RESUMEN
Recently, interest in the rat as an animal model of Alzheimer's disease (AD) has been growing. We have previously described the Tg6590 transgenic rat line expressing the amyloid precursor protein containing the Swedish AD mutation (K670M/N671L) that shows early stages of Abeta deposition, predominantly in cerebrovascular blood vessels, after 15 months of age. Here we show that by the age of 9 months, that is long before the appearance of Abeta deposits, the Tg6590 rats exhibit deficits in the Morris water maze spatial navigation task and altered spontaneous behaviour in the open-field test. The levels of soluble Abeta were elevated both in the hippocampus and cortex of transgenic animals. Magnetic resonance imaging showed no major changes in the brains of transgenic animals, although they tended to have enlarged lateral ventricles when compared to control animals. The Tg6590 transgenic rat line should prove a suitable model of early AD for advanced studies including serial cerebrospinal fluid sampling, electrophysiology, neuroimaging or complex behavioural testing.
Asunto(s)
Enfermedad de Alzheimer/complicaciones , Precursor de Proteína beta-Amiloide/metabolismo , Trastornos del Conocimiento/complicaciones , Modelos Animales de Enfermedad , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/fisiopatología , Animales , Conducta Animal , Biomarcadores/metabolismo , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Trastornos del Conocimiento/metabolismo , Trastornos del Conocimiento/patología , Trastornos del Conocimiento/fisiopatología , Hipocampo/metabolismo , Hipocampo/patología , Humanos , Imagen por Resonancia Magnética , Masculino , Aprendizaje por Laberinto , Neuronas/metabolismo , Neuronas/patología , Fosforilación , Ratas , Ratas Transgénicas , Sinapsis/metabolismo , Sinapsis/patología , Proteínas tau/metabolismoRESUMEN
PURPOSE: To estimate associations between use of ß-blockers, angiotensin-converting enzyme (ACE) inhibitors, or angiotensin receptor blockers (ARBs) and breast cancer recurrence in a large Danish cohort. PATIENTS AND METHODS: We enrolled 18,733 women diagnosed with nonmetastatic breast cancer between 1996 and 2003. Patient, treatment, and 10-year recurrence data were ascertained from the Danish Breast Cancer Cooperative Group registry. Prescription and medical histories were ascertained by linkage to the National Prescription Registry and Registry of Patients, respectively. ß-Blocker exposure was defined in aggregate and according to solubility, receptor selectivity, and individual drugs. ACE inhibitor and ARB exposures were defined in aggregate. Recurrence associations were estimated with multivariable Cox regression models in which time-varying drug exposures were lagged by 1 year. RESULTS: Compared with never users, users of any ß-blocker had a lower recurrence hazard in unadjusted models (unadjusted hazard ratio [HR] = 0.91; 95% CI, 0.81 to 1.0) and a slightly higher recurrence hazard in adjusted models (adjusted HR = 1.3; 95% CI, 1.1 to 1.5). Associations were similar for exposures defined by receptor selectivity and solubility. Although most individual ß-blockers showed no association with recurrence, metoprolol and sotalol were associated with increased recurrence rates (adjusted metoprolol HR = 1.5, 95% CI, 1.2 to 1.8; adjusted sotalol HR = 2.0, 95% CI, 0.99 to 4.0). ACE inhibitors were associated with a slightly increased recurrence hazard, whereas ARBs were not associated with recurrence (adjusted ACE inhibitor HR = 1.2, 95% CI, 0.97 to 1.4; adjusted ARBs HR = 1.1, 95% CI, 0.85 to 1.3). CONCLUSION: Our data do not support the hypothesis that ß-blockers attenuate breast cancer recurrence risk.