RESUMO
Exposure to childhood adversity is implicated in the etiology of adverse health outcomes, including depression, posttraumatic stress disorder (PTSD), and obesity. The relationship between childhood trauma and obesity may be related to the association of childhood trauma and risk for emotional eating. One pathway between trauma exposure, psychopathology, and emotional eating may be through emotion dysregulation and depression. The current study was undertaken to characterize demographic, environmental, and psychological risk factors for emotional eating in a primarily African American, low socioeconomic status (SES), inner-city population (N = 1110). Emotional eating was measured using the Dutch Eating Behavioral Questionnaire and the Emotional Dysregulation Scale was used to assess emotion regulation. The Beck Depression Inventory and the modified PTSD Symptom Scale were used to assess depression and PTSD, respectively. Higher levels of emotional eating were associated with body mass index, income, childhood and adulthood trauma exposure, depressive and PTSD symptoms, negative affect and emotion dysregulation. Childhood emotional abuse was the most associated with emotional eating in adulthood. Hierarchical linear regression and mediation analyses indicated that the association between childhood trauma exposure (and emotional abuse specifically) and emotional eating was fully mediated by depression symptoms and emotion dysregulation, with emotional dysregulation contributing more to the mediation effect. Together these findings support a model in which obesity and related adverse health outcomes in stress- and trauma-exposed populations may be directly related to self-regulatory coping strategies accompanying emotion dysregulation. Our data suggest that emotion dysregulation is a viable therapeutic target for emotional eating in at-risk populations.
Assuntos
Transtornos de Adaptação/psicologia , Adultos Sobreviventes de Eventos Adversos na Infância/psicologia , Depressão/psicologia , Ajustamento Emocional , Transtornos da Alimentação e da Ingestão de Alimentos/psicologia , Hiperfagia/psicologia , Modelos Psicológicos , Transtornos de Adaptação/fisiopatologia , Adolescente , Adulto , Idoso , Estudos Transversais , Depressão/fisiopatologia , Transtornos da Alimentação e da Ingestão de Alimentos/epidemiologia , Transtornos da Alimentação e da Ingestão de Alimentos/etiologia , Feminino , Georgia/epidemiologia , Hospitais Públicos , Hospitais Urbanos , Humanos , Hiperfagia/epidemiologia , Hiperfagia/etiologia , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Fatores de Risco , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Transtornos de Estresse Pós-Traumáticos/psicologia , Adulto JovemAssuntos
Derivação Arteriovenosa Cirúrgica/efeitos adversos , Mãos/irrigação sanguínea , Isquemia/etiologia , Isquemia/patologia , Falência Renal Crônica/terapia , Diálise Renal/efeitos adversos , Dispositivos de Acesso Vascular/efeitos adversos , Idoso , Biópsia por Agulha , Feminino , Humanos , Imuno-Histoquímica , Falência Renal Crônica/diagnóstico , Prognóstico , Fluxo Sanguíneo Regional , Diálise Renal/métodos , Medição de Risco , Visitas de PreceptoriaRESUMO
Verubecestat is a potent BACE1 enzyme inhibitor currently being investigated in Phase III trials for the treatment of mild-to-moderate and prodromal Alzheimer's disease. Multiple anti-amyloid immunotherapies have been dose-limited by adverse amyloid related imaging abnormalities such as vasogenic edema (ARIA-E) and microhemorrhage (ARIA-H) observed in human trials and mice. Verubecestat was tested in a 12-week nonclinical study for the potential to exacerbate microhemorrhage (ARIA-H) profiles in 18-22-month-old post-plaque Tg2576-AßPPswe mice. Animals were treated with verubecestat or controls including the anti-Aß antibody analog of bapineuzumab (3D6) as a positive control for ARIA induction. ARIA-H was measured using in-life longitudinal T2*-MRI and Prussian blue histochemistry at study end. Verubecestat reduced plasma and cerebrospinal fluid Aß40 and Aß42 byâ>90% and 62% to 68%, respectively. The ARIA-H profile of verubecestat-treated mice was not significantly different than controls. Anti-Aß treatment significantly increased ARIA-H detected by Prussian blue staining; however, anti-Aß antibody treatment did not impact plaque status. Verubecestat treatment significantly suppressed the accumulation of total levels of brain Aß40 and Aß42 and Thioflavin S positive plaque load. Stereological analysis of cortex and hippocampus plaque load similarly revealed significantly reduced area of Aß immunoreactivity and reduced plaque number in verubecestat-treated animals compared to controls. The absence of elevated ARIA events in verubecestat-treated mice was associated with a significant reduction in the level of accumulated CNS amyloid pathology and brain Aß peptides; effects consistent with the desired therapeutic mechanism of verubecestat in AD patients. These data will be compared with longitudinal MRI profiles from ongoing clinical trials.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Antipsicóticos/uso terapêutico , Óxidos S-Cíclicos/uso terapêutico , Placa Amiloide/patologia , Tiadiazinas/uso terapêutico , Doença de Alzheimer/complicações , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Animais , Anticorpos Monoclonais Humanizados/uso terapêutico , Colágeno Tipo IV/metabolismo , Óxidos S-Cíclicos/sangue , Óxidos S-Cíclicos/líquido cefalorraquidiano , Modelos Animais de Doenças , Humanos , Hemorragias Intracranianas/tratamento farmacológico , Hemorragias Intracranianas/etiologia , Estudos Longitudinais , Imageamento por Ressonância Magnética , Camundongos , Camundongos Transgênicos , Mutação/genética , Placa Amiloide/tratamento farmacológico , Presenilina-1/genética , Tiadiazinas/sangue , Tiadiazinas/líquido cefalorraquidianoRESUMO
Functional imaging studies have revealed that certain brainstem areas are activated during migraine attacks. The neuropeptide calcitonin gene-related peptide (CGRP) is associated with activation of the trigeminovascular system and transmission of nociceptive information and plays a key role in migraine pathophysiology. Therefore, to elucidate the role of CGRP, it is critical to identify the regions within the brainstem that process CGRP signaling. In situ hybridization and immunofluorescence were performed to detect mRNA expression and define cellular localization of calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1), respectively. To define CGRP receptor binding sites, in vitro autoradiography was performed with [(3)H]MK-3207 (a CGRP receptor antagonist). CLR and RAMP1 mRNA and protein expression were detected in the pineal gland, medial mammillary nucleus, median eminence, infundibular stem, periaqueductal gray, area postrema, pontine raphe nucleus, gracile nucleus, spinal trigeminal nucleus, and spinal cord. RAMP1 mRNA expression was also detected in the posterior hypothalamic area, trochlear nucleus, dorsal raphe nucleus, medial lemniscus, pontine nuclei, vagus nerve, inferior olive, abducens nucleus, and motor trigeminal nucleus; protein coexpression of CLR and RAMP1 was observed in these areas via immunofluorescence. [(3)H]MK-3207 showed high binding densities concordant with mRNA and protein expression. The present study suggests that several regions in the brainstem may be involved in CGRP signaling. Interestingly, we found receptor expression and antagonist binding in some areas that are not protected by the blood-brain barrier, which suggests that drugs inhibiting CGRP signaling may not be able to penetrate the central nervous system to antagonize receptors in these brain regions.
Assuntos
Tronco Encefálico/metabolismo , Proteína Semelhante a Receptor de Calcitonina/metabolismo , Macaca mulatta/metabolismo , Proteína 1 Modificadora da Atividade de Receptores/metabolismo , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo , Animais , Autorradiografia , Tronco Encefálico/anatomia & histologia , Compostos Bicíclicos Heterocíclicos com Pontes , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Feminino , Imunofluorescência , Hibridização In Situ , Macaca mulatta/anatomia & histologia , Masculino , Ligação Proteica , RNA Mensageiro/metabolismo , Compostos Radiofarmacêuticos , Transdução de Sinais , Medula Espinal/anatomia & histologia , Medula Espinal/metabolismo , Compostos de Espiro , TrítioRESUMO
BACKGROUND: Apolipoprotein E (apoE) is a major cholesterol transport protein found in association with brain amyloid from Alzheimer's disease (AD) patients and the ε4 allele of apoE is a genetic risk factor for AD. Previous studies have shown that apoE forms a stable complex with amyloid ß (Aß) peptides in vitro and that the state of apoE lipidation influences the fate of brain Aß, i.e., lipid poor apoE promotes Aß aggregation/deposition while fully lipidated apoE favors Aß degradation/clearance. In the brain, apoE levels and apoE lipidation are regulated by the liver X receptors (LXRs). RESULTS: We investigated the hypothesis that increased apoE levels and lipidation induced by LXR agonists facilitates Aß efflux from the brain to the cerebral spinal fluid (CSF). We also examined if the brain expression of major apoE receptors potentially involved in apoE-mediated Aß clearance was altered by LXR agonists. ApoE, cholesterol, Aß40, and Aß42 levels were all significantly elevated in the CSF of rats after only 3 days of treatment with LXR agonists. A significant reduction in soluble brain Aß40 levels was also detected after 6 days of LXR agonist treatment. CONCLUSIONS: Our novel findings suggest that central Aß lowering caused by LXR agonists appears to involve an apoE/cholesterol-mediated transport of Aß to the CSF and that differences between the apoE isoforms in mediating this clearance pathway may explain why individuals carrying one or two copies of APOE ε4 have increased risk for AD.
RESUMO
Amyloid plaque deposition in the brain is a hallmark of Alzheimer's disease, but recent evidence indicates that the disease may be primarily caused by soluble amyloid-beta (1-42) (Abeta) oligomers or Abeta-derived diffusible ligands (ADDLs). ADDLs induce cognitive deficits in animal models and are thought to assemble in vitro by a mechanism apart from plaque formation. To investigate the in vivo relationship of ADDLs and plaques, biotin-labeled ADDLs (bADDLs) or amylin oligomers (bAMs) were injected into the hippocampus of hAPP overexpressing mice. The brains were collected 1 or 5 weeks after the last treatment and were processed for immunohistochemistry. Staining of tissue 1 week post-treatment showed bADDLs had diffused throughout the tissue and incorporated into plaques. Additionally, small deposits of thioflavin S-negative bADDLs were observed. At 5 weeks post-treatment, thioflavin S-positive material continued to accumulate around plaques containing bADDLs. Thioflavin S-positive material also accrued around bADDL deposits, implying that bADDLs were capable of seeding new plaques. In contrast, bAMs cleared from the brain and did not accumulate in plaques. Together, these data indicate that ADDLs are able to contribute to in vivo plaque formation in a peptide-specific manner.
Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Amiloide/metabolismo , Fragmentos de Peptídeos/metabolismo , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Amiloide/química , Amiloide/genética , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/genética , Animais , Benzotiazóis , Biotina , Modelos Animais de Doenças , Humanos , Imuno-Histoquímica , Polipeptídeo Amiloide das Ilhotas Pancreáticas , Ligantes , Masculino , Camundongos , Camundongos Transgênicos , Microscopia de Força Atômica , Peso Molecular , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/genética , Tiazóis/metabolismoRESUMO
The capacities of urinary trefoil factor 3 (TFF3) and urinary albumin to detect acute renal tubular injury have never been evaluated with sufficient statistical rigor to permit their use in regulated drug development instead of the current preclinical biomarkers serum creatinine (SCr) and blood urea nitrogen (BUN). Working with rats, we found that urinary TFF3 protein levels were markedly reduced, and urinary albumin were markedly increased in response to renal tubular injury. Urinary TFF3 levels did not respond to nonrenal toxicants, and urinary albumin faithfully reflected alterations in renal function. In situ hybridization localized TFF3 expression in tubules of the outer stripe of the outer medulla. Albumin outperformed either SCr or BUN for detecting kidney tubule injury and TFF3 augmented the potential of BUN and SCr to detect kidney damage. Use of urinary TFF3 and albumin will enable more sensitive and robust diagnosis of acute renal tubular injury than traditional biomarkers.