Norepinephrine Drives Sleep Fragmentation Activation of Asparagine Endopeptidase, Locus Ceruleus Degeneration, and Hippocampal Amyloid-ß42 Accumulation.

Chronic sleep disruption (CSD), from insufficient or fragmented sleep and is an important risk factor for Alzheimer's disease (AD). Underlying mechanisms are not understood. CSD in mice results in degeneration of locus ceruleus neurons (LCn) and CA1 hippocampal neurons and increases hippocampal amyloid-ß42 (Aß42), entorhinal cortex (EC) tau phosphorylation (p-tau), and glial reactivity. LCn injury is increasingly implicated in AD pathogenesis. CSD increases NE turnover in LCn, and LCn norepinephrine (NE) metabolism activates asparagine endopeptidase (AEP), an enzyme known to cleave amyloid precursor protein (APP) and tau into neurotoxic fragments. We hypothesized that CSD would activate LCn AEP in an NE-dependent manner to induce LCn and hippocampal injury. Here, we studied LCn, hippocampal, and EC responses to CSD in mice deficient in NE [dopamine ß-hydroxylase (Dbh)-/-] and control male and female mice, using a model of chronic fragmentation of sleep (CFS). Sleep was equally fragmented in Dbh -/- and control male and female mice, yet only Dbh -/- mice conferred resistance to CFS loss of LCn, LCn p-tau, and LCn AEP upregulation and activation as evidenced by an increase in AEP-cleaved APP and tau fragments. Absence of NE also prevented a CFS increase in hippocampal AEP-APP and Aß42 but did not prevent CFS-increased AEP-tau and p-tau in the EC. Collectively, this work demonstrates AEP activation by CFS, establishes key roles for NE in both CFS degeneration of LCn neurons and CFS promotion of forebrain Aß accumulation, and, thereby, identifies a key molecular link between CSD and specific AD neural injuries.

The Effect of Age and Sex on Early Postoperative Outcomes after Surgical Treatment of Distal Radius Fractures.

Background: We aim to evaluate the impact of advanced age and sex on postoperative complications and radiographic outcomes after open reduction with internal fixation of distal radius fractures (DRF). Methods: We conducted a retrospective chart review, including all patients who underwent open reduction with internal fixation of a DRF between 2012 and 2018 at a single level 1 trauma centre. We recorded patient age, sex, fracture classification (Arbeitsgemeinschaft für Osteosynthesefragen/Orthopaedic Trauma Association [AO/OTA]), time from injury to surgical date, surgical duration, diabetes status, tobacco use, illicit drug use, history of osteoporosis, use of adjuvants, fixation type, postoperative radiographic restoration of normal parameters and early complications including loss of reduction within 30 days postoperatively. Advanced age was defined as age greater than 60 years. Results: A total of 521 patients underwent operative treatment - 264 males and 257 females. Males were twice as likely (23.5% vs. 10.1%; p < 0.0001) to sustain a type C3 fracture and be treated with a wrist spanning plate (5.3% vs. 0; p < 0.0001). A larger percentage of elderly patients undergoing operative treatment of DRF were female (20.2% vs. 5.7%; p < 0.0001) and females were more likely to carry a pre-injury diagnosis of osteoporosis (9.3% vs. 0%; p < 0.0001). And 100% of the elderly patients received were treated with a volar plate. The overall early loss of reduction was 7.5%. The overall complication rate was 8.2%. No differences in early postoperative complications were identified between sexes or age groups. Neither female sex nor advanced age was found to have increased risk of postoperative complications or early loss of reduction. Similar postoperative radiographic parameter measurements were obtained across groups as well. Conclusions: Our results support the idea that operative treatment of unstable DRF in elderly patients and women is a reasonable treatment option without significant increases in early postoperative complications. Level of Evidence: Level III (Therapeutic III).