RESUMO
Alzheimer's disease (AD) is a type of dementia whose cause is incompletely defined. Copper (Cu) involvement in AD etiology was confirmed by a meta-analysis on about 6000 participants, showing that Cu levels were decreased in AD brain specimens, while Cu and non-bound ceruloplasmin Cu (non-Cp Cu) levels were increased in serum/plasma samples. Non-Cp Cu was advocated as a stratification add-on biomarker of a Cu subtype of AD (CuAD subtype). To further circumstantiate this concept, we evaluated non-Cp Cu reliability in classifying subtypes of AD based on the characterization of the cognitive profile. The stratification of the AD patients into normal AD (non-Cp Cu ≤ 1.6 µmol/L) and CuAD (non-Cp Cu > 1.6 µmol/L) showed a significant difference in executive function outcomes, even though patients did not differ in disease duration and severity. Among the Cu-AD patients, a 76-year-old woman showed significantly abnormal levels in the Cu panel and underwent whole exome sequencing. The CuAD patient was detected with possessing the homozygous (c.1486T > C; p.(Ter496Argext*19) stop-loss variant in the RGS7 gene (MIM*602517), which encodes for Regulator of G Protein Signaling 7. Non-Cp Cu as an add-on test in the AD diagnostic pathway can provide relevant information about the underlying pathological processes in subtypes of AD and suggest specific therapeutic options.
Assuntos
Doença de Alzheimer , Proteínas RGS , Feminino , Humanos , Idoso , Cobre/metabolismo , Ceruloplasmina/genética , Ceruloplasmina/metabolismo , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Reprodutibilidade dos Testes , Cognição , Proteínas RGS/metabolismoRESUMO
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.
Assuntos
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
Patients affected by stroke, particularly subacute stroke patients, often complain of neuropathic pain (NP), which may severely impair their quality of life. The aim of this exploratory study was to characterize NP and to investigate whether there is a correlation between NP and serum brain-derived neurotrophic factor (BDNF) and serum markers of oxidative stress. We enrolled 50 patients divided in subacute (< 90 days from stroke onset) and chronic (> 90 and 180 < days from stroke onset). The Barthel Index, Deambulation Index, and Short Form 36 were used to assess the patients' degree of disability and quality of life. Pain-specific tools, namely the Numeric Rating Scale (NRS), Neuropathic Pain Diagnostic questionnaire (DN4), and Neuropathic Pain Symptom Inventory (NPSI), were also used. Serum levels of BDNF and markers of oxidative stress and of metal status were evaluated: copper, iron, transferrin, ferritin, ceruloplasmin concentration (iCp) and activity (eCp), Total Antioxidant status (TAS), Cp/Tf ratio, eCp/iCp ratio, and non-ceruloplasmin bound copper (Non-Cp Cu). We found the highest value of BDNF in subacute with NP (DN4 score ≥ 4). The TAS, Cp/Tf ratio, and eCp/iCp not only fell outside the normal reference range in a high percentage of subacute and chronic patients, but were also found to be related to specific NP symptoms. These preliminary results reveal altered BDNF and oxidative stress indices in subacute stroke patients who complain of NP. These investigative findings may shed more light on the mechanisms underlying NP and consequently lead to a more tailored therapeutic and/or rehabilitation procedure of subacute stroke patients.
Assuntos
Antioxidantes/metabolismo , Fator Neurotrófico Derivado do Encéfalo/sangue , Neuralgia/sangue , Neuralgia/etiologia , Acidente Vascular Cerebral/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Ceruloplasmina/metabolismo , Avaliação da Deficiência , Feminino , Ferritinas/sangue , Humanos , Masculino , Metais/sangue , Pessoa de Meia-Idade , Estresse Oxidativo/fisiologia , Medição da Dor , Qualidade de Vida , Estatísticas não Paramétricas , Acidente Vascular Cerebral/psicologia , Transferrina/metabolismoRESUMO
To evaluate whether the age-dependence of brain plasticity correlates with the levels of proteins involved in hormone and brain functions we executed a paired associative stimulation (PAS) protocol and blood tests. We measured the PAS-induced plasticity in the primary motor cortex. Blood levels of the brain-derived neurotrophic factor (BDNF), estradiol, the insulin-like growth factor (IGF)-1, the insulin-like growth factor binding protein (IGFBP)-3, progesterone, sex hormone-binding globulin (SHBG), testosterone, and the transforming growth factor beta 1 (TGF-ß1) were determined in 15 healthy men and 20 healthy women. We observed an age-related reduction of PAS-induced plasticity in females that it is not present in males. In females, PAS-induced plasticity displayed a correlation with testosterone (p = 0.006) that became a trend after the adjustment for the age effect (p = 0.078). In males, IGF-1 showed a nominally significant correlation with the PAS-induced plasticity (p = 0.043). In conclusion, we observed that hormone blood levels (testosterone in females and IGF-1 in males) may be involved in the age-dependence of brain plasticity.
Assuntos
Envelhecimento , Córtex Motor/fisiologia , Plasticidade Neuronal , Fatores Etários , Envelhecimento/sangue , Fator Neurotrófico Derivado do Encéfalo/sangue , Estimulação Elétrica/métodos , Estradiol/sangue , Potencial Evocado Motor , Feminino , Mãos/inervação , Humanos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Nervo Mediano/fisiologia , Músculo Esquelético/fisiologia , Globulina de Ligação a Hormônio Sexual/metabolismo , Testosterona/sangue , Estimulação Magnética Transcraniana/métodos , Fator de Crescimento Transformador beta1/sangueRESUMO
OBJECTIVE: Meta-analyses show that nonbound ceruloplasmin (non-Cp) copper (also known as free or labile copper) in serum is higher in patients with Alzheimer disease (AD). It differentiates subjects with mild cognitive impairment (MCI) from healthy controls. However, a longitudinal study on an MCI cohort has not yet been performed to assess the accuracy of non-Cp copper for the prediction of conversion from MCI to AD during a long-term follow-up. METHODS: The study included 42 MCI converters and 99 stable MCI subjects. We assessed levels of copper, ceruloplasmin, non-Cp copper, iron, transferrin, ferritin, and APOE genotype. A multiple Cox regression analysis-with age, sex, baseline Mini-Mental State Examination, APOE4, iron, non-Cp copper, transferrin, ferritin, hypercholesterolemia, and hypertension as covariates-was applied to predict the conversion from MCI to AD. RESULTS: Among the evaluated parameters, the only significant predictor of conversion to AD was non-Cp copper (hazard ratio = 1.23, 95% confidence interval = 1.03-1.47, p = 0.022); for each additional micromole per liter unit (µmol/l) of non-Cp copper, the hazard increased by ~20%. Subjects with non-Cp copper levels >1.6 µmol/l had a hazard conversion rate (50% of conversion in 4 years) that was ~3× higher than those with values ≤1.6 µmol/l (<20% in 4 years). The rate of conversion was similar between APOE4 carriers and noncarriers (p = 0.321), indicating that the non-Cp copper association was independent of APOE4. INTERPRETATION: Non-Cp copper appears to predict conversion from MCI to AD. These results encourage healthy life style choices and dietary intervention to modify this risk.
Assuntos
Doença de Alzheimer/sangue , Transtornos Cognitivos/sangue , Cobre/sangue , Doença de Alzheimer/genética , Apolipoproteína E4/genética , Ceruloplasmina/metabolismo , Transtornos Cognitivos/genética , Progressão da Doença , Feminino , Humanos , Estudos Longitudinais , Masculino , Testes Neuropsicológicos , Valor Preditivo dos Testes , Probabilidade , Fatores de RiscoRESUMO
INTRODUCTION: The wearing-off phenomenon is characterized by the recurrence of motor and non-motor symptoms of Parkinsonism during a period free from levodopa. It is a pivotal aspect marking the end of the pharmacological "honeymoon" period in Parkinson's disease (PD). A growing body of literature is connecting sex with the likelihood of developing fluctuations. We investigated such an association in a post-hoc analysis of the large WORK-PD study. METHODS: WORK-PD analyzed the usability of the wearing-off questionnaire 19 (WOQ19) in clinical practice and included cross-sectional data on age, disease duration, time on levodopa, Hoehn and Yahr stage, and WOQ19 scores of 532 PD patients. In the present study, we selected patients with an exposure time to levodopa of at least 1 year. RESULTS: A total of 380 patients were included. Women reported a higher number of wearing-off symptoms than men (6.09 ± 3.39 vs 4.96 ± 3.11, p = 0.0006). Sex groups also differed in non-motor symptoms (2 ± 1.9 vs 1.5 ± 1.5, p = 0.021), particularly behavioral wearing-off scores being higher in women (p < 0.001). The latter were primarily featured by anxiety-related phenomena. Finally, there was a significant interaction between behavioral symptoms, sex, and age at onset (df = 2, F = 9.79, p < 0.0001), whereas no such interaction was observed with levodopa exposure and motor impairment, unlike motor symptoms. DISCUSSION: Women showed a greater propensity than men to experience wearing-off, particularly non-motor fluctuations on the anxiety spectrum. The latter may demonstrate a lesser reliance on dopamine compared to motor symptoms. This observation could be underpinned by biological variances between genders at the neurotransmitter level.
Assuntos
Antiparkinsonianos , Levodopa , Doença de Parkinson , Humanos , Doença de Parkinson/psicologia , Doença de Parkinson/tratamento farmacológico , Masculino , Feminino , Pessoa de Meia-Idade , Levodopa/uso terapêutico , Idoso , Antiparkinsonianos/uso terapêutico , Estudos Transversais , Fatores Sexuais , Inquéritos e Questionários , Caracteres SexuaisRESUMO
BACKGROUND: Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide and a public health problem. Several clinical studies have shown that copper (Cu) is involved in carcinogenesis, possibly via cuproptosis, a new form of programmed cell death, but the conclusions from published reports are inconsistent. This study aimed at evaluating the potential of Cu dysregulation as a CRC susceptibility factor. METHODS: In this systematic review and meta-analysis, we searched Cochrane Library, EBSCOhost, EMBASE, ProQuest, PubMed/MEDLINE, Scopus, and Web of Science for studies reporting serum Cu concentrations in CRC patients and controls from articles published till June 2023. The studies included reported measurements of serum/plasma/blood Cu levels. Meta-analyses were performed as well as study quality, heterogeneity, and small study effects were assessed. Based on a random effects model, summary standardized mean differences (SMDs) and the corresponding 95% confidence intervals (95% CIs) were applied to compare the levels of Cu between CRC patients and controls. RESULTS: 26 studies with a pooled total of9628 participants and 2578 CRC cases were included. The pooled SMD was equal to 0.85 (95% CIs -0.44; 2.14) showing that the CRC patients had higher mean Cu levels than the control subjects, but the difference was not significant (p = 0.185) and the heterogeneity was very high, I2 = 97.9% (95% CIs: 97.5-98.3%; p < 0.001). CONCLUSION: The pooled results were inconclusive, likely due to discordant results and inaccuracy in reporting data of some studies; further research is needed to establish whether Cu dysregulation might contribute to the CRC risk and whether it might reflect different CRC grades.
Assuntos
Neoplasias Colorretais , Cobre , HumanosRESUMO
Semicarbazide-sensitive amine oxidase (SSAO) metabolizes the oxidative deamination of primary aromatic and aliphatic amines. The final cytotoxic products of its catalysis contribute to diseases involving vascular degeneration. The increasing interest in measuring SSAO activity has led to the development of several different methods. Herein, we compare SSAO activity results obtained with radiometric and fluorimetric methods in 49 plasma samples. Although not interchangeable, a significant correlation was obtained between methods. Considering these limitations, the fluorimetric method might replace the radioisotopic one.
Assuntos
Amina Oxidase (contendo Cobre)/sangue , Fluorometria/métodos , Radiometria/métodos , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Reactive oxygen species (ROS) play a key role in the neurodegeneration processes. Increased oxidative stress damages lipids, proteins, and nucleic acids in brain tissue, and it is tied to the loss of biometal homeostasis. For this reason, attention has been focused on transition metals involved in several biochemical reactions producing ROS. Even though a bulk of evidence has uncovered the role of metals in the generation of the toxic pathways at the base of Alzheimer's disease (AD), this matter has been sidelined by the advent of the Amyloid Cascade Hypothesis. However, the link between metals and AD has been investigated in the last two decades, focusing on their local accumulation in brain areas known to be critical for AD. Recent evidence revealed a relation between iron and AD, particularly in relation to its capacity to increase the risk of the disease through ferroptosis. In this review, we briefly summarize the major points characterizing the function of iron in our body and highlight why, even though it is essential for our life, we have to monitor its dysfunction, particularly if we want to control our risk of AD.
Assuntos
Doença de Alzheimer , Ácidos Nucleicos , Oligoelementos , Doença de Alzheimer/metabolismo , Humanos , Ferro/metabolismo , Lipídeos , Metais/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
BACKGROUND: The dynamics of essential metals such as Copper (Cu) and Zinc (Zn) may be associated with the novel coronavirus disease 2019 (COVID-19) that has spread across the globe. OBJECTIVES: The aim of this study is to investigate the relationship between serum levels of Cu and Zn, as well as the Cu:Zn ratio in the acute phase of COVID-19 along with the assessment of their connection to other laboratory parameters (hematological, biochemical, hemostatic). METHODS: Serum levels of Cu and Zn were measured by atomic absorption spectrometry in 75 patients in the acute COVID-19 phase and were compared with those of 22 COVID-19 patients evaluated three months after the acute phase of the disease ('non-acute' group) and with those of 68 healthy individuals. RESULTS: In comparison with both the non-acute patients and the healthy controls, the acute patients had lower levels of hemoglobulin and albumin, and higher levels of glucose, creatinine, liver transaminases, C-reactive protein (CRP), and higher values of the neutrophils to lymphocytes ratio (NLR) at the hospital admission. They also exhibited increased levels of Cu and decreased of Zn, well represented by the Cu:Zn ratio which was higher in the acute patients than in both non-acute patients (p = 0.001) and healthy controls (p < 0.001), with no statistical difference between the last two groups. The Cu:Zn ratio (log scale) positively correlated with CRP (log scale; r = 0.581, p < 0.001) and NLR (r = 0.436, p = 0.003). CONCLUSION: Current results demonstrate that abnormal dynamics of Cu and Zn levels in serum occur early during the course of COVID-19 disease, and are mainly associated with the inflammation response.
Assuntos
COVID-19 , Cobre , Humanos , Zinco , Espectrofotometria Atômica , Proteína C-ReativaRESUMO
Alzheimer's Disease (AD) is a type of dementia very common in the elderly. A growing body of recent evidence has linked AD pathogenesis to Copper (Cu) dysmetabolism in the body. In fact, a subset of patients affected either by AD or by its prodromal form known as Mild Cognitive Impairment (MCI) have been observed to be unable to maintain a proper balance of Cu metabolism and distribution and are characterized by the presence in their serum of increased levels of Cu not bound to ceruloplasmin (non-ceruloplasmin Cu). Since serum non-ceruloplasmin Cu is a biomarker of Wilson's Disease (WD), a well-known condition of Cu-driven toxicosis, in this review, we propose that in close analogy with WD, the assessment of non-ceruloplasmin Cu levels can be exploited as a cost-effective stratification and susceptibility/risk biomarker for the identification of some AD/MCI individuals. The approach can also be used as an eligibility criterion for clinical trials aiming at investigating Cu-related interventions against AD/MCI.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Idoso , Doença de Alzheimer/metabolismo , Biomarcadores , Ceruloplasmina/metabolismo , Cobre/metabolismo , HumanosRESUMO
Evidence indicates that patients with Alzheimer's dementia (AD) show signs of copper (Cu) dyshomeostasis. This study aimed at evaluating the potential of Cu dysregulation as an AD susceptibility factor. We performed a meta-analysis of 56 studies investigating Cu biomarkers in brain specimens (pooled total of 182 AD and 166 healthy controls, HC) and in serum/plasma (pooled total of 2929 AD and 3547 HC). We also completed a replication study of serum Cu biomarkers in 97 AD patients and 70 HC screened for rs732774 and rs1061472 ATP7B, the gene encoding for the Cu transporter ATPase7B. Our meta-analysis showed decreased Cu in AD brain specimens, increased Cu and nonbound ceruloplasmin (Non-Cp) Cu in serum/plasma samples, and unchanged ceruloplasmin. Serum/plasma Cu excess was associated with a three to fourfold increase in the risk of having AD. Our replication study confirmed meta-analysis results and showed that carriers of the ATP7B AG haplotype were significantly more frequent in the AD group. Overall, our study shows that AD patients fail to maintain a Cu metabolic balance and reveals the presence of a percentage of AD patients carrying ATP7B AG haplotype and presenting Non-Cp Cu excess, which suggest that a subset of AD subjects is prone to Cu imbalance. This AD subtype can be the target of precision medicine-based strategies tackling Cu dysregulation.
Assuntos
Doença de Alzheimer/metabolismo , ATPases Transportadoras de Cobre/genética , Cobre/metabolismo , Adenosina Trifosfatases/genética , Doença de Alzheimer/genética , Biomarcadores/análise , Encéfalo/metabolismo , Proteínas de Transporte de Cátions/genética , Ceruloplasmina/análise , Cobre/sangue , Suscetibilidade a Doenças , Haplótipos/genética , Homeostase , Humanos , Polimorfismo de Nucleotídeo Único/genética , Fatores de RiscoRESUMO
Zinc therapy is normally utilized for treatment of Wilson disease (WD), an inherited condition that is characterized by increased levels of non-ceruloplasmin bound ('free') copper in serum and urine. A subset of patients with Alzheimer's disease (AD) or its prodromal form, known as Mild Cognitive Impairment (MCI), fail to maintain a normal copper metabolic balance and exhibit higher than normal values of non-ceruloplasmin copper. Zinc's action mechanism involves the induction of intestinal cell metallothionein, which blocks copper absorption from the intestinal tract, thus restoring physiological levels of non-ceruloplasmin copper in the body. On this basis, it is employed in WD. Zinc therapy has shown potential beneficial effects in preliminary AD clinical trials, even though the studies have missed their primary endpoints, since they have study design and other important weaknesses. Nevertheless, in the studied AD patients, zinc effectively decreased non-ceruloplasmin copper levels and showed potential for improved cognitive performances with no major side effects. This review discusses zinc therapy safety and the potential therapeutic effects that might be expected on a subset of individuals showing both cognitive complaints and signs of copper imbalance.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Disfunção Cognitiva/tratamento farmacológico , Cobre/metabolismo , Zinco/uso terapêutico , Doença de Alzheimer/enzimologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Ceruloplasmina/metabolismo , Disfunção Cognitiva/enzimologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Humanos , Zinco/administração & dosagem , Zinco/efeitos adversos , Zinco/metabolismoRESUMO
Copper is an essential nutrient for plants, animals, and humans because it is an indispensable component of several essential proteins and either lack or excess are harmful to human health. Recent studies revealed that the breakdown of the regulation of copper homeostasis could be associated with Alzheimer's disease (AD), the most common form of dementia. Copper accumulation occurs in human aging and is thought to increase the risk of AD for individuals with a susceptibility to copper exposure. This review reports that one of the leading causes of copper accumulation in the environment and the human food chain is its use in agriculture as a plant protection product against numerous diseases, especially in organic production. In the past two decades, some countries and the EU have invested in research to reduce the reliance on copper. However, no single alternative able to replace copper has been identified. We suggest that agroecological approaches are urgently needed to design crop protection strategies based on the complementary actions of the wide variety of crop protection tools for disease control.
Assuntos
Agricultura/métodos , Doença de Alzheimer/etiologia , Cobre/metabolismo , Cobre/farmacologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Encéfalo/metabolismo , Cadeia Alimentar , Homeostase/fisiologia , Humanos , Fatores de RiscoRESUMO
The hypoxic brain damage induced by stroke is followed by an ischemia-reperfusion injury modulated by oxidative stress. Magnetoencephalographic (MEG) recording of rest and evoked cortical activities is a sensitive method to analyse functional changes following the acute ischemic damage. We aimed at investigating whether MEG signals are related to oxidative stress compounds in acute stroke. Eighteen stroke patients and 20 controls were enrolled. All subjects underwent MEG assessment to record background activity and somatosensory evoked responses (M20 and M30) of rolandic regions, neurological examination assessed by National Institute of Health Stroke Scale (NIHSS) and plasmatic measurement of copper, iron, zinc, ceruloplasmin, transferrin, total peroxides and Total Anti-Oxidant Status. Magnetic Resonance was performed to estimate the lesion site and volume. Delta power and M20 equivalent current dipole (ECD) strength in the affected hemisphere (AH) correlated with NIHSS scores (respectively, rho=.692, p=.006 and rho=-.627, p=.012) and taken together explained 67% of NIHSS variability (p=.004). Higher transferrin and lower peroxides levels correlated with better clinical status (respectively, rho=-.600, p=.014 and rho=.599, p=.011). Transferrin also correlated with AH M20 ECD strength (rho=.638 p=.014) and inversely with AH delta power (rho=-.646 p=.023) and the lesion volume, especially in cortico-subcortical stroke (p=.037). Our findings strengthen MEG reliability in honing the evaluation of neuronal damage in acute ischemic stroke also demonstrating an association between the MEG parameters most representing the clinical status and the oxidative stress compounds. Our results meet at a possible protective role of transferrin in limiting the oxidative damage in acute stroke.
Assuntos
Isquemia Encefálica/diagnóstico , Isquemia Encefálica/fisiopatologia , Magnetoencefalografia/métodos , Neurônios/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/fisiopatologia , Doença Aguda , Idoso , Isquemia Encefálica/complicações , Mapeamento Encefálico/métodos , Feminino , Humanos , Masculino , Estresse Oxidativo , Acidente Vascular Cerebral/complicaçõesRESUMO
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.
Assuntos
Transtorno Depressivo Maior/metabolismo , Fator A de Crescimento do Endotélio Vascular/sangue , Adulto , Antidepressivos de Segunda Geração/farmacologia , Biomarcadores/sangue , Citalopram/farmacologia , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Fator A de Crescimento do Endotélio Vascular/efeitos dos fármacosRESUMO
Oxidative status may play a role in chronic inflammation and neurodegeneration which are considered critical etiopathogenetic factors in Multiple Sclerosis (MS), both in the early phase of the disease and in the progressive one. The aim of this study is to explore oxidative status related to iron metabolism in peripheral blood of stable Relapsing-Remitting MS with low disability. We studied 60 Relapsing-Remitting MS patients (age 37.2 ± 9.06, EDSS median 1.0), and 40 healthy controls (age 40.3 ± 10.86). We measured total hydroperoxides (dROMs test) and Total Antioxidant Status (TAS), along with the iron metabolism biomarkers: Iron (Fe), ferritin (Ferr), transferrin (Tf), transferrin saturation (Tfsat), and ceruloplasmin (Cp) panel biomarkers [concentration (iCp) and enzymatic activity (eCp), copper (Cu), ceruloplasmin specific activity (eCp:iCp), copper to ceruloplasmin ratio (Cu:Cp), non-ceruloplasmin copper (nCp-Cu)]. We computed also the Cp:Tf ratio as an index of oxidative stress related to iron metabolism. We found lower TAS levels in MS patients than in healthy controls (CTRL) and normal reference level and higher dROMs and Cp:Tf ratio in MS than in healthy controls. Cp and Cu were higher in MS while biomarkers of iron metabolism were not different between patients and controls. Both in controls and MS, dROMs correlated with iCp (CTRL r = 0.821, p < 0.001; MS r = 0.775 p < 0.001) and eCp (CTRL r = 0.734, p < 0.001; MS r = 0.820 p < 0.001). Moreover, only in MS group iCp correlated negatively with Tfsat (r = -0.257, p = 0.047). Dividing MS patients in "untreated" group and "treated" group, we found a significant difference in Fe values [F(2, 97) = 10.136, p < 0.001]; in particular "MS untreated" showed higher mean values (mean = 114.5, SD = 39.37 µg/dL) than CTRL (mean 78.6, SD = 27.55 µg/dL p = 0.001) and "MS treated" (mean = 72.4, SD = 38.08 µg/dL; p < 0.001). Moreover, "MS untreated" showed significantly higher values of Cp:Tf (mean = 10.19, SD = 1.77∗10-2; p = 0.015), than CTRL (mean = 9.03, SD = 1.46 ∗10-2). These results suggest that chronic oxidative stress is relevant also in the remitting phase of the disease in patients with low disability and short disease duration. Therefore, treatment with antioxidants may be beneficial also in the early stage of the disease to preserve neuronal reserve.
RESUMO
BACKGROUND: Meta-analyses show that copper non-bound to ceruloplasmin (non-Cp Cu, also known as 'free' copper) in serum is higher in a percentage of Alzheimer's disease (AD) patients. Genetic heterogeneity in AD patients stratified on the basis of non-Cp Cu cut-off sustains the existence of a copper AD metabolic subtype. OBJECTIVE: In order to find evidence of the existence of a detectable metabolic subtype of AD associated to copper abnormalities, we explore the hypothesis of a neuroimaging pattern heterogeneity in an homogenous and well characterized AD population classified in two groups by the stratification of patients on the basis non-Cp Cu cut-off. METHOD: We assessed levels of copper, ceruloplasmin, non-Cp Cu, cerebrospinal levels of total Tau protein (h-tau), Thr 181 phosphorylated tau protein (P-tau) and ß-amyloid 1-42, and APOE4 genotype in 66 AD patients and compared neuroimaging indices of a visual rating scale of cerebral atrophy and neurovascular burden in AD patients stratified in 'Normal' and 'High' non-Cp Cu groups. RESULTS: The stratification for non-Cp Cu originated AD groups which did not differ for medial temporal lobe atrophy, periventricular hyperintensities, deeper hyperintensities (including frontal, parietooccipital and temporal white matter hyperintensities), infratentorial hyperintensities indices, while they differed for global atrophy. More specifically, AD patients within the high non-Cp Cu group had a less severe burden of global atrophy (p=0.042). CONCLUSION: This neuroimaging heterogeneity between AD groups is suggestive of the existence of a copper metabolic subtype of AD; non-Cp Cu appears a good marker of this copper AD.
Assuntos
Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Ceruloplasmina/metabolismo , Cobre/metabolismo , Neuroimagem/métodos , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Peptídeos beta-Amiloides , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Feminino , Humanos , Masculino , Entrevista Psiquiátrica Padronizada , Fragmentos de Peptídeos , Proteínas tau/líquido cefalorraquidianoRESUMO
Meta-analyses show that serum copper non-bound-to-ceruloplasmin (non-Cp-Cu) is higher in patients with Alzheimer's disease (AD). ATP7B gene variants associate with AD, modulating the size of non-Cp-Cu pool. However, a dedicated genetic study comparing AD patients after stratification for a copper biomarker to demonstrate the existence of a copper subtype of AD has not yet been carried out. An independent patient sample of 287 AD patients was assessed for non-Cp-Cu serum concentrations, rs1801243, rs1061472, and rs732774 ATP7B genetic variants and the APOE4 genotype. Patients were stratified into two groups based on a non-Cp-Cu cutoff (1.9 µM). Single-locus and haplotype-group analyses were performed to define their frequencies in dependence of the non-Cp-Cu group. The two AD subgroups did not differ regarding age, sex, MMSE score, or APOE4 frequency allele, while they did differ regarding non-Cp-Cu concentrations in serum, allele, genotype, and haplotype frequencies of rs1061472 A > G and rs732774 C > T after multiple testing corrections. AD patients with a GG genotype had a 1.76-fold higher risk of having a non-Cp-Cu higher than 1.9 µmol/L (p = 0.029), and those with a TT genotype for rs732774 C > T of 1.8-fold (p = 0.018). After 100,000 permutations for multiple testing corrections, the haplotype containing the AC alleles appeared more frequently in AD patients with normal non-Cp-Cu [43 vs. 33 %; Pm = 0.03], while the haplotype containing the GT risk alleles appeared more frequently in the higher non-Cp-Cu AD (66 vs. 55 %; Pm = 0.01). Genetic heterogeneity sustains a copper AD metabolic subtype; non-Cp-Cu is a marker of this copper AD.
Assuntos
Doença de Alzheimer/diagnóstico , Doença de Alzheimer/genética , Ceruloplasmina , ATPases Transportadoras de Cobre/genética , Cobre , Frequência do Gene/genética , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/epidemiologia , Estudos de Coortes , Feminino , Haplótipos/genética , Humanos , Itália/epidemiologia , MasculinoRESUMO
Reactive oxygen species (ROS) have been suggested to play an important role in physiopathology of schizophrenia. The polymorphisms in the genes encoding antioxidant enzymes, such as manganese superoxide dismutase (MnSOD) should, thus, result in predisposition to this psychiatric disorder. A functional amino acid polymorphism (Ala9Val) has been described in the signal sequence of enzyme associated with a decreased defense capacity against oxidative stress. Preliminary evidence in a Turkey population indicated that this polymorphism contributes to physiopathogenesis of schizophrenia. The object of this study was to verify the association between Ala9Val and schizophrenia in a representative Italian sample. The polymorphism was genotyped by PCR amplification and Single-Stranded Conformational Polymorphism (SSCP) analysis in 212 DSMIV schizophrenic patients and 257 healthy volunteers. No association was observed between cases and controls (genotype and allele frequencies: p = 0.72, p = 0.55, respectively) even when a sample stratification for gender, age at onset and diagnostic subtypes was performed. This suggests that the gene variant could not be a risk factor for schizophrenia susceptibility in an Italian sample.