Huntington disease is a neurodegenerative condition for which there is no cure to date. Activation of AMP-activated protein kinase has previously been shown to be beneficial in in vitro and in vivo models of Huntington’s disease. Moreover, a recent cross-sectional study demonstrated that treatment with metformin, a well-known activator of this enzyme, is associated with better cognitive scores in patients with this disease. We performed a preclinical study using metformin to treat phenotypes of the zQ175 mouse model of Huntington disease. We evaluated behavior (motor and neuropsychiatric function) and molecular phenotypes (aggregation of mutant huntingtin, levels of brain-derived neurotrophic factor, neuronal inflammation, etc.). We also used two models of polyglutamine toxicity in
Caenorhabditis elegans
to further explore potential mechanisms of metformin action. Our results provide strong evidence that metformin alleviates motor and neuropsychiatric phenotypes in zQ175 mice. Moreover, metformin intake reduces the number of nuclear aggregates of mutant huntingtin in the striatum. The expression of brain-derived neurotrophic factor, which is reduced in mutant animals, is partially restored in metformin-treated mice, and glial activation in mutant mice is reduced in metformin-treated animals. In addition, using worm models of polyglutamine toxicity, we demonstrate that metformin reduces polyglutamine aggregates and restores neuronal function through mechanisms involving AMP-activated protein kinase and lysosomal function. Our data indicate that metformin alleviates the progression of the disease and further supports AMP-activated protein kinase as a druggable target against Huntington’s disease.
Renal replacement treatment has not been generalized to the elderly for different reasons. The main objective of the present cohort study is to compare survival in patients older than 80 years with chronic kidney disease stage 5 on renal replacement treatment with those on conservative treatment. The use of healthcare resources is compared too. A Cox proportional hazards regression analysis was run with the outcome variable death during the follow‐up period. The independent variables were treatment type, age, gender, smoking habit, serum albumin, hemoglobin, Charlson Index, diabetes mellitus, arterial hypertension, ischemic cardiopathy, and neoplasm. For outcome variable “death,” renal replacement treatment obtained a hazard ratio of 0.273 (P .006, CI95% 0.108‐0.686) vs conservative treatment. In conclusion, patients older than 80 years with chronic kidney disease stage 5 on renal replacement treatment presented a lower mortality risk than those receiving conservative treatment. Comorbidity and age are both associated with mortality, but do not cancel out the survival advantage. In healthcare resources, the renal replacement treatment group made greater use of tests, medical visits and consumption of hospital dispensing drugs, but there were no differences with respect to the days of hospital admission or assistance in home hospitalization.
Background: Alzheimer disease (AD) is an increasingly common neurodegenerative disease, especially in countries with aging populations. Its diagnosis is complex and is usually carried out in advanced stages of the disease. In addition, lipids and oxidative stress have been related to AD since the earliest stages. A diagnosis in the initial or preclinical stages of the disease could help in a more effective action of the treatments. Methods: Isoprostanoid biomarkers were determined in plasma samples from preclinical AD participants (n = 12) and healthy controls (n = 31) by chromatography and mass spectrometry (UPLC-MS/MS). Participants were accurately classified according to cerebrospinal fluid (CSF) biomarkers and neuropsychological examination. Results: Isoprostanoid levels did not show differences between groups. However, some of them correlated with CSF biomarkers (t-tau, p-tau) and with cognitive decline. In addition, a panel including 10 biomarkers showed an area under curve (AUC) of 0.96 (0.903–1) and a validation AUC of 0.90 in preclinical AD prediction. Conclusions: Plasma isoprostanoids could be useful biomarkers in preclinical diagnosis for AD. However, these results would require a further validation with an external cohort.
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