Current understanding of AD pathophysiology and impact of amyloid‐beta targeted treatments on biomarkers and clinical endpoints
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ABSTRACT:
SUBMITTER: Petersen R
PROVIDER: S-EPMC9583953 | biostudies-literature | 2022 Jan
REPOSITORIES: biostudies-literature
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Project description:The discovery of effective therapeutics targeting amyloid-β (Aβ) aggregates for Alzheimer's disease (AD) has been very challenging, which suggests its complicated etiology associated with multiple pathogenic elements. In AD-affected brains, highly concentrated metals, such as copper and zinc, are found in senile plaques mainly composed of Aβ aggregates. These metal ions are coordinated to Aβ and affect its aggregation and toxicity profiles. In this review, we illustrate the current view on molecular insights into the assembly of Aβ peptides in the absence and presence of metal ions as well as the effect of metal ions on their toxicity.
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Project description:Introduction: Alzheimer's disease (AD) is a common, progressive neurological disorder whose incidence is reaching epidemic proportions. The prevailing "amyloid cascade hypothesis," which maintains that the aberrant proteolysis of beta-amyloid precursor protein (βAPP) into neurotoxic amyloid beta (Aβ) peptides is central to the etiopathology of AD, continues to dominate pharmacological approaches to the clinical management of this insidious disorder. This review is a compilation and update on current pharmacological strategies designed to down-regulate Aβ42 peptide generation in an effort to ameliorate the tragedy of AD. Areas covered: This review utilized online data searches at various open online-access websites including the Alzheimer Association, Alzheimer Research Forum; individual drug company databases; the National Institutes of Health (NIH) Medline; Pharmaprojects database; Scopus; inter-University research communications; and unpublished research data. Expert opinion: Anti-acetylcholinesterase-, chelation-, N-methyl-D-aspartate (NMDA) receptor antagonist-, statin-, Aβ immunization-, β-secretase-, γ-secretase-based, and other strategies to modulate βAPP processing, have dominated pharmacological approaches directed against AD-type neurodegenerative pathology. Cumulative clinical results of these efforts remain extremely disappointing, and have had little overall impact on the clinical management of AD. While a number of novel approaches are in consideration and development, to date there is still no effective treatment or cure for this expanding healthcare concern.
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Project description:Pre-eclampsia is characterized by new-onset hypertension and proteinuria at ≥20 weeks of gestation. In the absence of proteinuria, hypertension together with evidence of systemic disease (such as thrombocytopenia or elevated levels of liver transaminases) is required for diagnosis. This multisystemic disorder targets several organs, including the kidneys, liver and brain, and is a leading cause of maternal and perinatal morbidity and mortality. Glomeruloendotheliosis is considered to be a characteristic lesion of pre-eclampsia, but can also occur in healthy pregnant women. The placenta has an essential role in development of this disorder. Pathogenetic mechanisms implicated in pre-eclampsia include defective deep placentation, oxidative and endoplasmic reticulum stress, autoantibodies to type-1 angiotensin II receptor, platelet and thrombin activation, intravascular inflammation, endothelial dysfunction and the presence of an antiangiogenic state, among which an imbalance of angiogenesis has emerged as one of the most important factors. However, this imbalance is not specific to pre-eclampsia, as it also occurs in intrauterine growth restriction, fetal death, spontaneous preterm labour and maternal floor infarction (massive perivillous fibrin deposition). The severity and timing of the angiogenic imbalance, together with maternal susceptibility, might determine the clinical presentation of pre-eclampsia. This Review discusses the diagnosis, classification, clinical manifestations and putative pathogenetic mechanisms of pre-eclampsia.
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Project description:Adhesive shoulder capsulitis, or arthrofibrosis, describes a pathological process in which the body forms excessive scar tissue or adhesions across the glenohumeral joint, leading to pain, stiffness and dysfunction. It is a debilitating condition that can occur spontaneously (primary or idiopathic adhesive capsulitis) or following shoulder surgery or trauma (secondary adhesive capsulitis). Here, we review the pathophysiology of adhesive shoulder capsulitis, highlighting its clinical presentation, natural history, risk factors, pathoanatomy and pathogenesis. Both current non-operative and operative treatments for adhesive capsulitis are described, and evidence-based studies are presented in support for or against each corresponding treatment. Finally, the review also provides an update on the gene expression profile of adhesive capsulitis and how this new understanding can help facilitate development of novel pharmacological therapies.
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Project description:Anemia is a common complication in chronic kidney disease (CKD), and is associated with a reduced quality of life, and an increased morbidity and mortality. The mechanisms involved in anemia associated to CKD are diverse and complex. They include a decrease in endogenous erythropoietin (EPO) production, absolute and/or functional iron deficiency, and inflammation with increased hepcidin levels, among others. Patients are most commonly managed with oral or intravenous iron supplements and with erythropoiesis stimulating agents (ESA). However, these treatments have associated risks, and sometimes are insufficiently effective. Nonetheless, in the last years, there have been some remarkable advances in the treatment of CKD-related anemia, which have raised great expectations. On the one hand, a novel family of drugs has been developed: the hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs). These agents induce, among other effects, an increase in the production of endogenous EPO, improve iron availability and reduce hepcidin levels. Some of them have already received marketing authorization. On the other hand, recent clinical trials have elucidated important aspects of iron supplementation, which may change the treatment targets in the future. This article reviews the current knowledge of the pathophysiology CKD-related anemia, current and future therapies, the trends in patient management and the unmet goals.
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Project description:Heart Failure (HF) is the most common cause of hospitalization in the Western societies. HF is a heterogeneous and complex syndrome that may result from any dysfunction of systolic or diastolic capacity. Abnormal diastolic left ventricular function with impaired relaxation and increased diastolic stiffness is characteristic of heart failure with preserved ejection fraction (HFpEF). HFpEF accounts for more than 50% of all cases of HF. The prevalence increases with age: from around 1% for those aged <55 years to >10% in those aged 70 years or over. Nearly 50% of HF patients have HFrEF and the other 50% have HFpEF/HFmrEF, mainly based on studies in hospitalized patients. The ESC Long-Term Registry, in the outpatient setting, reports that 60% have HFrEF, 24% have HFmrEF, and 16% have HFpEF. To some extent, more than 50% of HF patients are female. HFpEF is closely associated with co-morbidities, age, and gender. Epidemiological evidence suggests that HFpEF is highly represented in older obese women and proposed as 'obese female HFpEF phenotype'. While HFrEF phenotype is more a male phenotype. In addition, metabolic abnormalities and hemodynamic perturbations in obese HFpEF patients appear to have a greater impact in women then in men (Sorimachi et al., European J of Heart Fail, 2022, 22). To date, numerous clinical trials of HFpEF treatments have produced disappointing results. This outcome suggests that a "one size fits all" approach to HFpEF may be inappropriate and supports the use of tailored, personalized therapeutic strategies with specific treatments for distinct HFpEF phenotypes. The most important mediators of diastolic stiffness are the cardiomyocytes, endothelial cells, and extracellular matrix (ECM). The complex physiological signal transduction networks that respond to the dual challenges of inflammatory and oxidative stress are major factors that promote the development of HFpEF pathologies. These signalling networks contribute to the development of the diseases. Inhibition and/or attenuation of these signalling networks also delays the onset of disease. In this review, we discuss the molecular mechanisms associated with the physiological responses to inflammation and oxidative stress and emphasize the nature of the contribution of most important cells to the development of HFpEF via increased inflammation and oxidative stress.
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Project description:BackgroundAlzheimer's disease (AD) cerebrospinal fluid (CSF) biomarker cutoffs from immunoassays with low interlaboratory variability in diverse ethnic groups are necessary for their use in clinics and clinical trials. With lack of cutoffs from fully automated immunoassay platforms in diverse races, the aim of this study is to evaluate the clinical utility of CSF AD biomarkers from the Lumipulse fully automated immunoassay based on β-amyloid (Aβ) positron emission tomography (PET) status comparing with these from two manual immunoassays, in Koreans.MethodsAmong 331 Korean participants enrolled from a prospective, 3-year longitudinal observational study of the validation cohort of Korean Brain Aging Study for the Early Diagnosis and Prediction of AD, 139 (29 CN, 58 SCD, 29 MCI, and 23 AD) provided CSF and 271 underwent baseline amyloid PET (n = 128 with overlapping CSF and Aβ-PET, and 143 without CSFs). Three annual cognitive and neuropsychiatric function tests were conducted. Aβ42, Aβ40, total-tau, and phosphorylated-tau181 were measured by Lumipulse fully automated immunoassay and two manual immunoassays (INNO-BIA AlzBio3, INNOTEST). Clinical utility of CSF biomarker cutoffs, based on 128 participants with Aβ-PET, was evaluated.ResultsCognitive and neuropsychological scores differed significantly among the groups, with descending performance among CN>SCD>MCI>AD. Biomarker levels among immunoassays were strongly intercorrelated. We determined the Aβ-PET status in a subgroup without CSF (n = 143), and then when we applied CSF biomarker cutoffs determined based on the Aβ-PET status, the CSF biomarkers (cutoffs of 642.1 pg/mL for Aβ42, 0.060 for Aβ42/Aβ40, 0.315 for t-tau/Aβ42, and 0.051 for p-tau/Aβ42, respectively) showed good agreement with Aβ-PET (overall AUC ranges of 0.840-0.898). Use of the Aβ-PET-based CSF cutoffs showed excellent diagnostic discrimination between AD and CN (Aβ42, Aβ42/Aβ40, t-tau/Aβ42, and p-tau/Aβ42) with overall AUC ranges of 0.876-0.952. During follow-up, participants with AD-like CSF signature determined by Aβ-PET-based cutoffs from Lumipulse showed rapid progression of cognitive decline in 139 subjects, after adjustment for potential confounders, compared with those with a normal CSF signature.ConclusionCSF AD biomarkers measured by different immunoassay platforms show strong intercorrelated agreement with Aβ-PET in Koreans. The Korean-specific Aβ-PET-based CSF biomarker cutoffs measured by the Lumipulse assay strongly predicts progression of cognitive decline. The clinical utility of CSF biomarkers from fully-automated immunoassay platforms should be evaluated in larger, more diverse cohorts.
| S-EPMC7802266 | biostudies-literature
Project description:Tacrolimus (TAC) has emerged as a potential therapy for Alzheimer's disease (AD), with the challenge of balancing its therapeutic benefits against its immunosuppressive effects. This study explores the efficacy of a sub-immunosuppressive TAC dosing regimen to ameliorate AD-related pathologies. TAC was administered daily for 14 days, with drug concentrations measured via liquid chromatography tandem mass spectrometry (LC-MS/MS) in whole blood and hippocampal tissue from C57BL6J mice, while immunofluorescence analyses and Western blotting (performed on hippocampal extracts) were conducted in 10-12 month old 3xTg-AD mice to evaluate levels of tau and amyloid-beta (Aβ) proteins. The results from LC-MS/MS revealed that lower TAC doses resulted in sub-immunosuppressive blood levels, while still penetrating the hippocampi. Immunofluorescence showed reductions in tau and Aβ proteins in 3xTg-AD mice. Additionally, Western blot analyses revealed reductions in tau and Aβ, along with increases in synaptic and autophagy-related proteins. These findings highlight the potential of sub-immunosuppressive TAC doses in effectively targeting AD pathology while minimizing the risk of chronic systemic immunosuppression. Further research and clinical trials are warranted to establish the optimal TAC dosing regimen for AD treatment.
| S-EPMC11898583 | biostudies-literature
Project description:IntroductionWe developed machine learning (ML) designed to analyze structural brain magnetic resonance imaging (MRI), and trained it on the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. In this study, we verified its utility in the Japanese population.MethodsA total of 535 participants were enrolled from the Japanese ADNI database, including 148 AD, 152 normal, and 235 mild cognitive impairment (MCI). Probability of AD was expressed as AD likelihood scores (ADLS).ResultsThe accuracy of AD diagnosis was 88.0% to 91.2%. The accuracy of predicting the disease progression in non-dementia participants over a 3-year observation was 76.0% to 79.3%. More than 90% of the participants with low ADLS did not progress to AD within 3 years. In the amyloid positron emission tomography (PET)-positive MCI, the hazard ratio of progression was 2.39 with low ADLS, and 5.77 with high ADLS. When high ADLS was defined as N+ and Pittsburgh compound B (PiB) PET positivity was defined as A+, the time to disease progression for 50% of MCI participants was 23.7 months in A+N+, whereas it was 52.3 months in A+N-.ConclusionThese results support the feasibility of our ML for the diagnosis of AD and prediction of the disease progression.
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