Lecanemab in Early Alzheimer’s Disease

New England Journal of Medicine, Год журнала: 2022, Номер 388(1), С. 9 - 21

Опубликована: Ноя. 30, 2022

The accumulation of soluble and insoluble aggregated amyloid-beta (Aβ) may initiate or potentiate pathologic processes in Alzheimer's disease. Lecanemab, a humanized IgG1 monoclonal antibody that binds with high affinity to Aβ protofibrils, is being tested persons early

Язык: Английский

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Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Июнь 30, 2023

Abstract Amyloid β protein (Aβ) is the main component of neuritic plaques in Alzheimer’s disease (AD), and its accumulation has been considered as molecular driver pathogenesis progression. Aβ prime target for development AD therapy. However, repeated failures Aβ-targeted clinical trials have cast considerable doubt on amyloid cascade hypothesis whether drug followed correct course. recent successes targeted assuaged those doubts. In this review, we discussed evolution over last 30 years summarized application diagnosis modification. particular, extensively pitfalls, promises important unanswered questions regarding current anti-Aβ therapy, well strategies further study more feasible approaches optimization prevention treatment.

Язык: Английский

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Diagnostic Accuracy of a Plasma Phosphorylated Tau 217 Immunoassay for Alzheimer Disease Pathology

JAMA Neurology, Год журнала: 2024, Номер 81(3), С. 255 - 255

Опубликована: Янв. 22, 2024

Importance Phosphorylated tau (p-tau) is a specific blood biomarker for Alzheimer disease (AD) pathology, with p-tau217 considered to have the most utility. However, availability of tests research and clinical use has been limited. Expanding access this highly accurate AD crucial wider evaluation implementation tests. Objective To determine utility novel commercially available immunoassay plasma detect pathology evaluate reference ranges abnormal amyloid β (Aβ) longitudinal change across 3 selected cohorts. Design, Setting, Participants This cohort study examined data from single-center observational cohorts: cross-sectional Translational Biomarkers in Aging Dementia (TRIAD) (visits October 2017–August 2021) Wisconsin Registry Alzheimer’s Prevention (WRAP) February 2007–November 2020) Sant Pau Initiative on Neurodegeneration (SPIN) (baseline visits March 2009–November 2021). included individuals without cognitive impairment grouped by (AT) status using PET or CSF biomarkers. Data were analyzed June 2023. Exposures Magnetic resonance imaging, Aβ positron emission tomography (PET), PET, cerebrospinal fluid (CSF) biomarkers (Aβ42/40 p-tau immunoassays), (ALZpath pTau217 assay). Main Outcomes Measures Accuracy detecting according baseline status. Results The 786 participants (mean [SD] age, 66.3 [9.7] years; 504 females [64.1%] 282 males [35.9%]). High accuracy was observed identifying elevated (area under curve [AUC], 0.92-0.96; 95% CI, 0.89-0.99) (AUC, 0.93-0.97; 0.84-0.99) all These accuracies comparable determining signal. detection 3-range yielded reproducible results reduced confirmatory testing approximately 80%. Longitudinally, values showed an annual increase only Aβ-positive individuals, highest those positivity. Conclusions Relevance found that accurately identified biological AD, biomarkers, cut-offs It detected changes, including at preclinical stage.

Язык: Английский

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Clinical applications of stem cell-derived exosomes

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Янв. 12, 2024

Abstract Although stem cell-based therapy has demonstrated considerable potential to manage certain diseases more successfully than conventional surgery, it nevertheless comes with inescapable drawbacks that might limit its clinical translation. Compared cells, cell-derived exosomes possess numerous advantages, such as non-immunogenicity, non-infusion toxicity, easy access, effortless preservation, and freedom from tumorigenic ethical issues. Exosomes can inherit similar therapeutic effects their parental cells embryonic adult through vertical delivery of pluripotency or multipotency. After a thorough search meticulous dissection relevant literature the last five years, we present this comprehensive, up-to-date, specialty-specific disease-oriented review highlight surgical application exosomes. derived (e.g., embryonic, induced pluripotent, hematopoietic, mesenchymal, neural, endothelial cells) are capable treating encountered in orthopedic neurosurgery, plastic general cardiothoracic urology, head neck ophthalmology, obstetrics gynecology. The diverse cells-derived hierarchical translation tissue-specific responses, cell-specific molecular signaling pathways. In review, viable potent alternative managing various conditions. We recommend future research combines wisdoms surgeons, nanomedicine practitioners, cell researchers intriguing area.

Язык: Английский

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Neuropathology of Alzheimer's Disease

Neurotherapeutics, Год журнала: 2021, Номер 19(1), С. 173 - 185

Опубликована: Ноя. 2, 2021

Язык: Английский

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Past, present and future of therapeutic strategies against amyloid-β peptides in Alzheimer’s disease: a systematic review

Ageing Research Reviews, Год журнала: 2021, Номер 72, С. 101496 - 101496

Опубликована: Окт. 22, 2021

Alzheimer's disease (AD) is the most prevalent neurodegenerative in ageing, affecting around 46 million people worldwide but few treatments are currently available. The etiology of AD still puzzling, and new drugs development clinical trials have high failure rates. Urgent outline an integral (multi-target) effective treatment needed. Accumulation amyloid-β (Aβ) peptides considered one fundamental neuropathological pillars disease, its dyshomeostasis has shown a crucial role onset. Therefore, many amyloid-targeted therapies been investigated. Here, we will systematically review recent (from 2014) investigational, follow-up studies focused on anti-amyloid strategies to summarize analyze their current potential. Combination anti-Aβ with developing early detection biomarkers other therapeutic agents acting functional changes be highlighted this review. Near-term approval seems likely for several against Aβ, FDA monoclonal oligomers antibody –aducanumab– raising hopes controversies. We conclude that, oligomer-epitope specific Aβ implementation multiple improved risk prediction methods allowing detection, together factors such as hyperexcitability AD, could key slowing global pandemic.

Язык: Английский

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Amyloid Beta in Aging and Alzheimer’s Disease

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(21), С. 12924 - 12924

Опубликована: Окт. 26, 2022

Alzheimer’s disease (AD), is a progressive neurodegenerative that affects behavior, thinking, learning, and memory in elderly individuals. AD occurs two forms, early onset familial late-onset sporadic; genetic mutations PS1, PS2, APP genes cause AD, combination of lifestyle, environment factors causes the sporadic form disease. However, accelerated progression noticed patients with AD. Disease-causing pathological changes are synaptic damage, mitochondrial structural functional changes, addition to increased production accumulation phosphorylated tau (p-tau), amyloid beta (Aβ) affected brain regions patients. Aβ peptide derived from precursor protein (APP) by proteolytic cleavage gamma secretases. glycoprotein plays significant role maintaining neuronal homeostasis like signaling, development, intracellular transport. reported have both protective toxic effects neurons. The purpose our article summarize recent developments its association synapses, mitochondria, microglia, astrocytes, interaction p-tau. Our also covers therapeutic strategies reduce toxicities discusses reasons for failures therapeutics.

Язык: Английский

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Recent advances in Alzheimer’s disease: Mechanisms, clinical trials and new drug development strategies

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Авг. 23, 2024

Abstract Alzheimer’s disease (AD) stands as the predominant form of dementia, presenting significant and escalating global challenges. Its etiology is intricate diverse, stemming from a combination factors such aging, genetics, environment. Our current understanding AD pathologies involves various hypotheses, cholinergic, amyloid, tau protein, inflammatory, oxidative stress, metal ion, glutamate excitotoxicity, microbiota-gut-brain axis, abnormal autophagy. Nonetheless, unraveling interplay among these pathological aspects pinpointing primary initiators require further elucidation validation. In past decades, most clinical drugs have been discontinued due to limited effectiveness or adverse effects. Presently, available primarily offer symptomatic relief often accompanied by undesirable side However, recent approvals aducanumab ( 1 ) lecanemab 2 Food Drug Administration (FDA) present potential in disrease-modifying Nevertheless, long-term efficacy safety need Consequently, quest for safer more effective persists formidable pressing task. This review discusses pathogenesis, advances diagnostic biomarkers, latest updates trials, emerging technologies drug development. We highlight progress discovery selective inhibitors, dual-target allosteric modulators, covalent proteolysis-targeting chimeras (PROTACs), protein-protein interaction (PPI) modulators. goal provide insights into prospective development application novel drugs.

Язык: Английский

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Association of MRI Indices of Glymphatic System With Amyloid Deposition and Cognition in Mild Cognitive Impairment and Alzheimer Disease

Neurology, Год журнала: 2022, Номер 99(24)

Опубликована: Сен. 19, 2022

The glymphatic system is a whole-brain perivascular network, which promotes CSF/interstitial fluid exchange. Alterations to this may play pivotal role in amyloid β (Aβ) accumulation. However, its involvement Alzheimer disease (AD) pathogenesis not fully understood. Here, we investigated the changes noninvasive MRI measurements related network patients with mild cognitive impairment (MCI) and AD. Additionally, explored associations of measures neuropsychological score, PET standardized uptake value ratio (SUVR), Aβ deposition.

Язык: Английский

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Anti-Amyloid Monoclonal Antibodies are Transformative Treatments that Redefine Alzheimer's Disease Therapeutics

Drugs, Год журнала: 2023, Номер 83(7), С. 569 - 576

Опубликована: Апрель 15, 2023

Two anti-amyloid monoclonal antibodies (MABs)—lecanemab (Leqembi®) and aducanumab (Aduhelm®)—have been approved in the USA for treatment of Alzheimer's disease (AD). Anti-amyloid are first disease-modifying therapies AD that achieve slowing clinical decline by intervening basic biological processes disease. These breakthrough agents can slow inevitable progression into more severe cognitive impairment. The results trials MABs support amyloid hypothesis as a target drug development. success reflects relentless application neuroscience knowledge to solving major challenges facing humankind. these transformative will foster development MABs, other types therapies, treatments targets biology, new approaches an array neurodegenerative disorders. Monoclonal have side effects and, during period initiation, patients must be closely monitored occurrence amyloid-related imaging abnormalities (ARIA) infusion reactions. A successful step therapy defines desirable features next phase therapeutic including less frequent ARIA, convenient administration, greater efficacy. Unprecedented make demands on care partners, clinicians, payers, health systems. Collaboration among stakeholders is essential take advantage benefits offered them widely available. usher era define landscape what possible

Язык: Английский

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