Management Of Alzheimer's Disease Research Articles

Blue paper on Alzheimer's disease in China(simplified version)

With the population aging in China, the prevalence and mortality rate of Alzheimer's disease (AD) have been rising in China. AD has become one of the major threats to people's health and social sustainable development. In order to support the Healthy China Initiative and promote health in China, "Chinese Alzheimer's Disease Blue Book (Simplified Edition)"(refer to as the Blue Book) was compiled by experts and scholars from the National Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University; the National Center for Chronic and Noncommunicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention; the National Health Commission Capacity Building and Continuing Education Center; and the China Population and Development Research Center. The epidemiological characteristics, diagnosis and treatment status, prevention and treatment management of AD and related cognitive disorders in China were systematically reviewed in the Blue Paper, aiming to provide references for the prevention of AD, provide support for the standardized diagnosis and treatment of the disease, and provide a reference for the government to formulate relevant health policies. Specifically, the Blue Book covers the following topics of AD and related cognitive disorders: (1)epidemiology characteristics; (2)economic burden; (3)influencing factors; (4)China Brain Cognitive Health Index; (5) diagnosis status; (6)treatment status; (7)construction of national center for cognitive disorders;(8)community-based prevention and control; (9) AD patients care; (10)public health resources for prevention and control.

Synthesis and Neurobehavioral Evaluation of a Potent Multitargeted Inhibitorfor the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) poses a significant health challenge worldwide, affecting millions of individuals, and projected to increase further as the global population ages. Current pharmacological interventions primarily target acetylcholine deficiency and amyloid plaque formation, but offer limited efficacy and are often associated with adverse effects. Given the multifactorial nature of AD, there is a critical need for novel therapeutic approaches that simultaneously target multiple pathological pathways. Targeting key enzymes involved in AD pathophysiology, such as acetylcholinesterase, butyrylcholinesterase, beta-site APP cleaving enzyme 1 (BACE1), and gamma-secretase, is a potential strategy to mitigate disease progression. To this end, our research group has conducted comprehensive in silico screening to identify some lead compounds, including IQ6 (SSZ), capable of simultaneously inhibiting the enzymes mentioned above. Building upon this foundation, we synthesized SSZ, a novel multitargeted ligand/inhibitor to address various pathological mechanisms underlying AD. Chemically, SSZ exhibits pharmacological properties conducive to AD treatment, featuring pyrrolopyridine and N-cyclohexyl groups. Preclinical experimental evaluation of SSZ in AD rat model showed promising results, with notable improvements in behavioral and cognitive parameters. Specifically, SSZ treatment enhanced locomotor activity, ameliorated gait abnormalities, and improved cognitive function compared to untreated AD rats. Furthermore, brain morphological analysis demonstrated the neuroprotective effects of SSZ, attenuating Aβ-induced neuronal damage and preserving brain morphology. Combined treatment of SSZ and conventional drugs (DON and MEM) showed synergistic effects, suggesting a potential therapeutic strategy for AD management. Overall, our study highlights the efficacy of multitargeted ligands like SSZ in combating AD by addressing the complex etiology of the disease. Further research is needed to elucidate the full therapeutic potential of SSZ and the exploration of similar compounds in clinical settings, offering hope for an effective AD treatment in the future.

Qifu-yin activates the Keap1/Nrf2/ARE signaling and ameliorates synaptic injury and oxidative stress in APP/PS1 mice

Ethnopharmacological relevanceThe traditional medicinal formulation, Qifu-yin (QFY), has been widely prescribed for Alzheimer's disease (AD) treatment in China, yet the comprehensive mechanisms through which QFY mitigates AD pathology remain to be fully delineated. Aim of the studyThis study aimed to explore the therapeutic implications of QFY on the synaptic injury and oxidative stress in the hippocampus of APPswe/PS1dE9 (APP/PS1) mice, with a concerted effort to elucidate the molecular mechanisms related to synaptic preservation and memory improvement. Materials and methodsThe components of QFY were identified by ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The neuroprotective effects of QFY was evaluated using six-month-old male APP/PS1 mice. Subsequent to a 15 days of QFY regimen, spatial memory was assessed utilizing the Morris water maze (MWM) test. Amyloid-beta (Aβ) aggregation was detected via immunostaining, while the quantification of Aβ1-40 and Aβ1-42 was achieved through enzyme-linked immunosorbent assay (ELISA). Transmission electron microscopy (TEM) was used to investigate the synaptic structure and mitochondrial morphology. Golgi staining was applied to examine dendritic spine density. Reactive oxygen species (ROS), 3-nitrotyrosine (3-NT) and 4-hydroxy-nonenal (4-HNE) assays were employed to assess oxidative stress. The expression profiles of Aβ metabolism-associated enzymes and the Keap1/Nrf2/ARE signaling pathway were determined by Western blot. ResultsA total of 20 principal compounds in QFY were identified. QFY mitigated memory deficits of APP/PS1 mice, including reducing escape latency and search distance and increasing the time and distance spent in the target quadrant. In addition, QFY increased platform crossings of APP/PS1 mice in the probe trial of MWM tests. TEM analysis showed that QFY increased synapse number in the CA1 region of APP/PS1 mice. Further studies indicated that QFY elevated the expression levels of Post synaptic density protein 95 (PSD95) and synaptophysin, and mitigated the loss of dendritic spine density in the hippocampus of APP/PS1 mice. QFY has been shown to ameliorated the structural abnormalities of mitochondria, including mitochondrial dissolution and degradation, up-regulate ATP synthesis and membrane potential in the hippocampus of APP/PS1 mice. Moreover, QFY activated the Keap1/Nrf2/ARE signaling pathway in the hippocampus of APP/PS1 mice, which might contribute to the neuroprotective effects of QFY. ConclusionQFY activates the Keap1/Nrf2/ARE signaling, and protects against synaptic and mitochondrial dysfunction in APP/PS1 mice, proposing a potential alternative therapeutic strategy for AD management.

Fisetin-loaded pluronic-based nanogel: Radiation synthesis for alleviating neurocognitive impairments in a rat model of alzheimer's disease via modulation of the apoptotic cascade

Alzheimer's disease (AD) is a neurodegenerative disorder marked by cognitive impairment and memory loss. In this study, AD was experimentally induced in rats using aluminum chloride (AlCl3) and D-galactose (D-gal). Fisetin (Fis), a natural compound with antioxidant and anti-inflammatory properties, has potential for neurodegeneration management, but its low bioavailability limits clinical applications. To address this, we synthesized and characterized Pluronic-2-Acrylamido-2-methylpropane sulfonic acid (PLUR-PAMPS) nanogels using gamma radiation and successfully loaded Fis onto them (Fis-PLUR-PAMPS). The optimal formulation exhibited minimal particle size, a highly acceptable polydispersity index, and the highest zeta-potential, enhancing stability and solubilization efficiency. Our goal was to improve Fis's bioavailability and assess its efficacy against AlCl3/D-gal-induced AD. Male albino Wistar rats were pre-treated orally with Fis (40 mg/kg) or Fis-PLUR-PAMPS for seven days, followed by a seven-day intraperitoneal injection of AlCl3 and D-gal. Behavioral assessments, histopathological analysis, and biochemical evaluation of markers related to AD pathology were conducted. Results demonstrated that Fis-PLUR-PAMPS effectively mitigated cognitive impairments and neurodegenerative signs induced by AlCl3/D-gal. These findings suggest that Fis-PLUR-PAMPS nanogels enhance Fis's bioavailability and therapeutic efficacy, offering a promising approach for AD management.

Exploring the therapeutic potential of Nelumbo nucifera leaf extract against amyloid-beta-induced toxicity in the Caenorhabditis elegans model of Alzheimer's disease.

Introduction: Alzheimer's disease (AD) represents a critical global health challenge with limited therapeutic options, prompting the exploration of alternative strategies. A key pathology in AD involves amyloid beta (Aβ) aggregation, and targeting both Aβ aggregation and oxidative stress is crucial for effective intervention. Natural compounds from medicinal and food sources have emerged as potential preventive and therapeutic agents, with Nelumbo nucifera leaf extract (NLE) showing promising properties. Methods: In this study, we utilized transgenic Caenorhabditis elegans (C. elegans) models to investigate the potential of NLE in countering AD and to elucidate the underlying mechanisms. Various assays were employed to assess paralysis rates, food-searching capabilities, Aβ aggregate accumulation, oxidative stress, lifespan under stress conditions, and the expression of stress-resistance-related proteins. Additionally, autophagy induction was evaluated by measuring P62 levels and the formation of LGG-1+ structures, with RNAi-mediated inhibition of autophagy-related genes to confirm the mechanisms involved. Results: The results demonstrated that NLE significantly reduced paralysis rates in CL4176 and CL2006 worms while enhancing food-searching capabilities in CL2355 worms. NLE also attenuated Aβ aggregate accumulation and mitigated Aβ-induced oxidative stress in C. elegans. Furthermore, NLE extended the lifespan of worms under oxidative and thermal stress conditions, while concurrently increasing the expression of stress-resistance-related proteins, including SOD-3, GST-4, HSP-4, and HSP-6. Moreover, NLE induced autophagy in C. elegans, as evidenced by reduced P62 levels in BC12921 worms and the formation of LGG-1+ structures in DA2123 worms. The RNAi-mediated inhibition of autophagy-related genes, such as bec-1 and vps-34, negated the protective effects of NLE against Aβ-induced paralysis and aggregate accumulation. Discussion: These findings suggest that NLE ameliorates Aβ-induced toxicity by activating autophagy in C. elegans. The study underscores the potential of NLE as a promising candidate for further investigation in AD management, offering multifaceted approaches to mitigate AD-related pathology and stress-related challenges.

AI for the prediction of early stages of Alzheimer's disease from neuroimaging biomarkers - A narrative review of a growing field.

The objectives of this narrative review are to summarize the current state of AI applications in neuroimaging for early Alzheimer's disease (AD) prediction and to highlight the potential of AI techniques in improving early AD diagnosis, prognosis, and management. We conducted a narrative review of studies using AI techniques applied to neuroimaging data for early AD prediction. We examined single-modality studies using structural MRI and PET imaging, as well as multi-modality studies integrating multiple neuroimaging techniques and biomarkers. Furthermore, they reviewed longitudinal studies that model AD progression and identify individuals at risk of rapid decline. Single-modality studies using structural MRI and PET imaging have demonstrated high accuracy in classifying AD and predicting progression from mild cognitive impairment (MCI) to AD. Multi-modality studies, integrating multiple neuroimaging techniques and biomarkers, have shown improved performance and robustness compared to single-modality approaches. Longitudinal studies have highlighted the value of AI in modeling AD progression and identifying individuals at risk of rapid decline. However, challenges remain in data standardization, model interpretability, generalizability, clinical integration, and ethical considerations. AI techniques applied to neuroimaging data have the potential to improve early AD diagnosis, prognosis, and management. Addressing challenges related to data standardization, model interpretability, generalizability, clinical integration, and ethical considerations is crucial for realizing the full potential of AI in AD research and clinical practice. Collaborative efforts among researchers, clinicians, and regulatory agencies are needed to develop reliable, robust, and ethical AI tools that can benefit AD patients and society.

Unveiling Immune-related feature genes for Alzheimer's disease based on machine learning.

The identification of diagnostic and therapeutic biomarkers for Alzheimer's Disease (AD) remains a crucial area of research. In this study, utilizing the Weighted Gene Co-expression Network Analysis (WGCNA) algorithm, we identified RHBDF2 and TNFRSF10B as feature genes associated with AD pathogenesis. Analyzing data from the GSE33000 dataset, we revealed significant upregulation of RHBDF2 and TNFRSF10B in AD patients, with correlations to age and gender. Interestingly, their expression profile in AD differs notably from that of other neurodegenerative conditions. Functional analysis unveiled their involvement in immune response and various signaling pathways implicated in AD pathogenesis. Furthermore, our study demonstrated the potential of RHBDF2 and TNFRSF10B as diagnostic biomarkers, exhibiting high discrimination power in distinguishing AD from control samples. External validation across multiple datasets confirmed the robustness of the diagnostic model. Moreover, utilizing molecular docking analysis, we identified dinaciclib and tanespimycin as promising small molecule drugs targeting RHBDF2 and TNFRSF10B for potential AD treatment. Our findings highlight the diagnostic and therapeutic potential of RHBDF2 and TNFRSF10B in AD management, shedding light on novel strategies for precision medicine in AD.

Navigating the future of Alzheimer’s care in Ireland - a service model for disease-modifying therapies in small and medium-sized healthcare systems

BackgroundA new class of antibody-based drug therapy with the potential for disease modification is now available for Alzheimer’s disease (AD). However, the complexity of drug eligibility, administration, cost, and safety of such disease modifying therapies (DMTs) necessitates adopting new treatment and care pathways. A working group was convened in Ireland to consider the implications of, and health system readiness for, DMTs for AD, and to describe a service model for the detection, diagnosis, and management of early AD in the Irish context, providing a template for similar small-medium sized healthcare systems.MethodsA series of facilitated workshops with a multidisciplinary working group, including Patient and Public Involvement (PPI) members, were undertaken. This informed a series of recommendations for the implementation of new DMTs using an evidence-based conceptual framework for health system readiness based on [1] material resources and structures and [2] human and institutional relationships, values, and norms.ResultsWe describe a hub-and-spoke model, which utilises the existing dementia care ecosystem as outlined in Ireland’s Model of Care for Dementia, with Regional Specialist Memory Services (RSMS) acting as central hubs and Memory Assessment and Support Services (MASS) functioning as spokes for less central areas. We provide criteria for DMT referral, eligibility, administration, and ongoing monitoring.ConclusionsHealthcare systems worldwide are acknowledging the need for advanced clinical pathways for AD, driven by better diagnostics and the emergence of DMTs. Despite facing significant challenges in integrating DMTs into existing care models, the potential for overcoming challenges exists through increased funding, resources, and the development of a structured national treatment network, as proposed in Ireland’s Model of Care for Dementia. This approach offers a replicable blueprint for other healthcare systems with similar scale and complexity.

Inequalities in the Prevention and Treatment of Alzheimer Disease.

Incidence of Alzheimer disease (AD) is going to rise in the next years and to become a health and social emergency. The prevention and the therapeutic management of AD still present unmet needs worldwide. The recent approval of monoclonal antibodies against amyloid β (anti-Aβ mAbs) for AD has increased the level of uncertainty regarding on how such drugs should be administered, to whom, and for how long. Concerns about cost-effectiveness ratios of anti-Aβ mAbs and the need for actual strategies of risk prevention have further dug barriers of inequalities between the national health care systems. Planning research to address questions on the real feasibility of the correct therapeutic management, improving international cooperation on surveillance of risk factors, implementing pathways for timely diagnosis, and effective medical and social support for patients with AD worldwide would be extremely valuable to fight against this upcoming pandemic.

A Comprehensive Analytical Review of Polyphenols: Evaluating Neuroprotection in Alzheimer's Disease.

Alzheimer's Disease (AD), a prevalent neurodegenerative disorder, is the primary cause of dementia. Despite significant advancements in neuroscience, a definitive cure or treatment for this debilitating disease remains elusive. A notable characteristic of AD is oxidative stress, which has been identified as a potential therapeutic target. Polyphenols, secondary metabolites of plant origin, have attracted attention due to their potent antioxidant properties. Epidemiological studies suggest a correlation between the consumption of polyphenol-rich foods and the prevention of chronic diseases, including neurodegenerative disorders, which underscores the potential of polyphenols as a therapeutic strategy in AD management. Hence, this comprehensive review focuses on the diverse roles of polyphenols in AD, with a particular emphasis on neuroprotective potential. Scopus, ScienceDirect, and Google Scholar were used as leading databases for study selection, from 2018 to late March 2024. Analytical chemistry serves as a crucial tool for characterizing polyphenols, with a nuanced exploration of their extraction methods from various sources, often employing chemometric techniques for a holistic interpretation of the advances in this field. Moreover, this review examines current in vitro and in vivo research, aiming to enhance the understanding of polyphenols' role in AD, and providing valuable insights for forthcoming approaches in this context.

Alzheimer's disease and its treatment-yesterday, today, and tomorrow.

Alois Alzheimer described the first patient with Alzheimer's disease (AD) in 1907 and today AD is the most frequently diagnosed of dementias. AD is a multi-factorial neurodegenerative disorder with familial, life style and comorbidity influences impacting a global population of more than 47 million with a projected escalation by 2050 to exceed 130 million. In the USA the AD demographic encompasses approximately six million individuals, expected to increase to surpass 13 million by 2050, and the antecedent phase of AD, recognized as mild cognitive impairment (MCI), involves nearly 12 million individuals. The economic outlay for the management of AD and AD-related cognitive decline is estimated at approximately 355 billion USD. In addition, the intensifying prevalence of AD cases in countries with modest to intermediate income countries further enhances the urgency for more therapeutically and cost-effective treatments and for improving the quality of life for patients and their families. This narrative review evaluates the pathophysiological basis of AD with an initial focus on the therapeutic efficacy and limitations of the existing drugs that provide symptomatic relief: acetylcholinesterase inhibitors (AChEI) donepezil, galantamine, rivastigmine, and the N-methyl-D-aspartate receptor (NMDA) receptor allosteric modulator, memantine. The hypothesis that amyloid-β (Aβ) and tau are appropriate targets for drugs and have the potential to halt the progress of AD is critically analyzed with a particular focus on clinical trial data with anti-Aβ monoclonal antibodies (MABs), namely, aducanumab, lecanemab and donanemab. This review challenges the dogma that targeting Aβ will benefit the majority of subjects with AD that the anti-Aβ MABs are unlikely to be the "magic bullet". A comparison of the benefits and disadvantages of the different classes of drugs forms the basis for determining new directions for research and alternative drug targets that are undergoing pre-clinical and clinical assessments. In addition, we discuss and stress the importance of the treatment of the co-morbidities, including hypertension, diabetes, obesity and depression that are known to increase the risk of developing AD.

Review of Pharmacotherapeutic Targets in Alzheimer's Disease and Its Management Using Traditional Medicinal Plants.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and impaired daily functioning. While there is currently no cure for AD, several pharmacotherapeutic targets and management strategies have been explored. Additionally, traditional medicinal plants have gained attention for their potential role in AD management. Pharmacotherapeutic targets in AD include amyloid-beta (Aβ) aggregation, tau protein hyperphosphorylation, neuroinflammation, oxidative stress, and cholinergic dysfunction. Traditional medicinal plants, such as Ginkgo biloba, Huperzia serrata, Curcuma longa (turmeric), and Panax ginseng, have demonstrated the ability to modulate these targets through their bioactive compounds. Ginkgo biloba, for instance, contains flavonoids and terpenoids that exhibit neuroprotective effects by reducing Aβ deposition and enhancing cerebral blood flow. Huperzia serrata, a natural source of huperzine A, has acetylcholinesterase-inhibiting properties, thus improving cholinergic function. Curcuma longa, enriched with curcumin, exhibits anti-inflammatory and antioxidant effects, potentially mitigating neuroinflammation and oxidative stress. Panax ginseng's ginsenosides have shown neuroprotective and anti-amyloidogenic properties. The investigation of traditional medicinal plants as a complementary approach to AD management offers several advantages, including a lower risk of adverse effects and potential multi-target interactions. Furthermore, the cultural knowledge and utilization of these plants provide a rich source of information for the development of new therapies. However, further research is necessary to elucidate the precise mechanisms of action, standardize preparations, and assess the safety and efficacy of these natural remedies. Integrating traditional medicinal-plant-based therapies with modern pharmacotherapies may hold the key to a more comprehensive and effective approach to AD treatment. This review aims to explore the pharmacotherapeutic targets in AD and assess the potential of traditional medicinal plants in its management.

A Critical Review Based on Preclinical Studies of Medicinal Plants for the Management of Alzheimer’s Disease

Abstract: Alzheimer’s disease (AD) is the most common neurodegenerative and progressive disorder that results in damage to memory and alters thinking and behavior, which represent critical problems the world’s aging population is faced with. Clinical symptoms of AD include cognitive decline, loss of memory, emotional and behavioral changes, loss of motor coordination, and mental impairments. Yet, neither a universally accepted diagnosis with respect to its pathogenesis nor an ideal therapy is available for the management of AD. The existing drugs cause many complications and adverse effects. Herbal drugs, supported by an abundance of traditional knowledge, may fulfill the need as they can target the pathogenesis of AD at various destinations, both at the cellular and molecular levels. In recent years, herbal drugs and formulations have been evaluated in preclinical setups, especially involving rat and mouse models of AD, which have shown their memoryenhancing, neuroprotective, and antioxidant activities. Several herbal drugs and phytochemicals have been evaluated for their effectiveness as antioxidative agents to prevent the occurrence of oxidative stress and ROS formation during AD pathogenesis and exhibit antiapoptotic properties by downregulating caspase-3, DNA fragmentation, NF-κB, interleukin-1 β (IL1β), and TNF levels. In this paper, we have primarily reviewed herbal remedies that have been recently evaluated as alternative treatments for AD in a preclinical setup, and discussed the role of herbal medicines in the management of AD and advances in their knowledge.

Reduced Expression of CLEC4G in Neurons Is Associated with Alzheimer's Disease.

CLEC4G, a glycan-binding receptor, has previously been demonstrated to inhibit Aβ generation, yet its brain localization and functions in Alzheimer's disease (AD) are not clear. We explored the localization, function, and regulatory network of CLEC4G via experiments and analysis of RNA-seq databases. CLEC4G transcripts and proteins were identified in brain tissues, with the highest expression observed in neurons. Notably, AD was associated with reduced levels of CLEC4G transcripts. Bioinformatic analyses revealed interactions between CLEC4G and relevant genes such as BACE1, NPC1, PILRA, TYROBP, MGAT1, and MGAT3, all displaying a negative correlation trend. We further identified the upstream transcriptional regulators NR2F6 and XRCC4 for CLEC4G and confirmed a decrease in CLEC4G expression in APP/PS1 transgenic mice. This study highlights the role of CLEC4G in protecting against AD progression and the significance of CLEC4G for AD research and management.

Appraisal of the Neuroprotective Potentials of Isoeugenol Using In-vitro, In-vivo and In-silico Approaches

Appraisal of the Neuroprotective Potentials of Isoeugenol Using In-vitro, In-vivo and In-silico Approaches

Lipid nanoparticle mediated small interfering RNA delivery as a potential therapy for Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative condition that exhibits a gradual decline in cognitive function and is prevalent among a significant number of individuals globally. The use of small interfering RNA (siRNA) molecules in RNA interference (RNAi) presents a promising therapeutic strategy for AD. Lipid nanoparticles (LNPs) have been developed as a delivery vehicle for siRNA, which can selectively suppress target genes, by enhancing cellular uptake and safeguarding siRNA from degradation. Numerous research studies have exhibited the effectiveness of LNP-mediated siRNA delivery in reducing amyloid beta (Aβ) levels and enhancing cognitive function in animal models of AD. The feasibility of employing LNP-mediated siRNA delivery as a therapeutic approach for AD is emphasized by the encouraging outcomes reported in clinical studies for other medical conditions. The use of LNP-mediated siRNA delivery has emerged as a promising strategy to slow down or even reverse the progression of AD by targeting the synthesis of tau phosphorylation and other genes linked to the condition. Improvement of the delivery mechanism and determination of the most suitable siRNA targets are crucial for the efficacious management of AD. This review focuses on the delivery of siRNA through LNPs as a promising therapeutic strategy for AD, based on the available literature.

Structure-Guided Design, Synthesis, and Biological Evaluation of Peripheral Anionic Site Selective and Brain Permeable Novel Oxadiazole-Piperazine Conjugates against Alzheimer's Disease with Antioxidant Potential.

Alzheimer's disease (AD) is a multifactorial and emerging neurological disorder, which has invoked researchers to develop multitargeted ligands. Herein, hybrid conjugates of 5-phenyl-1,3,4-oxadiazole and piperazines were rationally designed, synthesized, and pharmacologically evaluated against hAChE, hBChE, and hBACE-1 enzymes for the management of AD. Among the series, compound 5AD comprising pyridyl substitution at terminal nitrogen of piperazine contemplated as a paramount lead compound (hAChE, IC50 = 0.103 ± 0.0172 μM, hBChE, IC50 ≥ 10 μM, and hBACE-1, IC50 = 1.342 ± 0.078 μM). Compound 5AD showed mixed-type enzyme inhibition in enzyme kinetic studies against the hAChE enzyme. In addition, compound 5AD revealed a significant displacement of propidium iodide from the peripheral anionic site (PAS) of hAChE and excellent blood-brain barrier (BBB) permeability in a parallel artificial membrane permeation assay (PAMPA). Besides, 5AD also exhibited anti-Aβ aggregation activity in self- and AChE-induced thioflavin T assay. Further, compound 5AD has shown significant improvement in learning and memory (p < 0.001) against the in vivo scopolamine-induced cognitive dysfunction mice model. The ex vivo study implied that after treatment with compound 5AD, there was a decrease in AChE and malonaldehyde (MDA) levels with an increase in catalase (CAT, oxidative biomarkers) in the hippocampal brain homogenate. Hence, compound 5AD could be regarded as a lead compound and further be explored in the treatment of AD.

Impact of mechanical ventilation on clinical outcomes in ICU-admitted Alzheimer's disease patients: a retrospective cohort study.

Alzheimer's disease (AD) is increasingly recognized as a pressing global public health issue, demanding urgent development of scientific AD management strategies. In recent years, the proportion of AD patients in Intensive Care Units (ICU) has been on the rise. Simultaneously, the use of mechanical ventilation (MV) is becoming more prevalent among this specific patient group. Considering the pathophysiological characteristics of AD, the application of MV in AD patients may lead to different outcomes. However, due to insufficient research data, the significant impact of MV on the prognosis of AD patients in the ICU remains unclear. Therefore, we conducted this study to comprehensively evaluate the potential influence of MV on the survival rate of AD patients in the ICU. We obtained data from the MIMIC-IV database for patients diagnosed with AD. Using propensity score matching (PSM), we paired patients who received MV treatment with those who did not receive treatment. Next, we conducted Cox regression analysis to evaluate the association between MV and in-hospital mortality, 7-day mortality, 28-day mortality, 90-day mortality, 4-year mortality, length of hospital stay, and ICU stay. The data analysis involved a cohort of 641 AD patients spanning from 2008 to 2019, inclusive. Following a 1:2 propensity score matching (PSM) procedure, 300 patients were successfully paired, comprising 123 individuals who underwent MV treatment and 177 who did not. MV demonstrated an association with an elevated risk of in-hospital mortality (HR 5.782; 95% CI 2.981-11.216; p < 0.001), 7-day mortality (HR 6.353; 95% CI 3.014-13.392; p < 0.001), 28-day mortality (HR 3.210; 95% CI 1.977-5.210; p < 0.001), 90-day mortality (HR 2.334; 95% CI 1.537-3.544; p < 0.001), and 4-year mortality (HR 1.861; 95% CI 1.370-2.527; p < 0.001). Furthermore, it was associated with a prolonged length of ICU stay [3.6(2.2,5.8) vs. 2.2(1.6,3.7); p = 0.001]. In the subgroup analysis, we further confirmed the robustness of the results obtained from the overall population. Additionally, we observed a significant interaction (p-interaction <0.05) between age, admission type, aspirin use, statin use, and the use of MV. In patients with AD who are receiving treatment in the ICU, the use of MV has been linked to higher short-term, medium-term, and long-term mortality rates, as well as prolong ICU stays. Therefore, it is crucial to break away from conventional thinking and meticulously consider both the medical condition and personal preferences of these vulnerable patients. Personalized treatment decisions, comprehensive communication between healthcare providers and patients, formulation of comprehensive treatment plans, and a focus on collaboration between the ICU and community organizations become imperative.

Exploring Deep Learning Models for Accurate Alzheimer's Disease Classification based on MRI Imaging

INTRODUCTION: Alzheimer's disease (AD), a complex neurodegenerative condition, presents significant challenges in early and accurate diagnosis. Early prediction of AD severity holds the potential for improved patient care and timely interventions. This research investigates the use of deep learning methodologies to forecast AD severity utilizing data extracted from Magnetic Resonance Imaging (MRI) scans.&#x0D; OBJECTIVES: This study aims to explore the efficacy of deep learning models in predicting the severity of Alzheimer's disease using MRI data. Traditional diagnostic methods for AD, primarily reliant on cognitive assessments, often lead to late-stage detection. MRI scans offer a non-invasive means to examine brain structure and detect pathological changes associated with AD. However, manual interpretation of these scans is labor-intensive and subject to variability.&#x0D; METHODS: Various deep learning models, including Convolutional Neural Networks (CNNs) and advanced architectures like DenseNet, VGG16, ResNet50, MobileNet, AlexNet, and Xception, are explored for MRI scan analysis. The performance of these models in predicting AD severity is assessed and compared. Deep learning models autonomously learn hierarchical features from the data, potentially recognizing intricate patterns associated with different AD stages that may be overlooked in manual analysis.&#x0D; RESULTS: The study evaluates the performance of different deep learning models in predicting AD severity using MRI scans. The results highlight the efficacy of these models in capturing subtle patterns indicative of AD progression. Moreover, the comparison underscores the strengths and limitations of each model, aiding in the selection of appropriate methodologies for AD prognosis.&#x0D; CONCLUSION: This research contributes to the growing field of AI-driven healthcare by showcasing the potential of deep learning in revolutionizing AD diagnosis and prognosis. The findings emphasize the importance of leveraging advanced technologies, such as deep learning, to enhance the accuracy and timeliness of AD diagnosis. However, challenges remain, including the need for large, annotated datasets, model interpretability, and integration into clinical workflows. Continued efforts in this area hold promise for improving the management of AD and ultimately enhancing patient outcomes.

Design, Synthesis, and Biological Evaluation of Ferulic Acid Template-Based Novel Multifunctional Ligands Targeting NLRP3 Inflammasome for the Management of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common cause of dementia, which arises due to low levels of acetyl and butyrylcholines, an increase in oxidative stress, inflammation, metal dyshomeostasis, Aβ and tau aggregations. The currently available drugs for AD treatment can provide only symptomatic relief without interfering with pathological hallmarks of the disease. In our ongoing efforts to develop naturally inspired novel multifunctional molecules for AD, systematic SAR studies on EJMC-4e were caried out to improve its multifunctional properties. The rigorous medicinal efforts led to the development of 12o, which displayed a 15-fold enhancement in antioxidant properties and a 2-fold increase in the activity against AChE and BChE over EJMC-4e. Molecular docking and dynamics studies revealed the binding sites and stability of the complex of 12o with AChE and BChE. The PAMPA-BBB assay clearly demonstrated that 12o can easily cross the blood-brain barrier. Interestingly, 12o also expresses promising metal chelation activity, while EJMC-4e was found to be devoid of this property. Further, 12o inhibited metal-induced or self Aβ1-42 aggregation. Observing the neuroprotection ability of 12o against H2O2-induced oxidative stress in the PC-12 cell line is noteworthy. Furthermore, 12o also inhibited NLRP3 inflammasome activation and attenuated mitochondrial-induced ROS and MMP damage caused by LPS and ATP in HMC-3 cells. In addition, 12o is able to effectively reduce mitochondrial and cellular oxidative stress in the AD Drosophila model. Finally, 12o could reverse memory impairment in the scopolamine-induced AD mice model, as evident through in vivo and ex vivo studies. These findings suggest that this compound may act as a promising candidate for further improvement in the management of AD.