Moving beyond anti-amyloid therapy for the prevention and treatment of Alzheimer's disease.

BACKGROUND: High-profile Phase 3 clinical trials of bapineuzumab and solanezumab, antibodies targeted at amyloid-beta (Aß) removal, have failed to meet their primary endpoints. Neither drug improves clinical outcomes in patients with late onset AD, joining a long list of unsuccessful attempts to treat AD with anti-amyloid therapies. DISCUSSION: These therapies are based on the assumption that Aß accumulation is the primary pathogenic trigger of AD. Current evidence suggests that Aß may actually accumulate as part of an adaptive response to long-term chronic brain stress stimuli that would make more suitable candidates for therapeutic intervention. SUMMARY: At this juncture it is no longer unreasonable to suggest that further iterations of anti-Aß therapies should be halted. Clinicians and researchers should instead direct their attention toward greater understanding of the biological function of Aß both in healthy and demented brains, as well as the involvement of long-term chronic exposure to stress in the etiology of AD.

Insight into developmental mechanisms of global and focal migration disorders of cortical development.

Cortical development involves neurogenesis followed by migration, maturation, and myelination of immature neurons. Disruptions in these processes can cause malformations of cortical development (MCD). Radial glia (RG) are the stem cells of the brain, both generating neurons and providing the scaffold upon which immature neurons radially migrate. Germline mutations in genes required for cell migration, or cell-cell contact, often lead to global MCDs. Somatic mutations in RG in genes involved in homeostatic function, like mTOR signaling, often lead to focal MCDs. Two different mutations occurring in the same patient can combine in ways we are just beginning to understand. Our growing knowledge about MCD suggests mTOR inhibitors may have expanded utility in treatment-resistant epilepsy, while imaging techniques can better delineate the type and extent of these lesions.

Improving Accuracy of Handoff by Implementing an Electronic Health Record-generated Tool: An Improvement Project in an Academic Neonatal Intensive Care Unit.

BACKGROUND: Written patient handoffs are susceptible to errors or incompleteness. The accuracy is dependent on the person inputting the information. Thus, handoff printouts generated by electronic health records (EHR) with automation reduces the risk of transcription errors and improves consistency in format. This single-center quality improvement project aims to increase the accuracy of handoff printouts with an EHR-generated handoff tool. METHODS: This project used a plan-do-study-act methodology. Participants included registered nurses, neonatal nurse practitioners, neonatal hospitalists, pediatric residents, neonatal fellows, and neonatologists. The goals were to (1) increase accuracy of information to 80%, (2) reduce verbal handoff time by 20%, (3) reduce the frequency of incorrectly listed medications below 20%, and (4) improve user satisfaction by 1 point (on a 5-point Likert scale) over 6 months. Baseline assessment included a survey and a review of handoff reports 4 months before transitioning to the new handoff tool. We created a new handoff tool using EHR autogenerated phrases (Epic SmartPhrases) and autopopulated fields for pertinent Neonatal Intensive Care Unit patient data. RESULTS: After the unit-wide implementation of the new tool, the accuracy of 16 patient data points increased from 51% to 97%, while the frequency of patients with incorrectly listed medications decreased from 51% to 0%. Handoff time remained unchanged, while a 5-question user satisfaction survey showed an increase on the Likert scale. CONCLUSIONS: We demonstrated that handoff printouts generated by EHR have fewer inaccuracies than manually scripted versions and do not add to the time required to give verbal handoff.

On the origin of Alzheimer's disease. Trials and tribulations of the amyloid hypothesis.

The amyloid cascade hypothesis, which implicates the amyloid Aß peptide as the pathological initiator of both familial and sporadic, late onset Alzheimer's disease (AD), continues to guide the majority of research. We believe that current evidence does not support the amyloid cascade hypothesis for late onset AD. Instead, we propose that Aß is a key regulator of brain homeostasis. During AD, while Aß accumulation may occur in the long term in parallel with disease progression, it does not contribute to primary pathogenesis. This view predicts that amyloid-centric therapies will continue to fail, and that progress in developing successful alternative therapies for AD will be slow until closer attention is paid to understanding the physiological function of Aß and its precursor protein.

Rational heterodoxy: cholesterol reformation of the amyloid doctrine.

According to the amyloid cascade hypothesis, accumulation of the amyloid peptide Aß, derived by proteolytic processing from the amyloid precursor protein (APP), is the key pathogenic trigger in Alzheimer's disease (AD). This view has led researchers for more than two decades and continues to be the most influential model of neurodegeneration. Nevertheless, close scrutiny of the current evidence does not support a central pathogenic role for Aß in late-onset AD. Furthermore, the amyloid cascade hypothesis lacks a theoretical foundation from which the physiological generation of Aß can be understood, and therapeutic approaches based on its premises have failed. We present an alternative model of neurodegeneration, in which sustained cholesterol-associated neuronal distress is the most likely pathogenic trigger in late-onset AD, directly causing oxidative stress, inflammation and tau hyperphosphorylation. In this scenario, Aß generation is part of an APP-driven adaptive response to the initial cholesterol distress, and its accumulation is neither central to, nor a requirement for, the initiation of the disease. Our model provides a theoretical framework that places APP as a regulator of cholesterol homeostasis, accounts for the generation of Aß in both healthy and demented brains, and provides suitable targets for therapeutic intervention.

Differential responses of hippocampal neurons and astrocytes to nicotine and hypoxia in the fetal guinea pig.

In utero exposure to cigarette smoke has severe consequences for the developing fetus, including increased risk of birth complications and behavioral and learning disabilities later in life. Evidence from animal models suggests that the cognitive deficits may be a consequence of in utero nicotine exposure in the brain during critical developmental periods. However, maternal smoking exposes the fetus to not only nicotine but also a hypoxic intrauterine environment. Thus, both nicotine and hypoxia are capable of initiating cellular cascades, leading to long-term changes in synaptic patterning that have the potential to affect cognitive functions. This study investigates the combined effect of in utero exposure to nicotine and hypoxia on neuronal and glial elements in the hippocampal CA1 field. Fetal guinea pigs were exposed in utero to normoxic or hypoxic conditions in the presence or absence of nicotine. Hypoxia increased the protein levels of matrix metalloproteinase-9 (MMP-9) and synaptophysin and decreased the neural density as measured by NeuN immunoreactivity (ir). Nicotine exposure had no effect on these neuronal parameters but dramatically increased the density of astrocytes immunopositive for glial fibrillary acidic protein (GFAP). Further investigation into the effects of in utero nicotine exposure revealed that both GFAP-ir and NeuN-ir in the CA1 field were significantly reduced in adulthood. Taken together, our data suggest that prenatal exposure to nicotine and hypoxia not only alters synaptic patterning acutely during fetal development, but that nicotine also has long-term consequences that are observed well into adulthood. Moreover, these effects most likely take place through distinct mechanisms.