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Bibliography on: Alzheimer Disease — Treatment

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Robert J. Robbins is a biologist, an educator, a science administrator, a publisher, an information technologist, and an IT leader and manager who specializes in advancing biomedical knowledge and supporting education through the application of information technology. More About:  RJR | OUR TEAM | OUR SERVICES | THIS WEBSITE

RJR: Recommended Bibliography 21 Jun 2024 at 01:37 Created: 

Alzheimer Disease — Treatment

Alzheimer's disease is an irreversible, progressive brain disorder that slowly destroys memory and thinking skills, and eventually the ability to carry out the simplest tasks. In most people with Alzheimer's, symptoms first appear in their mid-60s. Alzheimer's is the most common cause of dementia among older adults. Dementia is the loss of cognitive functioning — thinking, remembering, and reasoning — and behavioral abilities to such an extent that it interferes with a person's daily life and activities. Dementia ranges in severity from the mildest stage, when it is just beginning to affect a person's functioning, to the most severe stage, when the person must depend completely on others for basic activities of daily living. Scientists don't yet fully understand what causes Alzheimer's disease in most people. There is a genetic component to some cases of early-onset Alzheimer's disease. Late-onset Alzheimer's arises from a complex series of brain changes that occur over decades. The causes probably include a combination of genetic, environmental, and lifestyle factors. The importance of any one of these factors in increasing or decreasing the risk of developing Alzheimer's may differ from person to person. Because of this lack of understanding of the root cause for Alzheimer's Disease, no direct treatment for the condition is yet available. However, this bibliography specifically searches for the idea of treatment in conjunction with Alzheimer's to make it easier to track literature that explores the possibility of treatment.

Created with PubMed® Query: ( alzheimer*[TIAB] AND treatment[TIAB] ) NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)

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RevDate: 2024-06-18
CmpDate: 2024-06-18

Goldenberg JZ, Wright TJ, Batson RD, et al (2024)

What is the association between the microbiome and cognition? An umbrella review protocol.

BMJ open, 14(6):e077873 pii:bmjopen-2023-077873.

INTRODUCTION: Cognitive impairment is reported in a variety of clinical conditions including Alzheimer's disease, Parkinson's and 'long-COVID'. Interestingly, many of these clinical conditions are also associated with microbial dysbiosis. This comanifestation of cognitive and microbiome findings in seemingly unrelated maladies suggests that they could share a common mechanism and potentially presents a treatment target. Although a rapidly growing body of literature has documented this comorbid presentation within specific conditions, an overview highlighting potential parallels across healthy and clinical populations is lacking. The objective of this umbrella review, therefore, is to summarise and synthesise the findings of these systematic reviews.

METHODS AND ANALYSIS: On 2 April 2023, we searched MEDLINE (Pubmed), Embase (Ovid), the Web of Science (Core Collection), the Cochrane Library of Systematic Reviews and Epistemonikos as well as grey literature sources, for systematic reviews on clinical conditions and interventions where cognitive and microbiome outcomes were coreported. An updated search will be conducted before completion of the project if the search-to-publication date is >1 year old. Screening, data abstraction and quality assessment (AMSTAR 2, A MeaSurement Tool to Assess systematic Reviews) will be conducted independently and in duplicate, with disagreements resolved by consensus. Evidence certainty statements for each review's conclusions (eg, Grading of Recommendations Assessment, Development and Evaluation (GRADE)) will be extracted or constructed de novo. A narrative synthesis will be conducted and delineated by the review question. Primary study overlap will be visualised using a citation matrix as well as calculated using the corrected covered area method.

ETHICS AND DISSEMINATION: No participant-identifying information will be used in this review. No ethics approval was required due to our study methodology. Our findings will be presented at national and international conferences and disseminated via social media and press releases. We will recruit at least one person living with cognitive impairment to collaborate on writing the plain language summary for the review.

PROSPERO REGISTRATION NUMBER: CRD42023412903.

RevDate: 2024-06-18

Wang L, Tang Z, Li B, et al (2024)

Myricetin ameliorates cognitive impairment in 3×Tg Alzheimer's disease mice by regulating oxidative stress and tau hyperphosphorylation.

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 177:116963 pii:S0753-3322(24)00847-3 [Epub ahead of print].

BACKGROUND: Alzheimer's disease is characterized by abnormal β-amyloid (Aβ) plaque accumulation, tau hyperphosphorylation, reactive oxidative stress, mitochondrial dysfunction and synaptic loss. Myricetin, a dietary flavonoid, has been shown to exert neuroprotective effects in vitro and in vivo. Here, we aimed to elucidate the mechanism and pathways involved in the protective effect of myricetin.

METHODS: The effect of myricetin was assessed on Aβ42 oligomer-treated neuronal SH-SY5Y cells and in 3×Tg mice. Behavioral tests were performed to assess the cognitive effects of myricetin (14 days, ip) in 3×Tg mice. The levels of beta-amyloid precursor protein (APP), synaptic and mitochondrial proteins, glycogen synthase kinase3β (GSK3β) and extracellular regulated kinase (ERK) 2 were assessed via Western blotting. Flow cytometry assays, immunofluorescence staining, and transmission electron microscopy were used to assess mitochondrial dysfunction and reactive oxidative stress.

RESULTS: We found that, compared with control treatment, myricetin treatment improved spatial cognition and learning and memory in 3×Tg mice. Myricetin ameliorated tau phosphorylation and the reduction in pre- and postsynaptic proteins in Aβ42 oligomer-treated neuronal SH-SY5Y cells and in 3×Tg mice. In addition, myricetin reduced reactive oxygen species generation, lipid peroxidation, and DNA oxidation, and rescued mitochondrial dysfunction via the associated GSK3β and ERK 2 signalling pathways.

CONCLUSIONS: This study provides new insight into the neuroprotective mechanism of myricetin in vitro in cell culture and in vivo in a mouse model of Alzheimer's disease.

RevDate: 2024-06-18

Zhu Y, Wang F, Xia Y, et al (2024)

Research progress on astrocyte-derived extracellular vesicles in the pathogenesis and treatment of neurodegenerative diseases.

Reviews in the neurosciences [Epub ahead of print].

Neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), pose significant global health risks and represent a substantial public health concern in the contemporary era. A primary factor in the pathophysiology of these disorders is aberrant accumulation and aggregation of pathogenic proteins within the brain and spinal cord. Recent investigations have identified extracellular vesicles (EVs) in the central nervous system (CNS) as potential carriers for intercellular transport of misfolded proteins associated with neurodegenerative diseases. EVs are involved in pathological processes that contribute to various brain disorders including neurodegenerative disorders. Proteins linked to neurodegenerative disorders are secreted and distributed from cell to cell via EVs, serving as a mechanism for direct intercellular communication through the transfer of biomolecules. Astrocytes, as active participants in CNS intercellular communication, release astrocyte-derived extracellular vesicles (ADEVs) that are capable of interacting with diverse target cells. This review primarily focuses on the involvement of ADEVs in the development of neurological disorders and explores their potential dual roles - both advantageous and disadvantageous in the context of neurological disorders. Furthermore, this review examines the current studies investigating ADEVs as potential biomarkers for the diagnosis and treatment of neurodegenerative diseases. The prospects and challenges associated with the application of ADEVs in clinical settings were also comprehensively reviewed.

RevDate: 2024-06-18

Oliveira-Lima OC, de Carvalho GA, do Prado Assunção L, et al (2024)

GlyT1 Inhibition by NFPS Promotes Neuroprotection in Amyloid-β-Induced Alzheimer's Disease Animal Model.

Neurochemical research [Epub ahead of print].

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid-β, leading to N-methyl-D-aspartate (NMDA) receptor-dependent synaptic depression, spine elimination, and memory deficits. Glycine transporter type 1 (GlyT1) modulates glutamatergic neurotransmission via NMDA receptors (NMDAR), presenting a potential alternative therapeutic approach for AD. This study investigates the neuroprotective potential of GlyT1 inhibition in an amyloid-β-induced AD mouse model. C57BL/6 mice were treated with N-[3-([1,1-Biphenyl]-4-yloxy)-3-(4-fluorophenyl)propyl]-N-methylglycine (NFPS), a GlyT1 inhibitor, 24 h prior to intrahippocampal injection of amyloid-β. NFPS pretreatment prevented amyloid-β-induced cognitive deficits in short-term and long-term memory, evidenced by novel object recognition and spatial memory tasks. Moreover, NFPS pretreatment curbed microglial activation, astrocytic reactivity, and subsequent neuronal damage from amyloid-β injection. An extensive label-free quantitative UPLC-MSE proteomic analysis was performed on the hippocampi of mice treated with NFPS. In proteomics, KEGG enrichment analysis revealed increased in dopaminergic synapse, purine-containing compound biosynthetic process and long-term potentiation, and a reduction in Glucose catabolic process and glycolytic process pathways. The western blot analysis confirmed that NFPS treatment elevated BDNF levels, correlating with enhanced TRKB phosphorylation and mTOR activation. Moreover, NFPS treatment reduced the GluN2B expression after 6 h, which was associated with an increase on CaMKIV and CREB phosphorylation. Collectively, these findings demonstrate that GlyT1 inhibition by NFPS activates diverse neuroprotective pathways, enhancing long-term potentiation signaling and countering amyloid-β-induced hippocampal damage.

RevDate: 2024-06-18

Dolma L, Damodaran A, Panonnummal R, et al (2024)

Exosomes isolated from citrus lemon: a promising candidate for the treatment of Alzheimer's disease.

Therapeutic delivery [Epub ahead of print].

Aim: To investigate the efficacy of exosome-like nanovesicles from citrus lemon (EXO-CLs) in combating oxidative stress associated with Alzheimer's disease. Materials & methods: EXO-CLs were isolated through differential ultracentrifugation, characterized for particle size and evaluated for antioxidant activity. Results: EXO-CLs exhibited a mean size of 93.77 ± 12.31 nm, demonstrated permeability across the blood-brain barrier (BBB) and displayed antioxidant activity comparable to ascorbic acid. Additionally, they were found to be non-toxic, with over 80% cell viability observed in SH-SY5Y cells. Conclusion: The study proposes that EXO-CLs could serve as an effective treatment for neurodegenerative diseases. This suggests a promising approach for targeted interventions in brain-related disorders, owing to the antioxidant properties and BBB permeability exhibited by EXO-CLs.

RevDate: 2024-06-18

Niu Z, Gui X, Feng S, et al (2024)

Aggregation mechanisms and molecular structures of amyloid-β in Alzheimer's disease.

Chemistry (Weinheim an der Bergstrasse, Germany) [Epub ahead of print].

Amyloid plaques are a major pathological hallmark involved in Alzheimer's disease and consist of deposits of the amyloid-β peptide (Aβ). The aggregation process of Aβ is highly complex, which leads to polymorphous aggregates with different structures. In addition to aberrant aggregation, Aβ oligomers can undergo liquid-liquid phase separation and form dynamic condensates. It has been hypothesized that these amyloid liquid droplets affect and modulate amyloid fibril formation. In this review, we briefly introduce the relationship between stress granules and amyloid protein aggregation that is associated with neurodegenerative diseases. Then we highlight the regulatory role of liquid-liquid phase separation in Aβ aggregation and discuss the potential relationship between Aβ phase transition and aggregation. Furthermore, we summarize the current structures of Aβ oligomers and amyloid fibrils, which have been determined using nuclear magnetic resonance and cryo-electron microscopy. The structural variations of Aβ aggregates provide an explanation for the different levels of toxicity, shed light on the aggregation mechanism and may pave the way towards structure-based drug design for both clinical diagnosis and treatment.

RevDate: 2024-06-18

Assfaw AD, Schindler SE, JC Morris (2024)

Advances in blood biomarkers for Alzheimer disease (AD): A review.

The Kaohsiung journal of medical sciences [Epub ahead of print].

Alzheimer disease (AD) and Alzheimer Disease and Related Dementias (AD/ADRD) are growing public health challenges globally affecting millions of older adults, necessitating concerted efforts to advance our understanding and management of these conditions. AD is a progressive neurodegenerative disorder characterized pathologically by amyloid plaques and tau neurofibrillary tangles that are the primary cause of dementia in older individuals. Early and accurate diagnosis of AD dementia is crucial for effective intervention and treatment but has proven challenging to accomplish. Although testing for AD brain pathology with cerebrospinal fluid (CSF) or positron emission tomography (PET) has been available for over 2 decades, most patients never underwent this testing because of inaccessibility, high out-of-pocket costs, perceived risks, and the lack of AD-specific treatments. However, in recent years, rapid progress has been made in developing blood biomarkers for AD/ADRD. Consequently, blood biomarkers have emerged as promising tools for non-invasive and cost-effective diagnosis, prognosis, and monitoring of AD progression. This review presents the evolving landscape of blood biomarkers in AD/ADRD and explores their potential applications in clinical practice for early detection, prognosis, and therapeutic interventions. It covers recent advances in blood biomarkers, including amyloid beta (Aβ) peptides, tau protein, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP). It also discusses their diagnostic and prognostic utility while addressing associated challenges and limitations. Future research directions in this rapidly evolving field are also proposed.

RevDate: 2024-06-18

Wang Y, Zhang X, Biverstål H, et al (2025)

Pro-resolving lipid mediator reduces amyloid-β42-induced gene expression in human monocyte-derived microglia.

Neural regeneration research, 20(3):873-886.

JOURNAL/nrgr/04.03/01300535-202503000-00031/figure1/v/2024-06-17T092413Z/r/image-tiff Specialized pro-resolving lipid mediators including maresin 1 mediate resolution but the levels of these are reduced in Alzheimer's disease brain, suggesting that they constitute a novel target for the treatment of Alzheimer's disease to prevent/stop inflammation and combat disease pathology. Therefore, it is important to clarify whether they counteract the expression of genes and proteins induced by amyloid-β. With this objective, we analyzed the relevance of human monocyte-derived microglia for in vitro modeling of neuroinflammation and its resolution in the context of Alzheimer's disease and investigated the pro-resolving bioactivity of maresin 1 on amyloid-β42-induced Alzheimer's disease-like inflammation. Analysis of RNA-sequencing data and secreted proteins in supernatants from the monocyte-derived microglia showed that the monocyte-derived microglia resembled Alzheimer's disease-like neuroinflammation in human brain microglia after incubation with amyloid-β42. Maresin 1 restored homeostasis by down-regulating inflammatory pathway related gene expression induced by amyloid-β42 in monocyte-derived microglia, protection of maresin 1 against the effects of amyloid-β42 is mediated by a re-balancing of inflammatory transcriptional networks in which modulation of gene transcription in the nuclear factor-kappa B pathway plays a major part. We pinpointed molecular targets that are associated with both neuroinflammation in Alzheimer's disease and therapeutic targets by maresin 1. In conclusion, monocyte-derived microglia represent a relevant in vitro microglial model for studies on Alzheimer's disease-like inflammation and drug response for individual patients. Maresin 1 ameliorates amyloid-β42-induced changes in several genes of importance in Alzheimer's disease, highlighting its potential as a therapeutic target for Alzheimer's disease.

RevDate: 2024-06-18

Yang X, Huang YA, J Marshall (2025)

Targeting TrkB-PSD-95 coupling to mitigate neurological disorders.

Neural regeneration research, 20(3):715-724.

Tropomyosin receptor kinase B (TrkB) signaling plays a pivotal role in dendritic growth and dendritic spine formation to promote learning and memory. The activity-dependent release of brain-derived neurotrophic factor at synapses binds to pre- or postsynaptic TrkB resulting in the strengthening of synapses, reflected by long-term potentiation. Postsynaptically, the association of postsynaptic density protein-95 with TrkB enhances phospholipase Cγ-Ca2+/calmodulin-dependent protein kinase II and phosphatidylinositol 3-kinase-mechanistic target of rapamycin signaling required for long-term potentiation. In this review, we discuss TrkB-postsynaptic density protein-95 coupling as a promising strategy to magnify brain-derived neurotrophic factor signaling towards the development of novel therapeutics for specific neurological disorders. A reduction of TrkB signaling has been observed in neurodegenerative disorders, such as Alzheimer's disease and Huntington's disease, and enhancement of postsynaptic density protein-95 association with TrkB signaling could mitigate the observed deficiency of neuronal connectivity in schizophrenia and depression. Treatment with brain-derived neurotrophic factor is problematic, due to poor pharmacokinetics, low brain penetration, and side effects resulting from activation of the p75 neurotrophin receptor or the truncated TrkB.T1 isoform. Although TrkB agonists and antibodies that activate TrkB are being intensively investigated, they cannot distinguish the multiple human TrkB splicing isoforms or cell type-specific functions. Targeting TrkB-postsynaptic density protein-95 coupling provides an alternative approach to specifically boost TrkB signaling at localized synaptic sites versus global stimulation that risks many adverse side effects.

RevDate: 2024-06-18

Wu B, Liu Y, Li H, et al (2025)

Liver as a new target organ in Alzheimer's disease: insight from cholesterol metabolism and its role in amyloid-beta clearance.

Neural regeneration research, 20(3):695-714.

Alzheimer's disease, the primary cause of dementia, is characterized by neuropathologies, such as amyloid plaques, synaptic and neuronal degeneration, and neurofibrillary tangles. Although amyloid plaques are the primary characteristic of Alzheimer's disease in the central nervous system and peripheral organs, targeting amyloid-beta clearance in the central nervous system has shown limited clinical efficacy in Alzheimer's disease treatment. Metabolic abnormalities are commonly observed in patients with Alzheimer's disease. The liver is the primary peripheral organ involved in amyloid-beta metabolism, playing a crucial role in the pathophysiology of Alzheimer's disease. Notably, impaired cholesterol metabolism in the liver may exacerbate the development of Alzheimer's disease. In this review, we explore the underlying causes of Alzheimer's disease and elucidate the role of the liver in amyloid-beta clearance and cholesterol metabolism. Furthermore, we propose that restoring normal cholesterol metabolism in the liver could represent a promising therapeutic strategy for addressing Alzheimer's disease.

RevDate: 2024-06-18

Shen Y, Zhang G, Wei C, et al (2025)

Potential role and therapeutic implications of glutathione peroxidase 4 in the treatment of Alzheimer's disease.

Neural regeneration research, 20(3):613-631.

Alzheimer's disease is an age-related neurodegenerative disorder with a complex and incompletely understood pathogenesis. Despite extensive research, a cure for Alzheimer's disease has not yet been found. Oxidative stress mediates excessive oxidative responses, and its involvement in Alzheimer's disease pathogenesis as a primary or secondary pathological event is widely accepted. As a member of the selenium-containing antioxidant enzyme family, glutathione peroxidase 4 reduces esterified phospholipid hydroperoxides to maintain cellular redox homeostasis. With the discovery of ferroptosis, the central role of glutathione peroxidase 4 in anti-lipid peroxidation in several diseases, including Alzheimer's disease, has received widespread attention. Increasing evidence suggests that glutathione peroxidase 4 expression is inhibited in the Alzheimer's disease brain, resulting in oxidative stress, inflammation, ferroptosis, and apoptosis, which are closely associated with pathological damage in Alzheimer's disease. Several therapeutic approaches, such as small molecule drugs, natural plant products, and non-pharmacological treatments, ameliorate pathological damage and cognitive function in Alzheimer's disease by promoting glutathione peroxidase 4 expression and enhancing glutathione peroxidase 4 activity. Therefore, glutathione peroxidase 4 upregulation may be a promising strategy for the treatment of Alzheimer's disease. This review provides an overview of the gene structure, biological functions, and regulatory mechanisms of glutathione peroxidase 4, a discussion on the important role of glutathione peroxidase 4 in pathological events closely related to Alzheimer's disease, and a summary of the advances in small-molecule drugs, natural plant products, and non-pharmacological therapies targeting glutathione peroxidase 4 for the treatment of Alzheimer's disease. Most prior studies on this subject used animal models, and relevant clinical studies are lacking. Future clinical trials are required to validate the therapeutic effects of strategies targeting glutathione peroxidase 4 in the treatment of Alzheimer's disease.

RevDate: 2024-06-17
CmpDate: 2024-06-17

Xiao Y, Yang C, Si N, et al (2024)

Epigallocatechin-3-gallate Inhibits LPS/AβO-induced Neuroinflammation in BV2 Cells through Regulating the ROS/TXNIP/NLRP3 Pathway.

Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology, 19(1):31.

Neuroinflammation is a key factor in cognitive dysfunction and neurodegenerative diseases such as Alzheimer's disease (AD), so inhibiting neuroinflammation is considered as a potential treatment for AD. Epigallocatechin-3-gallate (EGCG), a polyhydroxyphenol of green tea, has been found to exhibit anti-oxidative, anti-inflammatory and neuroprotective effects. The aim of this study was to investigate the inhibitory effect of EGCG on inflammation and its mechanism. In this study, BV2 cells were simultaneously exposed to lipopolysaccharides (LPS) and the amyloid-β oligomer (AβO) to induce inflammatory microenvironments. Inflammatory cytokines and NLRP3 inflammasome-related molecules were detected by RT-PCR and Western Blot. The results show that EGCG inhibits LPS/AβO-induced inflammation in BV2 cells through regulating IL-1β, IL-6, and TNF-α. Meanwhile, EGCG reduces the activation of the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome and levels of intracellular ROS in BV2 cells treated with LPS/AβO by affecting the mitochondrial membrane potential (MMP). Further research found that EGCG inhibited MMP through regulating thioredoxin-interacting protein (TXNIP) in LPS/AβO-induced neuroinflammation. In conclusion, EGCG may alleviate LPS/AβO-induced microglial neuroinflammation by suppressing the ROS/ TXNIP/ NLRP3 pathway. It may provide a potential mechanism underlying the anti-inflammatory properties of EGCG for alleviating AD.

RevDate: 2024-06-17

Shi SS, T Hu (2024)

Network pharmacology study on fermented soybeans for the prevention of Alzheimer's disease in older individuals.

Biomedical chromatography : BMC [Epub ahead of print].

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the disruption of synaptic communication among millions of neurons. Recent research has highlighted the potential therapeutic effectiveness of natural polyphenolic compounds in addressing AD. Soybeans are abundant in polyphenols, and their polyphenolic composition undergoes significant alteration through fermentation by Eurotium cristatum. Through comprehensive database searches, we identified active components within fermented soybean polyphenols and genes associated with AD. Subsequently, we utilized Venn diagrams to analyze the overlap between AD-related genes and these components. Furthermore, we visualized the network between intersecting targets and proteins using Cytoscape software. The anti-AD effects of soybeans were further explored through comprehensive analysis, including protein-protein interaction analysis, pathway enrichment analysis, and molecular docking studies. Our investigation unveiled 6-hydroxydaidzein as a major component of fermented soybean polyphenols, shedding light on its potential therapeutic significance in combating AD. The intersection between target proteins of fermented soybeans and disease-related targets in AD comprised 34 genes. Protein-protein interaction analysis highlighted key potential targets, including glyceraldehyde-3-phosphate dehydrogenase (GAPDH), glycogen synthase kinase 3 beta (GSK3B), amyloid precursor protein (APP), cyclin-dependent kinase 5 (CDK5), and beta-site APP cleaving enzyme 1 (BACE1). Molecular docking results demonstrated a robust binding effect between major components from fermented soybeans and the aforesaid key targets implicated in AD treatment. These findings suggest that fermented soybeans demonstrate a degree of efficacy and present promising prospects in the prevention of AD.

RevDate: 2024-06-17

Huan T, Intrator O, Simning A, et al (2024)

Mental Health Treatment Among Nursing Home Residents With Alzheimer's Disease and Related Dementias.

Journal of the American Medical Directors Association pii:S1525-8610(24)00510-3 [Epub ahead of print].

OBJECTIVES: To examine the prevalence of mental health treatment among nursing home (NH) long-stay residents with Alzheimer's disease and related dementias (ADRD) and explore factors associated with utilization.

DESIGN: Retrospective cohort study. Minimum Data Set data (April 2017-September 2018), Medicare Master Beneficiary Summary File, Part B Carrier file and Part D prescription file were used to identify mental illness and ADRD diagnoses, patient characteristics, and mental health treatment.

SETTING AND PARTICIPANTS: All US Medicare- or Medicaid-certified NHs. Fee-for-service Medicare beneficiaries aged 65 and older who had a quarterly or annual Minimum Data Set assessment with ADRD and were enrolled in Medicare Parts B and D. Two cohorts: residents with both ADRD and psychiatric disorders; residents with ADRD only.

METHODS: Primary outcomes: receipt of (1) any mental health treatment (medication or psychotherapy); (2) any psychotherapy in a calendar quarter.

SECONDARY OUTCOMES: antipsychotics, antidepressants, hypnotics, antiepileptics, short-session ( ≤ 30 minutes), long-session ( ≥ 45 minutes), and family/group psychotherapy. Covariates included predisposing, enabling characteristics, and needs factors. Generalized Estimating Equation models of quarterly data, nested within patients, were estimated for each outcome among each cohort.

RESULTS: Analyses included 1,913,945 resident-quarter observations from 503,077 unique NH long-stay residents. Overall, 68.5% of NH long-stay residents with ADRD have psychiatric disorders; of these, 85% received mental health treatment. African American or Hispanic residents were less likely to use antidepressants. African American residents or residents living in rural locations were less likely to receive long-session psychotherapy. Hispanic residents were more likely to receive long-session psychotherapy. Residents in minority groups were more likely to receive group/family psychotherapy.

CONCLUSIONS AND IMPLICATIONS: Most of NH long-stay residents with ADRD had psychiatric disorders and most of them received treatment. Antidepressants or long-session psychotherapy were less likely to be provided to African American residents. Factors that determine the efficacy of mental health treatment and reasons for the racial disparities require further exploration.

RevDate: 2024-06-17

Yin P, Wang H, Xue T, et al (2024)

Four-Dimensional Label-Free Quantitative Proteomics of Ginsenoside Rg2 Ameliorated Scopolamine-Induced Memory Impairment in Mice through the Lysosomal Pathway.

Journal of agricultural and food chemistry [Epub ahead of print].

Alzheimer's disease (AD) is a neurodegenerative disease. Ginsenoside Rg2 has shown potential in treating AD, but the underlying protein regulatory mechanisms associated with ginsenoside Rg2 treatment for AD remain unclear. This study utilized scopolamine to induce memory impairment in mice, and proteomics methods were employed to investigate the potential molecular mechanism of ginsenoside Rg2 in treating AD model mice. The Morris water maze, hematoxylin and eosin staining, and Nissl staining results indicated that ginsenoside Rg2 enhanced cognitive ability and decreased neuronal damage in AD mice. Proteomics, western blot, and immunofluorescence results showed that ginsenoside Rg2 primarily improved AD mice by downregulating the expression of LGMN, LAMP1, and PSAP proteins through the regulation of the lysosomal pathway. Transmission electron microscopy and network pharmacology prediction results showed a potential connection between the mechanism of ginsenoside Rg2 treatment for AD mice and lysosomes. The comprehensive results indicated that ginsenoside Rg2 may improve AD by downregulating LGMN, LAMP1, and PSAP through the regulation of the lysosomal pathway.

RevDate: 2024-06-19

Seto M, Hohman TJ, Mormino EC, et al (2024)

Parental History of Memory Impairment and β-Amyloid in Cognitively Unimpaired Older Adults.

JAMA neurology [Epub ahead of print].

IMPORTANCE: Studies have suggested that maternal history of late-onset Alzheimer disease, but not paternal, predisposes individuals to higher brain β-amyloid (Aβ) burden, reduced brain metabolism, and lower gray matter volumes.

OBJECTIVE: To characterize maternal vs paternal history of memory impairment in terms of brain Aβ-positron emission tomography (Aβ-PET) and baseline cognition among a large sample of cognitively unimpaired older adults.

This cross-sectional study leveraged data from 4413 individuals who were screened for the Anti-Amyloid Treatment in Asymptomatic Alzheimer (A4) study, a randomized clinical trial conducted across 67 sites in the US, Australia, Canada, and Japan aimed at Alzheimer disease prevention. Data were collected between April 2014 and December 2017 and analyzed from December 2022 to June 2023. Participants were cognitively unimpaired adults (Clinical Dementia Rating = 0 and/or Mini-Mental State Examination score ≥25) between the ages of 65 and 85 years who underwent PET imaging to assess cortical Aβ levels for trial eligibility. A total of 4492 participants were screened, and 79 missing data were excluded.

MAIN OUTCOMES AND MEASURES: Demographic characteristics (eg, age, sex, education), apolipoprotein E genotyping, participant-reported parental history of memory impairment and parental age at symptom onset were collected as variables. Parental history was assessed in terms of continuous neocortical 18F-florbetapir Aβ-PET and the Preclinical Alzheimer Cognitive Composite.

RESULTS: Of 4413 individuals (mean [SD] age, 71.27 [4.66] years, 2617 women [59.3%]), mean Aβ-PET was elevated in individuals with history of memory impairment in both parents (n = 455; mean [SD] standardized uptake value ratio [SUVR] = 1.12 [0.19]; Wilcoxon P = 1.1 × 10-5) and in those with only maternal history (n = 1772; mean [SD] SUVR = 1.10 [0.19]; Wilcoxon P = 2.70 × 10-5) compared with those with only paternal history (n = 632; mean [SD] SUVR = 1.08 [0.18]; Wilcoxon P = 1.1 × 10-5) or no family history (n = 1554; mean [SD] SUVR = 1.08 [0.19]; Wilcoxon P = 1.1 × 10-5). Paternal history of early-onset memory impairment (age <65 years) but not late-onset (age ≥65 years) was associated with elevated participant Aβ-PET (mean [SD] SUVR = 1.19 [0.21]; P = 3.00 × 10-6) in comparison with no paternal history (mean [SD] SUVR = 1.09 [0.19]) whereas maternal history was associated with elevated Aβ in both early-onset and late-onset groups. There was no association with cognition.

CONCLUSIONS AND RELEVANCE: In this study, maternal history (at any age) and paternal history of early-onset memory impairment were associated with Aβ burden among asymptomatic older individuals. Sex-specific parental history may help inform clinicians on likelihood of Aβ burden in offspring and help identify high-risk individuals at the earliest stages of disease for prevention.

RevDate: 2024-06-17

Park IK, Choi YS, SY Jo (2024)

Development of quantitative detection methods for four Alzheimer's disease specific biomarker panels using electrochemical immunosensors based on enzyme immunoassay.

Analytical sciences : the international journal of the Japan Society for Analytical Chemistry [Epub ahead of print].

Accurate and timely diagnosis of Alzheimer's disease (AD) is necessary to maximize the effectiveness of treatment and using biomarkers for diagnosis is attracting attention as a minimally invasive method with few side effects. Electrochemical immunosensor (EI) is a method that is in the spotlight in the medical and bioanalytical fields due to its portability and field usability. Here, we quantified four AD specific biomarkers using EIs based on enzyme immunoassay. We selected and developed quantitative methods for the biomarkers using screen-printed gold electrodes. For three biomarkers, quantification was performed using competition immunoassays in which antigen-antibody premix mixtures were applied to antigen-immobilized electrodes and the limit of detection (LOD) values were secured, 1.20 ng/ml, 1.30 ng/ml, and 1.74 ng/ml, respectively. For the other, a sandwich immunoassay using antibody pair was selected for quantification and LOD was also achieved as 0.077 ng/ml. All four biomarkers in buffer samples were successfully quantified and reliable R[2] values were obtained, and reliable calibration curves were secured for three biomarkers in spiked human serum samples. The immunosensors developed and will be optimized are expected to be used in various fields, including detection of biomarkers for not only AD but also related diseases.

RevDate: 2024-06-19
CmpDate: 2024-06-17

Ji L, Meng Z, Dong X, et al (2024)

ICA1 affects APP processing through the PICK1-PKCα signaling pathway.

CNS neuroscience & therapeutics, 30(6):e14754.

AIMS: Islet cell autoantigen 1 (ICA1) is involved in autoimmune diseases and may affect synaptic plasticity as a neurotransmitter. Databases related to Alzheimer's disease (AD) have shown decreased ICA1 expression in patients with AD. However, the role of ICA1 in AD remains unclear. Here, we report that ICA1 expression is decreased in the brains of patients with AD and an AD mouse model.

RESULTS: The ICA1 increased the expression of amyloid precursor protein (APP), disintegrin and metalloprotease 10 (ADAM10), and disintegrin and metalloprotease 17 (ADAM17), but did not affect protein half-life or mRNA levels. Transcriptome sequencing analysis showed that ICA1 regulates the G protein-coupled receptor signaling pathway. The overexpression of ICA1 increased PKCα protein levels and phosphorylation.

CONCLUSION: Our results demonstrated that ICA1 shifts APP processing to non-amyloid pathways by regulating the PICK1-PKCα signaling pathway. Thus, this study suggests that ICA1 is a novel target for the treatment of AD.

RevDate: 2024-06-18
CmpDate: 2024-06-17

Hou Z, Sun A, Li Y, et al (2024)

What Are the Reliable Plasma Biomarkers for Mild Cognitive Impairment? A Clinical 4D Proteomics Study and Validation.

Mediators of inflammation, 2024:7709277.

OBJECTIVE: At present, Alzheimer's disease (AD) lacks effective treatment means, and early diagnosis and intervention are the keys to treatment. Therefore, for mild cognitive impairment (MCI) and AD patients, blood sample analysis using the 4D nonstandard (label-free) proteomic in-depth quantitative analysis, looking for specific protein marker expression differences, is important. These marker levels change as AD progresses, and the analysis of these biomarkers changes with this method, which has the potential to show the degree of disease progression and can be used for the diagnosis and preventive treatment of MCI and AD.

MATERIALS AND METHODS: Patients were recruited according to the inclusion and exclusion criteria and divided into three groups according to scale scores. Elderly patients diagnosed with AD were selected as the AD group (n = 9). Patients diagnosed with MCI were classified into the MCI group (n = 10). Cognitively healthy elderly patients were included in the normal cognition control group (n = 10). Patients' blood samples were used for 4D label-free proteomic in-depth quantitative analysis to identify potential blood biomarkers. The sample size of each group was expanded (n = 30), and the selected biomarkers were verified by enzyme-linked immunosorbent assay (ELISA) to verify the accuracy of the proteomic prediction.

RESULTS: Six specific blood markers, namely, APOE, MMP9, UBR5, PLA2G7, STAT5B, and S100A8, were detected by 4D label-free proteomic quantitative analysis. These markers showed a statistically significant upregulation trend in the MCI and AD groups compared with the normal cognition control group (P < 0.05). ELISA results showed that the levels of these six proteins in the MCI group were significantly higher than those in the normal cognition control group, and the levels of these six proteins in the AD group were significantly higher than those in the MCI group (P < 0.05).

CONCLUSION: The plasma levels of APOE, MMP9, UBR5, PLA2G7, STAT5B, and S100A8 in cognitively healthy elderly patients and patients with MCI and AD were significantly different and, more importantly, showed a trend of increasing expression. These results indicate that these six human plasma markers have important diagnostic and therapeutic potential in the identification of cognitive impairment and have value for in-depth research and clinical application.

RevDate: 2024-06-18

Guo J, Cao Y, Zhang T, et al (2024)

Multisensory Fusion Training and 7, 8-Dihydroxyflavone Improve Amyloid-β-Induced Cognitive Impairment, Anxiety, and Depression-Like Behavior in Mice Through Multiple Mechanisms.

Neuropsychiatric disease and treatment, 20:1247-1270.

BACKGROUND: There is growing interest in the role of physical activity in patients with of Alzheimer's disease (AD), particularly regarding its impact of cognitive function, gut microbiota, metabolites, and neurotrophic factors.

OBJECTIVE: To investigate the impact of multisensory fusion training (MSFT) combined with 7, 8-dihydroxyflavone (DHF) on the behavioral characteristics, protein expression, microbiome, and serum metabolome using the AD model in mice induced with amyloid-β (Aβ).

METHODS: We assessed cognitive ability, anxiety-like and depression-like behaviors in Aβ mice using behavioral measures. Western blotting was employed to detect the expression of relevant proteins. The 16S rRNA gene sequencing and metabolomics were used to analyze changes in the intestinal microbial composition and serum metabolic profile, respectively, of Aβ mice.

RESULTS: The behavioral outcomes indicated that a 4-week intervention combining DHF and MSFT yielded remarkable improvements in cognitive function and reduced anxiety and depression-like behaviors in Aβ mice. In the hippocampus of Aβ mice, the combined intervention increased the levels of BDNF, VGF, PSD-95, Nrf2, p-GSK3β and p-CREB proteins. Analyses of sequence and metabolomic data revealed that Bacteroides and Ruminococcaceae were remarkably more abundant following the combined intervention, influencing the expression of specific metabolites directly linked to the maintenance of neuronal and neurobehavioral functions. These metabolites play a crucial role in vital processes, such as amino acid metabolism, lipid metabolism, and neurotransmitter metabolism in mice.

CONCLUSION: Our study highlighted that MSFT combined with DHF improves cognitive impairment, anxiety, and depression-like behavior in Aβ mice through multiple mechanisms, and further validated the correlation between the gut microbiome and serum metabolome. These findings open up a promising avenue for future investigations into potential treatment strategies for AD.

RevDate: 2024-06-18

Karimani F, Asgari Taei A, Abolghasemi-Dehaghani MR, et al (2024)

Impairment of entorhinal cortex network activity in Alzheimer's disease.

Frontiers in aging neuroscience, 16:1402573.

The entorhinal cortex (EC) stands out as a critical brain region affected in the early phases of Alzheimer's disease (AD), with some of the disease's pathological processes originating from this area, making it one of the most crucial brain regions in AD. Recent research highlights disruptions in the brain's network activity, characterized by heightened excitability and irregular oscillations, may contribute to cognitive impairment. These disruptions are proposed not only as potential therapeutic targets but also as early biomarkers for AD. In this paper, we will begin with a review of the anatomy and function of EC, highlighting its selective vulnerability in AD. Subsequently, we will discuss the disruption of EC network activity, exploring changes in excitability and neuronal oscillations in this region during AD and hypothesize that, considering the advancements in neuromodulation techniques, addressing the disturbances in the network activity of the EC could offer fresh insights for both the diagnosis and treatment of AD.

RevDate: 2024-06-18

Liu C, Gao S, S Li (2024)

The effect of physical exercise intervention on the ability of daily living in patients with Alzheimer's dementia: a meta-analysis.

Frontiers in aging neuroscience, 16:1391611.

OBJECTIVE: To systematically evaluate the effect of physical exercise intervention on the activities of daily living (ADL) on patients with Alzheimer's dementia (AD) and explore the optimal exercise scheme.

METHODS: PubMed, EMBASE, the Cochrane Library, Web of Science, and Science Direct databases were searched from 1987 to December 2023 to collect randomized controlled trials (RCTs). Two investigators independently screened the literature and extracted data according to the inclusion and exclusion criteria. The quality of the included studies was evaluated using Cochrane Review Manager 5.3. And STATA 16.0 was used for performing the meta-analysis.

RESULTS: Fifteen randomized controlled trials were included. The results of the meta-analysis showed that physical exercise had a positive effect on the improvement of ADL in patients with AD [standardized mean difference (SMD) = 0.312, 95% confidence interval (CI 0.039-0.585), P = 0.02], and the difference was statistically significant. The results of subgroup analysis showed that anaerobic exercises such as strength and balance training with a medium cycle of 12-16 weeks and lasting 30-45 min each time were more ideal for the improvement of basic daily living ability of AD patients.

CONCLUSION: Physical exercise can effectively improve activities of daily living in patients with Alzheimer's dementia and it may be a potential non-drug treatment for AD patients.

RevDate: 2024-06-18

Hernandez AR, Parker E, Babar M, et al (2024)

Microbiome-driven alterations in metabolic pathways and impaired cognition in aged female TgF344-AD rats.

Aging brain, 5:100119.

Alzheimer's disease (AD) not only affects cognition and neuropathology, but several other facets capable of negatively impacting quality of life and potentially driving impairments, including altered gut microbiome (GMB) composition and metabolism. Aged (20 + mo) female TgF344-AD and wildtype rats were cognitively characterized on several tasks incorporating several cognitive domains, including task acquisition, object recognition memory, anxiety-like behaviors, and spatial navigation. Additionally, metabolic phenotyping, GMB sequencing throughout the intestinal tract (duodenum, jejunum, ileum, colon, and feces), neuropathological burden assessment and marker gene functional abundance predictions (PICRUSt2) were conducted. TgF344-AD rats demonstrated significant cognitive impairment in multiple domains, as well as regionally specific GMB dysbiosis. Relationships between peripheral factors were investigated using Canonical Correspondence Analysis (CCA), revealing correlations between GMB changes and both cognitive and metabolic factors. Moreover, communities of gut microbes contributing to essential metabolic pathways were significantly altered in TgF344-AD rats. These data indicate dysbiosis may affect cognitive outcomes in AD through alterations in metabolism-related enzymatic pathways that are necessary for proper brain function. Moreover, these changes were mostly observed in intestinal segments required for carbohydrate digestion, not fecal samples. These data support the targeting of intestinal and microbiome health for the treatment of AD.

RevDate: 2024-06-18

Yan H, Wang W, Cui T, et al (2024)

Advances in the Understanding of the Correlation Between Neuroinflammation and Microglia in Alzheimer's Disease.

ImmunoTargets and therapy, 13:287-304.

Alzheimer's disease (AD) is a fatal neurodegenerative disease with a subtle and progressive onset and is the most common type of dementia. However, its etiology and pathogenesis have not yet been fully elucidated. The common pathological manifestations of AD include extraneuronal β-amyloid deposition (Aβ), intraneuronal tau protein phosphorylation leading to the formation of 'neurofibrillary tangles' (NFTs), neuroinflammation, progressive loss of brain neurons/synapses, and glucose metabolism disorders. Current treatment approaches for AD primarily focus on the 'Aβ cascade hypothesis and abnormal aggregation of hyperphosphorylation of tau proteins', but have shown limited efficacy. Therefore, there is an ongoing need to identify more effective treatment targets for AD. The central nervous system (CNS) inflammatory response plays a key role in the occurrence and development of AD. Neuroinflammation is an immune response activated by glial cells in the CNS that usually occurs in response to stimuli such as nerve injury, infection and toxins or in response to autoimmunity. Neuroinflammation ranks as the third most prominent pathological feature in AD, following Aβ and NFTs. In recent years, the focus on the role of neuroinflammation and microglia in AD has increased due to the advancements in genome-wide association studies (GWAS) and sequencing technology. Furthermore, research has validated the pivotal role of microglia-mediated neuroinflammation in the progression of AD. Therefore, this article reviews the latest research progress on the role of neuroinflammation triggered by microglia in AD in recent years, aiming to provide a new theoretical basis for further exploring the role of neuroinflammation in the process of AD occurrence and development.

RevDate: 2024-06-17

Yang Q, Yan C, Sun Y, et al (2024)

Extracellular Matrix Remodeling Alleviates Memory Deficits in Alzheimer's Disease by Enhancing the Astrocytic Autophagy-Lysosome Pathway.

Advanced science (Weinheim, Baden-Wurttemberg, Germany) [Epub ahead of print].

Extracellular matrix (ECM) remodeling is strongly linked to Alzheimer's disease (AD) risk; however, the underlying mechanisms are not fully understood. Here, it is found that the injection of chondroitinase ABC (ChABC), mimicking ECM remodeling, into the medial prefrontal cortex (mPFC) reversed short-term memory loss and reduced amyloid-beta (Aβ) deposition in 5xFAD mice. ECM remodeling also reactivated astrocytes, reduced the levels of aggrecan in Aβ plaques, and enhanced astrocyte recruitment to surrounding plaques. Importantly, ECM remodeling enhanced the autophagy-lysosome pathway in astrocytes, thereby mediating Aβ clearance and alleviating AD pathology. ECM remodeling also promoted Aβ plaque phagocytosis by astrocytes by activating the astrocytic phagocytosis receptor MERTK and promoting astrocytic vesicle circulation. The study identified a cellular mechanism in which ECM remodeling activates the astrocytic autophagy-lysosomal pathway and alleviates AD pathology. Targeting ECM remodeling may represent a potential therapeutic strategy for AD and serve as a reference for the treatment of this disease.

RevDate: 2024-06-19

Jakovljevic M, Deceuninck P, Pistollato F, et al (2024)

Return on investment in science: twenty years of European Commission funded research in Alzheimer's dementia, breast cancer and prostate cancer.

Cost effectiveness and resource allocation : C/E, 22(1):51.

Alzheimer's disease (AD), breast cancer (BC) and prostate cancer (PC) continue to be high in the research and innovation agenda of the European Commission (EC). This is due to their exceptionally large burden to the national health systems, the profound economic effects of opportunity costs attributable to decreased working ability, premature mortality and the ever-increasing demand for both hospital and home-based medical care. Over the last two decades, the EC has been steadily increasing both the number of proposals being funded and the amounts of financial resources being allocated to these fields of research. This trend has continued throughout four consecutive science funding cycles, namely framework programme (FP)5, FP6, FP7 and Horizon 2020 (H2020). We performed a retrospective assessment of the outputs and outcomes of EC funding in AD, BC and PC research over the 1999-2019 period by means of selected indicators. These indicators were assessed for their ability to screen the past, present and future for an array of causal relationships and long-term trends in clinical, epidemiological and public health sphere, while considering also the broader socioeconomic impact of funded research on the society at large. This analysis shows that public-private partnerships with large industry and university-based consortia have led to some of the most impactful proposals being funded over the analysed time period. New pharmaceuticals, small molecules and monoclonal antibodies alike, along with screening and prevention, have been the most prominent sources of innovation in BC and PC, extending patients' survival and enhancing their quality of life. Unlike oncology, dementia drug development has been way less successful, with only minor improvements related to the quality of supportive medical care for symptoms and more sensitive diagnostics, without any ground-breaking disease-modifying treatment(s). Significant progresses in imaging diagnostics and nanotechnology have been largely driven by the participation of medical device industry multinational companies. Clinical trials funded by the EC were conducted, leading to the development of brand-new drug molecules featuring novel mechanisms of action. Some prominent cases of breakthrough discoveries serve as evidence for the European capability to generate cutting-edge technological innovation in biomedicine. Less productive areas of research may be reconsidered as priorities when shaping the new agenda for forthcoming science funding programmes.

RevDate: 2024-06-16
CmpDate: 2024-06-16

Takeo T, Miyake M, H Mizuno (2024)

Neuroprotective Effects of Probucol against Rotenone-Induced Toxicity via Suppression of Reactive Oxygen Species Production in SH-SY5Y Cells.

Biological & pharmaceutical bulletin, 47(6):1154-1162.

Probucol is a hyperlipidemic drug with antioxidant properties. It has been reported to prevent mitochondrial dysfunction, reduce oxidative stress, and suppress neurotoxicity in neurodegenerative disease models, including Parkinson's disease models. However, the molecular mechanisms underlying the neuroprotective effects of probucol have been not examined yet. Thus, in this study, we investigated whether probucol can alleviate the effects of a mitochondrial complex I inhibitor, rotenone, on a human neuroblastoma cell line (SH-SY5Y). We evaluated the cell viability and cytotoxicity and apoptosis rates of SH-SY5Y cells treated with rotenone and probucol or edaravone, a known free-radical scavenger. Subsequently, mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) levels in the cells were evaluated to determine the effects of probucol on mitochondrial function. We found that rotenone caused cytotoxicity, cell apoptosis, and mitochondrial dysfunction, enhanced ROS generation, and impaired MMP. However, probucol could inhibit this rotenone-induced decrease in cell viability, MMP loss, intracellular ROS generation, and apoptosis. These results suggest that probucol exerts neuroprotective effects via MMP stabilization and the inhibition of ROS generation. Additionally, this effect of probucol was equal to or greater than and more persistent than that of edaravone. Thus, we believe probucol may be a promising drug for the treatment of neurodegenerative diseases, such as Parkinson's and Alzheimer's diseases.

RevDate: 2024-06-16

Menegaz de Almeida A, Leite M, Lopes LM, et al (2024)

Gantenerumab for early Alzheimer's disease: a systematic review and meta-analysis.

Expert review of neurotherapeutics [Epub ahead of print].

INTRODUCTION: Gantenerumab is a monoclonal antibody targeting amyloid β protein (Aβ) in early Alzheimer's disease (AD). The authors sought to evaluate gantenerumab safety and efficacy in early AD patients.

METHODS: MEDLINE, Embase, and Cochrane databases were systematically searched until 2 December 2023. Data were examined using the Mantel-Haenszel method and 95% confidence intervals (CIs). Meta-regression analysis was conducted to evaluate a possible link between baseline Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB) and amyloid-related imaging abnormalities (ARIA) at follow-up. R, version 4.2.3, was used for statistical analysis.

RESULTS: A total of 4 RCTs and 2848 patients were included, of whom 1580 (55%) received subcutaneous gantenerumab. Concerning clinical scores, the placebo group achieved better rates of change in the Disease Assessment Scale (ADAS-Cog13) (SMD -0.11; 95% CI -0.19- -0.03; p = 0.008569; I[2] = 0%). Gantenerumab was strongly associated with the occurrence of ARIA-E and ARIA-H: (19.67% vs. 2.31%; RR 9.46; 95% CI 5.55-16.11; p = <0.000001; I[2] = 10%) and (21.95% vs. 12.38%; RR 1.79; 95% CI 1.50-2.13; p = <0.000001; I[2] = 0%), respectively.

DISCUSSION: In this meta-analysis, consistent results suggest that gantenerumab is not safe and efficient for early AD, showing no improvement in clinical scores for AD and being associated with the occurrence of ARIA-E and ARIA-H.

RevDate: 2024-06-15

Tang R, Franz CE, Hauger RL, et al (2024)

Early cortical microstructural changes in aging are linked to vulnerability to Alzheimer's disease pathology.

Biological psychiatry. Cognitive neuroscience and neuroimaging pii:S2451-9022(24)00158-7 [Epub ahead of print].

BACKGROUND: Early identification of Alzheimer's disease (AD) risk is critical for improving treatment success. Cortical thickness is a macrostructural measure used to assess AD neurodegeneration. However, cortical microstructural changes appear to precede macrostructural atrophy and may improve early risk identification. Currently, whether cortical microstructural changes in aging are linked to vulnerability to AD pathophysiology remains unclear in non-clinical populations, who are precisely the target for early risk identification.

METHODS: In 194 adults, we calculated MRI-derived maps of changes in cortical mean diffusivity (microstructure) and cortical thickness (macrostructure) over 5-6 years (meanage: Time1=61.82; Time2=67.48). Episodic memory was assessed using three well-established tests. We obtained PET-derived maps of AD pathology deposition (beta-amyloid, tau) and neurotransmitter receptors (cholinergic, glutamatergic) implicated in AD pathophysiology. Spatial correlational analyses were used to compare pattern similarity among maps.

RESULTS: Spatial patterns of cortical macrostructural changes resembled patterns of cortical organization sensitive to age-related processes (r=-0.31, p<0.05), whereas microstructural changes resembled the patterns of tau (r=0.39, p=0.015) deposition in AD. Individuals with patterns of microstructural changes that more closely resembled stereotypical tau deposition exhibited greater memory decline (β=0.21, p=0.036). Microstructural changes and AD pathology deposition were enriched in areas with greater densities of cholinergic and glutamatergic receptors (ps<0.05).

CONCLUSIONS: Patterns of cortical microstructural changes were more AD-like than patterns of macrostructural changes, which appeared to reflect more general aging processes. Microstructural changes may better inform early risk prediction efforts as a sensitive measure of vulnerability to pathological processes prior to overt atrophy and cognitive decline.

RevDate: 2024-06-15

Mincic AM, Antal M, Filip L, et al (2024)

Modulation of gut microbiome in the treatment of neurodegenerative diseases: A systematic review.

Clinical nutrition (Edinburgh, Scotland), 43(7):1832-1849 pii:S0261-5614(24)00182-1 [Epub ahead of print].

BACKGROUND AND AIMS: Microbiota plays an essential role in maintaining body health, through positive influences on metabolic, defensive, and trophic processes and on intercellular communication. Imbalance in intestinal flora, with the proliferation of harmful bacterial species (dysbiosis) is consistently reported in chronic illnesses, including neurodegenerative diseases (ND). Correcting dysbiosis can have a beneficial impact on the symptoms and evolution of ND. This review examines the effects of microbiota modulation through administration of probiotics, prebiotics, symbiotics, or prebiotics' metabolites (postbiotics) in patients with ND like multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS).

METHODS: PubMed, Web of Science, Medline databases and ClinicalTrials.gov registry searches were performed using pre-/pro-/postbiotics and ND-related terms. Further references were obtained by checking relevant articles.

RESULTS: Although few compared to animal studies, the human studies generally show positive effects on disease-specific symptoms, overall health, metabolic parameters, on oxidative stress and immunological markers. Therapy with probiotics in various forms (mixtures of bacterial strains, fecal microbiota transplant, diets rich in fermented foods) exert favorable effects on patients' mental health, cognition, and quality of life, targeting pathogenetic ND mechanisms and inducing reparatory mechanisms at the cellular level. More encouraging results have been observed in prebiotic/postbiotic therapy in some ND.

CONCLUSIONS: The effects of probiotic-related interventions depend on the patients' ND stage and pre-existing allopathic medication. Further studies on larger cohorts and long term comprehensive neuropsychiatric, metabolic, biochemical testing, and neuroimaging monitoring are necessary to optimize therapeutic protocols in ND.

RevDate: 2024-06-15

Wang F, Wen H, Liu L, et al (2024)

A Pair of Epimers of Lignan Alleviate Neuroinflammatory Effects by Modulating iNOS/COX-2 and MAPK/NF-κB Signaling Pathways.

Inflammation [Epub ahead of print].

Neuroinflammation is a causative factor in neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis. Previous studies have shown that Artemisia mongolica has anti-inflammatory properties. Aschantin (AM3) has been shown to have anti-inflammatory effects. However, the mechanism of AM3 and its epimer epi-aschantin (AM2) remains controversial. Therefore, the present study explored the mechanism of neuroinflammation by AM2 and AM3 and attempted to reveal the relationship between the structure of AM2 and AM3 and anti-neuroinflammatory activity. We isolated for the first time 12 lignans from A. mongolica that inhibited NO content at 10 μM in LPS-stimulated BV2 cells. Among them, epi-aschantin (AM2) and Aschantin (AM3) showed significant inhibition in NO screening. With further studies, we found that both AM2 and AM3 effectively inhibited the overproduction of NO, PGE2, IL-6, TNF-α and MCP-1, as well as the overexpression of COX-2 and iNOS. Mechanistic studies have shown AM2 and AM3 significantly inhibited the phosphorylation of ERK, JNK and P-38 in the MAPK signaling pathway and p-IκBα,p-p65 and blocked p65 entry into the nucleus. The results suggested that the pair of epimers (AM2 and AM3) can be used as potential therapeutic agents in the treatment of various brain disorders and that structural differences do not differ in anti-neuroinflammatory effects.

RevDate: 2024-06-18

Zhang Q, Yang G, Luo Y, et al (2024)

Neuroinflammation in Alzheimer's disease: insights from peripheral immune cells.

Immunity & ageing : I & A, 21(1):38.

Alzheimer's disease (AD) is a serious brain disorder characterized by the presence of beta-amyloid plaques, tau pathology, inflammation, neurodegeneration, and cerebrovascular dysfunction. The presence of chronic neuroinflammation, breaches in the blood-brain barrier (BBB), and increased levels of inflammatory mediators are central to the pathogenesis of AD. These factors promote the penetration of immune cells into the brain, potentially exacerbating clinical symptoms and neuronal death in AD patients. While microglia, the resident immune cells of the central nervous system (CNS), play a crucial role in AD, recent evidence suggests the infiltration of cerebral vessels and parenchyma by peripheral immune cells, including neutrophils, T lymphocytes, B lymphocytes, NK cells, and monocytes in AD. These cells participate in the regulation of immunity and inflammation, which is expected to play a huge role in future immunotherapy. Given the crucial role of peripheral immune cells in AD, this article seeks to offer a comprehensive overview of their contributions to neuroinflammation in the disease. Understanding the role of these cells in the neuroinflammatory response is vital for developing new diagnostic markers and therapeutic targets to enhance the diagnosis and treatment of AD patients.

RevDate: 2024-06-18
CmpDate: 2024-06-15

Abdelbaset S, Ayoub IM, Mohamed OG, et al (2024)

Metabolic profiling of Vitex Pubescens Vahl bark via UPLC-ESI-QTOF/MS/MS analysis and evaluation of its antioxidant and acetylcholinesterase inhibitory activities.

BMC complementary medicine and therapies, 24(1):232.

BACKGROUND: Alzheimer's disease is a neurodegenerative age-related disease that primarily affects the elderly population leading to progressive memory impairments and neural deficits. It is counted as a major cause of geriatric dependency and disability. The pathogenesis of Alzheimer's disease incidence is complex and involves various hypotheses, including the cholinergic hypothesis, deposition of β-amyloid plaques, neuroinflammation, oxidative stress, and apoptosis. Conventional treatments such as donepezil aim to delay the symptoms but do not affect the progression of the disease and may cause serious side effects like hepatoxicity. The use of natural candidates for Alzheimer's disease treatment has drawn the attention of many researchers as it offers a multitargeted approach.

METHODS: This current study investigates the metabolic profiles of total defatted methanolic extract of Vitex pubescens bark and its polar fractions, viz. ethyl acetate and n-butanol, using ultra-performance liquid chromatography-electrospray ionization-quadrupole time-of-flight tandem mass spectrometry(UPLC-ESI-QTOF/MS/MS) technique as well as evaluate the antioxidant using free radical scavenging assays, viz. DPPH and ABTS assays and in-vitro acetylcholinesterase inhibitory activities using Ellman's microplate assay.

RESULTS: Metabolic profiling revealed a total of 71, 43, and 55 metabolites tentatively identified in the defatted methanolic extract, ethyl acetate, and n-butanol fractions, respectively. Phenolic acids were the most abundant class, viz. benzoic acids, and acyl quinic acid derivatives followed by flavonoids exemplified mainly by luteolin-C-glycosides and apigenin-C-glycosides. Quantification of the total phenolic and flavonoid contents in the total defatted methanolic extract confirmed its enrichment with phenolics and flavonoids equivalent to 138.61 ± 9.39 µg gallic acid/mg extract and 119.63 ± 4.62 µg rutin/mg extract, respectively. Moreover, the total defatted methanolic extract exhibited promising antioxidant activity confirmed through DPPH and ABTS assays with a 50% inhibitory concentration (IC50) value equivalent to 52.79 ± 2.16 µg/mL and 10.02 ± µg/mL, respectively. The inhibitory activity of acetylcholine esterase (AchE) was assessed using in-vitro Ellman's colorimetric assay, the total defatted methanolic extract, ethyl acetate, and n-butanol fractions exhibited IC50 values of 52.9, 15.1 and 108.8 µg/mL that they proved the significant inhibition of AchE activity.

CONCLUSION: The results obtained herein unraveled the potential use of the total methanolic extract of Vitex pubescens bark and its polar fractions as natural candidates for controlling Alzheimer's disease progression.

RevDate: 2024-06-14

Acun AD, D Kantar (2024)

Modulation of oxidative stress and apoptosis by alteration of bioactive lipids in the pancreas, and effect of zinc chelation in a rat model of Alzheimer's disease.

Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS), 85:127480 pii:S0946-672X(24)00100-7 [Epub ahead of print].

INTRODUCTION: Increasing epidemiological evidence highlights the association between systemic insulin resistance and Alzheimer's disease (AD). It is known that peripheral insulin resistance in the early stages of AD precedes and is a precursor to amyloid-β (Aβ) deposition. Although it is known that improving the CNS insulin sensitivity of AD patients is an important therapeutic goal and that the majority of insulin in the brain comes from the periphery, there has been little attention to the changes that occur in the pancreatic tissue of AD patients. Therefore, it is crucial to elucidate the mechanisms affecting insulin resistance in pancreatic tissue in AD. It is known that zinc (Zn2+) chelation is effective in reducing peripheral insulin resistance, cell apoptosis, cell death, and oxidative stress.

OBJECTIVE: It was aimed to determine the changes in bioactive lipids, amylin (AIPP), oxidative stress and apoptosis in pancreatic cells in the early stages of Alzheimer's disease. The main aim is to reveal the therapeutic effect of the Cyclo-Z agent on these changes seen in the pancreas due to AD disease.

METHODS: AD and ADC rats were intracerebroventricular (i.c.v.) Aβ1-42 oligomers. Cyclo-Z gavage was applied to ADC and SHC rats for 21 days. First of all, the effects of AIPP, bioactive ceramides, apoptosis and oxidative stress on the pancreatic tissue of AD group rats were evaluated. Then, the effect of Cyclo-Z treatment on these was examined. ELISA kit was used in biochemical analyses.

RESULTS: AIPP and ceramide (CER) levels and CER/ sphingosine-1 phosphate (S1P) ratio were increased in the pancreatic tissue of AD rats. It also increased the level of CER kinase (CERK), which is known to increase the concentration of CER 1-phosphate (C1P), which is known to be toxic to cells in the presence of excessive CER concentration. Due to the increase in CER level, it was observed that apoptosis and oxidative stress increased in the pancreatic cells of AD group rats.

CONCLUSION: Cyclo-Z, which has Zn2+ chelating properties, reduced AD model rats' AIPP level and oxidative stress and could prevent pancreatic apoptosis. Similar therapeutic effects were not observed in the pancreatic tissue of Cyclo-Z administered to the SH group. For this reason, it is thought that Cyclo-Z agent may have a therapeutic effect on the peripheral hyperinsulinemia observed in the early stages of AD disease and the resulting low amount of insulin transported to the brain, by protecting pancreatic cells from apoptosis and oxidative stress by regulating their bioactive metabolites.

RevDate: 2024-06-14

Loeffler DA (2024)

Approaches for Increasing Cerebral Efflux of Amyloid-β in Experimental Systems.

Journal of Alzheimer's disease : JAD pii:JAD240212 [Epub ahead of print].

Amyloid protein-β (Aβ) concentrations are increased in the brain in both early onset and late onset Alzheimer's disease (AD). In early onset AD, cerebral Aβ production is increased and its clearance is decreased, while increased Aβ burden in late onset AD is due to impaired clearance. Aβ has been the focus of AD therapeutics since development of the amyloid hypothesis, but efforts to slow AD progression by lowering brain Aβ failed until phase 3 trials with the monoclonal antibodies lecanemab and donanemab. In addition to promoting phagocytic clearance of Aβ, antibodies lower cerebral Aβ by efflux of Aβ-antibody complexes across the capillary endothelia, dissolving Aβ aggregates, and a "peripheral sink" mechanism. Although the blood-brain barrier is the main route by which soluble Aβ leaves the brain (facilitated by low-density lipoprotein receptor-related protein-1 and ATP-binding cassette sub-family B member 1), Aβ can also be removed via the blood-cerebrospinal fluid barrier, glymphatic drainage, and intramural periarterial drainage. This review discusses experimental approaches to increase cerebral Aβ efflux via these mechanisms, clinical applications of these approaches, and findings in clinical trials with these approaches in patients with AD or mild cognitive impairment. Based on negative findings in clinical trials with previous approaches targeting monomeric Aβ, increasing the cerebral efflux of soluble Aβ is unlikely to slow AD progression if used as monotherapy. But if used as an adjunct to treatment with lecanemab or donanemab, this approach might allow greater slowing of AD progression than treatment with either antibody alone.

RevDate: 2024-06-14

Lee CS, Ferguson AN, Gibbons LE, et al (2024)

Eye Adult Changes in Thought (Eye ACT) Study: Design and Report on the Inaugural Cohort.

Journal of Alzheimer's disease : JAD pii:JAD240203 [Epub ahead of print].

BACKGROUND: Conflicting research on retinal biomarkers of Alzheimer's disease and related dementias (AD/ADRD) is likely related to limited sample sizes, study design, and protocol differences.

OBJECTIVE: The prospective Eye Adult Changes in Thought (Eye ACT) seeks to address these gaps.

METHODS: Eye ACT participants are recruited from ACT, an ongoing cohort of dementia-free, older adults followed biennially until AD/ADRD, and undergo visual function and retinal imaging assessment either in clinic or at home.

RESULTS: 330 participants were recruited as of 03/2023. Compared to ACT participants not in Eye ACT (N = 1868), Eye ACT participants (N = 330) are younger (mean age: 70.3 versus 71.2, p = 0.014), newer to ACT (median ACT visits since baseline: 3 versus 4, p < 0.001), have more years of education (17.7 versus 16.2, p < 0.001) and had lower rates of visual impairment (12% versus 22%, p < 0.001). Compared to those seen in clinic (N = 300), Eye ACT participants seen at home (N = 30) are older (77.2 versus 74.9, p = 0.015), more frequently female (60% versus 49%, p = 0.026), and have significantly worse visual acuity (71.1 versus 78.9 Early Treatment Diabetic Retinopathy Study letters, p < 0.001) and contrast sensitivity (-1.9 versus -2.1 mean log units at 3 cycles per degree, p = 0.002). Cognitive scores and retinal imaging measurements are similar between the two groups.

CONCLUSIONS: Participants assessed at home had significantly worse visual function than those seen in clinic. By including these participants, Eye ACT provides a unique longitudinal cohort for evaluating potential retinal biomarkers of dementia.

RevDate: 2024-06-14

Toya S, Hashimoto M, Manabe Y, et al (2024)

Factors Associated with Quality of Life in Patients with Dementia with Lewy Bodies: Additional Analysis of a Cross-Sectional Study.

Journal of Alzheimer's disease : JAD pii:JAD231302 [Epub ahead of print].

BACKGROUND: Quality of life (QOL) and treatment needs of patients with dementia with Lewy bodies (DLB) and their caregivers are important factors to consider when developing treatment strategies.

OBJECTIVE: To investigate factors associated with QOL in patients with DLB, and to examine factors associated with activities of daily living (ADL) if ADL was associated with QOL.

METHODS: We previously conducted a questionnaire survey study to investigate the treatment needs of patients with DLB and their caregivers. This pre-specified additional analysis evaluated the Physical Component Score (PCS) and Mental Component Score (MCS) of the Short Form-8 for QOL, and the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part II total score for ADL.

RESULTS: In total, 231 patient- caregiver pairs and 38 physicians were included. Multivariable analysis of QOL showed that the MDS-UPDRS Part II total score (standard regression coefficient [β], - 0.432) was associated with the PCS, and presence of depression (β, - 0.330) was associated with the MCS. The severity of postural instability/gait disorder (PIGD) (β, 0.337) and rigidity (β, 0.266), presence of hallucinations (β, 0.165), male sex (β, 0.157), and use of "short stay" or "small-scale, multifunctional home care" (β, 0.156) were associated with worsened ADL.

CONCLUSIONS: In patients with DLB, QOL was negatively impacted by severity of ADL disability and depression, and ADL was negatively impacted by severity of PIGD and rigidity, hallucinations, male sex, and use of "short stay" or "small-scale, multifunctional home care."

RevDate: 2024-06-14

Desai S, Chen IY, Hom C, et al (2024)

Insomnia Symptoms Are Associated with Measures of Functional Deterioration and Dementia Status in Adults with Down Syndrome at High Risk for Alzheimer's Disease.

Journal of Alzheimer's disease : JAD pii:JAD220750 [Epub ahead of print].

BACKGROUND: While obstructive sleep apnea (OSA) and insomnia symptoms in neurotypical populations are associated with Alzheimer's disease (AD), their association with dementia in adults with Down syndrome (DS) remains less clear, even though these symptoms are prevalent and treatable in DS. Understanding their associations with AD-related dementia status, cognitive impairment, and functional deterioration may lead to interventions to slow decline or disease progression in adults with DS.

OBJECTIVE: To characterize differences in OSA and insomnia symptom expression by dementia status, and to determine which sleep factors support dementia diagnosis.

METHODS: Multimodal consensus conference was used to determine dementia status in 52 adults with DS (52.2 ± 6.4 years, 21 women). Cognitive impairment, adaptive behavior skills, and symptoms of OSA and insomnia were quantified using validated assessments for adults with DS and their primary informants.

RESULTS: A sex by dementia status interaction demonstrated that older women with DS and dementia had more severe terminal insomnia but not OSA symptoms relative to older women with DS who were cognitively stable (CS). Greater insomnia symptom severity was associated with greater functional impairments in social and self-care domains adjusting for age, sex, premorbid intellectual impairment, and dementia status.

CONCLUSIONS: Insomnia symptoms are more severe in women with DS with dementia than in women with DS and no dementia, and regardless of dementia status or sex, more severe insomnia symptoms are associated with greater impairment in activities of daily living. These findings underscore the potential importance of early insomnia symptom evaluation and treatment in women with DS at risk of developing AD.

RevDate: 2024-06-14

Gharai PK, Khan J, Pradhan K, et al (2024)

Power of Dopamine: Multifunctional Compound Assisted Conversion of the Most Risk Factor into Therapeutics of Alzheimer's Disease.

ACS chemical neuroscience [Epub ahead of print].

In Alzheimer's disease (AD), reactive oxygen species (ROS) plays a crucial role, which is produced from molecular oxygen with extracellular deposited amyloid-β (Aβ) aggregates through the reduction of a Cu[2+] ion. In the presence of a small amount of redox-active Cu[2+] ion, ROS is produced by the Aβ-Cu[2+] complex as Aβ peptide alone is unable to generate excess ROS. Therefore, Cu[2+] ion chelators are considered promising therapeutics against AD. Here, we have designed and synthesized a series of Schiff base derivatives (SB) based on 2-hydroxy aromatic aldehyde derivatives and dopamine. These SB compounds contain one copper chelating core, which captures the Cu[2+] ions from the Aβ-Cu[2+] complex. Thereby, it inhibits copper-induced amyloid aggregation as well as amyloid self-aggregation. It also inhibits copper-catalyzed ROS production through sequestering of Cu[2+] ions. The uniqueness of our designed ligands has the dual property of dopamine, which not only acts as a ROS scavenger but also chelates the copper ion. The crystallographic analysis proves the power of the dopamine unit. Therefore, dual exploration of dopamine core can be considered as potential therapeutics for future AD treatment.

RevDate: 2024-06-15

Oken BS, Kaplan J, Klee D, et al (2024)

Contributions of loneliness to cognitive impairment and dementia in older adults are independent of other risk factors and Alzheimer's pathology: a narrative review.

Frontiers in human neuroscience, 18:1380002.

Loneliness significantly contributes to cognitive impairment and dementia in older adults. Loneliness is a distressing feeling resulting from a perceived lack of social connection (i.e., a discrepancy between desired and actual social relationships), while social isolation is a related term that can be defined by number and type of social relationships. Importantly, loneliness is distinct from social isolation in that it is associated with a distressing self-perception. The primary focus of this narrative review is the impact of chronic loneliness on cognitive impairment and dementia among older adults. Loneliness has a significant association with many factors that are related to worse cognition, and therefore we include discussion on health, mental health, as well as the physiological effects of loneliness, neuropathology, and potential treatments. Loneliness has been shown to be related to development of dementia with a hazard ratio (HR) risk comparable to having a single APOE4 gene. The relationship of dementia to loneliness appears to be at least partially independent of other known dementia risk factors that are possibly associated with loneliness, such as depression, educational status, social isolation, and physical activity. Episodic memory is not consistently impacted by loneliness, which would be more typically impaired if the mild cognitive impairment (MCI) or dementia was due to Alzheimer's disease (AD) pathology. In addition, the several longitudinal studies that included neuropathology showed no evidence for a relationship between loneliness and AD neuropathology. Loneliness may decrease resilience, or produce greater cognitive change associated with the same level of AD neuropathology. Intervention strategies to decrease loneliness in older adults have been developed but need to consider key treatment targets beyond social isolation. Loneliness needs to be assessed in all studies of cognitive decline in elders, since it significantly contributes to the variance of cognitive function. It will be useful to better define the underlying mechanism of loneliness effects on cognition to determine if it is similar to other psychological factors related to excessive stress reactivity, such as neuroticism or even depression, which are also associated with cognitive decline. It is important from a health perspective to develop better strategies to decrease loneliness in older adults.

RevDate: 2024-06-15

Xie PL, Zheng MY, Han R, et al (2024)

Pharmacological mTOR inhibitors in ameliorating Alzheimer's disease: current review and perspectives.

Frontiers in pharmacology, 15:1366061.

Traditionally, pharmacological mammalian/mechanistic targets of rapamycin (mTOR) kinase inhibitors have been used during transplantation and tumor treatment. Emerging pre-clinical evidence from the last decade displayed the surprising effectiveness of mTOR inhibitors in ameliorating Alzheimer's Disease (AD), a common neurodegenerative disorder characterized by progressive cognitive function decline and memory loss. Research shows mTOR activation as an early event in AD development, and inhibiting mTOR may promote the resolution of many hallmarks of Alzheimer's. Aberrant protein aggregation, including amyloid-beta (Aβ) deposition and tau filaments, and cognitive defects, are reversed upon mTOR inhibition. A closer inspection of the evidence highlighted a temporal dependence and a hallmark-specific nature of such beneficial effects. Time of administration relative to disease progression, and a maintenance of a functional lysosomal system, could modulate its effectiveness. Moreover, mTOR inhibition also exerts distinct effects between neurons, glial cells, and endothelial cells. Different pharmacological properties of the inhibitors also produce different effects based on different blood-brain barrier (BBB) entry capacities and mTOR inhibition sites. This questions the effectiveness of mTOR inhibition as a viable AD intervention strategy. In this review, we first summarize the different mTOR inhibitors available and their characteristics. We then comprehensively update and discuss the pre-clinical results of mTOR inhibition to resolve many of the hallmarks of AD. Key pathologies discussed include Aβ deposition, tauopathies, aberrant neuroinflammation, and neurovascular system breakdowns.

RevDate: 2024-06-15

Yu X, Tao J, Xiao T, et al (2024)

4,4'-methylenediphenol reduces Aβ-induced toxicity in a Caenorhabditis elegans model of Alzheimer's disease.

Frontiers in aging neuroscience, 16:1393721.

INTRODUCTION: Gastrodia elata Blume is a widely used medicinal and edible herb with a rich chemical composition. Moreover, prescriptions containing Gastrodia elata are commonly used for the prevention and treatment of cardiovascular, cerebrovascular, and aging-related diseases. Recent pharmacological studies have confirmed the antioxidant and neuroprotective effects of Gastrodia elata, and, in recent years, this herb has also been used in the treatment of Alzheimer's disease (AD) and other neurodegenerative disorders. We have previously shown that 4,4'-methylenediphenol, a key active ingredient of Gastrodia elata, can mitigate amyloid-β (Aβ)-induced paralysis in AD model worms as well as prolong the lifespan of the animals, thus displaying potential as a treatment of AD.

METHODS: We investigated the effects of 4,4'-methylenediphenol on AD and aging through paralysis, lifespan, and behavioral assays. In addition, we determined the anti-AD effects of 4,4'-methylenediphenol by reactive oxygen species (ROS) assay, lipofuscin analysis, thioflavin S staining, metabolomics analysis, GFP reporter gene worm assay, and RNA interference assay and conducted in-depth studies on its mechanism of action.

RESULTS: 4,4'-Methylenediphenol not only delayed paralysis onset and senescence in the AD model worms but also enhanced their motility and stress tolerance. Meanwhile, 4,4'-methylenediphenol treatment also reduced the contents of reactive oxygen species (ROS) and lipofuscin, and decreased Aβ protein deposition in the worms. Broad-spectrum targeted metabolomic analysis showed that 4,4'-methylenediphenol administration had a positive effect on the metabolite profile of the worms. In addition, 4,4'-methylenediphenol promoted the nuclear translocation of DAF-16 and upregulated the expression of SKN-1, SOD-3, and GST-4 in the respective GFP reporter lines, accompanied by an enhancement of antioxidant activity and a reduction in Aβ toxicity; importantly, our results suggested that these effects of 4,4'-methylenediphenol were mediated, at least partly, via the activation of DAF-16.

CONCLUSION: We have demonstrated that 4,4'-methylenediphenol can reduce Aβ-induced toxicity in AD model worms, suggesting that it has potential for development as an anti-AD drug. Our findings provide ideas and references for further research into the anti-AD effects of Gastrodia elata and its active ingredients.

RevDate: 2024-06-15

Zhang H, Wang J, Su N, et al (2024)

Identification and validation of a novel Parkinson-Glioma feature gene signature in glioma and Parkinson's disease.

Frontiers in aging neuroscience, 16:1352681.

INTRODUCTION: The prognosis for glioma is generally poor, and the 5-year survival rate for patients with this disease has not shown significant improvement over the past few decades. Parkinson's disease (PD) is a prevalent movement disorder, ranking as the second most common neurodegenerative disease after Alzheimer's disease. Although Parkinson's disease and glioma are distinct diseases, they may share certain underlying biological pathways that contribute to their development.

OBJECTIVE: This study aims to investigate the involvement of genes associated with Parkinson's disease in the development and prognosis of glioma.

METHODS: We obtained datasets from the TCGA, CGGA, and GEO databases, which included RNA sequencing data and clinical information of glioma and Parkinson's patients. Eight machine learning algorithms were used to identify Parkinson-Glioma feature genes (PGFGs). PGFGs associated with glioma prognosis were identified through univariate Cox analysis. A risk signature was constructed based on PGFGs using Cox regression analysis and the Least Absolute Shrinkage and Selection Operator (LASSO) method. We subsequently validated its predictive ability using various methods, including ROC curves, calibration curves, KM survival analysis, C-index, DCA, independent prognostic analysis, and stratified analysis. To validate the reproducibility of the results, similar work was performed on three external test datasets. Additionally, a meta-analysis was employed to observe the heterogeneity and consistency of the signature across different datasets. We also compared the differences in genomic variations, functional enrichment, immune infiltration, and drug sensitivity analysis based on risk scores. This exploration aimed to uncover potential mechanisms of glioma occurrence and prognosis.

RESULTS: We identified 30 PGFGs, of which 25 were found to be significantly associated with glioma survival. The prognostic signature, consisting of 19 genes, demonstrated excellent predictive performance for 1-, 2-, and 3-year overall survival (OS) of glioma. The signature emerged as an independent prognostic factor for glioma overall survival (OS), surpassing the predictive performance of traditional clinical variables. Notably, we observed differences in the tumor microenvironment (TME), levels of immune cell infiltration, immune gene expression, and drug resistance analysis among distinct risk groups. These findings may have significant implications for the clinical treatment of glioma patients.

CONCLUSION: The expression of genes related to Parkinson's disease is closely associated with the immune status and prognosis of glioma patients, potentially regulating glioma pathogenesis through multiple mechanisms. The interaction between genes associated with Parkinson's disease and the immune system during glioma development provides novel insights into the molecular mechanisms and targeted therapies for glioma.

RevDate: 2024-06-16
CmpDate: 2024-06-13

Zhuang X, Xia Y, Liu Y, et al (2024)

SCG5 and MITF may be novel markers of copper metabolism immunorelevance in Alzheimer's disease.

Scientific reports, 14(1):13619.

The slow-developing neurological disorder Alzheimer's disease (AD) has no recognized etiology. A bioinformatics investigation verified copper metabolism indicators for AD development. GEO contributed AD-related datasets GSE1297 and GSE5281. Differential expression analysis and WGCNA confirmed biomarker candidate genes. Each immune cell type in AD and control samples was scored using single sample gene set enrichment analysis. Receiver Operating Characteristic (ROC) analysis, short Time-series Expression Miner (STEM) grouping, and expression analysis between control and AD samples discovered copper metabolism indicators that impacted AD progression. We test clinical samples and cellular function to ensure study correctness. Biomarker-targeting miRNAs and lncRNAs were predicted by starBase. Trust website anticipated biomarker-targeting transcription factors. In the end, Cytoscape constructed the TF/miRNA-mRNA and lncRNA-miRNA networks. The DGIdb database predicted biomarker-targeted drugs. We identified 57 differentially expressed copper metabolism-related genes (DE-CMRGs). Next, fourteen copper metabolism indicators impacting AD progression were identified: CCK, ATP6V1E1, SYT1, LDHA, PAM, HPRT1, SCG5, ATP6V1D, GOT1, NFKBIA, SPHK1, MITF, BRCA1, and CD38. A TF/miRNA-mRNA regulation network was then established with two miRNAs (hsa-miR-34a-5p and 34c-5p), six TFs (NFKB1, RELA, MYC, HIF1A, JUN, and SP1), and four biomarkers. The DGIdb database contained 171 drugs targeting ten copper metabolism-relevant biomarkers (BRCA1, MITF, NFKBIA, CD38, CCK2, HPRT1, SPHK1, LDHA, SCG5, and SYT1). Copper metabolism biomarkers CCK, ATP6V1E1, SYT1, LDHA, PAM, HPRT1, SCG5, ATP6V1D, GOT1, NFKBIA, SPHK1, MITF, BRCA1, and CD38 alter AD progression, laying the groundwork for disease pathophysiology and novel AD diagnostic and treatment.

RevDate: 2024-06-17

Song JY, Jia Y, Han H, et al (2024)

Increased expression of SLC25A18 is associated with Alzheimer's disease and is involved in Aβ42-induced mitochondrial dysfunction and apoptosis in neuronal cells.

Mitochondrion, 78:101918 pii:S1567-7249(24)00076-X [Epub ahead of print].

Alzheimer's disease (AD) is currently one of the most serious public health concerns in the world. However, the best approach to treat AD has yet to be discovered, implying that we must continue to work hard to find new AD target genes. In this study, we further analysed Gene Expression Omnibus (GEO) data and discovered that the expression of the Mitochondria glutamate carrier SLC25A18 is associated with AD by screening the differentially expressed genes in different regions of the brains of Alzheimer's disease patients. To verify the expression of SLC25A18 during Alzheimer's disease development, we analysed animal models (5×FAD transgenic AD animal model, chemically induced AD animal model, natural ageing animal model), and the results showed that the expression of SLC25A18 was increased in animal models of AD. Further investigation of the different regions found that SLC25A18 expression was elevated in the EC, TeA, and CA3, and expressed in neurons. Next, We found that Aβ42 treatment elevated SLC25A18 expression in Neuro 2A cells. Reducing SLC25A18 expression attenuated mitochondrial dysfunction and neuronal apoptosis caused by Aβ42. Overexpression of SLC25A18 increased ATP and intracellular superoxide anions but decreased mitochondrial membrane potential. The results indicate that SLC25A18 affects mitochondrial function and neuronal apoptosis, and is related to AD, which makes it a potential target for treating brain dysfunction.

RevDate: 2024-06-13

Stites SD, Lee BN, Largent EA, et al (2024)

Double-Edged Sword: A Positive Brain Scan Result Heightens Confidence in an Alzheimer's Diagnosis but also Leads to Higher Stigma among Older Adults in a Vignette-Based Experiment.

The journals of gerontology. Series B, Psychological sciences and social sciences pii:7692960 [Epub ahead of print].

OBJECTIVES: Early diagnosis of Alzheimer's disease (AD) using brain scans and other biomarker tests will be essential to increasing the benefits of emerging disease-modifying therapies, but AD biomarkers may have unintended negative consequences on stigma. We examined how a brain scan result affects AD diagnosis confidence and AD stigma.

METHODS: The study used a vignette-based experiment with a 2×2×3 factorial design of main effects: a brain scan result as positive or negative, treatment availability and symptom stage. We sampled 1,283 adults ages 65 and older between 11 June and 3 July 2019. Participants (1) rated their confidence in an AD diagnosis in each of four medical evaluations that varied in number and type of diagnostic tools and (2) read a vignette about a fictional patient with varied characteristics before completing the Modified Family Stigma in Alzheimer's Disease Scale (FS-ADS). We examined mean diagnosis confidence by medical evaluation type. We conducted between-group comparisons of diagnosis confidence and FS-ADS scores in the positive versus negative brain scan result conditions and, in the positive condition, by symptom stage and treatment availability.

RESULTS: A positive versus negative test result corresponds with higher confidence in an AD diagnosis independent of medical evaluation type (all p<0.001). A positive result correlates with stronger reactions on 6 of 7 FS-ADS domains (all p<0.001).

DISCUSSION: A positive biomarker result heightens AD diagnosis confidence but also correlates with more AD stigma. Our findings inform strategies to promote early diagnosis and clinical discussions with individuals undergoing AD biomarker testing.

RevDate: 2024-06-13

Kadam R, Gupta M, Lazarov O, et al (2024)

Brain-Immune interactions: Implication for Cognitive impairments in Alzheimer's Disease and autoimmune disorders.

Journal of leukocyte biology pii:7692812 [Epub ahead of print].

Progressive memory loss and cognitive dysfunction, encompassing deficits in learning, memory, problem-solving, spatial reasoning, verbal expression are characteristics of Alzheimer's disease and related dementia (ADRD). A wealth of studies has described multiple roles of the immune system in the development or exacerbation of dementia. Individuals with autoimmune disorders can also develop cognitive dysfunction, a phenomenon termed autoimmune dementia. Together, these findings underscore the pivotal role of the neuroimmune axis in both ADRD and autoimmune dementia. The dynamic interplay between adaptive and innate immunity, both in and outside the brain, significantly affects the etiology and progression of these conditions. Multidisciplinary research shows that cognitive dysfunction arises from a bidirectional relationship between the nervous and immune systems, though the specific mechanisms that drive cognitive impairments are not fully understood. Intriguingly, this reciprocal regulation occurs at multiple levels, where neuronal signals can modulate immune responses, and immune system-related processes can influence neuronal viability and function. In this review, we consider the implications of autoimmune responses in various autoimmune disorders and Alzheimer's disease and explore their effects on brain function. We also discuss the diverse cellular and molecular cross talk between the brain and the immune system as they may shed light on potential triggers of peripheral inflammation, their effect on the integrity of the blood-brain barrier (BBB) and brain function. Additionally, we assess challenges and possibilities associated with developing immune-based therapies for the treatment of cognitive decline.

RevDate: 2024-06-14
CmpDate: 2024-06-13

Ou CH, Liu TJ, Cheng CS, et al (2024)

Neuroimaging for Early Diagnosis of Alzheimer's Disease: a Review.

Clinical laboratory, 70(6):.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disease that primarily affects people above the age of 60 all around the world. As of now, the cause is unknown and there is no effective cure. The pathological changes of AD have occurred many years before the onset of the disease, and current treatment techniques can only delay the progression of the disease. Because disease-modifying therapies may be most beneficial in the early stages of AD, the clinical significance of an early diagnosis is emphasized. So far, a variety of imaging technologies and related biomarkers have been used to identify and monitor AD, but there are many imaging technologies; finding the most effective imaging technology can assist medical personnel in interpreting the early stages of AD and can also improve patient treatment opportunities. This is, therefore, the main purpose and back-ground of this study.

METHODS: PubMed and other repositories were used in this study to conduct a literature search with various keywords, and relevant articles were reviewed. In this review, different neuroimaging techniques are reviewed which are considered advanced tools to help establish the diagnosis, and in addition, the diagnostic utility, advantages, and limitations of contemporary AD imaging techniques are discussed.

RESULTS: The results of the literature review and synthesis show that the prevalence of several in vivo biomarkers helps distinguish affected individuals from healthy controls in the early stages of the disease. Additionally, each current imaging method has its advantages and disadvantages, so no single imaging method is the best diagnostic modality.

CONCLUSIONS: This article also reviews and draws conclusions on better ways to use the imaging techniques to improve the likelihood of an early diagnosis of AD. It is suggested that future research could focus on expanding the use of imaging technologies and on identifying novel biomarkers manifesting the earliest stages of AD pathology.

RevDate: 2024-06-14

Velioğlu HA, Sayman D, Hanoğlu L, et al (2024)

Repetitive Transcranial Magnetic Stimulation Improves Hippocampal N-Acetlaspartate Levels and Visual Memory Scores in Alzheimer's Disease.

Noro psikiyatri arsivi, 61(2):189-192.

The latest research into the pathophysiology of Alzheimer's Disease (AD) has included several cognitive deficits related to hippocampal functioning. However, current clinical research fails to consider the full extent of the heterogeneous cognitive spectrum of AD, resulting in a lack of the specific methods required to draw definitive diagnostic and therapeutic conclusions. This also includes in-vivo metabolic measurements for tailoring the diagnostic and therapeutic regimens in humans with AD. Magnetic resonance spectroscopy and repetitive transcranial magnetic stimulation (rTMS) are two novel diagnostic and therapeutic approaches that must be modified to treat AD. In the present study, we aimed to investigate the underlying therapeutic role of rTMS in humans with AD by evaluating the in-vivo hippocampal metabolites before and after rTMS treatment. Based on the data obtained using the fMRI data in our previous study and on the references reported in the literature, in the present study, we decided to use hippocampal NAA data after rTMS stimulation and found a significant increase in NAA levels. To the best of our knowledge, no other study has evaluated the effect of rTMS on hippocampal metabolites in humans with AD.

RevDate: 2024-06-14

Kim AY, Al Jerdi S, MacDonald R, et al (2024)

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

Frontiers in pharmacology, 15:1399121.

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.

RevDate: 2024-06-14

Kim S, Ullah I, Beloor J, et al (2024)

Systemic Treatment with siRNA Targeting Gamma-Secretase Activating Protein Inhibits Amyloid-β Accumulation in Alzheimer's Disease.

Biomaterials research, 28:0027.

Amyloid-β (Aβ) peptide aggregation in the brain is a key factor in Alzheimer's disease. However, direct inhibition of β-secretase or γ-secretase proves ineffective in reducing Aβ accumulation and improving cognition in Alzheimer's. Recent findings suggest that inhibiting gamma-secretase activating protein (GSAP) can decrease Aβ generation without affecting crucial γ-secretase substrates. Dimerization of Lep9R3LC (diLep9R3LC) was confirmed by Ellman's test. The peptide-small interfering RNA (siRNA) complex ratio, particle size, and surface charge were analyzed using electrophoretic mobility shift assay, and dynamic light scattering, respectively. In a 3xTg mice model of Alzheimer's disease, diLep9R3LC:siRNA complexes were intravenously administered twice a week for 8 weeks. Assessments included gene silencing, protein expression, and behavioral improvement using reverse transcription polymerase chain reaction, quantitative polymerase chain reaction, western blotting, Y-maze, and object recognition tests. The efficacy of Lep9R3LC dimerization was ~80% after a 3-d reaction by Ellman's test. In N2a cells, diLep9R3LC:siGSAP complexes achieved ~70% silencing at 48 h posttransfection. In 7-month-old male 3xTg mice, GSAP knockdown was ~30% in the cortex and ~50% in the hippocampus. The behavior improved in mice treated with diLep9R3LC:siGSAP complexes, showing a 60% increase in entries and an 80% increase object recognition. A novel dipeptide, diLep9R3LC, complexed with siRNA targeting GSAP (siGSAP), efficiently delivers siRNA to the mouse brain, targeting the hippocampus. The treatment inhibits Aβ accumulation, reduces GSK-3β-associated with tau hyperphosphorylation, and improves Alzheimer's behavior. Our findings highlight diLep9R3LC:siGSAP's potential for Alzheimer's and as a siRNA carrier for central nervous system-related diseases.

RevDate: 2024-06-14

Almohaimeed HM, Almars AI, Alsulaimani F, et al (2024)

Investigating the potential neuroprotective benefits of taurine and Dihydrotestosterone and Hydroxyprogesterone levels in SH-SY5Y cells.

Frontiers in aging neuroscience, 16:1379431.

BACKGROUND: Taurine, an amino acid abundantly found in the brain and other tissues, has potential neuroprotective properties. Alzheimer's disease (AD) is a commonly occurring type of dementia, which becomes more prevalent as people age. This experiment aimed to assess the neuroprotective effects of taurine on SH-SY5Y cells by examining its impact on Dihydrotestosterone (DHT), Dihydroprogesterone (DHP), as well as the expression of miRNA-21 and miRNA-181.

METHODS: The effects of various taurine concentrations (0.25, and 0.75 mg/mL), and LPS (0.1, and 12 mg/mL) on the SH-SY5Y cell line were assessed using the MTT assay. The levels of DHT and DHP were quantified using an ELISA kit. Additionally, the expression levels of miRNA-181 and miRNA-21 genes were examined through Real-Time PCR analysis.

RESULTS: The results of the MTT assay showed that treatment with taurine at concentrations of 0.25, and 0.75 mg/mL reduces the toxicity of LPS in SH-SY5Y cells. ELISA results indicated that taurine at a concentration of 0.25, and 0.75 mg/mL significantly elevated DHT and DHP hormones in the SH-SY5Y cell line compared to the untreated group (p < 0.01). The expression levels of IL-1β and IL-6 were decreased under the influence of LPS in SH-SY5Y cells after taurine treatment (p < 0.01). Gene expression analysis revealed that increasing taurine concentration resulted in heightened expression of miRNA-181 and miRNA-21, with the most significant increase observed at a concentration of 0.75 mg/mL (p < 0.001).

CONCLUSION: Our study findings revealed that the expression of miRNA-181 and miRNA-21 can be enhanced by taurine. Consequently, exploring the targeting of taurine, miRNA-181, and miRNA-21 or considering hormone therapy may offer potential therapeutic approaches for treating AD or alleviating severe symptoms. Nonetheless, in order to fully comprehend the precise mechanisms involved, additional research is required.

RevDate: 2024-06-15
CmpDate: 2024-06-13

Hossain MF, Husna AU, M Kharel (2024)

Use of lecanemab for the treatment of Alzheimer's disease: A systematic review.

Brain and behavior, 14(6):e3592.

PURPOSE: The US Food and Drug Administration authorized lecanemab for the therapeutic use of Alzheimer's disease (AD) in January 2023. To assess the effectiveness and safety of lecanemab in treating AD, we thoroughly examined the studies that are currently accessible.

METHOD: Preferred Reporting Items for Systematic Reviews and Meta-Analysis recommendations were followed. In order to find relevant studies on lecanemab, we carried out a thorough literature search utilizing the electronic databases MEDLINE via PubMed, Cochrane, Web of Science, EBSCOhost, and Scopus. Excluding any research using experimental animals, we looked at lecanemab's effectiveness and side effects in treating AD in human clinical trials. Three randomized controlled studies were included.

FINDINGS: According to studies, lecanemab lessens clinical deterioration and reduces brain amyloid-beta plaques (difference,.45; 95% confidence interval,.67 to.23; p < .001). Participants who received lecanemab saw a greater frequency of amyloid-related imaging abnormalities (ARIA)-H (17.3% vs. 9.0%) and ARIA-E (12.6% vs. 1.7%), which is a significant adverse outcome.

CONCLUSION: Lecanemab has been shown to have an impact on the two primary pathophysiologic indicators of AD (Aβ and tau). There are still a lot of unresolved issues related to lecanemab. Future research on the effectiveness and safety of lecanemab is advised in order to determine that the advantages of this medication exceed the disadvantages.

RevDate: 2024-06-15
CmpDate: 2024-06-13

Ning Z, Liu Y, Wan M, et al (2024)

APOE2 protects against Aβ pathology by improving neuronal mitochondrial function through ERRα signaling.

Cellular & molecular biology letters, 29(1):87.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disease and apolipoprotein E (APOE) genotypes (APOE2, APOE3, and APOE4) show different AD susceptibility. Previous studies indicated that individuals carrying the APOE2 allele reduce the risk of developing AD, which may be attributed to the potential neuroprotective role of APOE2. However, the mechanisms underlying the protective effects of APOE2 is still unclear.

METHODS: We analyzed single-nucleus RNA sequencing and bulk RNA sequencing data of APOE2 and APOE3 carriers from the Religious Orders Study and Memory and Aging Project (ROSMAP) cohort. We validated the findings in SH-SY5Y cells and AD model mice by evaluating mitochondrial functions and cognitive behaviors respectively.

RESULTS: The pathway analysis of six major cell types revealed a strong association between APOE2 and cellular stress and energy metabolism, particularly in excitatory and inhibitory neurons, which was found to be more pronounced in the presence of beta-amyloid (Aβ). Moreover, APOE2 overexpression alleviates Aβ1-42-induced mitochondrial dysfunction and reduces the generation of reactive oxygen species in SH-SY5Y cells. These protective effects may be due to ApoE2 interacting with estrogen-related receptor alpha (ERRα). ERRα overexpression by plasmids or activation by agonist was also found to show similar mitochondrial protective effects in Aβ1-42-stimulated SH-SY5Y cells. Additionally, ERRα agonist treatment improve the cognitive performance of Aβ injected mice in both Y maze and novel object recognition tests. ERRα agonist treatment increased PSD95 expression in the cortex of agonist-treated-AD mice.

CONCLUSIONS: APOE2 appears to enhance neural mitochondrial function via the activation of ERRα signaling, which may be the protective effect of APOE2 to treat AD.

RevDate: 2024-06-12

Gong L, Liu D, Zhang B, et al (2024)

Sex-Specific Entorhinal Cortex Functional Connectivity in Cognitively Normal Older Adults with Amyloid-β Pathology.

Molecular neurobiology [Epub ahead of print].

Sex and apolipoprotein E (APOE) genotype have been shown to influence the risk and progression of Alzheimer's disease (AD). However, the impact of these factors on the functional connectivity of the entorhinal cortex (ERC) in clinically unpaired older adults (CUOA) with amyloid-β (Aβ +) pathology remains unclear. A total of 1022 cognitively normal older adults with Aβ + (603 females and 586 APOE ε4 +) from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study were included in this study. The 2 × 2 (gender, 2 APOE genotypes) analysis of covariance was performed to compare the demographic information, cognitive performance, and volumetric MRI data among these groups. Voxel-wise comparisons of bilateral ERC functional connectivity (FC) were conducted, and partial correlation analyses were used to explore the associations between cognitive performance and ERC-FC strength. We found that the APOE genotype influenced ERC functional connectivity mainly in the sensorimotor network (SMN). Males exhibited higher ERC-FC in the salience network (SN), while females displayed higher ERC-FC in the default mode network (DMN), executive control network (ECN), and reward network. The interplay of sex and APOE genotype on ERC-FC was observed in the SMN and cerebellar lobe. The ERC-FC was associated with executive function and memory performance in individuals with CUOA-Aβ + . Our findings provide evidence of sex-specific ERC functional connectivity compensation mechanism in cognitively normal older adults with Aβ + pathology. This study may contribute to a better understanding of the mechanisms underlying the early stages of AD and may help develop personalized interventions in preclinical AD.

RevDate: 2024-06-14

Ishida T, Murayama T, S Kobayashi (2022)

A case report of nonsurgical idiopathic normal pressure hydrocephalus differentiated from Alzheimer's dementia: Levetiracetam was effective in symptomatic epilepsy.

PCN reports : psychiatry and clinical neurosciences, 1(3):e43.

BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is a common form of dementia that causes gait disturbance, cognitive impairment, and urinary incontinence. iNPH is a "treatable dementia" that can be treated with shunt surgery, but this can be ineffective in some cases and can be accompanied by complications. As a result, many patients with iNPH do not undergo surgery. However, there is insufficient evidence on effective treatments other than surgical therapy.

CASE PRESENTATION: A 75-year-old woman presented to our hospital with a chief complaint of cognitive decline. She showed reduced motivation and inactivity. Brain magnetic resonance imaging showed a high score on the Evans Index (maximum width between bilateral lateral ventricular anterior horns/maximum intracranial cavity in the same slice). The subarachnoid space was enlarged at and below the Sylvian fissure, and narrowed at the higher arcuate region. She was diagnosed with iNPH. However, no shunt surgery was performed; 11 months later, she had a generalized convulsive seizure with loss of consciousness. An electroencephalogram showed generalized epileptic discharges. The possibility of surgery for her iNPH was ruled out. Levetiracetam prevented seizure recurrence and cognitive functions such as spontaneity and motivation were improved.

CONCLUSION: It is often assumed that surgery is the only effective treatment for patients with iNPH. However, as in the present case, symptomatic epileptic seizures may be a factor in dementia. Even in the absence of surgical treatment, we should examine the cause of dementia in patients with iNPH and consider pharmacological treatment, including antiepileptic drugs.

RevDate: 2024-06-12

Schreiber CS, Wiesweg I, Stanelle-Bertram S, et al (2024)

Sex-specific biphasic alpha-synuclein response and alterations of interneurons in a COVID-19 hamster model.

EBioMedicine, 105:105191 pii:S2352-3964(24)00226-3 [Epub ahead of print].

BACKGROUND: Coronavirus disease 2019 (COVID-19) frequently leads to neurological complications after recovery from acute infection, with higher prevalence in women. However, mechanisms by which SARS-CoV-2 disrupts brain function remain unclear and treatment strategies are lacking. We previously demonstrated neuroinflammation in the olfactory bulb of intranasally infected hamsters, followed by alpha-synuclein and tau accumulation in cortex, thus mirroring pathogenesis of neurodegenerative diseases such as Parkinson's or Alzheimer's disease.

METHODS: To uncover the sex-specific spatiotemporal profiles of neuroinflammation and neuronal dysfunction following intranasal SARS-CoV-2 infection, we quantified microglia cell density, alpha-synuclein immunoreactivity and inhibitory interneurons in cortical regions, limbic system and basal ganglia at acute and late post-recovery time points.

FINDINGS: Unexpectedly, microglia cell density and alpha-synuclein immunoreactivity decreased at 6 days post-infection, then rebounded to overt accumulation at 21 days post-infection. This biphasic response was most pronounced in amygdala and striatum, regions affected early in Parkinson's disease. Several brain regions showed altered densities of parvalbumin and calretinin interneurons which are involved in cognition and motor control. Of note, females appeared more affected.

INTERPRETATION: Our results demonstrate that SARS-CoV-2 profoundly disrupts brain homeostasis without neuroinvasion, via neuroinflammatory and protein regulation mechanisms that persist beyond viral clearance. The regional patterns and sex differences are in line with neurological deficits observed after SARS-CoV-2 infection.

FUNDING: Federal Ministry of Health, Germany (BMG; ZMV I 1-2520COR501 to G.G.), Federal Ministry of Education and Research, Germany (BMBF; 03COV06B to G.G.), Ministry of Science and Culture of Lower Saxony in Germany (14-76403-184, to G.G. and F.R.).

RevDate: 2024-06-14
CmpDate: 2024-06-12

Peng C, Liu X, Meng X, et al (2024)

IPAD-DB: a manually curated database for experimentally verified inhibitors of proteins associated with Alzheimer's disease.

Database : the journal of biological databases and curation, 2024:.

Alzheimer's disease (AD) is a universal neurodegenerative disease with the feature of progressive dementia. Currently, there are only seven Food and Drug Administration-approved drugs for the treatment of AD, which merely offer temporary relief from symptom deterioration without reversing the underlying disease process. The identification of inhibitors capable of interacting with proteins associated with AD plays a pivotal role in the development of effective therapeutic interventions. However, a vast number of such inhibitors are dispersed throughout numerous published articles, rendering it inconvenient for researchers to explore potential drug candidates for AD. In light of this, we have manually compiled inhibitors targeting proteins associated with AD and constructed a comprehensive database known as IPAD-DB (Inhibitors of Proteins associated with Alzheimer's Disease Database). The curated inhibitors within this database encompass a diverse range of compounds, including natural compounds, synthetic compounds, drugs, natural extracts and nano-inhibitors. To date, the database has compiled >4800 entries, each representing a correspondent relationship between an inhibitor and its target protein. IPAD-DB offers a user-friendly interface that facilitates browsing, searching and downloading of its records. We firmly believe that IPAD-DB represents a valuable resource for screening potential AD drug candidates and investigating the underlying mechanisms of this debilitating disease. Access to IPAD-DB is freely available at http://www.lamee.cn/ipad-db/ and is compatible with all major web browsers. Database URL: http://www.lamee.cn/ipad-db/.

RevDate: 2024-06-12

Ding X, Yin L, Zhang L, et al (2024)

Diabetes accelerates Alzheimer's disease progression in the first year post mild cognitive impairment diagnosis.

Alzheimer's & dementia : the journal of the Alzheimer's Association [Epub ahead of print].

BACKGROUND: Mild cognitive impairment (MCI) heightens Alzheimer's disease (AD) risk, with diabetes mellitus (DM) potentially exacerbating this vulnerability. This study identifies the optimal intervention period and neurobiological targets in MCI to AD progression using the Alzheimer's Disease Neuroimaging Initiative dataset.

METHODS: Analysis of 980 MCI patients, categorized by DM status, used propensity score matching and inverse probability treatment weighting to assess rate of conversion from MCI to AD, neuroimaging, and cognitive changes.

RESULTS: DM significantly correlates with cognitive decline and an increased risk of progressing to AD, especially within the first year of MCI follow-up. It adversely affects specific brain structures, notably accelerating nucleus accumbens atrophy, decreasing gray matter volume and sulcal depth.

DISCUSSION: Findings suggest the first year after MCI diagnosis as the critical window for intervention. DM accelerates MCI-to-AD progression, targeting specific brain areas, underscoring the need for early therapeutic intervention.

HIGHLIGHTS: Diabetes mellitus (DM) accelerates mild cognitive impairment (MCI)-to-Alzheimer's disease (AD) progression within the first year after MCI diagnosis. DM leads to sharper cognitive decline within 12 months of follow-up. There is notable nucleus accumbens atrophy observed in MCI patients with DM. DM causes significant reductions in gray matter volume and sulcal depth. There are stronger correlations between cognitive decline and brain changes due to DM.

RevDate: 2024-06-13
CmpDate: 2024-06-12

Tan LY, Cunliffe G, Hogan MP, et al (2024)

Emergence of the brain-border immune niches and their contribution to the development of neurodegenerative diseases.

Frontiers in immunology, 15:1380063.

Historically, the central nervous system (CNS) was regarded as 'immune-privileged', possessing its own distinct immune cell population. This immune privilege was thought to be established by a tight blood-brain barrier (BBB) and blood-cerebrospinal-fluid barrier (BCSFB), which prevented the crossing of peripheral immune cells and their secreted factors into the CNS parenchyma. However, recent studies have revealed the presence of peripheral immune cells in proximity to various brain-border niches such as the choroid plexus, cranial bone marrow (CBM), meninges, and perivascular spaces. Furthermore, emerging evidence suggests that peripheral immune cells may be able to infiltrate the brain through these sites and play significant roles in driving neuronal cell death and pathology progression in neurodegenerative disease. Thus, in this review, we explore how the brain-border immune niches may contribute to the pathogenesis of neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). We then discuss several emerging options for harnessing the neuroimmune potential of these niches to improve the prognosis and treatment of these debilitative disorders using novel insights from recent studies.

RevDate: 2024-06-14
CmpDate: 2024-06-12

Zheng Q, Zhu H, Lv C, et al (2024)

Clioquinol rescues yeast cells from Aβ42 toxicity via the inhibition of oxidative damage.

Biotechnology journal, 19(6):e2300662.

Alzheimer's disease (AD), the most common form of dementia, has gotten considerable attention. Previous studies have demonstrated that clioquinol (CQ) as a metal chelator is a potential drug for the treatment of AD. However, the mode of action of CQ in AD is still unclear. In our study, the antioxidant effects of CQ on yeast cells expressing Aβ42 were investigated. We found that CQ could reduce Aβ42 toxicity by alleviating reactive oxygen species (ROS) generation and lipid peroxidation level in yeast cells. These alterations were mainly attributable to the increased reduced glutathione (GSH) content and independent of activities of superoxide dismutase (SOD) and/or catalase (CAT). CQ could affect antioxidant enzyme activity by altering the transcription level of related genes. Interestingly, it was noted for the first time that CQ could combine with antioxidant enzymes to reduce their enzymatic activities by molecular docking and circular dichroism spectroscopy. In addition, CQ restored Aβ42-mediated disruption of GSH homeostasis via regulating YAP1 expression to protect cells against oxidative stress. Our findings not only improve the current understanding of the mechanism of CQ as a potential drug for AD treatment but also provide ideas for subsequent drug research and development.

RevDate: 2024-06-11
CmpDate: 2024-06-12

Feng B, Zheng J, Cai Y, et al (2024)

An Epigenetic Manifestation of Alzheimer's Disease: DNA Methylation.

Actas espanolas de psiquiatria, 52(3):365-374.

Alzheimer's disease (AD), the most common form of dementia, has a complex pathogenesis. The number of AD patients has increased in recent years due to population aging, while a trend toward a younger age of onset has arisen, imposing a substantial burden on society and families, and garnering extensive attention. DNA methylation has recently been revealed to play an important role in AD onset and progression. DNA methylation is a critical mechanism regulating gene expression, and alterations in this mechanism dysregulate gene expression and disrupt important pathways, including oxidative stress responses, inflammatory reactions, and protein degradation processes, eventually resulting in disease. Studies have revealed widespread changes in AD patients' DNA methylation in the peripheral blood and brain tissues, affecting multiple signaling pathways and severely impacting neuronal cell and synaptic functions. This review summarizes the role of DNA methylation in the pathogenesis of AD, aiming to provide a theoretical basis for its early prevention and treatment.

RevDate: 2024-06-11
CmpDate: 2024-06-12

Lu H, Fang Y, Chen X, et al (2024)

Study on the Relationship between Cerebral Blood Perfusion, Neuronal Cytokines and Cognitive Function in Patients with Alzheimer's Disease.

Actas espanolas de psiquiatria, 52(3):238-247.

BACKGROUND: Alzheimer's disease (AD) is a common neurodegenerative disorder characterized by the progressive emergence of multiple cognitive deficits. Early diagnosis is of great significance for the intervention and treatment of AD. The objective of this study is to explore the relationship between cerebral blood perfusion, neuronal cytokines and cognitive function in patients with AD.

METHODS: AD patients admitted to the 903 Hospital of the People's Liberation Army Joint Logistics Support Force from June 2020 to January 2023 were retrospectively selected as the study objects, and 65 healthy people who underwent physical examination during the same period were included in the control group. Subjects in both groups underwent 3.0 T magnetic resonance imaging (MRI) to observe their cerebral blood perfusion parameters. The level of cognitive function in both groups was assessed using the Montreal Cognitive Assessment (MoCA). Venous blood was collected from both groups, and the serum levels of brain-derived neuronal factor (BDNF) and glial cell-derived neurotrophic factor (GDNF) were measured by enzyme-linked immunosorbent assay (ELISA). The correlation of serum BDNF and GDNF levels with cerebral blood perfusion parameters and MoCA score in the AD group was analyzed using Spearman analysis.

RESULTS: The cerebral blood flow signal intensity of the left frontal lobe, right frontal lobe, left temporal lobe, right temporal lobe, left parietal lobe, right parietal lobe, left occipital lobe, and right occipital lobe of the observation group was significantly lower than that of the control group (p < 0.001). The visuospatial, executive functions, naming, attention, language function, abstract generalization ability, memory ability, orientation, and total MoCA scale scores were significantly lower than those of the control group (p < 0.001). The serum levels of BDNF and GDNF in the observation group were significantly lower than those in the control group (p < 0.001). The results of Spearman analysis showed that cerebral blood perfusion parameters of the left frontal lobe, right frontal lobe, left temporal lobe, right temporal lobe, left parietal lobe, right parietal lobe, left occipital lobe, and right occipital lobe were positively correlated with cognitive function scores in AD patients, serum BDNF and GDNF levels were positively correlated with cognitive function scores in AD patients, and the correlation was statistically significant (p < 0.05).

CONCLUSION: In AD patients, blood perfusion parameters and serum BDNF and GDNF levels were significantly lower than those of healthy people. Cerebral blood perfusion parameters of the left frontal lobe, right frontal lobe, left temporal lobe, right temporal lobe, left parietal lobe, right parietal lobe, left occipital lobe, and right occipital lobe, and BDNF and GDNF levels were positively correlated with cognitive function scores in AD patients.

RevDate: 2024-06-11
CmpDate: 2024-06-12

Zúñiga MA, Acero-González Á, Restrepo-Castro JC, et al (2024)

Is EEG Entropy a Useful Measure for Alzheimer's Disease?.

Actas espanolas de psiquiatria, 52(3):347-364.

BACKGROUND: The number of individuals diagnosed with Alzheimer's disease (AD) has increased, and it is estimated to continue rising in the coming years. The diagnosis of this disease is challenging due to variations in onset and course, its diverse clinical manifestations, and the indications for measuring deposit biomarkers. Hence, there is a need to develop more precise and less invasive diagnostic tools. Multiple studies have considered using electroencephalography (EEG) entropy measures as an indicator of the onset and course of AD. Entropy is deemed suitable as a potential indicator based on the discovery that variations in its complexity can be associated with specific pathologies such as AD.

METHODOLOGY: Following PRISMA guidelines, a literature search was conducted in 4 scientific databases, and 40 articles were analyzed after discarding and filtering.

RESULTS: There is a diversity in entropy measures; however, Sample Entropy (SampEn) and Multiscale Entropy (MSE) are the most widely used (21/40). In general, it is found that when comparing patients with controls, patients exhibit lower entropy (20/40) in various areas. Findings of correlation with the level of cognitive decline are less consistent, and with neuropsychiatric symptoms (2/40) or treatment response less explored (2/40), although most studies show lower entropy with greater severity. Machine learning-based studies show good discrimination capacity.

CONCLUSIONS: There is significant difficulty in comparing multiple studies due to their heterogeneity; however, changes in Multiscale Entropy (MSE) scales or a decrease in entropy levels are considered useful for determining the presence of AD and measuring its severity.

RevDate: 2024-06-14
CmpDate: 2024-06-11

Wang Y, Ruan Y, Cui C, et al (2024)

[Jiaotaiwan improves brain glucose metabolism in a mouse model of Alzheimer's disease by activating the PI3K/AKT signaling pathway].

Nan fang yi ke da xue xue bao = Journal of Southern Medical University, 44(5):894-903.

OBJECTIVE: To investigate the effect of Jiaotaiwan on brain insulin-PI3K/AKT pathway in a mouse model of Alzheimer's disease (AD).

METHODS: Fifty 3-month-old male APP/PS1 double transgenic mice were randomized into AD model group, low-, medium- and high-dose Jiaotaiwan treatment groups, and donepezil treatment group. Cognitive functions of the mice were assessed using water maze and open field tests, and neuronal pathologies were observed with HE staining and Nissl staining; immunohistochemistry was used to detect amyloid Aβ deposition in the brain. Fasting serum insulin levels of the mice were measured, and the expressions of Aβ42, insulin-PI3K/AKT pathway components and downstream glucose transporters in the brain tissue were detected with RT-qPCR and Western blotting.

RESULTS: The AD mouse models exhibited obvious impairment of learning and memory abilities, significantly reduced hippocampal neurons, and obvious Aβ amyloid plaques in the brain tissue with increased Aβ42 protein expression (P < 0.05) and insulin resistance index, decreased hippocampal PI3K expressions, lowered expressions of AKT and InR, reduced expressions of GLUT1, GLUT3, and GLUT4, and increased expression of GSK3β in both the hippocampus and cortex. Treatment with Jiaotaiwan and donepezil both effectively improved memory ability of the mouse models, increased the number of hippocampal neurons, reduced Aβ amyloid plaques and increased the expressions of PI3K, AKT, InR, GLUT1, GLUT3 and GLUT4 in the hippocampus and cortex.

CONCLUSION: Jiaotaiwan improves learning and memory abilities of APP/PS1 double transgenic mice and delay the development of AD by activating the PI3K/AKT pathway and regulating the expression levels of its downstream GLUTs in the brain.

RevDate: 2024-06-11

Dobson R, Patterson K, Malik R, et al (2024)

Eligibility for antiamyloid treatment: preparing for disease-modifying therapies for Alzheimer's disease.

Journal of neurology, neurosurgery, and psychiatry pii:jnnp-2024-333468 [Epub ahead of print].

BACKGROUND: Disease-modifying therapies (DMTs) for Alzheimer's disease (AD) have early evidence of efficacy. Widespread delivery of DMTs will require major service reconfiguration. Treatment pathways will need to include triaging for eligibility, regular infusions and baseline and follow-up MRI scanning. A critical step in planning is provision of real-world estimates of patients likely to be eligible for triaging, but these are challenging to obtain.

METHODS: We performed a retrospective service evaluation of patients attending five memory services across North and East London and a national specialist cognitive disorders service. We examined the likely proportion of patients who would (1) be referred for triaging for DMTs and (2) potentially be suitable for treatments.

RESULTS: Data from a total of 1017 patients were included, 517 of whom were seen in community memory services and 500 in a specialist clinic. In the memory services, 367/517 (71%) were diagnosed with possible AD. After exclusions of those in whom cognitive and frailty scores, MRI contraindications or anticoagulant use indicated they would be unlikely to be suitable, an estimated 32% would be eligible for triaging. In the specialist cognitive clinic, where additional investigations are available, 14% of those seen (70/500) would be potentially eligible for treatment.

CONCLUSIONS: While a sizeable proportion of patients attending memory clinics may be referred for triaging for DMTs for AD, only a minority are likely to be suitable for these, as demonstrated in patients seen in specialist cognitive services. This will need to be considered when designing pathways for DMT delivery.

RevDate: 2024-06-11

Underwood BR (2024)

Predicting how many people might receive treatment with new therapies for Alzheimer's disease.

RevDate: 2024-06-13

Chittora R, Jain S, Roy A, et al (2024)

Multifactorial effects of short duration early exposure low intensity magnetic field stimulation in Streptozotocin induced Alzheimer's disease rat model.

Neuroscience letters, 836:137878 pii:S0304-3940(24)00256-8 [Epub ahead of print].

Alzheimer's disease (AD) is an approaching, progressive public health crisis which presently lacks an effective treatment. Various non-invasive novel therapies like repetitive transcranial magnetic stimulation have shown potential to improve cognitive performance in AD patients. In the present study, the effect of extremely low intensity magnetic field (MF) stimulation on neurogenesis and cortical electrical activity was explored. Adult Wistar rats were divided into Sham, AD and AD + MF groups. Streptozotocin (STZ) was injected intracerebroventricularly, at a dose of 3 mg/kg body weight for developing AD model. The AD rats were then exposed to MF (17.96 µT) from 8th day of STZ treatment until 15th day, followed by cognitive assessments and electrocortical recording. In brain tissue samples, cresyl violet staining and BrdU immunohistochemistry were done. MF exposure, improved passive avoidance and recognition memory, attenuated neuronal degeneration and enhanced cell proliferation (BrdU positive cells) in comparison to AD rats. It also significantly restores delta wave power from frontal lobe. Our results suggest that early-stage MF exposure could be an asset for AD research and open new avenues in slowing down the progression of Alzheimer's disease.

RevDate: 2024-06-11

Rodríguez-Fernández L, Zorzo C, JL Arias (2024)

Photobiomodulation in the aging brain: a systematic review from animal models to humans.

GeroScience [Epub ahead of print].

Aging is a multifactorial biological process that may be associated with cognitive decline. Photobiomodulation (PBM) is a non-pharmacological therapy that shows promising results in the treatment or prevention of age-related cognitive impairments. The aim of this review is to compile the preclinical and clinical evidence of the effect of PBM during aging in healthy and pathological conditions, including behavioral analysis and neuropsychological assessment, as well as brain-related modifications. 37 studies were identified by searching in PubMed, Scopus, and PsycInfo databases. Most studies use wavelengths of 800, 810, or 1064 nm but intensity and days of application were highly variable. In animal studies, it has been shown improvements in spatial memory, episodic-like memory, social memory, while different results have been found in recognition memory. Locomotor activity improved in Parkinson disease models. In healthy aged humans, it has been outlined improvements in working memory, cognitive inhibition, and lexical/semantic access, while general cognition was mainly enhanced on Alzheimer disease or mild cognitive impairment. Anxiety assessment is scarce and shows mixed results. As for brain activity, results outline promising effects of PBM in reversing metabolic alterations and enhancing mitochondrial function, as evidenced by restored CCO activity and ATP levels. Additionally, PBM demonstrated neuroprotective, anti-inflammatory, immunomodulatory and hemodynamic effects. The findings suggest that PBM holds promise as a non-invasive intervention for enhancing cognitive function, and in the modulation of brain functional reorganization. It is necessary to develop standardized protocols for the correct, beneficial, and homogeneous use of PBM.

RevDate: 2024-06-13
CmpDate: 2024-06-11

Fan S, Ponisio MR, Xiao P, et al (2024)

AmyloidPETNet: Classification of Amyloid Positivity in Brain PET Imaging Using End-to-End Deep Learning.

Radiology, 311(3):e231442.

Background Visual assessment of amyloid PET scans relies on the availability of radiologist expertise, whereas quantification of amyloid burden typically involves MRI for processing and analysis, which can be computationally expensive. Purpose To develop a deep learning model to classify minimally processed brain PET scans as amyloid positive or negative, evaluate its performance on independent data sets and different tracers, and compare it with human visual reads. Materials and Methods This retrospective study used 8476 PET scans (6722 patients) obtained from late 2004 to early 2023 that were analyzed across five different data sets. A deep learning model, AmyloidPETNet, was trained on 1538 scans from 766 patients, validated on 205 scans from 95 patients, and internally tested on 184 scans from 95 patients in the Alzheimer's Disease Neuroimaging Initiative (ADNI) fluorine 18 ([18]F) florbetapir (FBP) data set. It was tested on ADNI scans using different tracers and scans from independent data sets. Scan amyloid positivity was based on mean cortical standardized uptake value ratio cutoffs. To compare with model performance, each scan from both the Centiloid Project and a subset of the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study were visually interpreted with a confidence level (low, intermediate, high) of amyloid positivity/negativity. The area under the receiver operating characteristic curve (AUC) and other performance metrics were calculated, and Cohen κ was used to measure physician-model agreement. Results The model achieved an AUC of 0.97 (95% CI: 0.95, 0.99) on test ADNI [18]F-FBP scans, which generalized well to [18]F-FBP scans from the Open Access Series of Imaging Studies (AUC, 0.95; 95% CI: 0.93, 0.97) and the A4 study (AUC, 0.98; 95% CI: 0.98, 0.98). Model performance was high when applied to data sets with different tracers (AUC ≥ 0.97). Other performance metrics provided converging evidence. Physician-model agreement ranged from fair (Cohen κ = 0.39; 95% CI: 0.16, 0.60) on a sample of mostly equivocal cases from the A4 study to almost perfect (Cohen κ = 0.93; 95% CI: 0.86, 1.0) on the Centiloid Project. Conclusion The developed model was capable of automatically and accurately classifying brain PET scans as amyloid positive or negative without relying on experienced readers or requiring structural MRI. Clinical trial registration no. NCT00106899 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Bryan and Forghani in this issue.

RevDate: 2024-06-11

Roh S, Lee YS, Moon H, et al (2024)

Cognitive Impairment and Social Determinants of Health among Indigenous Women.

The Gerontologist pii:7691016 [Epub ahead of print].

BACKGROUND AND OBJECTIVES: Cognitive impairment and Alzheimer's disease and related dementias (ADRD) pose significant challenges for Indigenous populations, necessitating urgent research. Limited evidence suggests that high rates of ADRD among Indigenous peoples are associated with social determinants of health (SDOH), such as education, income, health literacy, religion, and social engagement.

RESEARCH DESIGN AND METHODS: Collaborating with a Northern Plains tribe, participants were recruited 123 self-identified Indigenous women aged 40 to 70 through a comprehensive recruitment strategy. Employing the SDOH framework, the research assessed cognitive impairment and Alzheimer's disease knowledge, utilizing the Ascertain Dementia 8 and AD knowledge scales (ADK-30). The investigation examined the relationships between selected SDOH variables and cognitive impairment status.

RESULTS: More than half of the participants showed signs of cognitive impairment, which correlated with lower income and education levels. Increased knowledge about Alzheimer's disease, particularly in terms of treatment management and its life impact subscales, was associated with lower odds of cognitive impairment. Conversely, higher levels of depressive symptoms and participation in religious activities were linked to increased odds of cognitive impairment.

DISCUSSION AND IMPLICATIONS: The findings underscore the importance of culturally grounded tools and SDOH frameworks tailored to Indigenous contexts in addressing ADRD disparities. Future research should integrate historical and cultural factors to advance health equity within Indigenous communities, ultimately mitigating the impact of ADRD and promoting overall well-being.

RevDate: 2024-06-11

Walsh MA, Latham AS, Zhang Q, et al (2024)

Non-transgenic guinea pig strains exhibit divergent age-related changes in hippocampal mitochondrial respiration.

Acta physiologica (Oxford, England) [Epub ahead of print].

AIM: Alzheimer's disease (AD) is the most common form of dementia. However, while 150+ animal models of AD exist, drug translation from preclinical models to humans for treatment usually fails. One factor contributing to low translation is likely the absence of neurodegenerative models that also encompass the multi-morbidities of human aging. We previously demonstrated that, in comparison to the PigmEnTed (PET) guinea pig strain which models "typical" brain aging, the Hartley strain develops hallmarks of AD like aging humans. Hartleys also exhibit age-related impairments in cartilage and skeletal muscle. Impaired mitochondrial respiration is one driver of both cellular aging and AD. In humans with cognitive decline, diminished skeletal muscle and brain respiratory control occurs in parallel. We previously reported age-related declines in skeletal muscle mitochondrial respiration in Hartleys. It is unknown if there is concomitant mitochondrial dysfunction in the brain.

METHODS: Therefore, we assessed hippocampal mitochondrial respiration in 5- and 12-month Hartley and PET guinea pigs using high-resolution respirometry.

RESULTS: At 12 months, PETs had higher complex I supported mitochondrial respiration paralleling their increase in body mass compared to 5 months PETs. Hartleys were also heavier at 12 months compared to 5 months but did not have higher complex I respiration. Compared to 5 months Hartleys, 12 months Hartleys had lower complex I mitochondrial efficiency and compensatory increases in mitochondrial proteins collectively suggesting mitochondrial dysfunction with age.

CONCLUSIONS: Therefore, Hartleys might be a relevant model to test promising therapies targeting mitochondria to slow brain aging and AD progression.

RevDate: 2024-06-11

Chen C, Lan Z, Tang X, et al (2024)

Human-Derived Induced GABAergic Progenitor Cells Improve Cognitive Function in Mice and Inhibit Astrocyte Activation with Anti-Inflammatory Exosomes.

Annals of neurology [Epub ahead of print].

OBJECTIVE: The role of gamma-aminobutyric acid-ergic (GABAergic) neuron impairment in Alzheimer's disease (AD), and if and how transplantation of healthy GABAergic neurons can improve AD, remain unknown.

METHODS: Human-derived medial ganglionic eminence progenitors (hiMGEs) differentiated from programmed induced neural precursor cells (hiNPCs) were injected into the dentate gyrus region of the hippocampus (HIP).

RESULTS: We showed that grafts migrate to the whole brain and form functional synaptic connections in amyloid precursor protein gene/ presenilin-1 (APP/PS1) chimeric mice. Following transplantation of hiMGEs, behavioral deficits and AD-related pathology were alleviated and defective neurons were repaired. Notably, exosomes secreted from hiMGEs, which are rich in anti-inflammatory miRNA, inhibited astrocyte activation in vitro and in vivo, and the mechanism was related to regulation of CD4[+] Th1 cells mediated tumor necrosis factor (TNF) pathway.

INTERPRETATION: Taken together, these findings support the hypothesis that hiMGEs transplantation is an alternative treatment for neuronal loss in AD and demonstrate that exosomes with anti-inflammatory activity derived from hiMGEs are important factors for graft survival. ANN NEUROL 2024.

RevDate: 2024-06-11

Adili A, Dilihumaer A, Zhu H, et al (2024)

Research progress on phosphodiesterase 4 inhibitors in central nervous system diseases.

Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences [Epub ahead of print].

Phosphodiesterase (PDE) hydrolyze cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), and involve in the regulation of cellular physiological processes and neurological functions, including neuronal plasticity, synaptogenesis, synaptic transmission, memory formation and cognitive function by catalyzing the hydrolysis of intracellular cAMP and cGMP. A large number of basic and clinical studies have shown that PDE4 inhibitors block or ameliorate the occurrence and development of central nervous system (CNS) diseases by inhibiting cAMP hydrolysis, increasing cAMP content and enhancing its downstream effects. PDE4 inhibitors have long-term potentiation effect, which can enhance phosphorylation of cAMP response element binding protein (CREB) and upregulate expression of memory related Arc genes in hippocampal neurons, thereby improving cognitive impairment and Alzheimer's disease-like symptoms; and also resist the occurrence and development of Parkinson's disease by reducing the cytotoxicity induced by α-syn and increasing the effect of miR-124-3p on cell activity. Alteration of PDE4 activity is the molecular basis of psychosis and cognitive disorders, therefore it is considered as one of the therapeutic targets for schizophrenia. PDE4 inhibitors play a role in depression; Autism spectrum and Huntington's disease by inhibiting the advanced glycation end product receptor (RAGE), TLR4 and NLRP3 pathways in the hippocampus, reducing the activation of microglia and the production of interleukin-1β, down-regulating HMGB1/RAGE signaling pathway and inhibiting inflammatory factors and Increase the nociception threshold. PDE4 inhibitors might be used in treatment of fragile X syndrome by regulating the level of cAMP and affecting the expression of fragile X mental retardation protein (FMRP). PDE4 inhibitors can also promote the differentiation of oligodendrocyte progenitor cells and enhance myelination, which has potential in the treatment of multiple sclerosis. PDE4 also related to Bipolar disorder which may be one of the therapeutic targets. At present, several PDE4 inhibitors are on clinical trials for treatment of CNS diseases. This article reviews and discusses the progress on basic researches and clinical trials of PDE4 inhibitors in CNS diseases, providing reference for the prevention and treatment of CNS diseases and the development of new drugs.

RevDate: 2024-06-11

Londhe SG, Shenoy M, Kini SG, et al (2024)

Computational Investigation of Novel Compounds as Dual Inhibitors of AChE and GSK-3β for the Treatment of Alzheimer's Disease.

Current topics in medicinal chemistry pii:CTMC-EPUB-140931 [Epub ahead of print].

BACKGROUND: Alzheimer's disease (AD) stands out as one of the most devastating and prevalent neurodegenerative disorders known today. Researchers have identified several enzymatic targets associated with AD among which Glycogen synthase kinase-3β (GSK-3β) and Acetylcholinesterase (AChE) are prominent ones. Unfortunately, the market offers very few drugs for treating or managing AD, and none have shown significant efficacy against it.

OBJECTIVES: To address this critical issue, the design and discovery of dual inhibitors will represent a potential breakthrough in the fight against AD. In the pursuit of designing novel dual inhibitors, we explored molecular docking and dynamics analyses of tacrine and amantadine uredio-linked amide analogs such as GSK-3β and AChE dual inhibitors for curtailing AD. Tacrine and adamantine are the FDA-approved drugs that were structurally modified to design and develop novel drug candidates that may demonstrate concurrently dual selectivity towards GSK-3β and AChE.

METHODS: In the following study, molecular docking was executed by employing AutoDock Vina, and molecular dynamics and ADMET predictions were made using Desmond, Qikprop modules of Schrödinger.

RESULTS: Our findings revealed that compounds DST2 and DST11 exhibited remarkable molecular interactions with active sites of GSK-3β and AChE, respectively. These compounds effectively interacted with key amino acids, namely Lys85, Val135, Asp200, and Phe295, resulting in highly favourable docking energies of -9.7 and -12.7 kcal/mol. Furthermore, through molecular dynamics simulations spanning a trajectory of 100 ns, we confirmed the stability of ligands DST2 and DST11 within the active cavities of GSK-3β and AChE. The compounds exhibiting the most promising docking results also demonstrated excellent ADMET profiles. Notably, DST21 displayed an outstanding human oral absorption rate of 76.358%, surpassing the absorption rates of other molecules.

CONCLUSION: Overall, our in-silico studies revealed that the designed molecules showed potential as novel anti-Alzheimer agents capable of inhibiting both GSK-3β and AChE simultaneously. So, in the future, the designing and development of dual inhibitors will harbinger a new era of drug design in AD treatment.

RevDate: 2024-06-11

Ke C, Shan S, Tan Y, et al (2024)

Signaling pathways in the treatment of Alzheimer's disease with acupuncture: a narrative review.

Acupuncture in medicine : journal of the British Medical Acupuncture Society [Epub ahead of print].

BACKGROUND: To date, there is no effective treatment for Alzheimer's disease (AD), a progressive neurodegenerative disorder that is increasing in prevalence worldwide. The objective of this review was to summarize the core targets and signaling pathways involved in acupuncture treatment for AD.

METHODS: We reviewed numerous signaling pathways, including mammalian target of rapamycin (mTOR), phosphatidylinositol 3-kinase-protein kinase B (PI3 K/Akt), adenosine monophosphate-activated protein kinase (AMPK), mitogen-activated protein kinase (MAPK), nuclear factor (NF)-kB, p53, Wnt, nitric oxide (NO), Janus kinase / signal transducer and activator of transcription (JAK/ STAT), RhoA/ROCK (Rho-associated protein kinase) and Ca[2+]/ calmodulin-dependent protein kinase II (CaMKII) / cyclic adenosine monophosphate-response element-binding protein (CREB). The relevant data were obtained from PubMed, EMBASE, Web of Science, China National Knowledge Infrastructure (CNKI) and Wanfang databases.

RESULTS: In summary, the effects of acupuncture are mediated by multiple targets and pathways. Furthermore, acupuncture can improve pathological changes associated with AD (such as abnormal deposition of amyloid (A)β, tau hyperphosphorylation, synaptic dysfunction and neuronal apoptosis) through multiple signaling pathways.

CONCLUSION: Overall, our findings provide a basis for future research into the effects of acupuncture on AD.

RevDate: 2024-06-10
CmpDate: 2024-06-10

Zeng L, Perin J, Gross AL, et al (2024)

Adverse effects of methylphenidate for apathy in patients with Alzheimer's disease (ADMET2 trial).

International journal of geriatric psychiatry, 39(6):e6108.

OBJECTIVES: To examine clinically important adverse events (AEs) associated with methylphenidate (MPH) treatment of apathy in Alzheimer's Disease (AD) versus placebo, including weight loss, vital signs, falls, and insomnia.

METHODS: The Apathy in Dementia Methylphenidate Trial 2 (ADMET2) trial was a multicenter randomized, placebo-controlled trial of MPH to treat apathy in individuals with apathy and AD. Participants in ADMET2 had vital signs and weight measured at monthly visits through 6 months. AEs, including insomnia, falls, and cardiovascular events, were reported at every visit by participants and families using a symptom checklist.

RESULTS: The study included 98 participants in the MPH group and 101 in the placebo group. Participants in the MPH group experienced greater weight loss on average than the placebo through the 6-month follow-up, with a difference in change between MPH and placebo of 2.8 lb (95% confidence interval, CI: 0.7, 4.9 lb). No treatment group differences in change during the trial were found in systolic and diastolic blood pressure. More participants in the MPH group reported falls during the follow-up, 10 versus 6 in MPH and placebo groups, respectively. No differences in post-baseline insomnia were observed between the treatment groups. No participants reported instances of myocardial infarction, congestive heart failure, arrhythmia, stroke, or cardiomyopathy throughout the study period.

CONCLUSIONS: MPH use in AD patients for treating apathy is relatively safe, particularly notable given the many medical comorbidities in this population. There was a statistically significant but modest weight loss associated with MPH use, and clinicians are thus advised to monitor weight during MPH treatment.

RevDate: 2024-06-10

Huo Y, Jing R, Li P, et al (2024)

Delineating the Heterogeneity of Alzheimer's Disease and Mild Cognitive Impairment Using Normative Models of the Dynamic Brain Functional Networks.

Biological psychiatry pii:S0006-3223(24)01365-9 [Epub ahead of print].

BACKGROUND: Alzheimer's Disease (AD), identified as the most common type of dementia, presents considerable heterogeneity in clinical manifestations. Early intervention at the stage of mild cognitive impairment (MCI) holds potential in AD prevention. However, characterizing the heterogeneity of neurobiological abnormalities and identifying MCI subtypes pose significant challenges.

METHODS: We constructed sex-specific normative age models of dynamic brain functional networks and mapped the deviations of the brain characteristics for individuals from multiple datasets, including 295 AD patients, 441 MCI patients, and 1160 normal controls (NC). Then, based on these individual deviation patterns, subtypes for both AD and MCI were identified using the clustering method and comprehensively assessed their similarity and differences.

RESULTS: Individuals with AD and MCI were clustered into 2 subtypes, and these subtypes exhibited significant differences in both their intrinsic brain functional phenotypes and spatial atrophy patterns, as well as in disease progression and cognitive decline trajectories. The subtypes with positive deviations in AD and MCI shared similar deviation patterns, as well as those with negative deviations. There was a potential transformation of MCI with negative deviation patterns into AD, and these MCI have a more severe cognitive decline rate.

CONCLUSIONS: This study quantifies neurophysiological heterogeneity by analyzing deviation patterns from the dynamic functional connectome normative model and identifies disease subtypes in AD and MCI using a comprehensive resting-state fMRI multicenter dataset. It provides new insights for developing early prevention and personalized treatment strategies for AD.

RevDate: 2024-06-10

Tripathi S, Bhawana (2024)

Epigenetic Orchestration of Neurodegenerative Disorders: A Possible Target for Curcumin as a Therapeutic.

Neurochemical research [Epub ahead of print].

Epigenetic modulations play a major role in gene expression and thus are responsible for various physiological changes including age-associated neurological disorders. Neurodegenerative diseases such as Alzheimer's (AD), Parkinson's (PD), Huntington's disease (HD), although symptomatically different, may share common underlying mechanisms. Most neurodegenerative diseases are associated with increased oxidative stress, aggregation of certain proteins, mitochondrial dysfunction, inactivation/dysregulation of protein degradation machinery, DNA damage and cell excitotoxicity. Epigenetic modulations has been reported to play a significant role in onset and progression of neurodegenerative diseases by regulating these processes. Previous studies have highlighted the marked antioxidant and neuroprotective abilities of polyphenols such as curcumin, by increased activity of detoxification systems like superoxide dismutase (SOD), catalase or glutathione peroxidase. The role of curcumin as an epigenetic modulator in neurological disorders and neuroinflammation apart from other chronic diseases have also been reported by a few groups. Nonetheless, the evidences for the role of curcumin mediated epigenetic modulation in its neuroprotective ability are still limited. This review summarizes the current knowledge of the role of mitochondrial dysfunction, epigenetic modulations and mitoepigenetics in age-associated neurological disorders such as PD, AD, HD, Amyotrophic Lateral Sclerosis (ALS), and Multiple Sclerosis (MS), and describes the neuroprotective effects of curcumin in the treatment and/or prevention of these neurodegenerative diseases by regulation of the epigenetic machinery.

RevDate: 2024-06-10

Abramowitz A, M Weber (2024)

Management of MCI in the Outpatient Setting.

Current psychiatry reports [Epub ahead of print].

PURPOSE OF REVIEW: We review current literature related to the clinical assessment of Mild Cognitive Impairment (MCI). We compile recommendations related to the evaluation of MCI and examine literature regarding the use of clinical biomarkers in this assessment, the role of non-pharmacologic therapy in the prevention of cognitive decline, and recent approval of anti-amyloid therapy in the treatment of MCI.

RECENT FINDINGS: The role of imaging and plasma biomarkers in the clinical assessment of MCI has expanded. There is data that non-pharmacologic therapy may have a role in the prevention of neurocognitive decline. Anti-amyloid therapies have recently been approved for clinical use. Clinical assessment of MCI remains multifactorial and includes screening and treating for underlying psychiatric and medical co-morbidities. The use of biomarkers in clinical settings is expanding with the rise of anti-amyloid therapies. These new diagnostics and therapeutics require nuanced discussion of risks and benefits. Psychiatrist's skillset is uniquely suited for these complex evaluations.

RevDate: 2024-06-10

Kumari S, Kamiya A, Karnik SS, et al (2024)

Novel Gene Therapy Approaches for Targeting Neurodegenerative Disorders: Focusing on Delivering Neurotrophic Genes.

Molecular neurobiology [Epub ahead of print].

Neurodegenerative illnesses (NDDs) like Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, spinal muscular atrophy, and Huntington's disease have demonstrated considerable potential for gene therapy as a viable therapeutic intervention. NDDs are marked by the decline of neurons, resulting in changes in both behavior and pathology within the body. Strikingly, only symptomatic management is available without a cure for the NDDs. There is an unmet need for a permanent therapeutic approach. Many studies have been going on to target the newer therapeutic molecular targets for NDDs including gene-based therapy. Gene therapy has the potential to provide therapeutic benefits to a large number of patients with NDDs by offering mechanisms including neuroprotection, neuro-restoration, and rectification of pathogenic pathways. Gene therapy is a medical approach that aims to modify the biological characteristics of living cells by controlling the expression of specific genes in certain neurological disorders. Despite being the most complex and well-protected organ in the human body, there is clinical evidence to show that it is possible to specifically target the central nervous system (CNS). This provides hope for the prospective application of gene therapy in treating NDDs in the future. There are several advanced techniques available for using viral or non-viral vectors to deliver the therapeutic gene to the afflicted region. Neurotrophic factors (NTF) in the brain are crucial for the development, differentiation, and survival of neurons in the CNS, making them important in the context of various neurological illnesses. Gene delivery of NTF has the potential to be used as a therapeutic approach for the treatment of neurological problems in the brain. This review primarily focuses on the methodologies employed for delivering the genes of different NTFs to treat neurological disorders. These techniques are currently being explored as a viable therapeutic approach for neurodegenerative diseases. The article exclusively addresses gene delivery approaches and does not cover additional therapy strategies for NDDs. Gene therapy offers a promising alternative treatment for NDDs by stimulating neuronal growth instead of solely relying on symptom relief from drugs and their associated adverse effects. It can serve as a long-lasting and advantageous treatment choice for the management of NDDs. The likelihood of developing NDDs increases with age as a result of neuronal degradation in the brain. Gene therapy is an optimal approach for promoting neuronal growth through the introduction of nerve growth factor genes.

RevDate: 2024-06-11

Muolokwu CE, Chaulagain B, Gothwal A, et al (2024)

Functionalized nanoparticles to deliver nucleic acids to the brain for the treatment of Alzheimer's disease.

Frontiers in pharmacology, 15:1405423.

Brain-targeted gene delivery across the blood-brain barrier (BBB) is a significant challenge in the 21st century for the healthcare sector, particularly in developing an effective treatment strategy against Alzheimer's disease (AD). The Internal architecture of the brain capillary endothelium restricts bio-actives entry into the brain. Additionally, therapy with nucleic acids faces challenges like vulnerability to degradation by nucleases and potential immune responses. Functionalized nanocarrier-based gene delivery approaches have resulted in safe and effective platforms. These nanoparticles (NPs) have demonstrated efficacy in protecting nucleic acids from degradation, enhancing transport across the BBB, increasing bioavailability, prolonging circulation time, and regulating gene expression of key proteins involved in AD pathology. We provided a detailed review of several nanocarriers and targeting ligands such as cell-penetrating peptides (CPPs), endogenous proteins, and antibodies. The utilization of functionalized NPs extends beyond a singular system, serving as a versatile platform for customization in related neurodegenerative diseases. Only a few numbers of bioactive regimens can go through the BBB. Thus, exploring functionalized NPs for brain-targeted gene delivery is of utmost necessity. Currently, genes are considered high therapeutic potential molecules for altering any disease-causing gene. Through surface modification, nanoparticulate systems can be tailored to address various diseases by replacing the target-specific molecule on their surface. This review article presents several nanoparticulate delivery systems, such as lipid NPs, polymeric micelles, exosomes, and polymeric NPs, for nucleic acids delivery to the brain and the functionalization strategies explored in AD research.

RevDate: 2024-06-11

Ch'en P, Patel PB, M Ramirez (2024)

Caregivers' and Health Care Providers' Cultural Perceptions of and Experiences With Latino Patients With Dementia.

Neurology. Clinical practice, 14(4):e200307.

BACKGROUND AND OBJECTIVES: The prevalence of Alzheimer dementia in the US Latino population in 2060 is projected to increase 7-fold, the highest among any other major ethnic/racial group. One vital question is how clinicians can tailor their care for Latinos. Given this rapidly growing prevalence, we sought to characterize the experiences and perspectives of Latino caregivers by analyzing interview data from both caregivers and experienced providers that specifically work with Latino populations. In this study, we present 6 themes that emerged along with tailored solutions and recommendations to implement in clinical practice to improve patient care and outcomes.

METHODS: This qualitative analysis uses coded interview transcripts from 2 studies, one in Southern California and another in Washington State. The combined dataset included interview transcripts with 51 caregivers and 20 providers. A thematic analysis was performed on the coded interview transcripts to identify themes related to tailoring care for Latino populations.

RESULTS: Six themes emerged from the analysis: (1) multiple caregivers involved within a family-oriented Latino household; (2) need for encouragement in advocating for loved ones in the clinician's office; (3) challenges in reaching and communicating with the Latino population; (4) increasing use of technology by patients and caregivers despite some challenges; (5) stigma associated with mental health issues within the Latino culture; and (6) limited understating of dementia leading to a delay in care in the Latino population.

DISCUSSION: Many Latino households have a strong sense of familism, thus care coordination with multiple caregivers is essential to high-quality care. Improved shared decision-making strategies tailored to a population that may be culturally deferential to authoritative figures can aid caregiver understanding and engagement with the provider. These interactions can often be more authentic when communicating with a member of the care team in Spanish. A cultural stigma of mental illness was also identified; clinicians can work toward normalizing discussion of mental illness and its treatment by openly discussing mental health during annual visits. Through these themes, we demonstrate some of the strengths and weaknesses of the current care delivery model within a sociocultural context to improve patient care and outcomes for Latino families caring for individuals living with dementia.

RevDate: 2024-06-11

Wang T, Ding Z, Yang X, et al (2024)

Detection of mild cognitive impairment based on attention mechanism and parallel dilated convolution.

PeerJ. Computer science, 10:e2056.

Mild cognitive impairment (MCI) is a precursor to neurodegenerative diseases such as Alzheimer's disease, and an early diagnosis and intervention can delay its progression. However, the brain MRI images of MCI patients have small changes and blurry shapes. At the same time, MRI contains a large amount of redundant information, which leads to the poor performance of current MCI detection methods based on deep learning. This article proposes an MCI detection method that integrates the attention mechanism and parallel dilated convolution. By introducing an attention mechanism, it highlights the relevant information of the lesion area in the image, suppresses irrelevant areas, eliminates redundant information in MRI images, and improves the ability to mine detailed information. Parallel dilated convolution is used to obtain a larger receptive field without downsampling, thereby enhancing the ability to acquire contextual information and improving the accuracy of small target classification while maintaining detailed information on large-scale feature maps. Experimental results on the public dataset ADNI show that the detection accuracy of the method on MCI reaches 81.63%, which is approximately 6.8% higher than the basic model. The method is expected to be used in clinical practice in the future to provide earlier intervention and treatment for MCI patients, thereby improving their quality of life.

RevDate: 2024-06-11
CmpDate: 2024-06-10

Zhou W, Wang X, Dong Y, et al (2024)

Stem cell-derived extracellular vesicles in the therapeutic intervention of Alzheimer's Disease, Parkinson's Disease, and stroke.

Theranostics, 14(8):3358-3384.

With the increase in the aging population, the occurrence of neurological disorders is rising. Recently, stem cell therapy has garnered attention due to its convenient sourcing, minimal invasiveness, and capacity for directed differentiation. However, there are some disadvantages, such as poor quality control, safety assessments, and ethical and logistical issues. Consequently, scientists have started to shift their attention from stem cells to extracellular vesicles due to their similar structures and properties. Beyond these parallels, extracellular vesicles can enhance biocompatibility, facilitate easy traversal of barriers, and minimize side effects. Furthermore, stem cell-derived extracellular vesicles can be engineered to load drugs and modify surfaces to enhance treatment outcomes. In this review, we summarize the functions of native stem cell-derived extracellular vesicles, subsequently review the strategies for the engineering of stem cell-derived extracellular vesicles and their applications in Alzheimer's disease, Parkinson's disease, and stroke, and discuss the challenges and solutions associated with the clinical translation of stem cell-derived extracellular vesicles.

RevDate: 2024-06-11

Majhi PK, Sayyad S, Gaur M, et al (2024)

Tinospora cordifolia Extract Enhances Dextromethorphan Bioavailability: Implications for Alzheimer's Disease.

ACS omega, 9(22):23634-23648.

Tinospora cordifolia (Willd.) Miers (Menispermaceae) is a traditional rejuvenator and a conventional medicine used to manage oxidative stress-related diseases, including those associated with the central nervous system. Decreased dextromethorphan (DEM) metabolism is necessary for high bioavailability and application against Alzheimer's disease (AD). Since T. cordifolia stem extract (TCE) can potentially inhibit several metabolic enzymes, it can also enhance dextromethorphan bioavailability. This study investigates the potential of TCE to improve DEM's bioavailability and efficacy for the management of AD. In silico analysis was carried out to find the inhibition potential of phytocomponents of T. cordifolia for CYP2D6 and CYP3A4. The LC-MS method was revalidated for the analysis of DEM and metabolite dextrorphan (DEX) in the presence of quinidine (QN). The ratio of DEM to DEX was estimated with varying doses of TCE following pharmacokinetic analysis. Network pharmacology analysis was carried out to understand the complementary potential of phytocomponents. This was further validated in the scopolamine-induced dementia model through behavioral and histopathological analyses. TCE (100 mg/kg) for 14 days increased the DEM to DEX ratio by 2.8-fold compared to QN treatment. While T max was comparable to that of QN treatment at this dose (100 mg/kg) of TCE, it increased significantly at the higher dose (400 mg/kg) of TCE pretreatment. All other pharmacokinetic parameters were also enhanced at this dose with a 4.7-fold increase in DEM/DEX compared with QN. Network pharmacology analysis indicated the ability of TCE to target multiple factors associated with AD. Furthermore, it improved spatial memory and reduced hyperactivity in rodents better than the combination of QN and DEM.

RevDate: 2024-06-10

Dilliott AA, Costanzo MC, Burtt NP, et al (2024)

The Neurodegenerative Disease Knowledge Portal: Propelling Discovery Through the Sharing of Neurodegenerative Disease Genomic Resources.

medRxiv : the preprint server for health sciences pii:2024.05.27.24307990.

Although large-scale genetic association studies have proven opportunistic for the delineation of neurodegenerative disease processes, we still lack a full understanding of the pathological mechanisms of these diseases, resulting in few appropriate treatment options and diagnostic challenges. To mitigate these gaps, the Neurodegenerative Disease Knowledge Portal (NDKP) was created as an open-science initiative with the aim to aggregate, enable analysis, and display all available genomic datasets of neurodegenerative disease, while protecting the integrity and confidentiality of the underlying datasets. The portal contains 218 genomic datasets, including genotyping and sequencing studies, of individuals across ten different phenotypic groups, including neurological conditions such as Alzheimer's disease, amyotrophic lateral sclerosis, Lewy body dementia, and Parkinson's disease. In addition to securely hosting large genomic datasets, the NDKP provides accessible workflows and tools to effectively utilize the datasets and assist in the facilitation of customized genomic analyses. Here, we summarize the genomic datasets currently included within the portal, the bioinformatics processing of the datasets, and the variety of phenotypes captured. We also present example use-cases of the various user interfaces and integrated analytic tools to demonstrate their extensive utility in enabling the extraction of high-quality results at the source, for both genomics experts and those in other disciplines. Overall, the NDKP promotes open-science and collaboration, maximizing the potential for discovery from the large-scale datasets researchers and consortia are expending immense resources to produce and resulting in reproducible conclusions to improve diagnostic and therapeutic care for neurodegenerative disease patients.

RevDate: 2024-06-10

Howe MD, Britton KJ, Joyce HE, et al (2024)

Clinical application of plasma P-tau217 to assess eligibility for amyloid-lowering immunotherapy in memory clinic patients with early Alzheimer's disease.

Research square pii:rs.3.rs-3755419.

Background With the approval of disease-modifying treatments (DMTs) for early Alzheimer's disease (AD), there is an increased need for efficient and non-invasive detection methods for cerebral amyloid-β (Aβ) pathology. Current methods, including positron emission tomography (PET) and cerebrospinal fluid (CSF) analysis, are costly and invasive methods that may limit access to new treatments. Plasma tau phosphorylated at threonine-217 (P-tau217) presents a promising alternative, yet optimal cutoffs for treatment eligibility with DMTs like aducanumab require further investigation. This study evaluates the efficacy of one- and two-cutoff strategies for determining DMT eligibility at the Butler Hospital Memory & Aging Program (MAP). Methods In this retrospective, cross-sectional diagnostic cohort study, we first developed P-tau217 cutoffs using site-specific training data and BioFINDER-2, which were then tested in potential DMT candidates from Butler MAP (total n = 150). ROC analysis was used to calculate the area under the curve (AUC) and accuracy of P-tau217 interpretation strategies, using Aβ-PET/CSF testing as the standard of truth. Results Potential DMT candidates at Butler MAP (n = 50), primarily diagnosed with mild cognitive impairment (n = 29 [58%]) or mild dementia (21 [42%]), were predominantly Aβ-positive (38 [76%]), and half (25 [50%]) were subsequently treated with aducanumab. Elevated P-tau217 predicted cerebral Aβ positivity in potential DMT candidates (AUC = 0.97 [0.92-1]), with diagnostic accuracy ranging from 0.88 (0.76-0.95, p = 0.028) to 0.96 (0.86-1, p < .001). When using site-specific cutoffs, a subset of DMT candidates (10%) exhibited borderline P-tau217 (between 0.273 and 0.399 pg/mL) that would have potentially required from confirmatory testing. Conclusions This study, which included participants treated with aducanumab, confirms the utility of one- and two-cutoff strategies for interpreting plasma P-tau217 in assessing DMT eligibility. Using P-tau217 could potentially replace more invasive diagnostic methods, and all aducanumab-treated participants would have been deemed eligible based on P-tau217. However, false positives remain a concern, particularly when applying externally derived cutoffs that exhibited lower specificity which could have led to inappropriate treatment of Aβ-negative participants. Future research should focus on prospective validation of P-tau217 cutoffs to enhance their generalizability and inform standardized treatment decision-making across diverse populations.

RevDate: 2024-06-09

Fan Y, Wang A, Liu Z, et al (2024)

Integrated spatial metabolomics and network pharmacology to explore the pharmacodynamic substances and mechanism of Radix ginseng-Schisandra chinensis Herb Couple on Alzheimer's disease.

Analytical and bioanalytical chemistry [Epub ahead of print].

Radix ginseng and Schisandra chinensis have been extensively documented in traditional Chinese medicine (TCM) for their potential efficacy in treating dementia. However, the precise mechanism of their therapeutic effects remains to be fully elucidated. In this study, air flow-assisted desorption electrospray ionization mass spectrometry imaging (AFADESI-MSI) and network pharmacology are used to investigate the pharmacodynamics and mechanism underlying the herbal combination consisting of Radix ginseng-Schisandra chinensis (RS) in a rodent model for Alzheimer's disease (AD). Brain histopathological findings suggested that RS attenuates hippocampal damage in AD mice, making this combination a potential AD treatment. Twenty-eight biomarkers were identified by spatial metabolomics analysis, which are intricately linked to neuroinflammation, neurotransmitter imbalance, energy deficiency, oxidative stress, and aberrant fatty acid metabolism in AD. The total extract of RS (TE) affected 22 of these biomarkers, with the small molecule components of RS (SN) significantly influencing 19 and the large molecule components of RS (PR) impacting 14. Nine small molecule components are likely to dominate the pharmacodynamics of RS. We constructed a target interaction network based on the corresponding bioactivities that revealed relationships amongst 11 key biomarkers, 8 active ingredients and 12 critical targets. This research illustrates the immense potential of spatial metabolomics and network pharmacology in the study of TCM, revealing the targets and mechanisms underlying herbal formulas.

RevDate: 2024-06-09

Turgutalp B, C Kizil (2024)

Multi-target drugs for Alzheimer's disease.

Trends in pharmacological sciences pii:S0165-6147(24)00097-X [Epub ahead of print].

Alzheimer's disease (AD), a leading cause of dementia, increasingly challenges our healthcare systems and society. Traditional therapies aimed at single targets have fallen short owing to the complex, multifactorial nature of AD that necessitates simultaneous targeting of various disease mechanisms for clinical success. Therefore, targeting multiple pathologies at the same time could provide a synergistic therapeutic effect. The identification of new disease targets beyond the classical hallmarks of AD offers a fertile ground for the design of new multi-target drugs (MTDs), and building on existing compounds have the potential to yield in successful disease modifying therapies. This review discusses the evolving landscape of MTDs, focusing on their potential as AD therapeutics. Analysis of past and current trials of compounds with multi-target activity underscores the capacity of MTDs to offer synergistic therapeutic effects, and the flourishing genetic understanding of AD will inform and inspire the development of MTD-based AD therapies.

RevDate: 2024-06-09

Xie Y, Xie D, C Chen (2024)

Hsa_circ_0049472 contributed to amyloid-beta peptide-induced neurotoxicity, apoptosis and inflammation via regulating PI3K-AKT signaling pathway by interacting with miR-22-3p/ZNF217 axis.

Brain research bulletin pii:S0361-9230(24)00137-0 [Epub ahead of print].

BACKGROUND: Circular RNAs (circRNAs) exhibited important roles in Alzheimer's disease (AD). Here, we focused on the dysregulation of hsa_circ_0049472 (circ_0049472) and potential functions in SK-N-SH cells with amyloid-beta peptide (Aβ) treatment in AD.

METHODS: RNA expression was detected by real-time quantitative PCR. Cell viability and proliferation were measured by MTS and Edu assays. Flow cytometry was used for apoptosis detection, and cell inflammation was assessed using enzyme-linked immunosorbent assay. Target interaction was validated by dual-luciferase reporter assay and RNA immunoprecipitation assay. Protein expression and phosphatidylinositol 3-kinase-protein kinase B (PI3K-AKT) pathway were examined by Immunoblotting.

RESULTS: Aβ treatment inhibited cell viability and proliferation of SK-N-SH cells, but enhanced apoptosis rate, apoptosis protein levels (Bcl2-associated X protein and cleaved-caspase-3) and inflammatory cytokines (interleukin -6, IL-1β, tumor necrosis factor-α). Then, circ_0049472 expression was shown to be upregulated in response to Aβ stimulation and knockdown of circ_0049472 has ameliorated Aβ-induced cell injury. Circ_0049472 was identified as a sponge for miR-22-3p, and miR-22-3p inhibition reversed the regulation of circ_0049472 knockdown in Aβ-treated cells. Furthermore, ZNF217 acted as a target of miR-22-3p and circ_0049472 could regulate ZNF217 expression via binding to miR-22-3p. Overexpression of miR-22-3p abated Aβ-induced apoptosis and inflammation via downregulating ZNF217. Furthermore, Aβ reduced proteins levels of p-PI3K and p-AKT, and this inhibition of PI3K-AKT pathway was restored by the regulation of circ_0049472/miR-22-3p/ZNF217 axis.

CONCLUSION: Circ_0049472 was involved in Aβ-induced neural injury by regulating miR-22-3p/ZNF217 axis to affect PI3K-AKT pathway. This study has discovered an innovative mechanism for AD.

RevDate: 2024-06-09

Sun Y, Zhang H, Liu R, et al (2024)

Zexieyin formula alleviates Alzheimer's disease via post-synaptic CaMKII modulating AMPA receptor: Involved in promoting neurogenesis to strengthen synaptic plasticity in mice hippocampus.

Phytomedicine : international journal of phytotherapy and phytopharmacology, 131:155802 pii:S0944-7113(24)00460-4 [Epub ahead of print].

BACKGROUND: Alzheimer's disease (AD) is a serious neurodegenerative disease and brings a serious burden to society and families. Due to lack of effective drugs for the treatment of AD, it's urgent to develop new and effective drug for the treatment of AD.

PURPOSE: The study aimed to investigate the potential of Zexieyin formula (ZXYF), a Chinese medicine formula, for the treatment of AD and its potential mechanism of action.

METHODS: We used chronic scopolamine (SCOP) induction mice model and APP/PS1 mice to reveal and confirm ZXYF for the treatment of AD with donepezil (DON) as a positive reference. The learning and memory function were detected by morris water maze test (MWM) and y-maze test. Moreover, western blot and immunofluorescence were used to detect the molecular mechanism of ZXYF for the alleviation of AD in hippocampus. Lastly, pharmacological technology was applied to evaluate AMPA receptor involved in the role of ZXYF in the treatment of AD.

RESULTS: The results showed that ZXYF could improve memory and learning deficits both in two AD models including scopolamine (SCOP)-induced mice model and APP/PS1mice. Moreover, ZXYF or not DON increased expressions of BrdU/DCX and Ki67 positive cells in dentate gyrus (DG), up-regulated the levels of AMPA subunit type (GluA1) and PKA in hippocampus in SCOP-induced mice model, although ZXYF and DON activated CaMKII, CaMKII-phosphorylation, CREB, CREB-phosphorylation and PSD95 in hippocampus in SCOP-induced mice model. ZXYF also activated CaMKII, CaMKII-phosphorylation and GluA1 in HT22 cells. Furthermore, transient inhibiting AMPA receptor was capable of blocking the effects of ZXYF to treat AD in MWM and suppressing the number of BrdU/DCX positive cells increased by ZXYF in DG in SCOP-induced mice model, but had no effect on the alteration of Ki67 positive cells.

CONCLUSION: ZXYF had the therapeutic effects on AD-treatment, which activated CaMKII to promote AMPA receptor (GluA1) and subsequently up-regulated PKA/CREB signaling to facilitate neurogenesis to achieve enhanced postsynaptic protein.

RevDate: 2024-06-08
CmpDate: 2024-06-08

Hu Y, Hao R, Li D, et al (2024)

Experimental verification about treatment of Bu-Shen-Yi-Jing-Fang in Alzheimer's disease by the analysis of the feasible signaling pathway of network pharmacology.

BMC complementary medicine and therapies, 24(1):222.

CONTEXT: Bu-shen-yi-jing-fang (BSYJF) has been reported to reduce amyloid-β (Aβ)1-42 deposition in the brain of APP/PS1 mice and ameliorate cognitive function. However, its neuroprotective mechanism remains unclear.

OBJECTIVE: This study aims to investigate whether BSYJF exerts a protective effect on Aβ1-42-induced oxidative stress injury and explore its possible mechanism.

MATERIALS AND METHODS: The platform databases TCMSP, Swiss, TTD, DrugBank, and GeneCards were used to mine the targets of Alzheimer's disease (AD) and BSYJF. The platform databases STRING and Metascape were used to build the interaction network of the target protein, and Cytoscape software was used to analyze this network and screen out the key pathways. Aβ1-42-treated SKNMC cells were established to verify the mechanism of BSYJF and the key proteins. The downstream proteins and antioxidants as well as apoptosis and ferroptosis of the PI3K/AKT/Nrf2 signaling pathway were validated using an in vitro SKNMC cell model experiment. The expression levels of related proteins were detected using Western blotting. Flow cytometry and immunofluorescence staining were used to analyze apoptosis and ferroptosis.

RESULTS: Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis considered the key signal pathways, mainly involving the PI3K/AKT signaling pathway. Experimental validation demonstrated that BSYJF treatment markedly increased the activity of the PI3K/AKT pathway, which could exert anti-AD effects.

CONCLUSIONS: Our data provided compelling evidence that the protective effects of BSYJF might be associated with their regulation of the PI3K/AKT/Nrf2 signaling pathway. These studies offered a potential therapy for natural herbal medicine treatment of AD.

RevDate: 2024-06-08

Gao X, Sun H, Wei Y, et al (2024)

Protective effect of melatonin against metabolic disorders and neuropsychiatric injuries in type 2 diabetes mellitus mice.

Phytomedicine : international journal of phytotherapy and phytopharmacology, 131:155805 pii:S0944-7113(24)00463-X [Epub ahead of print].

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a metabolic disease characterized by hyperglycemia and progressive cognitive dysfunction, and our clinical investigation revealed that the plasma concentration of melatonin (Mlt) decreased and was closely related to cognition in T2DM patients. However, although many studies have suggested that Mlt has a certain protective effect on glucose and lipid metabolism disorders and neuropsychiatric injury, the underlying mechanism of Mlt against T2DM-related metabolic and cognitive impairments remains unclear.

PURPOSE: The aim of the present study was to investigate the therapeutic effect of Mlt on metabolic disorders and Alzheimer's disease (AD)-like neuropsychiatric injuries in T2DM mice and to explore the possible underlying molecular mechanism involved.

METHODS: A T2DM mouse model was established by a combination of a high-fat diet (HFD) and streptozotocin (STZ, 100 mg/kg, i.p.), and Mlt (5, 10 or 20 mg/kg) was intragastrically administered for six consecutive weeks. The serum levels of glycolipid metabolism indicators were measured, behavioral performance was tested, and the protein expression of key molecules involved in the regulation of synaptic plasticity, circadian rhythms, and neuroinflammation in the hippocampus was detected. Moreover, the fluorescence intensities of glial fibrillary acidic protein (GFAP), ionized calcium binding adapter molecule 1 (IBA-1), amyloid β-protein (Aβ) and phosphorylated Tau (p-Tau) in the hippocampus were also observed.

RESULTS: Treatment with Mlt not only improved T2DM-related metabolic disorders, as indicated by increased serum concentrations of fasting blood glucose (FBG), glycosylated hemoglobin (HbAlc), insulin (INS), total cholesterol (TC) and triglyceride (TG), improved glucose tolerance and liver and pancreas function but also alleviated AD-like neuropsychiatric injuries in a HFD/STZ-induced mouse model, as indicated by decreased immobility time in the tail suspension test (TST) and forced swimming test (FST), increased preference indices of novel objects or novel arms in the novel object recognition test (NOR) and Y-maze test (Y-maze), and improved platform positioning capability in the Morris water maze (MWM) test. Moreover, treatment with Mlt also improved the hyperactivation of astrocytes and microglia in the hippocampus of mice, accompanied by reduced expression of interleukin 1β (IL-1β), interleukin 6 (IL-6), tumor necrosis factor (TNF-α), Aβ, and p-Tau and increased expression of brain-derived neurotrophic factor (BDNF), Synapsin I, Synaptotagmin I, melatonin receptor 1B (MT1B), brain muscle arnt-like protein 1 (Bmal1), circadian locomotor output cycles kaput (Clock), period 2 (Per2), and cryptochrome 2 (Cry2).

CONCLUSION: Mlt alleviated T2DM-related metabolic disorders and AD-like neuropsychiatric injuries in a HFD/STZ-induced mouse model, possibly through a mechanism involving the regulation of glial activation and associated neuroinflammation and the balancing of synaptic plasticity and circadian rhythms in the hippocampus.

RevDate: 2024-06-08

Iqbal MS, Belal Bin Heyat M, Parveen S, et al (2024)

Progress and trends in neurological disorders research based on deep learning.

Computerized medical imaging and graphics : the official journal of the Computerized Medical Imaging Society, 116:102400 pii:S0895-6111(24)00077-6 [Epub ahead of print].

In recent years, deep learning (DL) has emerged as a powerful tool in clinical imaging, offering unprecedented opportunities for the diagnosis and treatment of neurological disorders (NDs). This comprehensive review explores the multifaceted role of DL techniques in leveraging vast datasets to advance our understanding of NDs and improve clinical outcomes. Beginning with a systematic literature review, we delve into the utilization of DL, particularly focusing on multimodal neuroimaging data analysis-a domain that has witnessed rapid progress and garnered significant scientific interest. Our study categorizes and critically analyses numerous DL models, including Convolutional Neural Networks (CNNs), LSTM-CNN, GAN, and VGG, to understand their performance across different types of Neurology Diseases. Through particular analysis, we identify key benchmarks and datasets utilized in training and testing DL models, shedding light on the challenges and opportunities in clinical neuroimaging research. Moreover, we discuss the effectiveness of DL in real-world clinical scenarios, emphasizing its potential to revolutionize ND diagnosis and therapy. By synthesizing existing literature and describing future directions, this review not only provides insights into the current state of DL applications in ND analysis but also covers the way for the development of more efficient and accessible DL techniques. Finally, our findings underscore the transformative impact of DL in reshaping the landscape of clinical neuroimaging, offering hope for enhanced patient care and groundbreaking discoveries in the field of neurology. This review paper is beneficial for neuropathologists and new researchers in this field.

RevDate: 2024-06-08

Ebrahim N, Al Saihati HA, Alali Z, et al (2024)

Exploring the molecular mechanisms of MSC-derived exosomes in Alzheimer's disease: Autophagy, insulin and the PI3K/Akt/mTOR signaling pathway.

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 176:116836 pii:S0753-3322(24)00720-0 [Epub ahead of print].

Alzheimer's disease (AD) is a devastating neurological condition characterized by cognitive decline, motor coordination impairment, and amyloid plaque accumulation. The underlying molecular mechanisms involve oxidative stress, inflammation, and neuronal degeneration. This study aimed to investigate the therapeutic effects of mesenchymal stem cell-derived exosomes (MSC-exos) on AD and explore the molecular pathways involved, including the PI3K/Akt/mTOR axis, autophagy, and neuroinflammation. To assess the potential of MSC-exos for the treatment of AD, rats were treated with AlCl3 (17 mg/kg/once/day) for 8 weeks, followed by the administration of an autophagy activator (rapamycin), or MSC-exos with or without an autophagy inhibitor (3-methyladenin; 3-MA+ chloroquine) for 4 weeks. Memory impairment was tested, and brain tissues were collected for gene expression analyses, western blotting, histological studies, immunohistochemistry, and transmission electron microscopy. Remarkably, the administration of MSC-exos improved memory performance in AD rats and reduced the accumulation of amyloid-beta (Aβ) plaques and tau phosphorylation. Furthermore, MSC-exos promoted neurogenesis, enhanced synaptic function, and mitigated astrogliosis in AD brain tissues. These beneficial effects were associated with the modulation of autophagy and the PI3K/Akt/mTOR signalling pathway, as well as the inhibition of neuroinflammation. Additionally, MSC-exos were found to regulate specific microRNAs, including miRNA-21, miRNA-155, miRNA-17-5p, and miRNA-126-3p, further supporting their therapeutic potential. Histopathological and bioinformatic analyses confirmed these findings. This study provides compelling evidence that MSC-exos hold promise as a potential therapeutic approach for AD. By modulating the PI3K/Akt/mTOR axis, autophagy, and neuroinflammation, MSC-exos have the potential to improve memory, reduce Aβ accumulation, enhance neurogenesis, and mitigate astrogliosis. These findings shed light on the therapeutic potential of MSC-exos and highlight their role in combating AD.

RevDate: 2024-06-08

Lei B, Li Y, Fu W, et al (2024)

Alzheimer's disease diagnosis from multi-modal data via feature inductive learning and dual multilevel graph neural network.

Medical image analysis, 97:103213 pii:S1361-8415(24)00138-5 [Epub ahead of print].

Multi-modal data can provide complementary information of Alzheimer's disease (AD) and its development from different perspectives. Such information is closely related to the diagnosis, prevention, and treatment of AD, and hence it is necessary and critical to study AD through multi-modal data. Existing learning methods, however, usually ignore the influence of feature heterogeneity and directly fuse features in the last stages. Furthermore, most of these methods only focus on local fusion features or global fusion features, neglecting the complementariness of features at different levels and thus not sufficiently leveraging information embedded in multi-modal data. To overcome these shortcomings, we propose a novel framework for AD diagnosis that fuses gene, imaging, protein, and clinical data. Our framework learns feature representations under the same feature space for different modalities through a feature induction learning (FIL) module, thereby alleviating the impact of feature heterogeneity. Furthermore, in our framework, local and global salient multi-modal feature interaction information at different levels is extracted through a novel dual multilevel graph neural network (DMGNN). We extensively validate the proposed method on the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset and experimental results demonstrate our method consistently outperforms other state-of-the-art multi-modal fusion methods. The code is publicly available on the GitHub website. (https://github.com/xiankantingqianxue/MIA-code.git).

RevDate: 2024-06-07

Zhang W, Smith N, Zhou Y, et al (2024)

Carbon dots as dual inhibitors of tau and amyloid-beta aggregation for the treatment of Alzheimer's disease.

Acta biomaterialia pii:S1742-7061(24)00306-4 [Epub ahead of print].

Alzheimer's disease (AD) is the most common form of senile dementia, presenting a significant challenge for the development of effective treatments. AD is characterized by extracellular amyloid plaques and intraneuronal neurofibrillary tangles. Therefore, targeting both hallmarks through inhibition of amyloid beta (Aβ) and tau aggregation presents a promising approach for drug development. Carbon dots (CD), with their high biocompatibility, minimal cytotoxicity, and blood-brain barrier (BBB) permeability, have emerged as promising drug nanocarriers. Congo red, an azo dye, has gathered significant attention for inhibiting amyloid-beta and tau aggregation. However, Congo red's inability to cross the BBB limits its potential to be used as a drug candidate for central nervous system (CNS) diseases. Furthermore, current studies only focus on using Congo red to target single disease hallmarks, without investigating dual inhibition capabilities. In this study, we synthesized Congo red-derived CD (CRCD) by using Congo red and citric acid as precursors, resulting in three variants, CRCD1, CRCD2 and CRCD3, based on different mass ratios of precursors. CRCD2 and CRCD3 exhibited sustained low cytotoxicity, and CRCD3 demonstrated the ability to traverse the BBB in a zebrafish model. Moreover, thioflavin T (ThT) aggregation assays and AFM imaging revealed CRCD as potent inhibitors against both tau and Aβ aggregation. Notably, CRCD1 emerged as the most robust inhibitor, displaying IC50 values of 0.2 ± 0.1 and 2.1 ± 0.5 μg/mL against tau and Aβ aggregation, respectively. Our findings underscore the dual inhibitory role of CRCD against tau and Aβ aggregation, showcasing effective BBB penetration and positioning CRCD as potential nanodrugs and nanocarriers for the CNS. Hence, CRCD-based compounds represent a promising candidate in the realm of multi-functional AD therapeutics, offering an innovative formulation component for future developments in this area. STATEMENT OF SIGNIFICANCE: This article reports Congo red-derived carbon dots (CRCD) as dual inhibitors of tau and amyloid-beta (Aβ) aggregation for the treatment of Alzheimer's disease (AD). The CRCD are biocompatible and show strong fluorescence, high stability, the ability to cross the blood-brain barrier, and the function of addressing two major pathological features of AD.

RevDate: 2024-06-07

Pettersson M, Johnson DS, Humphrey JM, et al (2024)

Discovery of Clinical Candidate PF-06648671: A Potent γ-Secretase Modulator for the Treatment of Alzheimer's Disease.

Journal of medicinal chemistry [Epub ahead of print].

Herein, we describe the design and synthesis of γ-secretase modulator (GSM) clinical candidate PF-06648671 (22) for the treatment of Alzheimer's disease. A key component of the design involved a 2,5-cis-tetrahydrofuran (THF) linker to impart conformational rigidity and lock the compound into a putative bioactive conformation. This effort was guided using a pharmacophore model since crystallographic information was not available for the membrane-bound γ-secretase protein complex at the time of this work. PF-06648671 achieved excellent alignment of whole cell in vitro potency (Aβ42 IC50 = 9.8 nM) and absorption, distribution, metabolism, and excretion (ADME) parameters. This resulted in favorable in vivo pharmacokinetic (PK) profile in preclinical species, and PF-06648671 achieved a human PK profile suitable for once-a-day dosing. Furthermore, PF-06648671 was found to have favorable brain availability in rodent, which translated into excellent central exposure in human and robust reduction of amyloid β (Aβ) 42 in cerebrospinal fluid (CSF).

RevDate: 2024-06-07
CmpDate: 2024-06-07

Fang F, C Chen (2024)

MiRNA let-7d-5p Alleviates Inflammatory Responses by Targeting Map3k1 and Inactivating ERK/p38 MAPK Signaling in Microglia.

Critical reviews in immunology, 44(6):13-25.

Alzheimer's disease (AD) is the most common form of dementia. Aberrant regulation of microRNAs (miRNAs) has been implicated in the pathogenesis of AD. In a large case-control study recruiting 208 patients with AD and 205 elderly control subjects, miRNA-let-7d-5p attracted our attention for its downregulated level in patients with AD. However, the biological functions of let-7d-5p in AD pathogenesis have not been investigated. This study emphasized the functions and mechanisms of let-7d-5p in the pathogenesis of AD. Mouse microglial BV2 cells treated with amyloid-β (Aβ)1-42 were used as in vitro AD inflammation models. We reported that let-7d-5p was downregulated in Aβ1-42-stimulated BV2 cells, and upregulation of let-7d-5p promoted the transversion of microglial cells from Ml phenotype to M2 phenotype. Then, the binding relationship between let-7d-5p and Map3k1 was verified by luciferase reporter assays. Mechanistically, let-7d-5p could target Map3k1 3'UTR to inactivate ERK/p38 MAPK signaling. Therefore, it was suggested that let-7d-5p might be a novel modulator of microglial neuroinflammation and serve as a novel target for diagnosis and treatment of AD.

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RJR Experience and Expertise

Researcher

Robbins holds BS, MS, and PhD degrees in the life sciences. He served as a tenured faculty member in the Zoology and Biological Science departments at Michigan State University. He is currently exploring the intersection between genomics, microbial ecology, and biodiversity — an area that promises to transform our understanding of the biosphere.

Educator

Robbins has extensive experience in college-level education: At MSU he taught introductory biology, genetics, and population genetics. At JHU, he was an instructor for a special course on biological database design. At FHCRC, he team-taught a graduate-level course on the history of genetics. At Bellevue College he taught medical informatics.

Administrator

Robbins has been involved in science administration at both the federal and the institutional levels. At NSF he was a program officer for database activities in the life sciences, at DOE he was a program officer for information infrastructure in the human genome project. At the Fred Hutchinson Cancer Research Center, he served as a vice president for fifteen years.

Technologist

Robbins has been involved with information technology since writing his first Fortran program as a college student. At NSF he was the first program officer for database activities in the life sciences. At JHU he held an appointment in the CS department and served as director of the informatics core for the Genome Data Base. At the FHCRC he was VP for Information Technology.

Publisher

While still at Michigan State, Robbins started his first publishing venture, founding a small company that addressed the short-run publishing needs of instructors in very large undergraduate classes. For more than 20 years, Robbins has been operating The Electronic Scholarly Publishing Project, a web site dedicated to the digital publishing of critical works in science, especially classical genetics.

Speaker

Robbins is well-known for his speaking abilities and is often called upon to provide keynote or plenary addresses at international meetings. For example, in July, 2012, he gave a well-received keynote address at the Global Biodiversity Informatics Congress, sponsored by GBIF and held in Copenhagen. The slides from that talk can be seen HERE.

Facilitator

Robbins is a skilled meeting facilitator. He prefers a participatory approach, with part of the meeting involving dynamic breakout groups, created by the participants in real time: (1) individuals propose breakout groups; (2) everyone signs up for one (or more) groups; (3) the groups with the most interested parties then meet, with reports from each group presented and discussed in a subsequent plenary session.

Designer

Robbins has been engaged with photography and design since the 1960s, when he worked for a professional photography laboratory. He now prefers digital photography and tools for their precision and reproducibility. He designed his first web site more than 20 years ago and he personally designed and implemented this web site. He engages in graphic design as a hobby.

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Collection of publications by R J Robbins

Reprints and preprints of publications, slide presentations, instructional materials, and data compilations written or prepared by Robert Robbins. Most papers deal with computational biology, genome informatics, using information technology to support biomedical research, and related matters.

Research Gate page for R J Robbins

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Curriculum Vitae for R J Robbins

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Curriculum Vitae for R J Robbins

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