Critical Appraisal of Amyloid Lowering Agents in AD.
Ontology highlight
ABSTRACT: Purpose of review
According to the amyloid cascade hypothesis, removing amyloid beta (Aβ) should cure Alzheimer's disease (AD). In the past three decades, many agents have been tested to try to lower Aβ production, prevent Aβ aggregation, and dissolve Aβ deposits. However, the paucity in definitive preventative or curative properties of these agents in clinical trials has resulted in more avant-garde approaches to therapeutic investigations. Immunotherapy has become an area of focus for research on disease-modifying therapies for neurodegenerative diseases. In this review, we highlight the current clinical development landscape of monoclonal antibody (mAb) therapies that target Aβ plaque formation and removal in AD.Recent findings
Multiple potential disease-modifying therapeutics for AD are in active development. Targeting Aβ with mAbs has the potential to treat various stages of AD: prodromal, prodromal to mild, mild, and mild to moderate. Monoclonal antibodies discussed here include aducanumab, lecanemab, solanezumab, crenezumab, donanemab, and gantenerumab. The final decision by the FDA regarding the approval of aducanumab will offer valuable insight into the trajectory of drug development for mAbs in AD and other neurodegenerative diseases. Future directions for improving the treatment of AD will include more inquiry into the efficacy of mAbs as disease-modifying agents that specifically target Aβ peptides and/or multimers. In addition, a more robust trial design for AD immunotherapy agents should improve outcomes such that objective measures of clinical efficacy will eventually lead to higher chances of drug approval.
SUBMITTER: Decourt B
PROVIDER: S-EPMC8192384 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Multiple cellular changes have been identified as being involved in Alzheimer's disease (AD) pathogenesis, including mitochondrial damage, synaptic loss, amyloid beta (Aβ) production and/or accumulation, inflammatory responses, and phosphorylated tau formation and/or accumulation. Studies have established that Aβ-induced synaptic dysfunction is dependent on abnormal amyloid precursor protein (APP) processing caused by β- and γ-secretases, resulting in the generation of Aβ. The Aβ formed as a result of abnormal APP processing induces phosphorylated tau and activates glycogen synthase kinase-3β (GSK3β) and cyclin-dependent kinase-5 (CDK5). Here, we review the latest research on the development of Aβ modulators for neuroprotection in AD. We also review the use of molecular inhibitors as therapeutic targets in AD.
| S-EPMC5344027 | biostudies-literature
Project description:IntroductionThe objective of this study was to review and critically appraise the medical education literature pertaining to a flipped-classroom (FC) education model, and to highlight influential papers that inform our current understanding of the role of the FC in medical education.MethodsA search of the English-language literature querying Education Resources Information Center (ERIC), PsychINFO, PubMed, and Scopus identified 296 papers related to the FC using either quantitative, qualitative, or review methods. Two reviewers independently screened each category of publications using previously established exclusion criteria. Eight reviewers then independently scored the remaining 54 publications using either a qualitative, quantitative, or review-paper scoring system. Each scoring system consisted of nine criteria and used parallel metrics that have been previously used in critical appraisals of education research.ResultsA total of 54 papers (33 quantitative, four qualitative, and 17 review) on FC met a priori criteria for inclusion and were critically appraised and reviewed. The top 10 highest scoring articles (five quantitative studies, two qualitative studies, and three review papers) are summarized in this article.ConclusionThis installment of the Council of Emergency Medicine Residency Directors (CORD) Academy Critical Appraisal series highlights 10 papers that describe the current state of literature on the flipped classroom, including an analysis of the benefits and drawbacks of an FC approach, practical implications for emergency medicine educators, and next steps for future research.
| S-EPMC6526887 | biostudies-literature
Project description:Background & aimsSeveral observational studies have recently reported the outcomes of non-insulin anti-diabetic agents (ADA) in patients with T2DM and coronavirus disease 2019 (COVID-19). We sought to review the literature to appraise the clinicians on these outcomes.MethodsA literature search using the specific keywords was carried out in the database of PubMed, MedRxiv and Google Scholar up till December 11, 2020 applying Boolean method. Full text of all the relevant articles that reported the outcomes of ADA in patients with T2DM and COVID-19 were retrieved. Subsequently, an appraisal of literature report was narratively presented.ResultsAvailable studies that reported the outcomes of ADA are either case series or retrospective cohorts or prospective observational studies, in absence of the randomized controlled trials (RCTs). Results from these observational studies suggest that amongst all the non-insulin ADA, metformin users prior to the hospitalization had improved outcomes compared to the non-users. Data for dipeptidyl-peptidase-4 inhibitors (DPP-4i) are encouraging although inconsistent. No documentation of any harm or benefit has been observed for sulfonylureas (SUs), sodium glucose co-transporter-2 inhibitors (SGLT-2i) and glucagon-like peptide receptor agonists (GLP-1RAs). No data is yet available for pioglitazone.ConclusionMetformin and DPP-4i should be continued in patients with T2DM until hospitalization or unless contraindicated. No evidence of harm suggests that SUs, SGLT-2i or GLP-1RAs may not be stopped unless very sick, hospitalized or contraindicated. The results from RCTs are needed to claim any meaningful benefit with either metformin or DPP-4i in patients with T2DM and COVID-19.
| S-EPMC7832723 | biostudies-literature
Project description:BackgroundInterleukin-6 (IL-6) contributes to numerous inflammatory, metabolic, and physiologic pathways of disease. We evaluated four IL-6 immunoassays in order to identify a reliable assay for studies of metabolic and physical function. Serial plasma samples from intravenous glucose tolerance tests (IVGTTs), with expected rises in IL-6 concentrations, were used to test the face validity of the various assays.Methods and findingsIVGTTs, administered to 14 subjects, were performed with a single infusion of glucose (0.3 g/kg body mass) at time zero, a single infusion of insulin (0.025 U/kg body mass) at 20 minutes, and frequent blood collection from time zero to 180 minutes for subsequent Il-6 measurement. The performance metrics of four IL-6 detection methods were compared: Meso Scale Discovery immunoassay (MSD), an Invitrogen Luminex bead-based multiplex panel (LX), an Invitrogen Ultrasensitive Luminex bead-based singleplex assay (ULX), and R&D High Sensitivity ELISA (R&D). IL-6 concentrations measured with MSD, R&D and ULX correlated with each other (Pearson Correlation Coefficients r = 0.47-0.94, p<0.0001) but only ULX correlated (r = 0.31, p = 0.0027) with Invitrogen Luminex. MSD, R&D, and ULX, but not LX, detected increases in IL-6 in response to glucose. All plasma samples were measurable by MSD, while 35%, 1%, and 4.3% of samples were out of range when measured by LX, ULX, and R&D, respectively. Based on representative data from the MSD assay, baseline plasma IL-6 (0.90 ± 0.48 pg/mL) increased significantly as expected by 90 minutes (1.29 ± 0.59 pg/mL, p = 0.049), and continued rising through 3 hours (4.25 ± 3.67 pg/mL, p = 0.0048).ConclusionThis study established the face validity of IL-6 measurement by MSD, R&D, and ULX but not LX, and the superiority of MSD with respect to dynamic range. Plasma IL-6 concentrations increase in response to glucose and insulin, consistent with both an early glucose-dependent response (detectable at 1-2 hours) and a late insulin-dependent response (detectable after 2 hours).
| S-EPMC3276568 | biostudies-literature
Project description:A few cases of parkinsonism linked to COVID-19 infection have been reported so far, raising the possibility of a post-viral parkinsonian syndrome. The objective of this review is to summarize the clinical, biological, and neuroimaging features of published cases describing COVID-19-related parkinsonism and to discuss the possible pathophysiological mechanisms. A comprehensive literature search was performed using NCBI's PubMed database and standardized search terms. Thirteen cases of COVID-19-related parkinsonism were included (7 males; mean age: 51 years ± 14.51, range 31-73). Patients were classified based on the possible mechanisms of post-COVID-19 parkinsonism: extensive inflammation or hypoxic brain injury within the context of encephalopathy (n = 5); unmasking of underlying still non-symptomatic Parkinson's Disease (PD) (n = 5), and structural and functional basal ganglia damage (n = 3). The various clinical scenarios show different outcomes and responses to dopaminergic treatment. Different mechanisms may play a role, including vascular damage, neuroinflammation, SARS-CoV-2 neuroinvasive potential, and the impact of SARS-CoV-2 on α-synuclein. Our results confirm that the appearance of parkinsonism during or immediately after COVID-19 infection represents a very rare event. Future long-term observational studies are needed to evaluate the possible role of SARS-CoV-2 infection as a trigger for the development of PD in the long term.
| S-EPMC9313170 | biostudies-literature
Project description:BackgroundIn Parkinson's disease (PD), there is heterogeneity in the clinical presentation and underlying biology. Research on PD subtypes aims to understand this heterogeneity with potential contribution for the knowledge of disease pathophysiology, natural history and therapeutic development. There have been many studies of PD subtypes but their impact remains unclear with limited application in research or clinical practice.ObjectiveTo critically evaluate PD subtyping systems.MethodsWe conducted a systematic review of PD subtypes, assessing the characteristics of the studies reporting a subtyping system for the first time. We completed a critical appraisal of their methodologic quality and clinical applicability using standardized checklists.ResultsWe included 38 studies. The majority were cross-sectional (n = 26, 68.4%), used a data-driven approach (n = 25, 65.8%), and non-clinical biomarkers were rarely used (n = 5, 13.1%). Motor characteristics were the domain most commonly reported to differentiate PD subtypes. Most of the studies did not achieve the top rating across items of a Methodologic Quality checklist. In a Clinical Applicability Checklist, the clinical importance of differences between subtypes, potential treatment implications and applicability to the general population were rated poorly, and subtype stability over time and prognostic value were largely unknown.ConclusionSubtyping studies undertaken to date have significant methodologic shortcomings and most have questionable clinical applicability and unknown biological relevance. The clinical and biological signature of PD may be unique to the individual, rendering PD resistant to meaningful cluster solutions. New approaches that acknowledge the individual-level heterogeneity and that are more aligned with personalized medicine are needed.
| S-EPMC8150501 | biostudies-literature
Project description:Background Tobacco use is a leading preventable cause of morbidity and mortality globally. Clinical practice guidelines for the treatment of tobacco use dependence are of varied scope and quality, making it challenging for users to select and apply recommendations. Objective The study objective is to identify and critically appraise the quality of existing clinical practice guidelines for tobacco cessation. Setting The study occurred between collaborative academic institutions located in Qatar and New Zealand. Methods A systematic literature search was performed for the period 2006-2018 through the following databases: PubMed, EMBASE, CINAHL, ISI Web of Science, Scopus, National Guideline Clearing House, Campbell Library, Health System Evidence, Joanna Briggs Institute Evidence-Based Practice Database, Academic Search Complete, ProQuest, PROSPERO, and Google Scholar. Relevant professional societies' and health agencies' websites were also searched. Two reviewers independently extracted and assessed guidelines' quality using Appraisal of Guidelines, Research and Evaluation II (AGREE II) instrument. Main outcome measure Standardized domain scores according to the AGREE II instrument. Results 7741 hits were identified. After removing duplicates and screening, 24 guidelines were included. Highest guideline quality was for National Institute for Health and Care Excellence (NICE) guideline with an overall ranking score of 87.56% and least quality was for Japanese Circulation Society Joint Working Group with an overall score of 29.34%. Domain 4 of AGREE II (clarity of presentation) had the highest average quality score (70.95%), while the lowest average quality scores were for Domain 2 (Rigour of Development) (50.21%) and Domain 5 (Applicability) (45.05%). Conclusion Seven guidelines were judged to be of high quality (overall score of ≥ 70%). Future guidelines for tobacco dependence treatment should use rigorous methods of development and provide applicable recommendations.
| S-EPMC7878272 | biostudies-literature
Project description:Diabetes mellitus (DM) is a major risk factor for cardiovascular events, including ischemic stroke. Moreover, ischemic stroke appears to be more severe in these patients and to be associated with less favorable outcomes. However, strict glycemic control does not appear to reduce the risk of ischemic stroke. On the other hand, newer glucose-lowering agents (glucagon-like peptide 1 receptor agonists and sodium-glucose cotransporter 2 inhibitors) reduced the risk of cardiovascular events in recent randomized, placebo-controlled trials. Semaglutide also reduced the risk of ischemic stroke. These benefits are independent of glucose lowering and might be due to the favorable effects of these agents on body weight and blood pressure. Pioglitazone also reduced the risk of recurrent stroke in patients with insulin resistance or type 2 DM but the unfavorable safety profile limits its use. In contrast, sulfonylureas and dipeptidyl peptidase 4 inhibitors have a neutral effect on cardiovascular morbidity and might be less attractive options in this high-risk population.
| S-EPMC5483425 | biostudies-other
Project description:Ablation of atrial fibrillation is an established treatment for the management of patients with paroxysmal and persistent atrial fibrillation. The complex pathophysiology of persistent atrial fibrillation has fuelled the concept of adjunctive substrate modification on top of pulmonary vein isolation. However, recent studies have failed to demonstrate additive benefit from complex ablation approaches, thus supporting that standalone pulmonary vein isolation may prove sufficient, at least as the initial ablation strategy in persistent atrial fibrillation. In this premise, the new-generation cryoballoon is an attractive option in this demanding subgroup of patients due to its reliable efficacy in achieving pulmonary vein isolation combined with collateral debulking of the neighbouring atrial myocardium. In this review, we present a critical appraisal of the role of cryoablation in patients with persistent atrial fibrillation, discussing related technical considerations and existing scientific evidence.
| S-EPMC5005190 | biostudies-literature
Project description:Tissue engineering is defined as the combination of biomaterials and bioengineering principles together with cell transplantation or directed growth of host cells to develop a biological replacement tissue or organ that can be a substitute for normal tissue both in structure and function. Despite early promising preclinical studies, clinical translation of tissue engineering in pediatric urology into humans has been unsuccessful both for cell-seeded and acellular scaffolds. This can be ascribed to various factors, including the use of only non-diseased models that inaccurately describe the structural and functional modifications of diseased tissue. The paper addresses potential future strategies to overcome the limitations experienced in clinical applications so far. This includes the use of stem cells of various origins (mesenchymal stem cells, hematopoietic stem/progenitor cells, urine-derived stem cells, and progenitor cells of the urothelium) as well as the need for a deeper understanding of signaling pathways and directing tissue ingrowth and differentiation through the concept of dynamic reciprocity. The development of smart scaffolds that release trophic factors in a set and timely manner will probably improve regeneration. Modulation of innate immune response as a major contributor to tissue regeneration outcome is also addressed. It is unlikely that only one of these strategies alone will lead to clinically applicable tissue engineering strategies in pediatric urology. In the meanwhile, the fundamental new insights into regenerative processes already obtained in the attempts of tissue engineering of the lower urogenital tract remain our greatest gain.
| S-EPMC6604568 | biostudies-literature