Intranasal Drug Delivery by Nanotechnology: Advances in and Challenges for Alzheimer’s Disease Management

Pharmaceutics, Journal Year: 2023, Volume and Issue: 16(1), P. 58 - 58

Published: Dec. 29, 2023

Alzheimer's disease, a progressive neurodegenerative condition, is characterized by gradual decline in cognitive functions. Current treatment approaches primarily involve the administration of medications through oral, parenteral, and transdermal routes, aiming to improve function alleviate symptoms. However, these treatments face limitations, such as low bioavailability inadequate permeation. Alternative invasive methods, while explored, often entail discomfort require specialized assistance. Therefore, development non-invasive efficient delivery system crucial. Intranasal has emerged potential solution, although it constrained unique conditions nasal cavity. An innovative approach involves use nano-carriers based on nanotechnology for intranasal delivery. This strategy overcome current limitations providing enhanced bioavailability, improved permeation, effective traversal blood-brain barrier, extended retention within body, precise targeting brain. The comprehensive review focuses advancements designing various types nano-carriers, including polymeric nanoparticles, metal lipid liposomes, nanoemulsions, Quantum dots, dendrimers. These are specifically tailored therapeutic agents aimed at combatting disease. In summary, utilization systems show significant surmounting constraints disease strategies. Nevertheless, essential acknowledge regulatory well toxicity concerns associated with this route; meticulous consideration required when engineering carrier. underscores revolutionize management highlights importance addressing considerations safe implementations. Embracing could lead substantial field treatment.

Language: Английский

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The Enigma of Tau Protein Aggregation: Mechanistic Insights and Future Challenges

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(9), P. 4969 - 4969

Published: May 2, 2024

Tau protein misfolding and aggregation are pathological hallmarks of Alzheimer's disease over twenty neurodegenerative disorders. However, the molecular mechanisms tau in vivo remain incompletely understood. There two types aggregates brain: soluble (oligomers protofibrils) insoluble filaments (fibrils). Compared to filamentous aggregates, more toxic exhibit prion-like transmission, providing seeds for templated misfolding. Curiously, its native state, is a highly soluble, heat-stable that does not form fibrils by itself, even when hyperphosphorylated. In vitro studies have found negatively charged molecules such as heparin, RNA, or arachidonic acid generally required induce aggregation. Two recent breakthroughs provided new insights into mechanisms. First, an intrinsically disordered protein, undergo liquid-liquid phase separation (LLPS) both inside cells. Second, cryo-electron microscopy has revealed diverse fibrillar conformations associated with different Nonetheless, only core structurally resolved, remainder appears "fuzzy coat". From this review, it further (1) clarify role LLPS aggregation; (2) unveil structural features aggregates; (3) understand involvement fuzzy coat regions oligomer fibril formation.

Language: Английский

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Stress testing the Centiloid: Precision and variability of PET quantification of amyloid pathology

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: 20(8), P. 5102 - 5113

Published: July 4, 2024

Abstract INTRODUCTION Assessing the potential sources of bias and variability Centiloid (CL) scale is fundamental for its appropriate clinical application. METHODS We included 533 participants from AMYloid imaging to Prevent Alzheimer's Disease (AMYPAD DPMS) Neuroimaging Initiative (ADNI) cohorts. Thirty‐two CL pipelines were created using different combinations reference region (RR), RR target types, quantification spaces. Generalized estimating equations stratified by amyloid positivity used assess impact pipeline, radiotracer, age, brain atrophy, harmonization status on CL. RESULTS selection type most, particularly in amyloid‐negative individuals. The standard pipeline with whole cerebellum as robust against atrophy differences image resolution, 95% confidence intervals below ± 3.95 beta cutoffs (CL < 24). DISCUSSION recommended most scenarios. Confidence should be considered when operationalizing research settings. Highlights developed a framework evaluating factors. Reference delineation had highest values. Whole (WCB) plus brainstem (WCB+BSTM) regions yielded consistent results across tracers. resolution variation. Estimated within‐ between‐pipeline (95% interval) absolute units.

Language: Английский

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Once upon a time, the Amyloid Cascade Hypothesis

Ageing Research Reviews, Journal Year: 2023, Volume and Issue: 93, P. 102161 - 102161

Published: Dec. 6, 2023

Recent trials with monoclonal antibodies targeting amyloid-β (Aβ) in Alzheimer's disease (AD) have sparked a renewed interest disease-modifying therapies. Despite their promise, these leave the issue open and posit some doubts about validity of Amyloid Cascade Hypothesis (ACH). While scores neurocognitive tests improved upon treatment, real-world clinical benefits were minimal. This Viewpoint discusses additional, often overlooked findings from trials. We also emphasize multifactorial nature AD need for broader research perspective beyond simplistic model provided by ACH.

Language: Английский

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Considering challenges for the new Alzheimer's drugs: Clinical, population, and health system perspectives

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: 20(9), P. 6639 - 6646

Published: Aug. 6, 2024

Recent approvals of amyloid immunotherapy drugs for early Alzheimer's disease (AD) have been highly controversial. In this piece, we consider challenges from the clinical, population health, and health systems perspectives to role that new AD might be expected play, now in future, alleviating morbidity caused by population. Clinically, short-term effects are small, adverse events frequent, treatment regimens burdensome, and, crucially, long-term unknown. At a level, there is always likely trade-off between breadth access magnitude benefit any given individual. system roll out even only narrowly-defined patient groups will involve considerable resources identify treat eligible patients, with profound opportunity costs. Our considered view on current evidence each perspective imagining foreseeable future which significantly alleviates at scale. HIGHLIGHTS: met excitement but also controversy. Trial concerning, Results trial cohorts may not generalize broader, more complex patients. Significant resource requirements eligibility assessment drug administration. Use "presymptomatic" populations supported evidence.

Language: Английский

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Examining amyloid reduction as a surrogate endpoint through latent class analysis using clinical trial data for dominantly inherited Alzheimer's disease

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: 20(4), P. 2698 - 2706

Published: Feb. 23, 2024

Abstract INTRODUCTION Increasing evidence suggests that amyloid reduction could serve as a plausible surrogate endpoint for clinical and cognitive efficacy. The double‐blind phase 3 DIAN‐TU‐001 trial tested declines with increasing doses of solanezumab or gantenerumab. METHODS We used latent class (LC) analysis on data from the Dominantly Inherited Alzheimer Network Trials Unit 001 to test positron emission tomography (PET) potential biomarker. RESULTS LC categorized participants into three classes: no change, reduction, growth, based longitudinal Pittsburgh compound B PET standardized uptake value ratio data. amyloid‐no‐change was at an earlier disease stage amounts dementia. Despite similar baseline characteristics, amyloid‐reduction exhibited reductions in annual decline rates compared amyloid‐growth across multiple biomarker, clinical, outcomes. DISCUSSION indicates is associated improved outcomes supports its use biomarker trials. Highlights remarkably better measures. proves valuable testing trials lacking significant treatment effects.

Language: Английский

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[125I]IPC-Lecanemab: Synthesis and Evaluation of Aβ-Plaque-Binding Antibody and Comparison with Small-Molecule [18F]Flotaza and [125I]IBETA in Postmortem Human Alzheimer’s Disease

Neurology International, Journal Year: 2024, Volume and Issue: 16(2), P. 419 - 431

Published: April 8, 2024

Therapeutic antibodies for reducing Aβ plaque load in Alzheimer’s disease (AD) is currently making rapid progress. The diagnostic imaging of AD has been underway and now used clinical studies. Here, we report our preliminary findings on a therapeutic antibody, Lecanemab, postmortem brain anterior cingulate. [125I]5-iodo-3-pyridinecarboxamido-Lecanemab ([125I]IPC-Lecanemab) was prepared by coupling N-succinimidyl-5-([125I]iodo)-3-pyridinecarboxylate with Lecanemab modest yields. distinct binding [125I]IPC-Lecanemab to Aβ-rich regions human brains higher grey matter (GM) containing plaques compared white (WM) (GM/WM 1.6). Anti-Aβ immunostaining correlated regional the brains. consistent small molecules, [18F]flotaza [125I]IBETA, same subjects. [18F]Flotaza however, exhibited significantly GM/WM ratios (>20) [125I]IPC-Lecanemab. Our results suggest that radiolabeled retains ability bind may therefore be useful as PET radiotracer when labeled [124I]IPC-Lecanemab. directly visualize vivo promising antibody treatment planning dosing could complimentary small-molecule assess outcomes interventions.

Language: Английский

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The supersaturation perspective on the amyloid hypothesis

Chemical Science, Journal Year: 2023, Volume and Issue: 15(1), P. 46 - 54

Published: Oct. 16, 2023

The current amyloid hypothesis does not capture the full complexity of Aβ aggregation. Here we lay out a supersaturation framework to better understand molecular mechanism Alzheimer’s disease and develop more effective treatment strategies.

Language: Английский

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BACE1 Inhibitors for Alzheimer’s Disease: Current Challenges and Future Perspectives

Journal of Alzheimer s Disease, Journal Year: 2024, Volume and Issue: 101(s1), P. S53 - S78

Published: June 25, 2024

Disease-modifying therapies (DMT) for Alzheimer’s disease (AD) are highly longed-for. In this quest, anti-amyloid take center stage supported by genetic facts that highlight an imbalance between production and clearance of amyloid-β peptide (Aβ) in AD patients. Indeed, evidence from basic research, human biomarker studies, suggests the accumulation Aβ as a driver pathogenesis progression. The aspartic protease β-site AβPP cleaving enzyme (BACE1) is initiator production. Underpinning critical role BACE1 pathophysiology elevated concentration activity observed brain body fluids Therefore, prime drug target reducing levels early AD. Small-molecule inhibitors have been extensively developed last 20 years. However, clinical trials with these molecules discontinued futility or safety reasons. Most adverse side effects were due to other proteases cross-inhibition, including homologue BACE2, mechanism-based toxicity since has substrates important roles synaptic plasticity homeostasis besides protein precursor (AβPP). Despite setbacks, persists well-validated therapeutic which specific inhibitor high substrate selectivity may yet be found. review we provide overview evolution design pinpointing reached advanced phases liabilities precluded adequate trial effects. Finally, ponder on challenges must overcome achieve success.

Language: Английский

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[18F]Flotaza for Aβ Plaque Diagnostic Imaging: Evaluation in Postmortem Human Alzheimer’s Disease Brain Hippocampus and PET/CT Imaging in 5xFAD Transgenic Mice

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(14), P. 7890 - 7890

Published: July 18, 2024

The diagnostic value of imaging Aβ plaques in Alzheimer's disease (AD) has accelerated the development fluorine-18 labeled radiotracers with a longer half-life for easier translation to clinical use. We have developed [

Language: Английский

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