Treatment of dementia with cholinesterase inhibitors and memantine can result in statistically significant but clinically marginal improvement in measures of cognition and global assessment of dementia.

Background Immune system activation is frequently reported in patients with Alzheimer's disease (AD). However, it remains unknown whether this is a cause, a consequence, or an epiphenomenon of brain degeneration. Objective The present study examines whether immunological abnormalities occur in a well-established murine AD model and if so, how they relate temporally to behavioral deficits and neuropathology. Methods A broad battery of tests was employed to assess behavioral performance and autoimmune/inflammatory markers in 3xTg-AD (AD) mice and wild type controls from 1.5 to 12 months of age. Results Aged AD mice displayed severe manifestations of systemic autoimmune/inflammatory disease, as evidenced by splenomegaly, hepatomegaly, elevated serum levels of anti-nuclear/anti-dsDNA antibodies, low hematocrit, and increased number of double-negative T splenocytes. However, anxiety-related behavior and altered spleen function were evident as early as 2 months of age, thus preceding typical AD-like brain pathology. Moreover, AD mice showed altered olfaction and impaired “cognitive” flexibility in the first 6 months of life, suggesting mild cognitive impairment-like manifestations before general learning/memory impairments emerged at an older age. Interestingly, all of these features were present in 3xTg-AD mice prior to significant amyloid-β or tau pathology. Conclusion The results indicate that behavioral deficits in AD mice develop in parallel with systemic autoimmune/inflammatory disease. These changes antedate AD-like neuropathology, thus supporting a causal link between autoimmunity and aberrant behavior. Consequently, 3xTg-AD mice may be a useful model in elucidating the role of immune system in the etiology of AD.

Background: Observational studies have suggested that accelerated surgery is associated with improved outcomes in patients with a hip fracture. The HIP ATTACK trial assessed whether accelerated surgery could reduce mortality and major complications. Methods:We randomised 2970 patients from 69 hospitals in 17 countries. Patients with a hip fracture that required surgery and were ≥45 years of age were eligible. Patients were randomly assigned to accelerated surgery (goal of surgery within 6 hours of diagnosis; 1487 patients) or standard care (1483 patients). The co-primary outcomes were 1.) mortality, and 2.) a composite of major complications (i.e., mortality and non-fatal myocardial infarction, stroke, venous thromboembolism, sepsis, pneumonia, life-threatening bleeding, and major bleeding) at 90 days after randomisation. Outcome adjudicators were masked to treatment allocation, and patients were analysed according to the intention-to-treat principle; ClinicalTrials.gov, NCT02027896. Findings:The median time from hip fracture diagnosis to surgery was 6 hours (interquartile range [IQR] 4-9) in the accelerated-surgery group and 24 hours (IQR 10-42) in the standard-care group, p<0.0001. Death occurred in 140 patients (9%) assigned to accelerated surgery and 154 patients (10%) assigned to standard care; hazard ratio (HR) 0.91, 95% CI 0.72-1.14; absolute risk reduction (ARR) 1%, 95% CI -1-3%; p=0.40. The primary composite outcome occurred in 321 patients (22%) randomised to accelerated surgery and 331 patients (22%) randomised to standard care; HR 0.97, 95% CI 0.83-1.13; ARR 1%, 95% CI -2-3%; p=0.71.Interpretation: Among patients with a hip fracture, accelerated surgery did not significantly lower the risk of mortality or a composite of major complications compared to standard care.

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A nnually in North America, 0.8% of women and 0.4% of men aged 65 years or older experience a hip fracture.