Alzheimer disease (AD) is a complex pathology related to multiple causes including oxidative stress. Brain-derived neurotrophic factor (BDNF) is a neutrotrophic factor essential for the survival and differentiation of neurons and is considered a key target in the pathophysiology of various neurodegenerative diseases, as for example AD. Contrarily to BDNF, the precursor form of BDNF (proBDNF) induces apoptosis through the specific interaction with p75 and its co-receptor, Sortilin. We used hippocampal tissue and cerebrospinal fluid from AD patients and controls. to study the localization and the levels of proBDNF, p75 and Sortilin as well as the post-traduccional modifications of proBDNF induced by Radical Oxygen Species, by immunofluorescence and Western blot. Differentiation and survival were assessed on differentiated mouse hippocampal neurons derived from postnatal neural stem cells from WT animals or from the transgenic AD animal model APP/PS1∆E9, based on mutations of familiar AD. In AD patients we observe a significative increase of proBDNF and Sortilin expression and a significative increase of the ratio proBDNF/BDNF in their cerebrospinal fluid compared to controls. In addition, the proBDNF of AD patients is modified by ROS-derived advanced glycation end products, which prevent the processing of the proBDNF to the mature BDNF, leading to an increase of pathogenicity and a decrease of trophic effects. The cerebrospinal fluid from AD patients, but not from controls, induces apoptosis in differentiated hippocampal neurons mainly by the action of AGE-modified proBDNF present in the cerebrospinal fluid of the patients. This effect is triggered by the activation and processing of p75 that stimulate the internalization of the intracellular domain (ICD) within the nucleus causing apoptosis. Induction of apoptosis and p75 ICD internalization by AD patients-derived proBDNF is further enhanced in neuron cultures from the AD model expressing the APP/PS1∆E9 transgene. Our results indicate the importance of proBDNF neurotoxic signaling in AD pathology essentially by three mechanisms: i) by an increase of proBDNF stability due to ROS-induced post-traductional modifications; ii) by the increase of expression of the p75 co-receptor, Sortilin and iii) by the increase of the basal levels of p75 processing found in AD.

Background: The high prevalence and long-term use of benzodiazepines (BZDs) treatment are debated topics because of the risk they can cause to the patients. Despite the current information on the risk-benefit balance of these drugs, their consumption remains particularly high. We determined the trend in the consumption prevalence of benzodiazepines (BZDs) and drugs related to BZDs (Z-drugs) in the population of the Health Region of Lleida to explore patterns of use and the associated characteristics associated between 2002 and 2015. Methods: An analysis of secular trends was carried out between 2002 and 2015; the databased included all individuals from the Health Region of Lleida, which had 358,157 inhabitants in 2015, that consumed BZDs. The consumption of BZDs was evaluated using prescription billing data from the Public Health System. All types of BZDs and BZD analogues that had been approved by the drug agency were included. Trends by age and sex were investigated. Results: Over the whole study period, a total of 161,125 individuals accounted for 338,148 dispensations. Overall, 59% were women, and the mean age was 56 years. The dispensing prevalence of BZDs use in 2015 was 14.2% overall —18.8% in women and 9.6% in men—and was 36% in those over 65 years. According to the half-life of BZDs, the prevalence of short-intermediate BZD use, intermediate-long BZD use, and Z-drugs use was 9.7, 5.5 and 0.8%, respectively. The evolution of the annual prevalence of BZD dispensing showed a progressive decline, from 15.3% in 2002 to 14.2% in 2015, which was attributed to a decrease in the consumption of intermediate-long half-life BZDs (8.0% vs. 5.5%) and Z-drugs (1.4% vs. 0.8%). Conclusion: The dispensing prevalence of BZDs and Z-drugs was high, although a small reduction was observed during this time period. The dispensing prevalence was especially high in the population over 65, despite the risk of cognitive decline and falls. Integral actions are required to lower the BZD prescription rate.

Background: Proton pump inhibitors (PPIs) are one of the most commonly prescribed pharmacological groups. Their high prevalence and duration of use are of important health concern due to the risk they can cause to patients. Despite these risks, their use remains particularly high, especially in the elderly population. We determined the trend in the prevalence of PPI consumption in the population of the Lleida Health Region between 2002 and 2015 to explore patterns of use and associated characteristics. Methods: An analysis of secular trends between 2002 and 2015 was performed. The database included all individuals who used PPIs in the Lleida Health Region, which had 358.070 inhabitants in 2015. PPI use was evaluated using prescription dispensing data from the public health system. All types of PPIs approved by the pharmaceutical agency were included. Trends were investigated by age and sex. Results: For the whole study period, a total of 215,417 individuals accounted for 292,122 dispensations. Overall, 48% were women, and the mean age was 62 years. The dispensing prevalence of PPI use in 2015 was 18.0% overall—20.4% for women and 15.7% for men—and was 54.6% for those over 65 years. In terms of the subtypes of PPIs, 16.8% of prescriptions were for omeprazole, 0.66% were for pantoprazole, and 0.48% were for lansoprazole. The evolution of the annual PPIs dispensation prevalence showed a progressive increase from 11.3% in 2002 to 18.0% in 2015, which was attributable to an increase in the use of omeprazole (9.0% vs. 16.8%) and, to a lesser extent, esomeprazole (0.02% vs. 0.4%). Conclusion: An increase in the prevalence of PPI dispensation was observed over 14 years of follow-up. The prevalence of dispensation was especially high for the population older than 65 years, despite the risk of cognitive decline and falls. Comprehensive actions are required to to increase rational prescribing of PPIs, especially in high-risk populations.

Manual ELISA assays are the most commonly used methods for quantification of biomarkers; however, they often show inter- and intra-laboratory variability that limits their wide use. Here, we compared the Innotest ELISA method with two fully automated platforms (Lumipulse and Elecsys) to determine whether these new methods can provide effective substitutes for ELISA assays. We included 149 patients with AD (n = 34), MCI (n = 94) and non-AD dementias (n = 21). Aβ42, T-tau, and P-tau were quantified using the ELISA method (Innotest, Fujirebio Europe), CLEIA method on a Lumipulse G600II (Fujirebio Diagnostics), and ECLIA method on a Cobas e 601 (Roche Diagnostics) instrument. We found a high correlation between the three methods, although there were systematic differences between biomarker values measured by each method. Both Lumipulse and Elecsys methods were highly concordant with clinical diagnoses, and the combination of Lumipulse Aβ42 and P-tau had the highest discriminating power (AUC 0.915, 95% CI 0.822–1.000). We also assessed the agreement of AT(N) classification for each method with AD diagnosis. Although differences were not significant, the use of Aβ42/Aβ40 ratio instead of Aβ42 alone in AT(N) classification enhanced the diagnostic accuracy (AUC 0.798, 95% CI 0.649–0.947 vs. AUC 0.778, 95% CI 0.617–0.939). We determined the cut-offs for the Lumipulse and Elecsys assays based on the Aβ42/Aβ40 ratio ± status as a marker of amyloid pathology, and these cut-offs were consistent with those recommended by manufacturers, which had been determined based on visual amyloid PET imaging or diagnostic accuracy. Finally, the biomarker ratios (P-tau/Aβ42 and T-tau/Aβ42) were more consistent with the Aβ42/Aβ40 ratio for both Lumipulse and Elecsys methods, and Elecsys P-tau/Aβ42 had the highest consistency with amyloid pathology (AUC 0.994, 95% CI 0.986–1.000 and OPA 96.4%) at the ≥0.024 cut-off. The Lumipulse and Elecsys cerebrospinal fluid (CSF) AD assays showed high analytical and clinical performances. As both automated platforms were standardized for reference samples, their use is recommended for the measurement of CSF AD biomarkers compared with unstandardized manual methods, such as Innotest ELISA, that have demonstrated a high inter and intra-laboratory variability.