β-Secretase (BACE1) is the rate-limiting protease for the generation of the amyloid β-peptide (Aβ) in Alzheimer disease. Mice in which the bace1 gene is inactivated are reported to be healthy. However, the presence of a homologous gene encoding BACE2 raises the possibility of compensatory mechanisms. Therefore, we have generated bace1, bace2, and double knockout mice. We report here that BACE1 mice display a complex phenotype. A variable but significant number of BACE1 offspring died in the first weeks after birth. The surviving mice remained smaller than their littermate controls and presented a hyperactive behavior. Electrophysiologically, subtle alterations in the steady-state inactivation of voltage-gated sodium channels in BACE1-deficient neurons were observed. In contrast, bace2 knockout mice displayed an overall healthy phenotype. However, a combined deficiency of BACE2 and BACE1 enhanced the bace1^–/– lethality phenotype. At the biochemical level, we have confirmed that BACE1 deficiency results in an almost complete block of Aβ generation in neurons, but not in glia. As glia are 10 times more abundant in brain compared with neurons, our data indicate that BACE2 could indeed contribute to Aβ generation in the brains of Alzheimer disease and, in particular, Down syndrome patients. In conclusion, our data challenge the general idea of BACE1 as a safe drug target and call for some caution when claiming that no major side effects should be expected from blocking BACE1 activity.

Background: Frailty is an aging syndrome caused by exceeding a threshold of decline across multiple organ systems leading to a decreased resistance to stressors. Treatment for frailty focuses on multi-domain interventions to target multiple affected functions in order to decrease the adverse outcomes of frailty. No systematic reviews on the effectiveness of multi-domain interventions exist in a well-defined frail population. Objectives: This systematic review aimed to determine the effect of multi-domain compared to mono-domain interventions on frailty status and score, cognition, muscle mass, strength and power, functional and social outcomes in (pre)frail elderly (≥65 years). It included interventions targeting two or more domains (physical exercise, nutritional, pharmacological, psychological, or social interventions) in participants defined as (pre)frail by an operationalized frailty definition.
Methods: The databases PubMed, EMBASE, CINAHL, PEDro, CENTRAL, and the Cochrane Central register of Controlled Trials were searched from inception until September 14, 2016. Additional articles were searched by citation search, author search, and reference lists of relevant articles. The protocol for this review was registered on PROSPERO (CRD42016032905). Results: Twelve studies were included, reporting a large diversity of interventions in terms of content, duration, and follow-up period. Overall, multi-domain interventions tended to be more effective than mono-domain interventions on frailty status or score, muscle mass and strength, and physical functioning. Results were inconclusive for cognitive, functional, and social outcomes. Physical exercise seems to play an essential role in the multi-domain intervention, whereby additional interventions can lead to further improvement (eg, nutritional intervention). Conclusion: Evidence of beneficial effects of multi-domain compared to mono-domain interventions is limited but increasing. Additional studies are needed, focusing on a well-defined frail population and with specific attention to the design and the individual contribution of mono-domain interventions. This will contribute to the development of more effective interventions for frail elderly.

Objective: We evaluated microRNAs (miRNAs) as potential biomarkers for Alzheimer disease (AD) by analyzing the expression level of miRNAs in CSF of patients with AD dementia and nonaffected control subjects. Methods: Using quantitative PCR, we profiled the expression level of 728 miRNAs in CSF of nonaffected control subjects and patients with clinically ascertained AD dementia, and we further compared the expression level of candidate miRNAs in 37 control subjects and 35 patients with AD dementia. Results: The level of hsa-miR-27a-3p in CSF is reduced in patients with dementia due to AD in 2 different cohorts of subjects (cohort 1: p = 0.008; cohort 2: p = 0.015; 2-tailed unpaired Welch t test). Moreover, low levels of hsa-miR-27a-3p were accompanied by high CSF tau levels and low CSF β-amyloid levels. Conclusions: Our pilot study highlights hsa-miR-27a-3p as a candidate biomarker for AD and provides the groundwork for further confirmation studies in larger cohorts and in other hospitals.

Geriatric consultation teams have failed to impact clinical outcomes prompting geriatric co-management programmes to emerge as a promising strategy to manage frail patients on non-geriatric wards. to conduct a systematic review of the effectiveness of in-hospital geriatric co-management. MEDLINE, EMBASE, CINAHL and CENTRAL were searched from inception to 6 May 2016. Reference lists, trial registers and PubMed Central Citations were additionally searched. randomised controlled trials and quasi-experimental studies of in-hospital patients included in a geriatric co-management study. Two investigators performed the selection process independently. standardised data extraction and assessment of risk of bias were performed independently by two investigators. twelve studies and 3,590 patients were included from six randomised and six quasi-experimental studies. Geriatric co-management improved functional status and reduced the number of patients with complications in three of the four studies, but studies had a high risk of bias and outcomes were measured heterogeneously and could not be pooled. Co-management reduced the length of stay (pooled mean difference, −1.88 days [95% CI, −2.44 to −1.33]; 11 studies) and may reduce in-hospital mortality (pooled odds ratio, 0.72 [95% CI, 0.50–1.03]; 7 studies). Meta-analysis identified no effect on the number of patients discharged home (5 studies), post-discharge mortality (3 studies) and readmission rate (4 studies). there was low-quality evidence of a reduced length of stay and a reduced number of patients with complications, and very low-quality evidence of better functional status as a result of geriatric co-management.