compulsive disorder (OCD). The aims of the present study were (1) to analyze putative alterations of IGF-1 serum content in patients with OCD compared to patients with major depressive disorder (MDD) and healthy controls, and (2) to analyze putative changes of IGF-1 levels during drug treatment in subjects with OCD compared to patients with MDD. METHODS: We recruited 40 OCD patients, 37 MDD patients, and 43 healthy controls. All participants were adults. Serum IGF-1 levels were measured by the ELISA method on venous blood samples collected at baseline and after 10 ± 1 weeks of drug treatment. RESULTS: IGF-1 levels were increased in OCD patients compared to controls (149.9 ± 60.2 vs. 121.2 ± 51.6 ng/ml; p = 0.040). No correlations were observed between baseline IGF-1 levels, clinical features, and response to treatment at follow-up in OCD or MDD patients. No changes in serum IGF-1 were observed after drug treatment. CONCLUSION: Our results show for the first time that serum IGF-1 levels are altered in patients with OCD. Further research on the role of IGF-1 in OCD is warranted.
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Fator de Crescimento Insulin-Like I/metabolismo , Transtorno Obsessivo-Compulsivo/metabolismo , Adulto , Estudos de Casos e Controles , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Inibidores Seletivos de Recaptação de Serotonina/uso terapêuticoRESUMO
It has been proposed that the neurotrophin brain-derived neurotrophic factor (BDNF) may be involved in attention deficit-hyperactivity disorder (ADHD) etiopathogenesis. Alterations in BDNF serum levels have been observed in childhood/adulthood neurodevelopmental pathologies, but no evidence is available for BDNF serum concentrations in ADHD. The study includes 45 drug-naïve ADHD children and 45 age-sex matched healthy subjects. Concentration of serum BDNF was determined by the ELISA method. BDNF serum levels in patients with ADHD were not different from those of controls (mean ± SD; ADHD: 39.33 ± 10.41 ng/ml; controls: 38.82 ± 8.29 ng/ml, t = -0.26, p = 0.80). Our findings indicate no alteration of serum BDNF levels in untreated patients with ADHD. A further stratification for cognitive, neuropsychological and psychopathological assessment in a larger sample could be useful to clarify the role of BDNF in the endophenotype characterization of ADHD.
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Transtorno do Deficit de Atenção com Hiperatividade/sangue , Fator Neurotrófico Derivado do Encéfalo/sangue , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Índice de Massa Corporal , Estudos de Casos e Controles , Criança , Feminino , Humanos , Masculino , Fatores SocioeconômicosRESUMO
BACKGROUND: Low amyloid ß42 (Aß42) and high total tau and phosphorylated tau (p-tau) concentrations in the cerebrospinal fluid (CSF) are biomarkers of Alzheimer's disease (AD), reflecting brain deposition of amyloid plaques and tangles. Age and apolipoprotein E allele E4 are two strong risk factors for AD, but few data are still available on their effect on CSF markers in normal aging. OBJECTIVE: To study the effect of age on CSF Aß42, total tau, and p-tau levels in a well-characterized group of cognitively normal subjects. METHODS: CSF Aß42 levels of 81 subjects (27% female, 53 ± 15.3 years, range: 21-88) were determined with sandwich enzyme-linked immunosorbent assay; of these, total tau and p-tau levels were measured in 61 (75%) and 42 (52%) cases, respectively. A linear regression analysis between age and CSF markers was carried out on the whole sample and separately in apolipoprotein E allele É4 carriers and noncarriers. RESULTS: The median levels of all markers were significantly different between young (<65 years) and old (≥65 years) subjects (Aß42: P = .03; tau: P = .02; p-tau: P = .002; tau/Aß42: P = .004; p-tau/Aß42: P = .03). The association of marker levels with age was confirmed in linear regression models, where a positive relationship with age was observed for total tau (B = 2.3; 95% confidence interval [CI]: 0.89 to 3.7; P = .002), p-tau (B = 0.5; 95% CI: 0.1 to 0.9; P = .02), and tau/Aß42 ratio (B = 0.006; 95% CI: 0.002 to 0.01; P = .002). No subjects showed abnormal tau, whereas 19% showed abnormal CSF Aß42 concentrations. CONCLUSION: In cognitively normal subjects, the concentrations of CSF biomarkers of AD are associated with age. Further longitudinal studies could clarify whether Aß42 low levels represent a preclinical AD biomarker.
Assuntos
Envelhecimento/líquido cefalorraquidiano , Doença de Alzheimer/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Adulto , Idoso , Idoso de 80 Anos ou mais , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Differential diagnosis of neurological disorders and their subtype classification are challenging without specific biomarkers. Genetic forms of these disorders, typified by an autosomal dominant family history, could offer a window to identify potential biomarkers by exploring the presymptomatic stages of the disease. Frontotemporal dementia (FTD) is the second cause of dementia with an age of onset < 65, and its most common mutations are in GRN, C9orf72, and MAPT genes. Several studies have demonstrated that the main proteins involved in FTD pathogenesis can be secreted in exosomes, a specific subtype of extracellular vesicles able to transfer biomolecules between cells avoiding cell-to-cell contact. Neurofilament light chain (NfL) levels in central nervous system have been advocated as biomarkers of axonal injury. NfL concentrations have been found increased in FTD and have been related to disease severity and prognosis. Little information on the relationship between NfL and exosomes in FTD has been collected, deriving mainly from traumatic brain injury. Current review deals with this matter in the attempt to provide an updated discussion of the role of NfL and exosomes as biomarkers of genetic forms of FTD.
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Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD) represent the three major neurodegenerative dementias characterized by abnormal brain protein accumulation. In this study, we investigated extracellular vesicles (EVs) and neurotrophic factors in the cerebrospinal fluid (CSF) of 120 subjects: 36 with AD, 30 with DLB, 34 with FTD and 20 controls. Specifically, CSF EVs were analyzed by Nanoparticle Tracking Analysis and neurotrophic factors were measured with ELISA. We found higher EV concentration and lower EV size in AD and DLB groups compared to the controls. Classification tree analysis demonstrated EV size as the best parameter able to discriminate the patients from the controls (96.7% vs. 3.3%, respectively). The diagnostic performance of the EV concentration/size ratio resulted in a fair discrimination level with an area under the curve of 0.74. Moreover, the EV concentration/size ratio was associated with the p-Tau181/Aß42 ratio in AD patients. In addition, we described altered levels of cystatin C and progranulin in the DLB and AD groups. We did not find any correlation between neurotrophic factors and EV parameters. In conclusion, the results of this study suggest a common involvement of the endosomal pathway in neurodegenerative dementias, giving important insight into the molecular mechanisms underlying these pathologies.
Assuntos
Doença de Alzheimer , Vesículas Extracelulares , Demência Frontotemporal , Doença por Corpos de Lewy , Doença de Alzheimer/líquido cefalorraquidiano , Peptídeos beta-Amiloides , Biomarcadores/metabolismo , Demência Frontotemporal/líquido cefalorraquidiano , Humanos , Doença por Corpos de Lewy/líquido cefalorraquidiano , Fatores de Crescimento Neural , Fragmentos de Peptídeos , Proteínas tauRESUMO
BACKGROUND: Beta-site APP cleaving enzyme 1 (BACE1) is the rate-limiting enzyme in amyloid-ß (Aß) plaques formation. BACE1 activity is increased in brains of patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI) and plasma levels of BACE1 appears to reflect those in the brains. OBJECTIVE: In this work, we investigated the role of serum BACE1 activity as biomarker for AD, estimating the diagnostic accuracy of the assay and assessing the correlation of BACE1 activity with levels of Aß1 - 40, Aß1 - 42, and Aß40/42 ratio in serum, known biomarkers of brain amyloidosis. METHODS: Serum BACE1 activity and levels of Aß1 - 40, Aß1 - 42, were assessed in 31 AD, 28 MCI, diagnosed as AD at follow-up (MCI-AD), and 30 controls. The BACE1 analysis was performed with a luciferase assay, where interpolation of relative fluorescence units with a standard curve of concentration reveals BACE1 activity. Serum levels of Aß1 - 40, Aß1 - 42 were measured with the ultrasensitive Single Molecule Array technology. RESULTS: BACE1 was increased (higher than 60%) in AD and MCI-AD: a cut-off of 11.04âkU/L discriminated patients with high sensitivity (98.31%) and specificity (100%). Diagnostic accuracy was higher for BACE1 than Aß40/42 ratio. High BACE1 levels were associated with worse cognitive performance and earlier disease onset, which was anticipated by 8 years in patients with BACE1 values above the median value (>â16.67âkU/L). CONCLUSION: Our results provide new evidence supporting serum/plasma BACE1 activity as an early biomarker of AD.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Doença de Alzheimer/diagnóstico , Secretases da Proteína Precursora do Amiloide , Peptídeos beta-Amiloides , Ácido Aspártico Endopeptidases , Biomarcadores , Disfunção Cognitiva/diagnóstico , Humanos , Agitação PsicomotoraRESUMO
BACKGROUND: Alcohol dependence is a chronic relapsing disorder characterized by repetitive alcohol drinking patterns and a loss of control over alcohol consumption. Recent studies have hypothesized that dysregulations in brain neurotrophic support regulated by neurotrophins may be involved in the vulnerability to dependence and in the brain damage caused by chronic alcohol consumption. The neurotrophin brain-derived neurotrophic factor (BDNF) plays a pivotal role in neurodevelopment and in the maintenance of adult brain homeostasis through the regulation of neurogenesis and neuronal plasticity. The role of BDNF and its signaling in the mechanisms of alcohol dependence has been well documented in studies of animal models, but a few studies have been conducted in human peripheral tissues. On the basis of this rationale, we compared BDNF levels in both serum and plasma in alcohol-dependent patients and healthy volunteers. METHODS: Thirty-seven patients with a principal diagnosis of alcohol dependence were recruited. In parallel, a control group of 37 unrelated volunteers matched for gender and age was enrolled. Serum and plasma BDNF levels were measured by ELISA. RESULTS: A significant reduction in BDNF serum levels was observed in the patient group compared to healthy subjects (p = 0.028). On the contrary, no difference in BDNF plasma levels was evident between patients and controls. CONCLUSIONS: In conclusion, our data show an alteration of BDNF peripheral content in patients with alcohol dependence, suggesting the involvement of this neurotrophin in this psychopathology.
Assuntos
Alcoolismo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/sangue , Fatores de Crescimento Neural/efeitos dos fármacos , Adulto , Idoso , Alcoolismo/epidemiologia , Alcoolismo/fisiopatologia , Fator Neurotrófico Derivado do Encéfalo/fisiologia , Doença Crônica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Crescimento Neural/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , Plasma/efeitos dos fármacos , Soro/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacosRESUMO
Consisting evidence in animal models has suggested that alterations in brain-derived neurotrophic factor (BDNF) brain expression and release are involved in the pathogenesis of mental illnesses, such as, mood, anxiety, and eating disorders. This hypothesis is supported by data emerging from biochemical studies on serum BDNF levels and genetic studies on the functional polymorphism Val66Met in the BDNF gene in patients and control subjects. Anxiety-related personality traits are associated with several mental disorders. However, they are also measurable in non-affected subjects and, so, may represent a useful "endophenotype" to study the biological correlation of the vulnerability factors in the general population. In this study, we analyzed putative correlations in subjects unaffected by mental disorders between personality traits, serum BDNF levels (N = 107), and the BDNF Val66Met genotype (N = 217). Furthermore, we tested the possible interactions between these variables. A significant correlation has been observed between high scores of harm avoidance (HA) measured by the temperament and character inventory (TCI), and low BDNF serum concentration (r = -0.253, P = 0.009). In addition, an association has been evidenced between low BDNF levels in serum and the BDNF Val/Val genotype (P = 0.021). By analyzing putative concomitant effects of different variables on HA scores in a regression model, we observed a significant correlation only with BDNF serum concentrations (P = 0.022). The study results suggest that a decrease in serum BDNF concentrations may represent a biochemical marker associated with anxiety personality traits also retrievable in the general population.
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Fator Neurotrófico Derivado do Encéfalo/sangue , Fator Neurotrófico Derivado do Encéfalo/genética , Metionina/genética , Personalidade/genética , Valina/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Ensaio de Imunoadsorção Enzimática , Feminino , Genótipo , Humanos , Masculino , Entrevista Psiquiátrica Padronizada , Pessoa de Meia-Idade , Testes de Personalidade , Polimorfismo de Nucleotídeo Único/genética , Estatística como Assunto , Adulto JovemRESUMO
Alzheimer's disease (AD), frontotemporal dementia (FTD), and dementia with Lewy bodies (DLB) are the three major neurodegenerative dementias. In this study, we provide evidence that an alteration in extracellular vesicles (EVs) release is common across the three most common neurodegenerative dementias, AD, DLB, and FTD. Specifically, we analyzed plasma EVs in three groups of patients affected by AD, DLB, and FTD, and we found a significant reduction in EVs concentration and larger EVs size in all patient groups. We then investigated whether the loss of neurotrophic factors is also a common pathogenic mechanism among FTD, DLB, and AD, and if levels of neurotrophic factors might affect EVs release. Plasma levels of progranulin and cystatin C (CysC) were partially altered; however, taking together all variables significantly associated with the diagnostic groups only EVs size and concentration were able to distinguish patients from controls. The diagnostic performance of these two EVs parameters together (ratio) was high, with a sensitivity of 83.3% and a specificity of 86.7%, able to distinguish patients from controls but not to differentiate the different forms of dementias. Among the candidate neurotrophic factors, only CysC levels were associated with EVs concentration. Our study suggests that an alteration in the intercellular communication mediated by EVs might be a common molecular pathway underlying neurodegenerative dementias. The identification of shared disease mechanisms is of pivotal importance to develop treatments to delay disease progression. To this aim, further studies investigating plasma EVs size and concentration as early biomarkers of dementia are required.
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BACKGROUND: Brain-Derived Neurotrophic Factor (BDNF) is a neurotrophin which plays survival- and growth-promoting activity in neuronal cells and it is involved in cellular plasticity mechanisms as it controls activity dependent synaptic transmission. A functional polymorphism (Val66Met) in the pro-region of BDNF, which affects the intracellular trafficking of proBDNF has been associated with memory and cognitive deficits as well as to an increased susceptibility for several psychiatric disorders especially those with a neurodevelopmental origin. To date, no study has evaluated the influence of the Val66Met polymorphism on BDNF levels in a peripheral system that may reflect fetal neurodevelopment. Therefore we investigated in amniotic fluids (AF) obtained from 139 healthy women during 15-17 week of pregnancy, BDNF protein levels in correlation with the Val66Met polymorphism. RESULTS: Interestingly we found a significant BDNF protein levels reduction in 55 Met carriers (Val/Met and Met/Met) (p = 0.002) as compared to 84 non carriers (Val/Val), and no effect of fetus gender, maternal age or gestation week on BDNF levels has been observed. CONCLUSION: These results, although explorative, indicate that during fetal life the Val66Met genotype might influences BDNF protein levels in AF supporting the involvement of this polymorphism in behavioral and functional brain individual differences in the adulthood.
Assuntos
Líquido Amniótico/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Mutação de Sentido Incorreto , Polimorfismo Genético , Adulto , Envelhecimento , Ensaio de Imunoadsorção Enzimática , Feminino , Genótipo , Heterozigoto , Humanos , Masculino , Gravidez , Segundo Trimestre da Gravidez , Análise de Sequência de DNA , Caracteres Sexuais , População BrancaRESUMO
Consistent data coming from biochemical studies have evidenced a brain-derived neurotrophic factor (BDNF) serum reduction in depressed patients compared to controls and a restoration following antidepressant treatment. However, to date, no study has evaluated whether BDNF synthesis in leukocytes could contribute to such modulation. Therefore, in this study, we analysed BDNF mRNA levels in leukocytes from 21 depressed patients prior to and during escitalopram treatment and from 23 control subjects showing that BDNF mRNA levels were decreased in drug-free depressed patients and that 12 wk escitalopram treatment was able to reverse this deficit. Interestingly, changes in BDNF mRNA levels paralleled BDNF serum increase during antidepressant treatment, and were correlated with symptoms improvement. Our results indicate that BDNF serum modulation observed in depressed patients is associated with BDNF synthesis alteration in leukocytes and suggest that these peripheral cells might play an active role in the mechanisms of action of antidepressants.
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Fator Neurotrófico Derivado do Encéfalo/sangue , Citalopram/farmacologia , Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/genética , Leucócitos/efeitos dos fármacos , RNA Mensageiro/sangue , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Adolescente , Adulto , Idoso , Fator Neurotrófico Derivado do Encéfalo/genética , Citalopram/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Leucócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Resultado do TratamentoRESUMO
In the last decade, cognitive frailty has gained great attention from the scientific community. It is characterized by high inflammation and oxidant state, endocrine and metabolic alterations, mitochondria dysfunctions and slowdown in regenerative processes and immune system, with a complex and multifactorial aetiology. Although several treatments are available, challenges regarding the efficacy and the costs persist. Here, we proposed an alternative non-pharmacological, non-side-effect, low cost therapy based on anti-inflammation, antioxidant, regenerative and anti-pathogens properties of ozone, through the activation of several molecular mechanisms (Nrf2-ARE, NF-κB, NFAT, AP-1, HIFα). We highlighted how these specific processes could be implicated in cognitive frailty to identify putative therapeutic targets for its treatment. The oxigen-ozone (O2-O3) therapy has never been tested for cognitive frailty. This work provides thus wide scientific background to build a consistent rationale for testing for the first time this therapy, that could modulate the immune, inflammatory, oxidant, metabolic, endocrine, microbiota and regenerative processes impaired in cognitive frailty. Although insights are needed, the O2-O3 therapy could represent a faster, easier, inexpensive monodomain intervention working in absence of side effects for cognitive frailty.
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Senescência Celular , Envelhecimento Cognitivo/fisiologia , Inflamação , Ozônio/farmacologia , Senescência Celular/efeitos dos fármacos , Senescência Celular/fisiologia , Humanos , Inflamação/metabolismo , Inflamação/terapia , Oxidantes Fotoquímicos/farmacologiaRESUMO
AIMS: There is a strong interest in identifying the biological mechanisms involved in the genetic risk for psychotic disorders. In this study, we evaluated the correlation between serum concentrations of specific molecular markers and the genetic component for schizophrenia and bipolar disorder. METHODS: We analysed the association between the polygenic risk score (PRS) and the serum levels of different inflammatory/metabolic markers in a sample of 81 first-episode psychosis patients (FEP) with a diagnosis of schizophrenia or bipolar disorder and 33 controls. RESULTS: A positive correlation of schizophrenia and bipolar disorder PRS with the inflammatory marker C-C Motif Chemokine Ligand 4 serum concentration (ρ = 0.42, P = 1.56 × 10-04 and ρ = 0.40, P = 1.65 × 10-03 , respectively) and a negative correlation with the serum ghrelin content (ρ = - 0.35, P = 4.27 × 10-03 and ρ = - 0.45, P = 6.05 × 10-04 , respectively) were observed. CONCLUSION: These findings provide new insight into the biological underpinnings of the PRS component, thus supporting a role of the genetic liability on the inflammatory and metabolic alterations that characterize psychosis onset.
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Transtorno Bipolar/sangue , Quimiocina CCL4/sangue , Grelina/sangue , Esquizofrenia/sangue , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Herança Multifatorial , Fatores de Risco , Adulto JovemRESUMO
Although the associations between first-episode psychosis (FEP) and metabolic abnormalities on one side, and childhood trauma (CT) and risk of developing psychosis on the other are both well established, evidence on the relationship between CT and metabolic dysregulation in terms of abnormal glucose metabolism is very limited. We tested whether, already at illness onset, FEP patients with a history of CT show dysregulation of a broad range of glucose metabolism markers. In particular, in 148 FEP patients we evaluated serum concentrations of c-peptide, insulin, plasminogen-activator-inhibitor-1 (PAI-1), resistin, visfatin, glucagon, glucagon-like peptide-1 (GLP-1), gastric-inhibitor-peptide (GIP), leptin, and ghrelin. We also assessed CT with the Childhood Experience of Care and Abuse Questionnaire, and stressful life events (SLEs) with a semi-structured interview. Psychopathology, cannabis and tobacco habits, Body Mass Index (BMI) were recorded. Serum concentrations of markers were analyzed from peripheral blood. Ninety-five patients (56 % males, mean age 29.5) reported CT. Multivariate models showed that CT is associated only with the concentrations of c-peptide and insulin after adjusting for age, sex, BMI and SLEs. FEP patients who had experienced CT showed higher c-peptide and insulin serum concentrations. Our study reports that CT might be associated with the metabolic abnormalities in the first stage of psychosis, suggesting that a thorough anamnestic evaluation at psychosis onset that would include the history of CT could be helpful for clinicians in order to implement early programmes of healthy lifestyle education and to guide choice of therapeutic interventions for trauma.
Assuntos
Glucose/metabolismo , Transtornos Psicóticos/metabolismo , Transtornos Psicóticos/psicologia , Adulto , Experiências Adversas da Infância/psicologia , Antipsicóticos/uso terapêutico , Biomarcadores/sangue , Peptídeo C/análise , Peptídeo C/sangue , Feminino , Grelina/sangue , Glucagon/sangue , Peptídeo 1 Semelhante ao Glucagon/sangue , Humanos , Insulina/análise , Insulina/sangue , Resistência à Insulina/fisiologia , Leptina/sangue , Masculino , Pessoa de Meia-Idade , Nicotinamida Fosforribosiltransferase/sangue , Inibidor 1 de Ativador de Plasminogênio/sangue , Transtornos Psicóticos/fisiopatologia , Resistina/sangueRESUMO
Small extracellular vesicles (EVs) are able to pass from the central nervous system (CNS) into peripheral blood and contain molecule markers of their parental origin. The aim of our study was to isolate and characterize total and neural-derived small EVs (NDEVs) and their micro RNA (miRNA) cargo in Alzheimer's disease (AD) patients. Small NDEVs were isolated from plasma in a population consisting of 40 AD patients and 40 healthy subjects (CTRLs) using high throughput Advanced TaqMan miRNA OpenArrays®, which enables the simultaneous determination of 754 miRNAs. MiR-23a-3p, miR-223-3p, miR-100-3p and miR-190-5p showed a significant dysregulation in small NDEVs from AD patients as compared with controls (1.16 ± 0.49 versus 7.54 ± 2.5, p = 0.026; 9.32 ± 2.27 versus 0.66 ± 0.18, p <0.0001; 0.069 ± 0.01 versus 0.5 ± 0.1, p < 0.0001 and 2.9 ± 1.2 versus 1.93 ± 0.9, p < 0.05, respectively). A further validation analysis confirmed that miR-23a-3p, miR-223-3p and miR-190a-5p levels in small NDEVs from AD patients were significantly upregulated as compared with controls (p = 0.008; p = 0.016; p = 0.003, respectively) whereas miR-100-3p levels were significantly downregulated (p = 0.008). This is the first study that carries out the comparison between total plasma small EV population and NDEVs, demonstrating the presence of a specific AD NDEV miRNA signature.
Assuntos
Doença de Alzheimer/genética , MicroRNAs/sangue , MicroRNAs/genética , Idoso , Doença de Alzheimer/sangue , Estudos de Casos e Controles , Vesículas Extracelulares/genética , Vesículas Extracelulares/metabolismo , Feminino , Perfil Genético , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Recent evidence indicates that the vascular endothelial growth factor (VEGF) may be involved in the neuronal mechanisms underlying both the depression aetiology and the response to pharmacological and non pharmacological antidepressant treatments. To investigate whether VEGF peripheral levels are altered in depression and are modulated by antidepressant therapies, we analyzed the serum VEGF concentrations in 25 subjects affected by major depression (MD) before (T0) and after 8 (T8) and 12 (T12) weeks of escitalopram treatment. No significant alterations in VEGF serum levels were found at T0, even considering possible effects of confounders such as gender and smoking habit (r2=0.227 p=0.74). No changes appeared during the treatment (F(1.83, 43.86)=0.962; p=0.383) and there was no correlation between percentage VEGF variations at T12 and symptoms improvements (p=0.823). The present work represents the first report on the evaluation of serum VEGF levels in MD patients. However, before discarding serum VEGF as a biochemical marker in the diagnosis and treatment of depression, our negative results need to be confirmed in larger patient samples stratified for clinical characteristics, co-morbidities, cardiovascular diseases and confounding factors.