Alzheimer Disease Clinical Trials Targeting Amyloid: Lessons Learned From Success in Mice and Failure in Humans
BACKGROUND:The goal of slowing or halting the development of Alzheimer disease (AD) has resulted in the huge allocation of resources by academic institutions and pharmaceutical companies to the development of new treatments. The etiology of AD is elusive, but the aggregation of amyloid-Î² and tau peptide and oxidative processes are considered critical pathologic mechanisms. The failure of drugs with multiple mechanisms to meet efficacy outcomes has caused several companies to decide not to pursue further AD studies and has left the field essentially where it has been for the past 15 years. Efforts are underway to develop biomarkers for detection and monitoring of AD using genetic, imaging, and biochemical technology, but this is of minimal use if no intervention can be offered. REVIEW SUMMARY/RESULTS:In this review, we consider the natural progression of AD and how it continues despite present attempts to modify the amyloid-related machinery to alter the disease trajectory. We describe the mechanisms and approaches to AD treatment targeting amyloid, including both passive and active immunotherapy as well as inhibitors of enzymes in the amyloidogenic pathway. CONCLUSION/CONCLUSIONS:Lessons learned from clinical trials of amyloid reduction strategies may prove crucial for the leap forward toward novel therapeutic targets to treat AD.
Identification of a Novel Natriuretic Protein in Patients With Cerebral-Renal Salt Wasting-Implications for Enhanced Diagnosis
BACKGROUND:The most vexing problem in hyponatremic conditions is to differentiate the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) from cerebral/renal salt wasting (C-RSW). Both have identical clinical parameters but diametrically opposite therapeutic goals of water- restricting water-logged patients with SIADH or administering salt and water to dehydrated patients with C-RSW. While C-RSW is considered a rare condition, the report of a high prevalence of C-RSW in the general hospital wards creates an urgency to differentiate one syndrome from the other on first encounter. We decided to identify the natriuretic factor (NF) we previously demonstrated in plasma of neurosurgical and Alzheimer diseases (AD) who had findings consistent with C-RSW. METHODS:We performed the same rat renal clearance studies to determine natriuretic activity (NA) in serum from a patient with a subarachnoid hemorrhage (SAH) and another with AD and demonstrated NA in their sera. The sera were subjected to proteomic and SWATH (Sequential Windowed Acquisition of All) analyses which identified increased levels of haptoglobin related protein (Hpr) without signal peptide (Hpr-WSP). RESULTS:Recombinant Hpr with His tag at the N terminus had no NA. Hpr-WSP had a robust NA in a dose-dependent manner when injected into rats. Serum after recovery from C-RSW in the SAH patient had no NA. CONCLUSIONS:Hpr-WSP may be the NF in C-RSW which should be developed as a biomarker to differentiate C-RSW from SIADH on first encounter, introduces a new syndrome of C-RSW in AD and can serve as a proximal diuretic to treat congestive heart failure.
Effect of oxytocin on lipid accumulation under inflammatory conditions in human macrophages
INTRODUCTION AND AIMS/OBJECTIVE:Oxytocin (OT) is a neuropeptide hormone secreted by the posterior pituitary gland. Deficits in OT action have been observed in patients with behavioral and mood disorders, some of which correlate with an increased risk of cardiovascular disease (CVD). Recent research has revealed a wider systemic role that OT plays in inflammatory modulation and development of atherosclerotic plaques. This study investigated the role that OT plays in cholesterol transport and foam cell formation in LPS-stimulated THP-1 human macrophages. METHODS:THP-1 differentiated macrophages were treated with media, LPS (100â€¯ng/ml), LPSâ€¯+â€¯OT (10 pM), or LPSâ€¯+â€¯OT (100 pM). Changes in gene expression and protein levels of cholesterol transporters were analyzed by real time quantitative PCR (RT-qPCR) and Western blot, while ox-LDL uptake and cholesterol efflux capacity were evaluated with fluorometric assays. RESULTS:RT-qPCR analysis revealed a significant increase in ABCG1 gene expression upon OTâ€¯+â€¯LPS treatment, compared to LPS alone (pâ€¯=â€¯0.0081), with Western blotting supporting the increase in expression of the ABCG1 protein. Analysis of ox-LDL uptake showed a significantly lower fluorescent value in LPSâ€¯+â€¯OT (100pM) -treated cells when compared to LPS alone (pâ€¯<â€¯0.0001). While not statistically significant (pâ€¯=â€¯0.06), cholesterol efflux capacity increased with LPSâ€¯+â€¯OT treatment. CONCLUSION/CONCLUSIONS:We demonstrate here that OT can attenuate LPS-mediated lipid accumulation in THP-1 macrophages. These findings support the hypothesis that OT could be used to reduce pro-inflammatory and potentially atherogenic changes observed in patients with heightened CVD risk. This study suggests further exploration of OT effects on monocyte and macrophage cholesterol handling in vivo.
Alzheimer's disease: many failed trials, so where do we go from here?
Alzheimer's disease (AD) is a neurodegenerative brain disorder associated with relentlessly progressive cognitive impairment and memory loss. AD pathology proceeds for decades before cognitive deficits become clinically apparent, opening a window for preventative therapy. Imbalance of clearance and buildup of amyloid Î² and phosphorylated tau proteins in the central nervous system is believed to contribute to AD pathogenesis. However, multiple clinical trials of treatments aimed at averting accumulation of these proteins have yielded little success, and there is still no disease-modifying intervention. Here, we discuss current knowledge of AD pathology and treatment with an emphasis on emerging biomarkers and treatment strategies.
Toward prevention of behavioral emergencies in a general hospital insights from a one-year series
BACKGROUND:Behavioral emergencies endanger hospital staff and patients. The objective of this study was to identify patient characteristics that could be used to predict and prevent these incidents. METHODS:We analyzed a one-year consecutive series of behavioral emergencies that triggered the rapid response team at a general hospital, comparing study patients with controls who did not trigger a rapid response. Standard parametric or nonparametric tests, as appropriate, were used to compare the 2 groups in univariate analyses, and multivariable logistic regression analysis was used to identify the best combination of variables for stratifying the risk of such an event. RESULTS:There were 109 behavioral emergencies involving 83 patients. Comparison of patients who did (nÂ =Â 83) or did not (nÂ =Â 22,849) trigger a rapid response revealed marked differences between the two groups with respect to age, sex, and the prevalence of psychiatric comorbidities and various conditions that can diminish cognitive function. Substance use disorder was the most frequent principal diagnosis in the study group, accounting for 10.8% (9/83) of study patients vs. 0.6% (132/22849) of controls (pÂ <Â 0.0001). The presence of a condition that can impair cognition (substance intoxication and withdrawal, epilepsy, cerebrovascular disease, traumatic brain injury, delirium, dementia) was associated with a 13-fold increase in the risk of a behavioral disturbance (95% CI, 8 to 22-fold). CONCLUSIONS:Brief cognitive assessment of patients susceptible to cognitive impairment, along with diligent prophylaxis and management of substance withdrawal and delirium, may facilitate prevention of behavioral emergencies.
QTc monitoring in adults with medical and psychiatric comorbidities: Expert consensus from the Association of Medicine and Psychiatry
OBJECTIVE:Several psychiatric medications have the potential to prolong the QTc interval and subsequently increase the risk for ventricular arrhythmias such as torsades de pointes (TdP). There is limited guidance for clinicians to balance the risks and benefits of treatments. METHODS:After a review of the existing literature, clinical-educators from the Association of Medicine and Psychiatry developed expert consensus guidelines for ECG monitoring of the QTc interval for patients with medical and psychiatric comorbidities who are prescribed medications with the potential to prolong the QTc interval. A risk score was developed based on risk factors for QTc prolongation to guide clinical decision-making. RESULTS:A baseline ECG may not be necessary for individuals at low risk for arrythmia. Those individuals with a risk score of two or more should have an ECG prior to the start of a potentially QTc-prolonging medication or be started on a lower risk agent. Antipsychotics are not equivalent in causing QTc prolongation. A consensus-based algorithm is presented for the management of those identified at high (QTc >500Â msec), intermediate (males with QTc 450-499Â msec or females with QTcÂ >Â 470-499Â msec), or low risk. CONCLUSIONS:The proposed algorithm can help clinicians in determining whether ECG monitoring should be considered for a given patient. These guidelines preserve a role for clinical judgment in selection of treatments that balance the risks and benefits, which may be particularly relevant for complex patients with medical and psychiatric comorbidities. Additional studies are needed to determine whether baseline and serial ECG monitoring reduces mortality.
Reinventing Behavioral Health During the COVID-19 Pandemic
Cholesterol deficiency as a mechanism for autism: A valproic acid model (3367755) [Meeting Abstract]
Purpose of Study Autism spectrum disorders (ASDs) are neurodevelopmental disorders with lifelong consequences and poorly understood pathophysiology. Dysregulated cholesterol metabolism is implicated in ASD etiology. Cholesterol is essential for neuroactive steroid production, myelin sheath formation, and normal brain development. Early postnatal or in utero exposure to the antiepileptic drug valproic acid (VPA), a branched short-chain fatty acid, causes autism-like neural and behavioral deficits in humans and rodents. This study examines the link between VPA and cholesterol deficit in cultured human neurons and microglia. Methods Used SHSY-5Y human neuroblastoma cells and HMC3 human microglial cells were exposed to VPA at 0, 250, 1000 and 5000 muM for 24h, N=3 per condition. Expression of critical genes that regulate cholesterol transport were quantified by RT-PCR using specific primers for each. These include the efflux proteins ABCA1, ABCG1, 27-hydroxylase (27-OHase) and 24-hydroxylase (24-OHase), and the influx scavenger receptor CD36 - all vital for brain cholesterol balance. Expression of these target genes was normalized to concurrently measured GAPDH mRNA levels. Summary of Results In SH-SY5Y neurons, VPA exposure caused a concentration-dependent increase in ABCA1 (P <0.001), ABCG1, 27-OHase (P <0.001) (figure 1), and CD36 (P=0.015). In HMC3, VPA exposure caused a concentration- dependent increase in ABCG1 (80-fold at highest dose, P<=0.001) and 24-OHase (P < 0.001) with a reduction in ABCA-1 (P=0.002) and an increase in CD36 (P<0.001). Conclusions This study shows that VPA has a dramatic hypocholesterolemic effect on two key cell types that compose the developing brain. The net impact of the changes observed in these cholesterol-related genes would be outflow and metabolism. Further, enhanced 27-OHase activity produces an oxysterol metabolite with neurotoxic effects that include downregulating synaptic proteins and decreasing neurite number and length. Together, our results suggest that VPA impairs brain cholesterol homeostasis. A better understanding of the involvement of cholesterol in the mechanisms by which VPA leads to ASDs may translate into novel preventative therapies for this serious disorder
Innovations for integrated care: The Association of Medicine and Psychiatry recognizes new models [Editorial]
This editorial looks at the current state of the integration of medicine and psychiatry in clinical practice. We note selected recent triumphs and barriers to implementing integrated care, highlighting some gaps and priorities for future innovations. In contrast to the relatively more orderly culture of health services research, where some notable innovations in integrated care were funded, tested, and published, the health care marketplace can be a difficult place to identify and track the innovations that could shape health care reform. Recognizing the need to find, describe, and disseminate the most innovative models in integrated care, the Association of Medicine and Psychiatry (AMP) launched in 2016 the Innovative Models for Integrated Care Awards. Although many service innovations solve local problems, some can also act as models to be adopted in multiple settings. The projects that win AMP Innovative Models for Integrated Care Awards are selected for their innovativeness, their clinical importance, their generalizability, and their effectiveness. We briefly describe here the four models that earned these awards at the 2017 AMP Annual Meeting. They demonstrate innovations across a range of settings and populations: inpatient general hospital patients under constant observation in New York, severely mentally ill patients in a federally qualified health center in San Francisco, outpatients in a VA women's health center in Chicago, and HIV patients in an academic infectious disease clinic in Charleston, south Carolina. These model descriptions aim to encourage the implementation of innovative models that advance the integration of medicine and psychiatry.
Cycloid Psychosis Comorbid with Prader-Willi Syndrome: A Case Series
Psychosis is a relatively common psychiatric phenomenon seen in patients with Prader-Willi Syndrome (PWS). However, the presentation is atypical and difficult to classify within currently defined affective or psychotic disorders. This distinct presentation may be better understood as a phenomenon called "cycloid psychosis," described as an episodic psychosis with rapid full recovery between episodes. This study retrospectively analyzed the cases of 12 patients with genetically confirmed PWS who presented to an ambulatory psychiatric center for a change in behavior consistent with psychosis. Each case was then assessed for symptoms of cycloid psychosis, bipolar disorder, depression with psychotic features, schizophrenia, and schizoaffective disorder. Out of the 12 patients, 11 (91.7%) met the currently described diagnostic criteria for cycloid psychosis. Of the 12 patients, 7 (58.3%) also met the diagnostic criteria for bipolar disorder, and 1 (8.3%) also met the diagnostic criteria for schizoaffective disorder. None of the patients met the criteria for schizophrenia or depression with psychotic features. The findings in this study suggest that cycloid psychosis and bipolar disorder may both be comorbid with PWS. Psychiatric comorbidities in patients with PWS are atypical and clinicians should be aware of conditions such as cycloid psychosis when managing this vulnerable population.