Mild cognitive impairment (part 2): biological markers for diagnosis and prediction of dementia in Alzheimer's disease

To present a critical review of publications reporting on the rationale and clinical implications of the use of biomarkers for the early diagnosis of Alzheimer's disease (AD). Methods: We conducted a systematic search of the PubMed and Web of Science electronic databases, limited to articles published in English between 1999 and 2012, and based on the following terms: mild cognitive impairment, Alzheimer's disease OR dementia, biomarkers. We retrieved 1,130 articles, of which 175 were reviews. Overall, 955 original articles were eligible. Results: The following points were considered relevant for the present review: a) rationale for biomarkers research in AD and mild cognitive impairment (MCI); b) usefulness of distinct biomarkers for the diagnosis and prediction of AD; c) the role of multimodality biomarkers for the diagnosis and prediction of AD; d) the role of biomarkers in clinical trials of patients with AD and MCI; and e) current limitations to the widespread use of biomarkers in research and clinical settings. Conclusion: Different biomarkers are useful for the early diagnosis and prediction of AD in at-risk subjects. Nonetheless, important methodological limitations need to be overcome for widespread use of biomarkers in research and clinical settings. © 2013 Associação Brasileira de Psiquiatria.Laboratory of Neuroscience (LIM-27) Department and Institute of Psychiatry School of Medicine, Universidade de São Paulo (USP), São Paulo, SPDepartment of Mental Health School of Medicine Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MGNeuroimmunology Group Laboratory of Immunopharmacology Institute of Biological Sciences, UFMG, Belo Horizonte, MGDepartment of Internal Medicine School of Medicine UFMG, Belo Horizonte, MGBiosciences Institute Universidade Estadual Paulista (UNESP), Rio Claro, SPBiosciences Institute Universidade Estadual Paulista (UNESP), Rio Claro, S

Pharmacokinetics of Anti-hepcidin Monoclonal Antibody Ab 12B9m and Hepcidin in Cynomolgus Monkeys

Hepcidin is a key regulator responsible for systemic iron homeostasis. A semi-mechanistic PK model for hepcidin and a fully human anti-hepcidin monoclonal antibody (Ab 12B9m) was developed to describe their total (free + bound) serum concentration-time data after single and multiple weekly intravenous or subcutaneous doses of Ab 12B9m. The model was based on target mediated drug disposition and the IgG–FcRn interaction concepts published previously. Both total Ab 12B9m and total hepcidin exhibited nonlinear kinetics due to saturable Fc–FcRn interaction. Ab 12B9m showed a limited volume of distribution and negligible linear elimination from serum. The nonlinear elimination of Ab 12B9m was attributed to the endosomal degradation of Ab 12B9m that was not bound to the FcRn receptor. The terminal half-life, assumed to be the same for free and total serum Ab 12B9m, was estimated to be 16.5 days. The subcutaneous absorption of Ab 12B9m was described with a first-order absorption rate constant ka of 0.0278 h−1, with 86% bioavailability. The model suggested a rapid hepcidin clearance of approximately 800 mL h−1 kg−1. Only the highest-tested Ab 12B9m dose of 300 mg kg−1 week−1 was able to maintain free hepcidin level below the baseline during the dosing intervals. Free Ab 12B9m and free hepcidin concentrations were simulated, and their PK profiles were nonlinear as affected by their binding to each other. Additionally, the total amount of FcRn receptor involved in Ab 12B9m recycling at a given time was calculated empirically, and the temporal changes in the free FcRn levels upon Ab 12B9m administration were inferred

Importância da resitência insulínica na hepatite C crônica Insulin resistance in chronic hepatitits C

OBJETIVO: Revisar a importância da resistência insulínica no desenvolvimento da hepatite C crônica e sua interferência na resposta ao tratamento antiviral de pacientes infectados pelo vírus da hepatite C. FONTE DE DADOS: Revisão bibliográfica de trabalhos publicados pelo MEDLINE e dados dos próprios autores. SÍNTESE DE DADOS: Nos últimos anos, grande número de publicações tem demonstrado importante associação entre resistência insulínica e hepatite C crônica. Aumento na prevalência de diabetes mellitus tipo 2, desenvolvimento de esteatose hepática (principalmente nos pacientes com infecção pelo genótipo não-3), progressão mais rápida da doença e redução na taxa de resposta virológica sustentada ao tratamento com interferon peguilado e ribavirina, têm sido todos associados à presença de resistência insulínica nos pacientes infectados pelo vírus da hepatite C. A produção aumentada de fator de necrose tumoral pelo core do vírus da hepatite C é o principal mecanismo responsável pelo aparecimento da resistência insulínica. O fator de necrose tumoral afetaria a fosforilação do substrato do receptor de insulina diminuindo a captação de glicose e acarretando hiperinsulinemia compensatória. Aumento da siderose hepática e alterações dos níveis circulantes das adipocitocinas podem ter efeito adicional sobre a sensibilidade à insulina na hepatite C crônica. CONCLUSÕES: O diagnóstico e o tratamento da resistência insulínica nesses pacientes podem não só evitar o aparecimento das complicações, mas também prevenir a progressão da doença e, possivelmente, aumentar a taxa de resposta virológica sustentada ao tratamento com interferon peguilado e ribavirina.<br>OBJECTIVE: To revise the importance of insulin resistance in the development of chronic hepatitis C and its interference in the response to the antiviral treatment of these patients. DATA SOURCE: Bibliographic revision of published papers in the MEDLINE and the authors’ data. DATA SYNTHESIS: In the last years several published papers have demonstrated an important relationship between insulin resistance and chronic hepatitis C. Increased prevalence of type 2 diabetes mellitus, the development of hepatic steatosis (specially in non-3 genotype), a more rapid progression of hepatic disease and reduction in the sustained virological response to treatment with pegylated interferon plus ribavirin have been associated with insulin resistance in patients infected with HCV. The mechanism implied in the insulin resistance is the enhanced production of tumor necrosis factor by the HCV core. Tumor necrosis factor affects insulin receptor substrate phosphorylation, resulting in decreased glucose uptake and compensatory hyperinsulinemia. Increased liver iron accumulation and modification in the levels of adipocytokinemia can have an additional effect on insulin sensitivity in chronic C hepatitis. CONCLUSIONS: Diagnosing and treating insulin resistance in patients with chronic hepatitis C could not only avoid complications but also prevent disease progression and increased the sustained virological rate to treatment with pegylated interferon plus ribavarin