@article {pmid38651790,
year = {2024},
author = {Behrens, LL and Anderson, HL and Kowalchik, KH and Mogle, J and Roman Jones, J and Van Haitsma, K and Hodgson, N and Boltz, M},
title = {"I'm not a risk taker": Risk Perceptions of Nursing Home Residents With Dementia.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
pmid = {38651790},
issn = {1546-4156},
abstract = {BACKGROUND: Persons living with Alzheimer's disease and related dementia (ADRD) in nursing homes (NH) are often excluded from conversations about their health/safety. These omissions impinge on personhood and the rights to have care preferences heard and honored. While persons with ADRD maintain the ability to communicate their preferences long after their decision-making abilities are affected, little is known about how persons with ADRD understand the risks associated with their preferences.

METHODS: As part of a larger focused ethnography, in-depth interviews and an adapted risk propensity questionnaire explored the risk perceptions of NH residents with ADRD (N=7) associated with their preferences for care and activities of daily living.

RESULTS: Residents generally self-identified as risk avoiders (M=3.2±1.84) on the risk propensity scale and were able to rate risk associated with preferences described within 5 thematic categories: 1) participation in decision-making, 2) risk awareness, 3) paying attention to safety, 4) reliance on nursing home staff and family, and 5) impacts on quality of life and quality of care.

DISCUSSION: Results suggest NH residents with ADRD can express risk surrounding their preferences and should be encouraged to participate in discussions about their health and safety.},
}

@article {pmid38651489,
year = {2024},
author = {Marinova, P and Tamahkyarova, K},
title = {Synthesis and Biological Activities of Some Metal Complexes of Peptides: A Review.},
journal = {Biotech (Basel (Switzerland))},
volume = {13},
number = {2},
pages = {},
doi = {10.3390/biotech13020009},
pmid = {38651489},
issn = {2673-6284},
support = {project СП 23-ХФ-006//We acknowledge the financial support from the Fund for Scientific Research of the Plovdiv University/ ; },
abstract = {Peptides, both natural and synthetic, are well suited for a wide range of purposes and offer versatile applications in different fields such as biocatalysts, injectable hydrogels, tumor treatment, and drug delivery. The research of the better part of the cited papers was conducted using various database platforms such as MetalPDB. The rising prominence of therapeutic peptides encompasses anticancer, antiviral, antimicrobial, and anti-neurodegenerative properties. The metals Na, K, Mg, Ca, Fe, Mn, Co, Cu, Zn, and Mo are ten of the twenty elements that are considered essential for life. Crucial for understanding the biological role of metals is the exploration of metal-bound proteins and peptides. Aside from essential metals, there are other non-essential metals that also interact biologically, exhibiting either therapeutic or toxic effects. Irregularities in metal binding contribute to diseases like Alzheimer's, neurodegenerative disorders, Wilson's, and Menkes disease. Certain metal complexes have potential applications as radiopharmaceuticals. The examination of these complexes was achieved by preforming UV-Vis, IR, EPR, NMR spectroscopy, and X-ray analysis. This summary, although unable to cover all of the studies in the field, offers a review of the ongoing experimentation and is a basis for new ideas, as well as strategies to explore and gain knowledge from the extensive realm of peptide-chelated metals and biotechnologies.},
}

@article {pmid38651483,
year = {2024},
author = {Rodríguez-Alcázar, FJ and Juárez-Vela, R and Sánchez-González, JL and Martín-Vallejo, J},
title = {Interventions Effective in Decreasing Burden in Caregivers of Persons with Dementia: A Meta-Analysis.},
journal = {Nursing reports (Pavia, Italy)},
volume = {14},
number = {2},
pages = {931-945},
doi = {10.3390/nursrep14020071},
pmid = {38651483},
issn = {2039-4403},
abstract = {Introduction: Chronic non-communicable diseases, including diseases of mental origin such as Alzheimer's, affect all age groups and countries. These diseases have a major impact on the patient and their family environment. It is interesting that different questionnaires are measured in the same direction, given that different health questionnaires are used to measure caregiver burden. Objectives: To identify which type of intervention is the most appropriate to improve the health of the primary caregiver in patients with dementia. To understand the role played by the nurse within multidisciplinary teams and to know whether the different questionnaires used in the studies measure caregiver health in the same direction. Methods: A systematic search of the published and gray literature was carried out without restriction of the language used in the studies. Caregiver burden of patients with dementia, receiving an intervention to improve caregiver burden, was assessed. Standardized mean difference was used as the effect size measure, and there were possible causes of heterogeneity in the effect size. Results: In total, 1512 records were found, and 39 articles with 4715 participants were included. We found individual information with an effect of 0.48 (CI95%: 0.18; 0.79; I2 = 0%); group therapy with an effect of 0.20 (CI95%: 0.08; 0.31; I2 = 6%); workshops with an effect of 0.21 (CI95%: 0.01; I2 = 48%) and 0.32 (CI95%: 0.01; 0.54; I2 = 0%) when a nurse intervenes; respite care with an effect of 0.22 (CI95%: 0.05; 0.40; I2 = 66%); individual therapy with an effect of 0.28 (CI95%: 0.15; 0.4; I2 = 68%); and support groups with an effect of 0.07 (CI95%: 0; 0.15; I2 = 78%). Conclusions: The magnitude of the effects of the interventions has been low-moderate. Different instruments are not associated with the magnitude of the effect. The presence of nurses improves the effect of the intervention on caregivers when it is carried out in the form of workshops.},
}

@article {pmid38651367,
year = {2024},
author = {Sanders, KL and Manuel, AM and Liu, A and Leng, B and Chen, X and Zhao, Z},
title = {Unveiling Gene Interactions in Alzheimer's Disease by Integrating Genetic and Epigenetic Data with a Network-Based Approach.},
journal = {Epigenomes},
volume = {8},
number = {2},
pages = {},
doi = {10.3390/epigenomes8020014},
pmid = {38651367},
issn = {2075-4655},
support = {U01AG079847//National Institute of Health/ ; R01LM012806//National Institute of Health/ ; RP180734//Cancer Prevention and Research Institute of Texas/ ; T15LM007093//United States National Library of Medicine/ ; T32ES027801//Gulf Coast Consortia on Training in Precision Environmental Health Sciences/ ; },
abstract = {Alzheimer's Disease (AD) is a complex disease and the leading cause of dementia in older people. We aimed to uncover aspects of AD's pathogenesis that may contribute to drug repurposing efforts by integrating DNA methylation and genetic data. Implementing the network-based tool, a dense module search of genome-wide association studies (dmGWAS), we integrated a large-scale GWAS dataset with DNA methylation data to identify gene network modules associated with AD. Our analysis yielded 286 significant gene network modules. Notably, the foremost module included the BIN1 gene, showing the largest GWAS signal, and the GNAS gene, the most significantly hypermethylated. We conducted Web-based Cell-type-Specific Enrichment Analysis (WebCSEA) on genes within the top 10% of dmGWAS modules, highlighting monocyte as the most significant cell type (p < 5 × 10[-12]). Functional enrichment analysis revealed Gene Ontology Biological Process terms relevant to AD pathology (adjusted p < 0.05). Additionally, drug target enrichment identified five FDA-approved targets (p-value = 0.03) for further research. In summary, dmGWAS integration of genetic and epigenetic signals unveiled new gene interactions related to AD, offering promising avenues for future studies.},
}

@article {pmid38651344,
year = {2024},
author = {Zheng, B and Chen, J and Cao, M and Zhang, Y and Chen, S and Yu, H and Liang, K},
title = {The effect of intermittent theta burst stimulation for cognitive dysfunction: a meta-analysis.},
journal = {Brain injury},
volume = {},
number = {},
pages = {1-12},
doi = {10.1080/02699052.2024.2344087},
pmid = {38651344},
issn = {1362-301X},
abstract = {BACKGROUND: Growing evidence suggests that cognitive dysfunction significantly impacts patients' quality of life. Intermittent theta burst stimulation (iTBS) has emerged as a potential intervention for cognitive dysfunction. However, consensus on the iTBS protocol for cognitive impairment is lacking.

METHODS: We conducted searches in the Cochrane Central Register of Controlled Trials, EMBASE, PubMed, Chinese National Knowledge Infrastructure, Wanfang Database and the Chongqing VIP Chinese Science and Technology Periodical Database from their inception to January 2024. Random-effects meta-analyzes were used to calculate standardized mean differences and 95% confidence intervals. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation approach.

RESULTS: Twelve studies involving 506 participants were included in the meta-analysis. The analysis showed a trend toward improvement of total cognitive function, activities of daily living and P300 latency compared to sham stimulation in patients with cognitive dysfunction. Subgroup analysis demonstrated that these effects were restricted to patients with post-stroke cognitive impairment but not Alzheimer's disease or Parkinson's disease. Furthermore, subthreshold stimulation also exhibited a significant improvement.

CONCLUSIONS: The results suggest that iTBS may improve cognitive function in patients with cognitive dysfunction, although the quality of evidence remains low. Further studies with better methodological quality should explore the effects of iTBS on cognitive function.},
}

@article {pmid38651272,
year = {2024},
author = {Jing, XJ and Zan, ZY and Zhou, X and Xiong, YL and Ren, SJ and Zhang, H and , },
title = {The associations of serum isoleucine with Alzheimer`s disease on assisting diagnosis, predicting conversion and assessing cognition.},
journal = {Annals of geriatric medicine and research},
volume = {},
number = {},
pages = {},
doi = {10.4235/agmr.23.0216},
pmid = {38651272},
issn = {2508-4909},
abstract = {BACKGROUND: Advances in blood biomarker discovery have enabled the improved diagnosis and prognosis of Alzheimer's disease (AD). Most branched-chain amino acids, except isoleucine (Ile), are correlated with both mild cognitive impairment (MCI) and AD. Therefore, this study investigated the association between serum Ile levels and MCI/AD.

METHODS: This study stratified 700 participants from the Alzheimer's Disease Neuroimaging Initiative database into four diagnostic groups: cognitively normal, stable MCI, progressive MCI, and AD. Analysis of covariance and chi-square analyses were used to test the demographic data. Receiver operating curve analyses were used to calculate the diagnostic accuracy of different biomarkers and were compared using MedCalc 20. Additionally, Cox proportional hazards models were used to measure the ability of serum Ile levels to predict disease conversion. Finally, a linear mixed-effects model was used to evaluate the associations between serum Ile levels and cognition, brain structure, and metabolism.

RESULTS: Serum Ile concentration was decreased in AD and demonstrated significant diagnostic efficacy. The combination of serum Ile and cerebrospinal fluid (CSF) phosphorylated tau (P-tau) levels improved the diagnostic accuracy in AD compared to T-tau alone. Serum Ile levels significantly predicted the conversion from MCI to AD (cutoff value = 78.3 μM). Finally, the results of this study also revealed a correlation between serum Ile levels and the Alzheimer's Disease Assessment Scale cognitive subscale Q4.

CONCLUSIONS: Serum Ile level may be a potential biomarker of AD. Ile had independent diagnostic efficacy and significantly improved the diagnostic accuracy of CSF P-tau in AD. Patients with MCI with a lower serum Ile level had a higher risk of progression to AD and a worse cognition assessment.},
}

@article {pmid38651179,
year = {2024},
author = {Li, J and Wu, Z and Wu, Y and Hu, XY and Yang, J and Zhu, D and Wu, M and Li, X and Bentum-Ennin, L and Hu, W},
title = {IL-22, a vital cytokine in autoimmune diseases.},
journal = {Clinical and experimental immunology},
volume = {},
number = {},
pages = {},
doi = {10.1093/cei/uxae035},
pmid = {38651179},
issn = {1365-2249},
abstract = {Interleukin-22 (IL-22) is a vital cytokine that is dysregulated in various autoimmune conditions including rheumatoid arthritis (RA), multiple sclerosis (MS), and Alzheimer's disease (AD). As the starting point for the activation of numerous signaling pathways, IL-22 plays an important role in the initiation and development of autoimmune diseases. Specifically, imbalances in IL-22 signaling can interfere with other signaling pathways, causing cross regulation of target genes which ultimately leads to the development of immune disorders. This review delineates the various connections between the IL-22 signaling pathway and autoimmune disease, focusing on the latest understanding of the cellular sources of IL-22 and its effects on various cell types. We further explore progress with pharmacological interventions related to targeting IL-22, describing how such therapeutic strategies promise to usher in a new era in the treatment of autoimmune disease.},
}

@article {pmid38651161,
year = {2024},
author = {Hong, H and Chen, Y and Liu, W and Luo, X and Zhang, M and , },
title = {Distinct patterns of voxel- and connection-based white matter hyperintensity distribution and associated factors in early-onset and late-onset Alzheimer's disease.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {16},
number = {2},
pages = {e12585},
pmid = {38651161},
issn = {2352-8729},
abstract = {INTRODUCTION: The distribution of voxel- and connection-based white matter hyperintensity (WMH) patterns in early-onset Alzheimer's disease (EOAD) and late-onset Alzheimer's disease (LOAD), as well as factors associated with these patterns, remain unclear.

METHOD: We analyzed the WMH distribution patterns in EOAD and LOAD at the voxel and connection levels, each compared with their age-matched cognitively unimpaired participants. Linear regression assessed the independent effects of amyloid and vascular risk factors on WMH distribution patterns in both groups.

RESULTS: Patients with EOAD showed increased WMH burden in the posterior region at the voxel level, and in occipital region tracts and visual network at the connection level, compared to controls. LOAD exhibited extensive involvement across various brain areas in both levels. Amyloid accumulation was associated WMH distribution in the early-onset group, whereas the late-onset group demonstrated associations with both amyloid and vascular risk factors.

DISCUSSION: EOAD showed posterior-focused WMH distribution pattern, whereas LOAD was with a wider distribution. Amyloid accumulation was associated with connection-based WMH patterns in both early-onset and late-onset groups, with additional independent effects of vascular risk factors in late-onset group.

HIGHLIGHTS: Both early-onset Alzheimer's disease (EOAD) and late-onset AD (LOAD) showed increased white matter hyperintensity (WMH) volume compared with their age-matched cognitively unimpaired participants.EOAD and LOAD exhibited distinct patterns of WMH distribution, with EOAD showing a posterior-focused pattern and LOAD displaying a wider distribution across both voxel- and connection-based levels.In both EOAD and LOAD, amyloid accumulation was associated with connection-based WMH patterns, with additional independent effects of vascular risk factors observed in LOAD.},
}

@article {pmid38651160,
year = {2024},
author = {Pivac, LN and Brown, BM and Sewell, KR and Doecke, JD and Villemagne, VL and Doré, V and Weinborn, M and Sohrabi, HR and Gardener, SL and Bucks, RS and Laws, SM and Taddei, K and Maruff, P and Masters, CL and Rowe, C and Martins, RN and Rainey-Smith, SR},
title = {Suboptimal self-reported sleep efficiency and duration are associated with faster accumulation of brain amyloid beta in cognitively unimpaired older adults.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {16},
number = {2},
pages = {e12579},
pmid = {38651160},
issn = {2352-8729},
abstract = {INTRODUCTION: This study investigated whether self-reported sleep quality is associated with brain amyloid beta (Aβ) accumulation.

METHODS: Linear mixed effect model analyses were conducted for 189 cognitively unimpaired (CU) older adults (mean ± standard deviation 74.0 ± 6.2; 53.2% female), with baseline self-reported sleep data, and positron emission tomography-determined brain Aβ measured over a minimum of three time points (range 33.3-72.7 months). Analyses included random slopes and intercepts, interaction for apolipoprotein E (APOE) ε4 allele status, and time, adjusting for sex and baseline age.

RESULTS: Sleep duration <6 hours, in APOE ε4 carriers, and sleep efficiency <65%, in the whole sample and APOE ε4 non-carriers, is associated with faster accumulation of brain Aβ.

DISCUSSION: These findings suggest a role for self-reported suboptimal sleep efficiency and duration in the accumulation of Alzheimer's disease (AD) neuropathology in CU individuals. Additionally, poor sleep efficiency represents a potential route via which individuals at lower genetic risk may progress to preclinical AD.

HIGHLIGHTS: In cognitively unimpaired older adults self-report sleep is associated with brain amyloid beta (Aβ) accumulation.Across sleep characteristics, this relationship differs by apolipoprotein E (APOE) genotype.Sleep duration <6 hours is associated with faster brain Aβ accumulation in APOE ε4 carriers.Sleep efficiency < 65% is associated with faster brain Aβ accumulation in APOE ε4 non-carriers.Personalized sleep interventions should be studied for potential to slow Aβ accumulation.},
}

@article {pmid38651012,
year = {2024},
author = {Prasuhn, J and Xu, J and Hua, J and van Zijl, P and Knutsson, L},
title = {Exploring neurodegenerative disorders using advanced magnetic resonance imaging of the glymphatic system.},
journal = {Frontiers in psychiatry},
volume = {15},
number = {},
pages = {1368489},
pmid = {38651012},
issn = {1664-0640},
abstract = {The glymphatic system, a macroscopic waste clearance system in the brain, is crucial for maintaining neural health. It facilitates the exchange of cerebrospinal and interstitial fluid, aiding the clearance of soluble proteins and metabolites and distributing essential nutrients and signaling molecules. Emerging evidence suggests a link between glymphatic dysfunction and the pathogenesis of neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's disease. These disorders are characterized by the accumulation and propagation of misfolded or mutant proteins, a process in which the glymphatic system is likely involved. Impaired glymphatic clearance could lead to the buildup of these toxic proteins, contributing to neurodegeneration. Understanding the glymphatic system's role in these disorders could provide insights into their pathophysiology and pave the way for new therapeutic strategies. Pharmacological enhancement of glymphatic clearance could reduce the burden of toxic proteins and slow disease progression. Neuroimaging techniques, particularly MRI-based methods, have emerged as promising tools for studying the glymphatic system in vivo. These techniques allow for the visualization of glymphatic flow, providing insights into its function under healthy and pathological conditions. This narrative review highlights current MRI-based methodologies, such as motion-sensitizing pulsed field gradient (PFG) based methods, as well as dynamic gadolinium-based and glucose-enhanced methodologies currently used in the study of neurodegenerative disorders.},
}

@article {pmid38650867,
year = {2024},
author = {Liang, K and Zhang, X},
title = {Association between Life's Essential 8 and cognitive function: insights from NHANES 2011-2014.},
journal = {Frontiers in aging neuroscience},
volume = {16},
number = {},
pages = {1386498},
pmid = {38650867},
issn = {1663-4365},
abstract = {INTRODUCTION: Life's Essential 8 (LE8) is prompted by the American Heart Association (AHA) to assess cardiovascular health. The association between LE8 and cognitive function in America is unknown. Our study was to investigate the association of LE8 with cognitive function in general adults.

MATERIALS AND METHODS: A total of 2,301 participants were enrolled in the National Health and Nutrition Examination Surveys (NHANES). LE8 scores (range 0-100) were obtained from measurements based on American Heart Association definitions, divided into health behavior and health factor scores. Cognitive function was assessed by three tests including the Consortium to Establish a Registry for Alzheimer's Disease (CERAD), Animal fluency test (AFT), and Digit Symbol Substitution test (DSST). The multivariable linear regression analysis explored the associations between LE8 and cognitive function. Smooth curve fitting was explored using restricted cubic splines. The inflection point was determined by the two-piecewise linear regression.

RESULTS: In the multivariable linear regression model with full adjustment for confounding variables, AFT scores were 1.2 points higher in participants with LE8 scores >80 than in those with LE8 scores <50 (high LE8 score group: β = 1.20, 95% CI 0.37, 2.03), and 3.32 points higher in DSST (high LE8 score group: β = 3.32, 95% CI 1.24, 5.39). Although high LE8 scores show a Negative association with high CERAD, we found a significant association between higher LE8 scores and higher CERAD when LE8 scores were higher than 82.5 (β = 0.21 95%CI 0.04, 0.39, p-value = 0.0179).

CONCLUSION: Our study highlighted a positive association between Life's Essential 8 and cognitive function in older adults.},
}

@article {pmid38650866,
year = {2024},
author = {Jiao, L and Kang, H and Geng, Y and Liu, X and Wang, M and Shu, K},
title = {The role of the nucleus basalis of Meynert in neuromodulation therapy: a systematic review from the perspective of neural network oscillations.},
journal = {Frontiers in aging neuroscience},
volume = {16},
number = {},
pages = {1376764},
pmid = {38650866},
issn = {1663-4365},
abstract = {As a crucial component of the cerebral cholinergic system and the Papez circuit in the basal forebrain, dysfunction of the nucleus basalis of Meynert (NBM) is associated with various neurodegenerative disorders. However, no drugs, including existing cholinesterase inhibitors, have been shown to reverse this dysfunction. Due to advancements in neuromodulation technology, researchers are exploring the use of deep brain stimulation (DBS) therapy targeting the NBM (NBM-DBS) to treat mental and neurological disorders as well as the related mechanisms. Herein, we provided an update on the research progress on cognition-related neural network oscillations and complex anatomical and projective relationships between the NBM and other cognitive structures and circuits. Furthermore, we reviewed previous animal studies of NBM lesions, NBM-DBS models, and clinical case studies to summarize the important functions of the NBM in neuromodulation. In addition to elucidating the mechanism of the NBM neural network, future research should focus on to other types of neurons in the NBM, despite the fact that cholinergic neurons are still the key target for cell type-specific activation by DBS.},
}

@article {pmid38650831,
year = {2024},
author = {Bøgh, N and Sørensen, CB and Alstrup, AKO and Hansen, ESS and Andersen, OM and Laustsen, C},
title = {Mice and minipigs with compromised expression of the Alzheimer's disease gene SORL1 show cerebral metabolic disturbances on hyperpolarized [1-[13]C]pyruvate and sodium MRI.},
journal = {Brain communications},
volume = {6},
number = {2},
pages = {fcae114},
pmid = {38650831},
issn = {2632-1297},
abstract = {The sortilin-related receptor 1 (SORL1) gene, encoding the cellular endosomal sorting-related receptor with A-type repeats (SORLA), is now established as a causal gene for Alzheimer's disease. As the latest addition to the list of causal genes, the pathophysiological effects and biomarker potential of SORL1 variants remain relatively undiscovered. Metabolic dysfunction is, however, well described in patients with Alzheimer's disease and is used as an imaging biomarker in clinical diagnosis settings. To understand the metabolic consequences of loss-of-function SORL1 mutations, we applied two metabolic MRI technologies, sodium ([23]Na) MRI and MRI with hyperpolarized [1-[13]C]pyruvate, in minipigs and mice with compromised expression of SORL1. At the age analysed here, both animal models display no conventional imaging evidence of neurodegeneration but show biochemical signs of elevated amyloid production, thus representing the early preclinical disease. With hyperpolarized MRI, the exchange from [1-[13]C]pyruvate to [1-[13]C]lactate and [13]C-bicarbonate was decreased by 32 and 23%, respectively, in the cerebrum of SORL1-haploinsufficient minipigs. A robust 11% decrease in the sodium content was observed with [23]Na-MRI in the same minipigs. Comparably, the brain sodium concentration gradually decreased from control to SORL1 haploinsufficient (-11%) to SORL1 knockout mice (-23%), suggesting a gene dose dependence in the metabolic dysfunction. The present study highlights that metabolic MRI technologies are sensitive to the functional, metabolic consequences of Alzheimer's disease and Alzheimer's disease-linked genotypes. Further, the study suggests a potential avenue of research into the mechanisms of metabolic alterations by SORL1 mutations and their potential role in neurodegeneration.},
}

@article {pmid38650747,
year = {2024},
author = {Cary, GA and Wiley, JC and Gockley, J and Keegan, S and Amirtha Ganesh, SS and Heath, L and Butler, RR and Mangravite, LM and Logsdon, BA and Longo, FM and Levey, A and Greenwood, AK and Carter, GW},
title = {Genetic and multi-omic risk assessment of Alzheimer's disease implicates core associated biological domains.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {10},
number = {2},
pages = {e12461},
pmid = {38650747},
issn = {2352-8737},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is the predominant dementia globally, with heterogeneous presentation and penetrance of clinical symptoms, variable presence of mixed pathologies, potential disease subtypes, and numerous associated endophenotypes. Beyond the difficulty of designing treatments that address the core pathological characteristics of the disease, therapeutic development is challenged by the uncertainty of which endophenotypic areas and specific targets implicated by those endophenotypes to prioritize for further translational research. However, publicly funded consortia driving large-scale open science efforts have produced multiple omic analyses that address both disease risk relevance and biological process involvement of genes across the genome.

METHODS: Here we report the development of an informatic pipeline that draws from genetic association studies, predicted variant impact, and linkage with dementia associated phenotypes to create a genetic risk score. This is paired with a multi-omic risk score utilizing extensive sets of both transcriptomic and proteomic studies to identify system-level changes in expression associated with AD. These two elements combined constitute our target risk score that ranks AD risk genome-wide. The ranked genes are organized into endophenotypic space through the development of 19 biological domains associated with AD in the described genetics and genomics studies and accompanying literature. The biological domains are constructed from exhaustive Gene Ontology (GO) term compilations, allowing automated assignment of genes into objectively defined disease-associated biology. This rank-and-organize approach, performed genome-wide, allows the characterization of aggregations of AD risk across biological domains.

RESULTS: The top AD-risk-associated biological domains are Synapse, Immune Response, Lipid Metabolism, Mitochondrial Metabolism, Structural Stabilization, and Proteostasis, with slightly lower levels of risk enrichment present within the other 13 biological domains.

DISCUSSION: This provides an objective methodology to localize risk within specific biological endophenotypes and drill down into the most significantly associated sets of GO terms and annotated genes for potential therapeutic targets.},
}

@article {pmid38650695,
year = {2024},
author = {Hassouneh, A and Bazuin, B and Danna-Dos-Santos, A and Acar, I and Abdel-Qader, I and , },
title = {Feature Importance Analysis and Machine Learning for Alzheimer's Disease Early Detection: Feature Fusion of the Hippocampus, Entorhinal Cortex, and Standardized Uptake Value Ratio.},
journal = {Digital biomarkers},
volume = {8},
number = {1},
pages = {59-74},
pmid = {38650695},
issn = {2504-110X},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurological disorder characterized by mild memory loss and ranks as a leading cause of mortality in the USA, accounting for approximately 120,000 deaths per year. It is also the primary form of dementia. Early detection is critical for timely intervention as the neurodegenerative process often starts 15-20 years before cognitive symptoms manifest. This study focuses on determining feature importance in AD classification using fused texture features from 3D magnetic resonance imaging hippocampal and entorhinal cortex and standardized uptake value ratio (SUVR) derived from positron emission tomography (PET) images.

METHODS: To achieve this objective, we employed four distinct classifiers (Linear Support Vector Classification, Linear Discriminant Analysis, Logistic Regression, and Logistic Regression Classifier with Stochastic Gradient Descent Learning). These classifiers were used to derive both average and top-ranked importance scores for each feature based on their outputs. Our framework is designed to distinguish between two classes, AD-negative (or mild cognitive impairment stable [MCIs]) and AD-positive (or MCI conversion [MCIc]), using a probabilistic neural network classifier and the Alzheimer's Disease Neuroimaging Initiative (ADNI) database.

RESULTS: The findings from the feature importance highlight the crucial role of the GLCM texture features extracted from the hippocampus and entorhinal cortex, demonstrating their superior performance compared to the volume and SUVR. GLCM texture AD classification achieved approximately 90% sensitivity in identifying MCIc cases while maintaining low false positives (below 30%) when fused with other features. Moreover, the receiver operating characteristic curves validate the GLCMs' superior performance in distinguishing between MCIs and MCIc. Additionally, fusing different types of features improved classification performance compared to relying solely on any single feature category.

CONCLUSION: Our study emphasizes the pivotal role of GLCM texture features in early Alzheimer's detection.},
}

@article {pmid38650656,
year = {2024},
author = {Spanos, F and Gerenu, G and Goikolea, J and Latorre-Leal, M and Balleza-Tapia, H and Gomez, K and Álvarez-Jiménez, L and Piras, A and Gómez-Galán, M and Fisahn, A and Cedazo-Minguez, A and Maioli, S and Loera-Valencia, R},
title = {Impaired astrocytic synaptic function by peripheral cholesterol metabolite 27-hydroxycholesterol.},
journal = {Frontiers in cellular neuroscience},
volume = {18},
number = {},
pages = {1347535},
pmid = {38650656},
issn = {1662-5102},
abstract = {Astrocytes represent the most abundant cell type in the brain, where they play critical roles in synaptic transmission, cognition, and behavior. Recent discoveries show astrocytes are involved in synaptic dysfunction during Alzheimer's disease (AD). AD patients have imbalanced cholesterol metabolism, demonstrated by high levels of side-chain oxidized cholesterol known as 27-hydroxycholesterol (27-OH). Evidence from our laboratory has shown that elevated 27-OH can abolish synaptic connectivity during neuromaturation, but its effect on astrocyte function is currently unclear. Our results suggest that elevated 27-OH decreases the astrocyte function in vivo in Cyp27Tg, a mouse model of brain oxysterol imbalance. Here, we report a downregulation of glutamate transporters in the hippocampus of CYP27Tg mice together with increased GFAP. GLT-1 downregulation was also observed when WT mice were fed with high-cholesterol diets. To study the relationship between astrocytes and neurons, we have developed a 3D co-culture system that allows all the cell types from mice embryos to differentiate in vitro. We report that our 3D co-cultures reproduce the effects of 27-OH observed in 2D neurons and in vivo. Moreover, we found novel degenerative effects in astrocytes that do not appear in 2D cultures, together with the downregulation of glutamate transporters GLT-1 and GLAST. We propose that this transporter dysregulation leads to neuronal hyperexcitability and synaptic dysfunction based on the effects of 27-OH on astrocytes. Taken together, these results report a new mechanism linking oxysterol imbalance in the brain and synaptic dysfunction through effects on astrocyte function.},
}

@article {pmid38650384,
year = {2024},
author = {Tam, S and Wear, D and Morrone, CD and Yu, WH},
title = {The complexity of extracellular vesicles: Bridging the gap between cellular communication and neuropathology.},
journal = {Journal of neurochemistry},
volume = {},
number = {},
pages = {},
doi = {10.1111/jnc.16108},
pmid = {38650384},
issn = {1471-4159},
support = {AG069130/NH/NIH HHS/United States ; AG079774/NH/NIH HHS/United States ; },
abstract = {Brain-derived extracellular vesicles (EVs) serve a prominent role in maintaining homeostasis and contributing to pathology in health and disease. This review establishes a crucial link between physiological processes leading to EV biogenesis and their impacts on disease. EVs are involved in the clearance and transport of proteins and nucleic acids, responding to changes in cellular processes associated with neurodegeneration, including autophagic disruption, organellar dysfunction, aging, and other cell stresses. In neurodegenerative disorders (e.g., Alzheimer's disease, Parkinson's disease, etc.), EVs contribute to the spread of pathological proteins like amyloid β, tau, ɑ-synuclein, prions, and TDP-43, exacerbating neurodegeneration and accelerating disease progression. Despite evidence for both neuropathological and neuroprotective effects of EVs, the mechanistic switch between their physiological and pathological functions remains elusive, warranting further research into their involvement in neurodegenerative disease. Moreover, owing to their innate ability to traverse the blood-brain barrier and their ubiquitous nature, EVs emerge as promising candidates for novel diagnostic and therapeutic strategies. The review uniquely positions itself at the intersection of EV cell biology, neurophysiology, and neuropathology, offering insights into the diverse biological roles of EVs in health and disease.},
}

@article {pmid38649866,
year = {2024},
author = {Jiang, S and Cai, G and Yang, Z and Shi, H and Zeng, H and Ye, Q and Hu, Z and Wang, Z},
title = {Biomimetic Nanovesicles as a Dual Gene Delivery System for the Synergistic Gene Therapy of Alzheimer's Disease.},
journal = {ACS nano},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsnano.3c13150},
pmid = {38649866},
issn = {1936-086X},
abstract = {The association between dysfunctional microglia and amyloid-β (Aβ) is a fundamental pathological event and increases the speed of Alzheimer's disease (AD). Additionally, the pathogenesis of AD is intricate and a single drug may not be enough to achieve a satisfactory therapeutic outcome. Herein, we reported a facile and effective gene therapy strategy for the modulation of microglia function and intervention of Aβ anabolism by ROS-responsive biomimetic exosome-liposome hybrid nanovesicles (designated as TSEL). The biomimetic nanovesicles codelivery β-site amyloid precursor protein cleaving enzyme-1 (BACE1) siRNA (siBACE1) and TREM2 plasmid (pTREM2) gene drug efficiently penetrate the blood-brain barrier and enhance the drug accumulation at AD lesions with the help of exosomes homing ability and angiopep-2 peptides. Specifically, an upregulation of TREM2 expression can reprogram microglia from a pro-inflammatory M1 phenotype to an anti-inflammatory M2 phenotype while also restoring its capacity to phagocytose Aβ and its nerve repair function. In addition, siRNA reduces the production of Aβ plaques at the source by knocking out the BACE1 gene, which is expected to further enhance the therapeutic effect of AD. The in vivo study suggests that TSEL through the synergistic effect of two gene drugs can ameliorate APP/PS1 mice cognitive impairment by regulating the activated microglial phenotype, reducing the accumulation of Aβ, and preventing the retriggering of neuroinflammation. This strategy employs biomimetic nanovesicles for the delivery of dual nucleic acids, achieving synergistic gene therapy for AD, thus offering more options for the treatment of AD.},
}

@article {pmid38649596,
year = {2024},
author = {Kamble, SA and Barale, SS and Mohammed, AA and Paymal, SB and Naik, NM and Sonawane, KD},
title = {Structural insights into the potential binding sites of Cathepsin D using molecular modelling techniques.},
journal = {Amino acids},
volume = {56},
number = {1},
pages = {33},
pmid = {38649596},
issn = {1438-2199},
abstract = {Alzheimer's disease (AD) is the most prevalent type of dementia caused by the accumulation of amyloid beta (Aβ) peptides. The extracellular deposition of Aβ peptides in human AD brain causes neuronal death. Therefore, it has been found that Aβ peptide degradation is a possible therapeutic target for AD. CathD has been known to breakdown amyloid beta peptides. However, the structural role of CathD is not yet clear. Hence, for the purpose of gaining a deeper comprehension of the structure of CathD, the present computational investigation was performed using virtual screening technique to predict CathD's active site residues and substrate binding mode. Ligand-based virtual screening was implemented on small molecules from ZINC database against crystal structure of CathD. Further, molecular docking was utilised to investigate the binding mechanism of CathD with substrates and virtually screened inhibitors. Localised compounds obtained through screening performed by PyRx and AutoDock 4.2 with CathD receptor and the compounds having highest binding affinities were picked as; ZINC00601317, ZINC04214975 and ZINCC12500925 as our top choices. The hydrophobic residues Viz. Gly35, Val31, Thr34, Gly128, Ile124 and Ala13 help stabilising the CathD-ligand complexes, which in turn emphasises substrate and inhibitor selectivity. Further, MM-GBSA approach has been used to calculate binding free energy between CathD and selected compounds. Therefore, it would be beneficial to understand the active site pocket of CathD with the assistance of these discoveries. Thus, the present study would be helpful to identify active site pocket of CathD, which could be beneficial to develop novel therapeutic strategies for the AD.},
}

@article {pmid38649330,
year = {2024},
author = {Comptdaer, T and Tardivel, M and Schirmer, C and Buée, L and Galas, MC},
title = {Cell redistribution of G quadruplex-structured DNA is associated with morphological changes of nuclei and nucleoli in neurons during tau pathology progression.},
journal = {Brain pathology (Zurich, Switzerland)},
volume = {},
number = {},
pages = {e13262},
doi = {10.1111/bpa.13262},
pmid = {38649330},
issn = {1750-3639},
support = {/MRC_/Medical Research Council/United Kingdom ; },
abstract = {While the double helical structure has long been its iconic representation, DNA is structurally dynamic and can adopt alternative secondary configurations. Specifically, guanine-rich DNA sequences can fold in guanine quadruplexes (G4) structures. These G4 play pivotal roles as regulators of gene expression and genomic stability, and influence protein homeostasis. Despite their significance, the association of G4 with neurodegenerative diseases such as Alzheimer's disease (AD) has been underappreciated. Recent findings have identified DNA sequences predicted to form G4 in sarkosyl-insoluble aggregates from AD brains, questioning the involvement of G4-structured DNA (G4 DNA) in the pathology. Using immunofluorescence coupled to confocal microscopy analysis we investigated the impact of tau pathology, a hallmark of tauopathies including AD, on the distribution of G4 DNA in murine neurons and its relevance to AD brains. In healthy neurons, G4 DNA is detected in nuclei with a notable presence in nucleoli. However, in a transgenic mouse model of tau pathology (THY-Tau22), early stages of the disease exhibit an impairment in the nuclear distribution of G4 DNA. In addition, G4 DNA accumulates in the cytoplasm of neurons exhibiting oligomerized tau and oxidative DNA damage. This altered distribution persists in the later stage of the pathology when larger tau aggregates are present. Still cytoplasmic deposition of G4 DNA does not appear to be a critical factor in the tau aggregation process. Similar patterns are observed in neurons from the AD cortex. Furthermore, the disturbance in G4 DNA distribution is associated with various changes in the size of neuronal nuclei and nucleoli, indicative of responses to stress and the activation of pro-survival mechanisms. Our results shed light on a significant impact of tau pathology on the dynamics of G4 DNA and on nuclear and nucleolar mechanobiology in neurons. These findings reveal new dimensions in the etiopathogenesis of tauopathies.},
}

@article {pmid38649307,
year = {2024},
author = {Pang, C and Wang, R and Liu, K and Yuan, X and Ni, J and Cao, Q and Chen, Y and Dong, PL and Han, H},
title = {Serum and urine metabolomics based on UPLC-QTOF/MS reveal the effect and potential mechanism of "schisandra-evodia" herb pair in the treatment of Alzheimer's disease.},
journal = {Biomedical chromatography : BMC},
volume = {},
number = {},
pages = {e5882},
doi = {10.1002/bmc.5882},
pmid = {38649307},
issn = {1099-0801},
support = {LH2019H053//Natural Science Foundation of Heilongjiang Province/ ; 2017XY01//Heilongjiang University of Traditional Chinese Medicine Scientific Research Fund Project/ ; },
abstract = {The "schisandra-evodia" herb pair (S-E) is a herbal preparation to treat Alzheimer's disease (AD). This study aims to investigate the therapeutic efficacy and potential mechanism of S-E in AD rats, utilizing pharmacodynamic assessments and serum- and urine-based metabolomic analyses. Pharmacodynamic assessments included Morris water maze test, hematoxylin-eosin staining and immunohistochemistry experiments. The results of the study showed that the AD model was successful; the S-E significantly enhanced long-term memory and spatial learning in AD rats. Meanwhile, S-E notably ameliorated Aβ25-35-induced cognitive impairment, improved hippocampal neuron morphology, decreased Aβ deposition in the hippocampus and mitigated inflammatory damage. We then analyzed serum and urine samples using UPLC-MS/MS to identify potential biomarkers and metabolic pathways. Metabolomic analysis revealed alterations in 40 serum metabolites and 38 urine metabolites following S-E treatment, predominantly affecting pathways related to taurine and hypotaurine metabolism, linoleic acid metabolism, α-linolenic acid metabolism, glycerophospholipid metabolism and arachidonic acid metabolism. This study elucidates the biochemical mechanism underlying AD and the metabolic pathway influenced by S-E, laying the groundwork for future clinical applications.},
}

@article {pmid38649269,
year = {2024},
author = {Murakami, R and Watanabe, H and Hashimoto, H and Kashiwagi-Hakozaki, M and Hashimoto, T and Karch, CM and , and Iwatsubo, T and Okano, H},
title = {Inhibitory roles of Apolipoprotein E Christchurch astrocytes in curbing tau propagation using human pluripotent stem cell-derived models.},
journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1523/JNEUROSCI.1709-23.2024},
pmid = {38649269},
issn = {1529-2401},
abstract = {Genetic variants in the apolipoprotein E (APOE) gene affect the onset and progression of Alzheimer's disease (AD). The APOE Christchurch (APOE Ch) variant has been identified as the most prominent candidate for preventing the onset and progression of AD. In this study, we generated isogenic APOE3Ch/3Ch human induced pluripotent stem cells (iPSCs) from APOE3/3 healthy control female iPSCs and induced them into astrocytes. RNA expression analysis revealed the inherent resilience of APOE3Ch/3Ch astrocytes to induce a reactive state in response to inflammatory cytokines. Moreover, cytokine treatment changed astrocytic morphology with more complexity in APOE3/3 astrocytes, but not in APOE3Ch/3Ch astrocytes, indicating resilience of the rare variant to a reactive state. Interestingly, we observed robust morphological alterations containing more intricate processes when cocultured with iPSC-derived cortical neurons, in which APOE3Ch/3Ch astrocytes reduced complexity compared with APOE3/3 astrocytes. To assess the impacts of tau propagation effects, we next developed a sophisticated and sensitive assay utilizing cortical neurons derived from human iPSCs, previously generated from donors of both sexes. We showed that APOE3Ch/3Ch astrocytes effectively mitigated tau propagation within iPSC-derived neurons. This study provides important experimental evidence of the characteristic functions exhibited by APOE3Ch/3Ch astrocytes, thereby offering valuable insights for the advancement of novel clinical interventions in AD research.Significance Statement Alzheimer's disease (AD) is a degenerative disease that causes cognitive decline. Familial AD is a severe form caused by mutations in the PSEN1, PSEN2, or APP genes. One carrier of the PSEN1 mutation did not develop dementia. This carrier also had a rare variant of the APOE gene, the Christchurch variant. The APOE Christchurch variant may protect against familial AD. The mechanism of this protection is not fully understood. In the present study, we have successfully demonstrated that the APOE Christchurch variant suppresses the propagation of tau and exhibits a diminished capacity to convert native astrocytes into reactive astrocytes. These significant findings contribute novel insights to the field of the APOE gene and AD research.},
}

@article {pmid38648960,
year = {2024},
author = {Liu, YL and Cao, YG and Hao, FX and Zeng, MN and Niu, Y and Chen, L and Chen, X and Zheng, XK and Feng, WS},
title = {Chemical constituents from stipes of Lentinus edodes and their protective effects against Aβ25-35-induced N9 microglia cells injury.},
journal = {Phytochemistry},
volume = {},
number = {},
pages = {114098},
doi = {10.1016/j.phytochem.2024.114098},
pmid = {38648960},
issn = {1873-3700},
abstract = {Nine undescribed compounds, along with eight known compounds, were isolated from the stipes of Lentinus edodes. Their structures were established by extensive spectroscopic and circular dichroism analyses. The protective effects against Aβ25-35-induced N9 microglia cells injury of these compounds were tested by MTT method, and the levels of apoptosis and ROS were detected by flow cytometry. In addition, the binding sites and interactions of compound with amyloid precursor protein were revealed using molecular docking simulations. These findings further establish the structural diversity and bioactivity of stipes of L. edodes, and provide an experimental basis for targeting Alzheimer's disease as a potential strategy.},
}

@article {pmid38648940,
year = {2024},
author = {Shippy, DC and Oliai, SF and Ulland, TK},
title = {Zinc utilization by microglia in Alzheimer's disease.},
journal = {The Journal of biological chemistry},
volume = {},
number = {},
pages = {107306},
doi = {10.1016/j.jbc.2024.107306},
pmid = {38648940},
issn = {1083-351X},
abstract = {Alzheimer's disease (AD) is the most common form of dementia defined by two key pathological characteristics in the brain, amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. Microglia, the primary innate immune cells of the central nervous system (CNS), provide neuroprotection through Aβ and tau clearance, but may also be neurotoxic by promoting neuroinflammation to exacerbate Aβ and tau pathogenesis in AD. Recent studies have demonstrated the importance of microglial utilization of nutrients and trace metals in controlling their activation and effector functions. Trace metals, such as zinc, have essential roles in brain health and immunity, and zinc dyshomeostasis has been implicated in AD pathogenesis. As a result of these advances, the mechanisms by which zinc homeostasis influences microglial-mediated neuroinflammation in AD is a topic of continuing interest since new strategies to treat AD are needed. Here, we review the roles of zinc in AD, including zinc activation of microglia, the associated neuroinflammatory response, and the application of these findings in new therapeutic strategies.},
}

@article {pmid38648920,
year = {2024},
author = {Reid, GA and Darvesh, S},
title = {Interaction of Exogenous Acetylcholinesterase and Butyrylcholinesterase with Amyloid-β Plaques in Human Brain Tissue.},
journal = {Chemico-biological interactions},
volume = {},
number = {},
pages = {111012},
doi = {10.1016/j.cbi.2024.111012},
pmid = {38648920},
issn = {1872-7786},
abstract = {Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are associated with amyloid-β (Aβ) plaques and exhibit altered biochemical properties in human Alzheimer's disease (AD), as well as in the transgenic 5XFAD mouse model of AD amyloidosis. In the brains of the 5XFAD mouse model devoid of BChE enzyme (5XFAD/BChE-KO), incubation of tissue sections with exogenous BChE purified from human plasma (pl-BChE) leads to its association with Aβ plaques and its biochemical properties are comparable to those reported for endogenous BChE associated with plaques in both human AD and in 5XFAD mouse brain tissue. We sought to determine whether these observations in 5XFAD/BChE-KO mice also apply to human brain tissues. To do so, endogenous ChE activity in human AD brain tissue sections was quenched with 50% aqueous acetonitrile (MeCNaq) leaving the tissue intact for further studies. Quenched sections were then incubated with recombinant AChE (r-AChE) or pl-BChE and stained for each enzymes' activity. Exogenous r-AChE or pl-BChE became associated with Aβ plaques, and when bound, had properties that were comparable to the endogenous ChE enzymes associated with plaques in AD brain tissues without acetonitrile treatment. These findings in human AD brain tissue extend previous observations in the 5XFAD/BChE-KO mouse model and demonstrate that exogenously applied r-AChE and pl-BChE have high affinity for Aβ plaques in human brain tissues. This association alters the biochemical properties of these enzymes, most likely due a conformational change. If incorporation of AChE and BChE in Aβ plaques facilitates AD pathogenesis, blocking this association could lead to disease-modifying approaches to AD. This work provides a method to study the mechanism of AChE and BChE interaction with Aβ plaque pathology in post-mortem human brain tissue.},
}

@article {pmid38648886,
year = {2024},
author = {D'Amelio, M and Costa, C},
title = {Clarifying the role of D1 receptor signalling in Alzheimer's-related epilepsy commentary on Szabo et al. (2024).},
journal = {The European journal of neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1111/ejn.16359},
pmid = {38648886},
issn = {1460-9568},
support = {AARG-21-851219/ALZ/Alzheimer's Association/United States ; },
}

@article {pmid38648843,
year = {2024},
author = {Barry, HC},
title = {Brexpiprazole Improves Agitation Scores in Adults With Alzheimer Disease and Agitated Behaviors.},
journal = {American family physician},
volume = {109},
number = {4},
pages = {373},
pmid = {38648843},
issn = {1532-0650},
}

@article {pmid38648467,
year = {2024},
author = {Harding, E and Sullivan, MP and Camic, PM and Yong, KXX and Stott, J and Crutch, SJ},
title = {"I Want to Do Something" - Exploring What Makes Activities Meaningful for Community-Dwelling People Living With Dementia: A Focused Ethnographic Study.},
journal = {Qualitative health research},
volume = {},
number = {},
pages = {10497323241239487},
doi = {10.1177/10497323241239487},
pmid = {38648467},
issn = {1049-7323},
abstract = {Supporting ageing in place, quality of life, and activity engagement are public health priorities for people with dementia. The importance of maintaining opportunities for meaningful activities has been widely acknowledged for those with dementia in long-term care, but little is known about what makes activities meaningful for, and how they are experienced by, people with different types of dementia in their own homes. This study used focussed ethnographic methods to explore the motivations and meanings of everyday activity engagement within the homes of 10 people with memory-led Alzheimer's disease and 10 people with posterior cortical atrophy. While participants' interactions with their everyday environments were challenged by their diagnoses, they were all finding ways to continue meaning-making via various activities. The main findings are encapsulated in three themes: (1) The fun and the function of activities; (2) Reciprocities of care, and (3) The constitution and continuity of (a changing) self. Ongoing engagement with both fun and functional activities offered participants living with different dementias opportunities to connect with others, to offer care and support (as well as receive it), and to maintain a sense of self and identity. Implications are discussed regarding the development and delivery of tailored interventions and support to enable continued engagement in meaningful activities for people with different types of dementia living in the community.},
}

@article {pmid38648449,
year = {2024},
author = {Macoir, J and Tremblay, P and Beaudoin, S and Parent, M and Hudon, C},
title = {Impaired lexical access for unique entities in individuals with subjective cognitive decline.},
journal = {Applied neuropsychology. Adult},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/23279095.2024.2344636},
pmid = {38648449},
issn = {2327-9109},
abstract = {Subjective cognitive decline (SCD) may serve as an early indicator of Alzheimer's disease (AD). However, accurately quantifying cognitive impairment in SCD is challenging, mainly because existing assessment tools lack sensitivity. This study examined how tasks specifically designed to assess knowledge of famous people, could potentially aid in identifying cognitive impairment in SCD. A total of 60 adults with SCD and 60 healthy controls (HCs) aged 50 to 82 years performed a famous people verbal fluency task and a famous people naming task. In the famous people fluency task, the results showed that the individuals with SCD produced significantly fewer famous names in the total time allowed than the HCs, and this difference was also found in the first and the second time interval. In the famous people naming task, the performance of the SCD group was significantly lower than that of the HC group only in the more recent period of fame. Overall, these results suggest that retrieving the names of famous people was more difficult for people with SCD than for people without cognitive complaints. They also suggest that famous people verbal fluency and naming tasks could be useful in detecting cognitive decline at the preclinical stage of AD.},
}

@article {pmid38648448,
year = {2024},
author = {Tahan, K and Cayrier, A and Baratgin, J and N'kaoua, B},
title = {ZORA robot to assist a caregiver in prospective memory tasks: A preliminary study.},
journal = {Applied neuropsychology. Adult},
volume = {},
number = {},
pages = {1-8},
doi = {10.1080/23279095.2024.2343766},
pmid = {38648448},
issn = {2327-9109},
abstract = {The objective of the present study was to evaluate the interest of an assistance robot to help caregivers manage the activities of daily living of institutionalized elderly people with Alzheimer's disease. Twenty-three institutionalized persons (60% women; average age 89; average MMSE score of 20.8) with Alzheimer Disease (AD) were recruited and invited to participate in prospective memory exercise sessions, conducted either by a caregiver or by a robot (assisted by a caregiver). They were divided into two groups equivalent in age, level of education and MMSE score. In addition, the sessions were recorded in order to compare the interaction behaviors of the 2 groups, using a validated observation grid. The results showed that: 1) prospective memory tasks are better performed when offered by the caregiver; 2) when strong help linked to the recovery index is provided to perform the tasks, the robot or caregiver no longer show significant differences; 3) participants interact more with the caregiver than with the robot. Our results confirm that the use of companion robots is a promising way to help caregivers manage the daily activities of people with Alzheimer's. However, to optimize this assistance, further investigations should be conducted to improve the fluidity of interactions between the patient and the robot.},
}

@article {pmid38648391,
year = {2024},
author = {Hu, C and Li, H and Huang, L and Wang, R and Wang, Z and Ma, R and Chang, B and Li, S and Li, H and Li, G},
title = {Periodontal disease and risk of Alzheimer's disease: A two-sample Mendelian randomization.},
journal = {Brain and behavior},
volume = {14},
number = {4},
pages = {e3486},
doi = {10.1002/brb3.3486},
pmid = {38648391},
issn = {2162-3279},
support = {2022LJ02//Innovative leading talents program of The Affiliated Stomatological Hospital of Southwest Medical University/ ; 2022Z01//Project of Affiliated Stomatological Hospital of Southwest Medical University/ ; 2022ZD015//Program of Southwest Medical University/ ; 2022BS02//Talent Introduction Program of The Affiliated Stomatological Hospital of Southwest Medical University/ ; S21063//Foundation Project of Sichuan Medical Association/ ; 2022-GYF-12//Key Research and Development Program of Luzhou/ ; 2022-SYF-33//Key Research and Development Program of Luzhou/ ; 2022YFS0634//Sichuan Science and Technology Program/ ; 2022YFS0634-C2//Sichuan Science and Technology Program/ ; },
abstract = {BACKGROUND: Evidence from observational studies and clinical trials suggests an association between periodontal disease and Alzheimer's disease (AD). However, the causal relationship between periodontal disease and AD remains to be determined.

METHODS: We obtained periodontal disease data from the FinnGen database and two sets of AD data from the IEU consortium and PGC databases. Subsequently, we conducted a two-sample Mendelian randomization (MR) analysis to investigate the causal relationship between periodontal disease and AD.

RESULTS: The results of the random-effects IVW analysis revealed no evidence of a genetic causal relationship between periodontal disease and AD, regardless of whether the AD data from the IEU consortium or the AD data from the PGC database were utilized. No heterogeneity, multiple effects of levels, or outliers were observed in this study.

CONCLUSIONS: Our findings indicate that there is no causal relationship between periodontal disease and AD at the genetic level.},
}

@article {pmid38648354,
year = {2024},
author = {Zhang, J and Chen, H and Wang, J and Huang, Q and Xu, X and Wang, W and Xu, W and Guan, Y and Liu, J and Wardlaw, JM and Deng, Y and Xie, F and Li, B},
title = {Linking white matter hyperintensities to regional cortical thinning, amyloid deposition, and synaptic density loss in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {},
number = {},
pages = {},
doi = {10.1002/alz.13845},
pmid = {38648354},
issn = {1552-5279},
support = {82271441//National Natural Science Foundation of China/ ; 82071962//National Natural Science Foundation of China/ ; 82171473//National Natural Science Foundation of China/ ; 81871388//National Natural Science Foundation of China/ ; 21QA1405800//Shanghai Rising-Star Program/ ; 2022ZD0213800//National Key Research and Development Program of China, Scientific and technological innovation 2030 - "Brain science"/ ; UKDRI - Edin002//UK Dementia Research Institute, funded by the UK Medical Research Council, Alzheimer's Society and Alzheimer's Research UK/ ; DRIEdi17/18//UK Dementia Research Institute, funded by the UK Medical Research Council, Alzheimer's Society and Alzheimer's Research UK/ ; MRC MC_PC_17113//UK Dementia Research Institute, funded by the UK Medical Research Council, Alzheimer's Society and Alzheimer's Research UK/ ; AD.ROW4.35. BRO-D.FID3668413//The Row Fogo Centre for Research into Ageing and the Brain/ ; 16 CVD 05//Fondation Leducq Transatlantic Network of Excellence for the Study of Perivascular Spaces in Small Vessel Disease/ ; },
abstract = {INTRODUCTION: We investigated the association between white matter hyperintensities (WMH) and regional cortical thickness, amyloid and tau deposition, and synaptic density in the WMH-connected cortex using multimodal images.

METHODS: We included 107 participants (59 with Alzheimer's disease [AD]; 27 with mild cognitive impairment; 21 cognitively normal controls) with amyloid beta (Aβ) positivity on amyloid positron emission tomography (PET). The cortex connected to WMH was identified using probabilistic tractography.

RESULTS: We found that WMH connected to the cortex with more severe regional degeneration as measured by cortical thickness, Aβ and tau deposition, and synaptic vesicle glycoprotein 2 A (SV2A) density using [18]F-SynVesT-1 PET. In addition, higher ratios of Aβ in the deep WMH-connected versus WMH-unconnected cortex were significantly related to lower cognitive scores. Last, the cortical thickness of WMH-connected cortex reduced more than WMH-unconnected cortex over 12 months.

DISCUSSION: Our results suggest that WMH may be associated with AD-intrinsic processes of degeneration, in addition to vascular mechanisms.

HIGHLIGHTS: We studied white matter hyperintensities (WMHs) and WMH-connected cortical changes. WMHs are associated with more severe regional cortical degeneration. Findings suggest WMHs may be associated with Alzheimer's disease-intrinsic processes of degeneration.},
}

@article {pmid38648267,
year = {2024},
author = {Salvador, AFM and Abduljawad, N and Kipnis, J},
title = {Meningeal Lymphatics in Central Nervous System Diseases.},
journal = {Annual review of neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1146/annurev-neuro-113023-103045},
pmid = {38648267},
issn = {1545-4126},
abstract = {Since its recent discovery, the meningeal lymphatic system has reshaped our understanding of central nervous system (CNS) fluid exchange, waste clearance, immune cell trafficking, and immune privilege. Meningeal lymphatics have also been demonstrated to functionally modify the outcome of neurological disorders and their responses to treatment, including brain tumors, inflammatory diseases such as multiple sclerosis, CNS injuries, and neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. In this review, we discuss recent evidence of the contribution of meningeal lymphatics to neurological diseases, as well as the available experimental methods for manipulating meningeal lymphatics in these conditions. Finally, we also provide a discussion of the pressing questions and challenges in utilizing meningeal lymphatics as a prime target for CNS therapeutic intervention and possibly drug delivery for brain disorders.},
}

@article {pmid38648167,
year = {2024},
author = {Warren, HT and Saeger, HN and Tombari, RJ and Chytil, M and Rasmussen, K and Olson, DE},
title = {Psychoplastogenic DYRK1A Inhibitors with Therapeutic Effects Relevant to Alzheimer's Disease.},
journal = {Journal of medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jmedchem.3c01696},
pmid = {38648167},
issn = {1520-4804},
abstract = {Tauopathy, neuronal atrophy, and psychological impairments are hallmarks of neurodegenerative diseases, such as Alzheimer's disease, that currently lack efficacious clinical treatments capable of rectifying these issues. To address these unmet needs, we used rational drug design to combine the pharmacophores of DYRK1A inhibitors and isoDMTs to develop psychoplastogenic DYRK1A inhibitors. Using this approach, we discovered a nonhallucinogenic compound capable of promoting cortical neuron growth and suppressing tau hyperphosphorylation while also having the potential to mitigate the biological and psychological symptoms of dementia. Together, our results suggest that hybridization of the DYRK1A and psychoplastogen pharmacophores represents a promising strategy for identifying compounds that might address the cognitive as well as the behavioral and psychological symptoms of dementia.},
}

@article {pmid38648143,
year = {2024},
author = {Bringas, S and Duque, R and Lage, C and Montana, JL},
title = {CLADSI: Deep Continual Learning for Alzheimer's Disease Stage Identification using accelerometer data.},
journal = {IEEE journal of biomedical and health informatics},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/JBHI.2024.3392354},
pmid = {38648143},
issn = {2168-2208},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder that can cause a significant impairment in physical and cognitive functions. Gait disturbances are also reported as a symptom of AD. Previous works have used Convolutional Neural Networks (CNNs) to analyze data provided by motion sensors that monitor Alzheimer's patients. However, these works have not explored continual learning algorithms that allow the CNN to configure itself as it receives new data from these sensors. This work proposes a method aimed at enabling CNNs to learn from a continuous stream of data from motion sensors without having full access to previous data. The CNN identifies the stage of AD from the analysis of data provided by motion sensors. The work includes an experimentation with data captured by accelerometers that monitored the activity of 35 Alzheimer's patients for a week in a daycare center. The CNN achieves an accuracy of 86,94%, 86,48% and 84,37% for 2, 3 and 4 experiences respectively. The proposal provides advantages to working with a continuous stream of data so that the CNN are constantly self-configuring without the intervention of a human. The work can be considered as promising and helpful in finding deep learning solutions in medical cases in which patients are constantly monitored.},
}

@article {pmid38647111,
year = {2024},
author = {Chemparathy, DT and Ray, S and Ochs, C and Ferguson, N and Gawande, DY and Dravid, SM and Callen, S and Sil, S and Buch, S},
title = {Neuropathogenic role of astrocyte-derived extracellular vesicles in HIV-associated neurocognitive disorders.},
journal = {Journal of extracellular vesicles},
volume = {13},
number = {4},
pages = {e12439},
pmid = {38647111},
issn = {2001-3078},
support = {/RG/CSR NIH HHS/United States ; R21AG069541/GF/NIH HHS/United States ; RO1DA050545/GF/NIH HHS/United States ; },
abstract = {Our previous findings demonstrated that astrocytic HIF-1α plays a major role in HIV-1 Tat-mediated amyloidosis which can lead to Alzheimer's-like pathology-a comorbidity of HIV-Associated Neurocognitive Disorders (HAND). These amyloids can be shuttled in extracellular vesicles, and we sought to assess whether HIV-1 Tat stimulated astrocyte-derived EVs (ADEVs) containing the toxic amyloids could result in neuronal injury in vitro and in vivo. We thus hypothesized that blocking HIF-1α could likely mitigate HIV-1 Tat-ADEV-mediated neuronal injury. Rat hippocampal neurons when exposed to HIV-1 Tat-ADEVs carrying the toxic amyloids exhibited amyloid accumulation and synaptodendritic injury, leading to functional loss as evidenced by alterations in miniature excitatory post synaptic currents. The silencing of astrocytic HIF-1α not only reduced the biogenesis of ADEVs, as well as amyloid cargos, but also ameliorated neuronal synaptodegeneration. Next, we determined the effect of HIV-1 Tat-ADEVs carrying amyloids in the hippocampus of naive mice brains. Naive mice receiving the HIV-1 Tat-ADEVs, exhibited behavioural changes, and Alzheimer's 's-like pathology accompanied by synaptodegeneration. This impairment(s) was not observed in mice injected with HIF-1α silenced ADEVs. This is the first report demonstrating the role of amyloid-carrying ADEVs in mediating synaptodegeneration leading to behavioural changes associated with HAND and highlights the protective role of HIF-1α.},
}

@article {pmid38647048,
year = {2024},
author = {Niess, F and Strasser, B and Hingerl, L and Bader, V and Frese, S and Clarke, WT and Duguid, A and Niess, E and Motyka, S and Krššák, M and Trattnig, S and Scherer, T and Lanzenberger, R and Bogner, W},
title = {Whole-brain deuterium metabolic imaging via concentric ring trajectory readout enables assessment of regional variations in neuronal glucose metabolism.},
journal = {Human brain mapping},
volume = {45},
number = {6},
pages = {e26686},
pmid = {38647048},
issn = {1097-0193},
support = {R01EB031787/NH/NIH HHS/United States ; 225924/Z/22/Z/WT_/Wellcome Trust/United Kingdom ; },
abstract = {Deuterium metabolic imaging (DMI) is an emerging magnetic resonance technique, for non-invasive mapping of human brain glucose metabolism following oral or intravenous administration of deuterium-labeled glucose. Regional differences in glucose metabolism can be observed in various brain pathologies, such as Alzheimer's disease, cancer, epilepsy or schizophrenia, but the achievable spatial resolution of conventional phase-encoded DMI methods is limited due to prolonged acquisition times rendering submilliliter isotropic spatial resolution for dynamic whole brain DMI not feasible. The purpose of this study was to implement non-Cartesian spatial-spectral sampling schemes for whole-brain [2]H FID-MR Spectroscopic Imaging to assess time-resolved metabolic maps with sufficient spatial resolution to reliably detect metabolic differences between healthy gray and white matter regions. Results were compared with lower-resolution DMI maps, conventionally acquired within the same session. Six healthy volunteers (4 m/2 f) were scanned for ~90 min after administration of 0.8 g/kg oral [6,6']-[2]H glucose. Time-resolved whole brain [2]H FID-DMI maps of glucose (Glc) and glutamate + glutamine (Glx) were acquired with 0.75 and 2 mL isotropic spatial resolution using density-weighted concentric ring trajectory (CRT) and conventional phase encoding (PE) readout, respectively, at 7 T. To minimize the effect of decreased signal-to-noise ratios associated with smaller voxels, low-rank denoising of the spatiotemporal data was performed during reconstruction. Sixty-three minutes after oral tracer uptake three-dimensional (3D) CRT-DMI maps featured 19% higher (p = .006) deuterium-labeled Glc concentrations in GM (1.98 ± 0.43 mM) compared with WM (1.66 ± 0.36 mM) dominated regions, across all volunteers. Similarly, 48% higher (p = .01) [2]H-Glx concentrations were observed in GM (2.21 ± 0.44 mM) compared with WM (1.49 ± 0.20 mM). Low-resolution PE-DMI maps acquired 70 min after tracer uptake featured smaller regional differences between GM- and WM-dominated areas for [2]H-Glc concentrations with 2.00 ± 0.35 mM and 1.71 ± 0.31 mM, respectively (+16%; p = .045), while no regional differences were observed for [2]H-Glx concentrations. In this study, we successfully implemented 3D FID-MRSI with fast CRT encoding for dynamic whole-brain DMI at 7 T with 2.5-fold increased spatial resolution compared with conventional whole-brain phase encoded (PE) DMI to visualize regional metabolic differences. The faster metabolic activity represented by 48% higher Glx concentrations was observed in GM- compared with WM-dominated regions, which could not be reproduced using whole-brain DMI with the low spatial resolution protocol. Improved assessment of regional pathologic alterations using a fully non-invasive imaging method is of high clinical relevance and could push DMI one step toward clinical applications.},
}

@article {pmid38648023,
year = {2024},
author = {Desai, P and Ng, TKS and Krueger, KR and Wilson, RS and Evans, DA and Rajan, KB},
title = {Perceived Stress, Blood Biomarkers, and Cognitive Functioning in Older Adults.},
journal = {Psychosomatic medicine},
volume = {},
number = {},
pages = {},
doi = {10.1097/PSY.0000000000001317},
pmid = {38648023},
issn = {1534-7796},
abstract = {INTRODUCTION: There is a substantial gap in knowledge regarding how perceived stress may influence the relationship between serum-measured biomarkers for Alzheimer's disease and cognitive decline.

METHODS: This study consists of 1,118 older adult participants from the Chicago Health and Aging Project (CHAP) (60% Black participants and 63% female participants). Linear mixed effects regression models were conducted to examine the role of perceived stress in the association between three blood biomarkers: total tau (t-tau), glial fibrillary acid protein (GFAP), and neurofilament light chain (NfL) on global cognitive decline. Stratified analysis by stress level was also conducted to evaluate the associations between each blood biomarker and baseline cognitive function and decline. All models adjusted for age, race, sex, education, time, and their interactions with time.

RESULTS: The interaction of stress, NfL concentration, and time was statistically significant on global cognition (β = -0.064 (SE = 0.028), p-value = 0.023) and on episodic memory (β = -0.097 (SE = 0.036), p-value = 0.007).

CONCLUSIONS: Greater stress level worsens the association between high NfL concentration and cognitive decline. Stress management interventions may be helpful to reduce rate of cognitive decline in individuals with high concentrations of NfL.},
}

@article {pmid38647924,
year = {2024},
author = {Wagatsuma, K and Sakata, M and Miwa, K and Hamano, Y and Kawakami, H and Kamitaka, Y and Yamao, T and Miyaji, N and Ishibashi, K and Tago, T and Toyohara, J and Ishii, K},
title = {Phantom and clinical evaluation of the Bayesian penalised likelihood reconstruction algorithm Q.Clear without PSF correction in amyloid PET images.},
journal = {EJNMMI physics},
volume = {11},
number = {1},
pages = {37},
pmid = {38647924},
issn = {2197-7364},
support = {JP20K16747//Japan Society for the Promotion of Science/ ; },
abstract = {PURPOSE: Bayesian penalised likelihood (BPL) reconstruction, which incorporates point-spread-function (PSF) correction, provides higher signal-to-noise ratios and more accurate quantitation than conventional ordered subset expectation maximization (OSEM) reconstruction. However, applying PSF correction to brain PET imaging is controversial due to Gibbs artefacts that manifest as unpredicted cortical uptake enhancement. The present study aimed to validate whether BPL without PSF would be useful for amyloid PET imaging.

METHODS: Images were acquired from Hoffman 3D brain and cylindrical phantoms for phantom study and 71 patients administered with [[18]F]flutemetamol in clinical study using a Discovery MI. All images were reconstructed using OSEM, BPL with PSF correction, and BPL without PSF correction. Count profile, %contrast, recovery coefficients (RCs), and image noise were calculated from the images acquired from the phantoms. Amyloid β deposition in patients was visually assessed by two physicians and quantified based on the standardised uptake value ratio (SUVR).

RESULTS: The overestimated radioactivity in profile curves was eliminated using BPL without PSF correction. The %contrast and image noise decreased with increasing β values in phantom images. Image quality and RCs were better using BPL with, than without PSF correction or OSEM. An optimal β value of 600 was determined for BPL without PSF correction. Visual evaluation almost agreed perfectly (κ = 0.91-0.97), without depending on reconstruction methods. Composite SUVRs did not significantly differ between reconstruction methods.

CONCLUSION: Gibbs artefacts disappeared from phantom images using the BPL without PSF correction. Visual and quantitative evaluation of [[18]F]flutemetamol imaging was independent of the reconstruction method. The BPL without PSF correction could be the standard reconstruction method for amyloid PET imaging, despite being qualitatively inferior to BPL with PSF correction for [[18]F]flutemetamol amyloid PET imaging.},
}

@article {pmid38647433,
year = {2024},
author = {Mousavi, H and Rimaz, M and Zeynizadeh, B},
title = {Practical Three-Component Regioselective Synthesis of Drug-Like 3-Aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnolines as Potential Non-Covalent Multi-Targeting Inhibitors To Combat Neurodegenerative Diseases.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.4c00055},
pmid = {38647433},
issn = {1948-7193},
abstract = {Neurodegenerative diseases (NDs) are one of the prominent health challenges facing contemporary society, and many efforts have been made to overcome and (or) control it. In this research paper, we described a practical one-pot two-step three-component reaction between 3,4-dihydronaphthalen-1(2H)-one (1), aryl(or heteroaryl)glyoxal monohydrates (2a-h), and hydrazine monohydrate (NH2NH2•H2O) for the regioselective preparation of some 3-aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnoline derivatives (3a-h). After synthesis and characterization of the mentioned cinnolines (3a-h), the in silico multi-targeting inhibitory properties of these heterocyclic scaffolds have been investigated upon various Homo sapiens-type enzymes, including hMAO-A, hMAO-B, hAChE, hBChE, hBACE-1, hBACE-2, hNQO-1, hNQO-2, hnNOS, hiNOS, hPARP-1, hPARP-2, hLRRK-2[(G2019S)], hGSK-3β, hp38α MAPK, hJNK-3, hOGA, hNMDA receptor, hnSMase-2, hIDO-1, hCOMT, hLIMK-1, hLIMK-2, hRIPK-1, hUCH-L1, hPARK-7, and hDHODH, which have confirmed their functions and roles in the neurodegenerative diseases (NDs), based on molecular docking studies, and the obtained results were compared with a wide range of approved drugs and well-known (with IC50, EC50, etc.) compounds. In addition, in silico ADMET prediction analysis was performed to examine the prospective drug properties of the synthesized heterocyclic compounds (3a-h). The obtained results from the molecular docking studies and ADMET-related data demonstrated that these series of 3-aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnolines (3a-h), especially hit ones, can really be turned into the potent core of new drugs for the treatment of neurodegenerative diseases (NDs), and/or due to the having some reactionable locations, they are able to have further organic reactions (such as cross-coupling reactions), and expansion of these compounds (for example, with using other types of aryl(or heteroaryl)glyoxal monohydrates) makes a new avenue for designing novel and efficient drugs for this purpose.},
}

@article {pmid38647399,
year = {2024},
author = {Lin, RR and Jin, LL and Xue, YY and Zhang, ZS and Huang, HF and Chen, DF and Liu, Q and Mao, ZW and Wu, ZY and Tao, QQ},
title = {Hybrid Membrane-Coated Nanoparticles for Precise Targeting and Synergistic Therapy in Alzheimer's Disease.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e2306675},
doi = {10.1002/advs.202306675},
pmid = {38647399},
issn = {2198-3844},
support = {2021ZD0201103//Science Innovation 2030-Brain Science and Brain-Inspired Intelligence Technology Major Projects/ ; 2021ZD0201803//Science Innovation 2030-Brain Science and Brain-Inspired Intelligence Technology Major Projects/ ; 2024SSYS0018//Key R&D Program of Zhejiang Province/ ; LBY21H090003//Natural Science Foundation of Zhejiang Province/ ; 2022ZDYF22//Key Science & Technologies R&D Program of Lishui City/ ; },
abstract = {The blood brain barrier (BBB) limits the application of most therapeutic drugs for neurological diseases (NDs). Hybrid cell membrane-coated nanoparticles derived from different cell types can mimic the surface properties and functionalities of the source cells, further enhancing their targeting precision and therapeutic efficacy. Neuroinflammation has been increasingly recognized as a critical factor in the pathogenesis of various NDs, especially Alzheimer's disease (AD). In this study, a novel cell membrane coating is designed by hybridizing the membrane from platelets and chemokine (C-C motif) receptor 2 (CCR2) cells are overexpressed to cross the BBB and target neuroinflammatory lesions. Past unsuccessful endeavors in AD drug development underscore the challenge of achieving favorable outcomes when utilizing single-mechanism drugs.Two drugs with different mechanisms of actions into liposomes are successfully loaded to realize multitargeting treatment. In a transgenic mouse model for familial AD (5xFAD), the administration of these drug-loaded hybrid cell membrane liposomes results in a significant reduction in amyloid plaque deposition, neuroinflammation, and cognitive impairments. Collectively, the hybrid cell membrane-coated nanomaterials offer new opportunities for precise drug delivery and disease-specific targeting, which represent a versatile platform for targeted therapy in AD.},
}

@article {pmid38647314,
year = {2024},
author = {Moorthy, H and Ramesh, M and Padhi, D and Baruah, P and Govindaraju, T},
title = {Polycatechols inhibit ferroptosis and modulate tau liquid-liquid phase separation to mitigate Alzheimer's disease.},
journal = {Materials horizons},
volume = {},
number = {},
pages = {},
doi = {10.1039/d4mh00023d},
pmid = {38647314},
issn = {2051-6355},
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder that affects learning, memory, and cognition. Current treatments targeting amyloid-β (Aβ) and tau have shown limited effectiveness, necessitating further research on the aggregation and toxicity mechanisms. One of these mechanisms involves the liquid-liquid phase separation (LLPS) of tau, contributing to the formation of pathogenic tau aggregates, although their conformational details remain elusive. Another mechanism is ferroptosis, a type of iron-dependent lipid peroxidation-mediated cell death, which has been implicated in AD. There is a lack of therapeutic strategies that simultaneously target amyloid toxicity and ferroptosis. This study aims to explore the potential of polycatechols, PDP and PLDP, consisting of dopamine and L-Dopa, respectively, as multifunctional agents to modulate the pathological nexus between ferroptosis and AD. Polycatechols were found to sequester the labile iron pool (LIP), inhibit Aβ and tau aggregation, scavenge free radicals, protect mitochondria, and prevent ferroptosis, thereby rescuing neuronal cell death. Interestingly, PLDP promotes tau LLPS, and modulates their intermolecular interactions to inhibit the formation of toxic tau aggregates, offering a conceptually innovative approach to tackle tauopathies. This is a first-of-its-kind polymer-based integrative approach that inhibits ferroptosis, counteracts amyloid toxicity, and modulates tau LLPS to mitigate the multifaceted toxicity of AD.},
}

@article {pmid38647197,
year = {2024},
author = {Saadmaan, G and Dalmasso, MC and Ramirez, A and Hiltunen, M and Kemppainen, N and Lehtisalo, J and Mangialasche, F and Ngandu, T and Rinne, J and Soininen, H and Stephen, R and Kivipelto, M and Solomon, A},
title = {Alzheimer's disease genetic risk score and neuroimaging in the FINGER lifestyle trial.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {},
number = {},
pages = {},
doi = {10.1002/alz.13843},
pmid = {38647197},
issn = {1552-5279},
support = {804371/ERC_/European Research Council/International ; },
abstract = {INTRODUCTION: We assessed a genetic risk score for Alzheimer's disease (AD-GRS) and apolipoprotein E (APOE4) in an exploratory neuroimaging substudy of the FINGER trial.

METHODS: 1260 at-risk older individuals without dementia were randomized to multidomain lifestyle intervention or health advice. N = 126 participants underwent magnetic resonance imaging (MRI), and N = 47 positron emission tomography (PET) scans (Pittsburgh Compund B [PiB], Fluorodeoxyglucose) at baseline; N = 107 and N = 38 had repeated 2-year scans.

RESULTS: The APOE4 allele, but not AD-GRS, was associated with baseline lower hippocampus volume (β = -0.27, p = 0.001), greater amyloid deposition (β = 0.48, p = 0.001), 2-year decline in hippocampus (β = -0.27, p = 0.01), total gray matter volume (β = -0.25, p = 0.01), and cortical thickness (β = -0.28, p = 0.003). In analyses stratified by AD-GRS (below vs above median), the PiB composite score increased less in intervention versus control in the higher AD-GRS group (β = -0.60, p = 0.03).

DISCUSSION: AD-GRS and APOE4 may have different impacts on potential intervention effects on amyloid, that is, less accumulation in the higher-risk group (AD-GRS) versus lower-risk group (APOE).

HIGHLIGHTS: First study of neuroimaging and AD genetics in a multidomain lifestyle intervention. Possible intervention effect on brain amyloid deposition may rely on genetic risk. AD-GRS and APOE4 allele may have different impacts on amyloid during intervention.},
}

@article {pmid38646816,
year = {2024},
author = {Longo, S and Messi, ML and Wang, ZM and Meeker, W and Delbono, O},
title = {Accelerated sarcopenia precedes learning and memory impairments in the P301S mouse model of tauopathies and Alzheimer's disease.},
journal = {Journal of cachexia, sarcopenia and muscle},
volume = {},
number = {},
pages = {},
doi = {10.1002/jcsm.13482},
pmid = {38646816},
issn = {2190-6009},
support = {R01AG071545/NH/NIH HHS/United States ; R01AG80586/NH/NIH HHS/United States ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) impairs cognitive functions and peripheral systems, including skeletal muscles. The PS19 mouse, expressing the human tau P301S mutation, shows cognitive and muscular pathologies, reflecting the central and peripheral atrophy seen in AD.

METHODS: We analysed skeletal muscle morphology and neuromuscular junction (NMJ) through immunohistochemistry and advanced image quantification. A factorial Analysis of Variance assessed muscle weight, NCAM expression, NMJ, myofibre type distribution, cross-sectional areas, expression of single or multiple myosin heavy-chain isoforms, and myofibre grouping in PS19 and wild type (WT) mice over their lifespan (1-12 months).

RESULTS: Significant weight differences in extensor digitorum longus (EDL) and soleus muscles between WT and PS19 mice were noted by 7-8 months. For EDL muscle in females, WT weighed 0.0113 ± 0.0005 compared with PS19's 0.0071 ± 0.0008 (P < 0.05), and in males, WT was 0.0137 ± 0.0001 versus PS19's 0.0069 ± 0.0006 (P < 0.005). Similarly, soleus muscle showed significant differences; females (WT: 0.0084 ± 0.0004; PS19: 0.0057 ± 0.0005, P < 0.005) and males (WT: 0.0088 ± 0.0003; PS19: 0.0047 ± 0.0004, P < 0.0001). Analysis of the NMJ in PS19 mice revealed a marked reduction in myofibre innervation at 5 months, with further decline by 10 months. NMJ pre-terminals in PS19 mice became shorter and simpler by 5 months, showing a steep decline by 10 months. Genotype and age strongly influenced muscle NCAM immunoreactivity, denoting denervation as early as 5-6 months in EDL muscle Type II fibres, with earlier effects in soleus muscle Type I and II fibres at 3-4 months. Muscle denervation and subsequent myofibre atrophy were linked to a reduction in Type IIB fibres in the EDL muscle and Type IIA fibres in the soleus muscle, accompanied by an increase in hybrid fibres. The EDL muscle showed Type IIB fibre atrophy with WT females at 1505 ± 110 μm[2] versus PS19's 1208 ± 94 μm[2], and WT males at 1731 ± 185 μm[2] versus PS19's 1227 ± 116 μm[2]. Similarly, the soleus muscle demonstrated Type IIA fibre atrophy from 5 to 6 months, with WT females at 1194 ± 52 μm[2] versus PS19's 858 ± 62 μm[2], and WT males at 1257 ± 43 μm[2] versus PS19's 1030 ± 55 μm[2]. Atrophy also affected Type IIX, I + IIA, and IIA + IIX fibres in both muscles. The timeline for both myofibre and overall muscle atrophy in PS19 mice was consistent, indicating a simultaneous decline.

CONCLUSIONS: Progressive and accelerated neurogenic sarcopenia may precede and potentially predict cognitive deficits observed in AD.},
}

@article {pmid38646795,
year = {2024},
author = {Maru, K and Singh, A and Jangir, R and Jangir, KK},
title = {Amyloid detection in neurodegenerative diseases using MOFs.},
journal = {Journal of materials chemistry. B},
volume = {},
number = {},
pages = {},
doi = {10.1039/d4tb00373j},
pmid = {38646795},
issn = {2050-7518},
abstract = {Neurodegenerative diseases (amyloid diseases such as Alzheimer's and Parkinson's), stemming from protein misfolding and aggregation, encompass a spectrum of disorders with severe systemic implications. Timely detection is pivotal in managing these diseases owing to their significant impact on organ function and high mortality rates. The diverse array of amyloid disorders, spanning localized and systemic manifestations, underscores the complexity of these conditions and highlights the need for advanced detection methods. Traditional approaches have focused on identifying biomarkers using imaging techniques (PET and MRI) or invasive procedures. However, recent efforts have focused on the use of metal-organic frameworks (MOFs), a versatile class of materials known for their unique properties, in revolutionizing amyloid disease detection. The high porosity, customizable structures, and biocompatibility of MOFs enable their integration with biomolecules, laying the groundwork for highly sensitive and specific biosensors. These sensors have been employed using electrochemical and photophysical techniques that target amyloid species under neurodegenerative conditions. The adaptability of MOFs allows for the precise detection and quantification of amyloid proteins, offering potential advancements in early diagnosis and disease management. This review article delves into how MOFs contribute to detecting amyloid diseases by categorizing their uses based on different sensing methods, such as electrochemical (EC), electrochemiluminescence (ECL), fluorescence, Förster resonance energy transfer (FRET), up-conversion luminescence resonance energy transfer (ULRET), and photoelectrochemical (PEC) sensing. The drawbacks of MOF biosensors and the challenges encountered in the field are also briefly explored from our perspective.},
}

@article {pmid38646682,
year = {2024},
author = {Singh, A and Maheshwari, S and Yadav, JP and Varshney, AP and Singh, S and Prajapati, BG},
title = {A Review on Tau Targeting Biomimetics Nano Formulations: Novel Approach for Targeting Alzheimer's Diseases.},
journal = {Central nervous system agents in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715249289120240321065936},
pmid = {38646682},
issn = {1875-6166},
abstract = {Central nervous system disorders are prevalent, profoundly debilitating, and poorly managed. Developing innovative treatments for these conditions, including Alzheimer's disease, could significantly improve patients' quality of life and reduce the future economic burden on healthcare systems. However, groundbreaking drugs for central nervous system disorders have been scarce in recent years, highlighting the pressing need for advancements in this field. One significant challenge in the realm of nanotherapeutics is ensuring the precise delivery of drugs to their intended targets due to the complex nature of Alzheimer's disease. Although numerous therapeutic approaches for Alzheimer's have been explored, most drug candidates targeting amyloid-β have failed in clinical trials. Recent research has revealed that tau pathology can occur independently of amyloid-β and is closely correlated with the clinical progression of Alzheimer's symptoms. This discovery suggests that tau could be a promising therapeutic target. One viable approach to managing central nervous system disorders is the administration of nanoparticles to neurons, intending to inhibit tau aggregation by directly targeting p-tau. In Alzheimer's disease, beta-amyloid plaques and neurofibrillary tau tangles hinder neuron transmission and function. The disease also triggers persistent inflammation, compromises the blood-brain barrier, leads to brain shrinkage, and causes neuronal loss. While current medications primarily manage symptoms and slow cognitive decline, there is no cure for Alzheimer's.},
}

@article {pmid38646677,
year = {2024},
author = {Yu, FF and Rathnakar, J and Ryder, B and Hitt, B and Kashmer, OM and Sherry, AD and Vinogradov, E},
title = {Differentiation and characterization of healthy versus pathological tau using chemical exchange saturation transfer.},
journal = {NMR in biomedicine},
volume = {},
number = {},
pages = {e5160},
doi = {10.1002/nbm.5160},
pmid = {38646677},
issn = {1099-1492},
support = {//Texas Alzheimer's Research and Care Consortium/ ; },
abstract = {Neurofibrillary tangles of tau constitute one of the key biological hallmarks of Alzheimer's disease. Currently, the assessment of regional tau accumulation requires intravenous administration of radioactive tracers for PET imaging. A noninvasive MRI-based solution would have significant clinical implications. Herein, we utilized an MRI technique known as chemical exchange saturation transfer (CEST) to determine the imaging signature of tau in both its monomeric and pathologic fibrillated conformations. Three sets of purified recombinant full-length (4R) tau protein were prepared for collection of CEST spectra using a 9.4 T NMR spectrometer at varying temperatures (25, 37, and 42 °C) and RF intensities (0.7, 1.0, 1.5, and 2.2 μT). Monomeric and fibrillated tau were readily distinguished based on their Z-spectrum profiles. Fibrillated tau demonstrated a less prominent peak at 3.5 ppm with additional peaks near 0.5 and 1.5 ppm. No significant differences were identified between fibrillated tau prepared using heparin versus seed-competent tau. In conclusion, monomeric and fibrillated tau can be readily detected and distinguished based on their CEST-derived Z-spectra, pointing to the potential utility of CEST-MRI as a noninvasive biomarker of regional pathologic tau accumulation in the brain. Further testing and validation in vitro and in vivo will be necessary before this can be applied clinically.},
}

@article {pmid38646608,
year = {2024},
author = {Yamada, Y and Shinkawa, K and Kobayashi, M and Nemoto, M and Ota, M and Nemoto, K and Arai, T},
title = {Distinct eye movement patterns to complex scenes in Alzheimer's disease and Lewy body disease.},
journal = {Frontiers in neuroscience},
volume = {18},
number = {},
pages = {1333894},
pmid = {38646608},
issn = {1662-4548},
abstract = {BACKGROUND: Alzheimer's disease (AD) and Lewy body disease (LBD), the two most common causes of neurodegenerative dementia with similar clinical manifestations, both show impaired visual attention and altered eye movements. However, prior studies have used structured tasks or restricted stimuli, limiting the insights into how eye movements alter and differ between AD and LBD in daily life.

OBJECTIVE: We aimed to comprehensively characterize eye movements of AD and LBD patients on naturalistic complex scenes with broad categories of objects, which would provide a context closer to real-world free viewing, and to identify disease-specific patterns of altered eye movements.

METHODS: We collected spontaneous viewing behaviors to 200 naturalistic complex scenes from patients with AD or LBD at the prodromal or dementia stage, as well as matched control participants. We then investigated eye movement patterns using a computational visual attention model with high-level image features of object properties and semantic information.

RESULTS: Compared with matched controls, we identified two disease-specific altered patterns of eye movements: diminished visual exploration, which differentially correlates with cognitive impairment in AD and with motor impairment in LBD; and reduced gaze allocation to objects, attributed to a weaker attention bias toward high-level image features in AD and attributed to a greater image-center bias in LBD.

CONCLUSION: Our findings may help differentiate AD and LBD patients and comprehend their real-world visual behaviors to mitigate the widespread impact of impaired visual attention on daily activities.},
}

@article {pmid38646507,
year = {2024},
author = {Zhang, X and Zhu, Z and Huang, Y and Shang, X and O'Brien, TJ and Kwan, P and Ha, J and Wang, W and Liu, S and Zhang, X and Kiburg, K and Bao, Y and Wang, J and Yu, H and He, M and Zhang, L},
title = {Shared genetic aetiology of Alzheimer's disease and age-related macular degeneration by APOC1 and APOE genes.},
journal = {BMJ neurology open},
volume = {6},
number = {1},
pages = {e000570},
pmid = {38646507},
issn = {2632-6140},
abstract = {BACKGROUND: Alzheimer's disease (AD) and age-related macular degeneration (AMD) share similar pathological features, suggesting common genetic aetiologies between the two. Investigating gene associations between AD and AMD may provide useful insights into the underlying pathogenesis and inform integrated prevention and treatment for both diseases.

METHODS: A stratified quantile-quantile (QQ) plot was constructed to detect the pleiotropy among AD and AMD based on genome-wide association studies data from 17 008 patients with AD and 30 178 patients with AMD. A Bayesian conditional false discovery rate-based (cFDR) method was used to identify pleiotropic genes. UK Biobank was used to verify the pleiotropy analysis. Biological network and enrichment analysis were conducted to explain the biological reason for pleiotropy phenomena. A diagnostic test based on gene expression data was used to predict biomarkers for AD and AMD based on pleiotropic genes and their regulators.

RESULTS: Significant pleiotropy was found between AD and AMD (significant leftward shift on QQ plots). APOC1 and APOE were identified as pleiotropic genes for AD-AMD (cFDR <0.01). Network analysis revealed that APOC1 and APOE occupied borderline positions on the gene co-expression networks. Both APOC1 and APOE genes were enriched on the herpes simplex virus 1 infection pathway. Further, machine learning-based diagnostic tests identified that APOC1, APOE (areas under the curve (AUCs) >0.65) and their upstream regulators, especially ZNF131, ADNP2 and HINFP, could be potential biomarkers for both AD and AMD (AUCs >0.8).

CONCLUSION: In this study, we confirmed the genetic pleiotropy between AD and AMD and identified APOC1 and APOE as pleiotropic genes. Further, the integration of multiomics data identified ZNF131, ADNP2 and HINFP as novel diagnostic biomarkers for AD and AMD.},
}

@article {pmid38646460,
year = {2024},
author = {Shaheen, H and Melnik, R and Singh, S and , },
title = {Data-driven Stochastic Model for Quantifying the Interplay Between Amyloid-beta and Calcium Levels in Alzheimer's Disease.},
journal = {Statistical analysis and data mining},
volume = {17},
number = {2},
pages = {},
pmid = {38646460},
issn = {1932-1864},
support = {U01 AG024904/AG/NIA NIH HHS/United States ; },
abstract = {The abnormal aggregation of extracellular amyloid-β(Aβ) in senile plaques resulting in calcium Ca+2 dyshomeostasis is one of the primary symptoms of Alzheimer's disease (AD). Significant research efforts have been devoted in the past to better understand the underlying molecular mechanisms driving Aβ deposition and Ca+2 dysregulation. Importantly, synaptic impairments, neuronal loss, and cognitive failure in AD patients are all related to the buildup of intraneuronal Aβ accumulation. Moreover, increasing evidence show a feed-forward loop between Aβ and Ca+2 levels, i.e. Aβ disrupts neuronal Ca+2 levels, which in turn affects the formation of Aβ. To better understand this interaction, we report a novel stochastic model where we analyze the positive feedback loop between Aβ and Ca+2 using ADNI data. A good therapeutic treatment plan for AD requires precise predictions. Stochastic models offer an appropriate framework for modelling AD since AD studies are observational in nature and involve regular patient visits. The etiology of AD may be described as a multi-state disease process using the approximate Bayesian computation method. So, utilizing ADNI data from 2-year visits for AD patients, we employ this method to investigate the interplay between Aβ and Ca+2 levels at various disease development phases. Incorporating the ADNI data in our physics-based Bayesian model, we discovered that a sufficiently large disruption in either Aβ metabolism or intracellular Ca+2 homeostasis causes the relative growth rate in both Ca+2 and Aβ, which corresponds to the development of AD. The imbalance of Ca+2 ions causes Aβ disorders by directly or indirectly affecting a variety of cellular and subcellular processes, and the altered homeostasis may worsen the abnormalities of Ca+2 ion transportation and deposition. This suggests that altering the Ca+2 balance or the balance between Aβ and Ca+2 by chelating them may be able to reduce disorders associated with AD and open up new research possibilities for AD therapy.},
}

@article {pmid38646161,
year = {2024},
author = {De Waegenaere, S and van den Berg, M and Keliris, GA and Adhikari, MH and Verhoye, M},
title = {Early altered directionality of resting brain network state transitions in the TgF344-AD rat model of Alzheimer's disease.},
journal = {Frontiers in human neuroscience},
volume = {18},
number = {},
pages = {1379923},
pmid = {38646161},
issn = {1662-5161},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disease resulting in memory loss and cognitive decline. Synaptic dysfunction is an early hallmark of the disease whose effects on whole-brain functional architecture can be identified using resting-state functional MRI (rsfMRI). Insights into mechanisms of early, whole-brain network alterations can help our understanding of the functional impact of AD's pathophysiology.

METHODS: Here, we obtained rsfMRI data in the TgF344-AD rat model at the pre- and early-plaque stages. This model recapitulates the major pathological and behavioral hallmarks of AD. We used co-activation pattern (CAP) analysis to investigate if and how the dynamic organization of intrinsic brain functional networks states, undetectable by earlier methods, is altered at these early stages.

RESULTS: We identified and characterized six intrinsic brain states as CAPs, their spatial and temporal features, and the transitions between the different states. At the pre-plaque stage, the TgF344-AD rats showed reduced co-activation of hub regions in the CAPs corresponding to the default mode-like and lateral cortical network. Default mode-like network activity segregated into two distinct brain states, with one state characterized by high co-activation of the basal forebrain. This basal forebrain co-activation was reduced in TgF344-AD animals mainly at the pre-plaque stage. Brain state transition probabilities were altered at the pre-plaque stage between states involving the default mode-like network, lateral cortical network, and basal forebrain regions. Additionally, while the directionality preference in the network-state transitions observed in the wild-type animals at the pre-plaque stage had diminished at the early-plaque stage, TgF344-AD animals continued to show directionality preference at both stages.

DISCUSSION: Our study enhances the understanding of intrinsic brain state dynamics and how they are impacted at the early stages of AD, providing a nuanced characterization of the early, functional impact of the disease's neurodegenerative process.},
}

@article {pmid38645989,
year = {2024},
author = {Peng, Y and Zhou, C},
title = {Network Pharmacology and Molecular Docking Identify the Potential Mechanism and Therapeutic Role of Scutellaria baicalensis in Alzheimer's Disease.},
journal = {Drug design, development and therapy},
volume = {18},
number = {},
pages = {1199-1219},
pmid = {38645989},
issn = {1177-8881},
abstract = {AIM: Scutellaria baicalensis, a traditional Chinese medicinal herb renowned for its anti-inflammatory, antioxidant, and anti-tumor properties, has shown promise in alleviating cognitive impairment associated with Alzheimer's disease. Nonetheless, the exact neuroprotective mechanism of Scutellaria baicalensis against Alzheimer's disease remains unclear. In this study, network pharmacology was employed to explore the possible mechanisms by which Scutellaria baicalensis protects against Alzheimer's disease.

METHODS: The active compounds of Scutellaria baicalensis were retrieved from the TCMSP database, and their corresponding targets were identified. Alzheimer's disease-related targets were obtained through searches in the GeneCards and OMIM databases. Cytoscape 3.6.0 software was utilized to construct a regulatory network illustrating the "active ingredient-target" relationships. Subsequently, the target genes affected by Scutellaria baicalensis in the context of Alzheimer's disease were input into the String database to establish a PPI network. GO analysis and KEGG analysis were conducted using the DAVID database to predict the potential pathways associated with these key targets. Following this, the capacity of these active ingredients to bind to core targets was confirmed through molecular docking. In vitro experiments were then carried out for further validation.

RESULTS: A total of 36 active ingredients from Scutellaria baicalensis were screened out, which corresponded to 365 targets. Molecular docking results demonstrated the robust binding abilities of Baicalein, Wogonin, and 5,2'-Dihydroxy-6,7,8-trimethoxyflavone to key target proteins (SRC, PIK3R1, and STAT3). In vitro experiments showed that the active components of Scutellaria baicalensis can inhibit STAT3 expression by downregulating the PIK3R1/SRC pathway in Neuro 2A cells.

CONCLUSION: In summary, these findings collectively suggest that Scutellaria baicalensis holds promise as a viable treatment option for Alzheimer's disease.},
}

@article {pmid38645778,
year = {2024},
author = {Varinthra, P and Anwar, SNMN and Shih, SC and Liu, IY},
title = {The role of the GABAergic system on insomnia.},
journal = {Tzu chi medical journal},
volume = {36},
number = {2},
pages = {103-109},
pmid = {38645778},
issn = {2223-8956},
abstract = {Sleep is an essential activity for the survival of mammals. Good sleep quality helps promote the performance of daily functions. In contrast, insufficient sleep reduces the efficiency of daily activities, causes various chronic diseases like Alzheimer's disease, and increases the risk of having accidents. The GABAergic system is the primary inhibitory neurotransmitter system in the central nervous system. It transits the gamma-aminobutyric acid (GABA) neurotransmitter via GABAA and GABAB receptors to counterbalance excitatory neurotransmitters, such as glutamate, noradrenaline, serotonin, acetylcholine, orexin, and dopamine, which release and increase arousal activities during sleep. Several studies emphasized that dysfunction of the GABAergic system is related to insomnia, the most prevalent sleep-related disorder. The GABAergic system comprises the GABA neurotransmitter, GABA receptors, GABA synthesis, and degradation. Many studies have demonstrated that GABA levels correlate with sleep quality, suggesting that modulating the GABAergic system may be a promising therapeutic approach for insomnia. In this article, we highlight the significance of sleep, the classification and pathology of insomnia, and the impact of the GABAergic system changes on sleep. In addition, we also review the medications that target the GABAergic systems for insomnia, including benzodiazepines (BZDs), non-BZDs, barbiturates, GABA supplements, and Chinese herbal medicines.},
}

@article {pmid38645748,
year = {2024},
author = {Yap, LE and Hunt, JE and Turner, RS},
title = {Aging as a target for the prevention and treatment of Alzheimer's disease.},
journal = {Frontiers in neurology},
volume = {15},
number = {},
pages = {1376104},
pmid = {38645748},
issn = {1664-2295},
abstract = {Alzheimer's disease (AD), the most common etiology of dementia in older adults, is projected to double in prevalence over the next few decades. Current treatments for AD manage symptoms or slow progressive decline, but are accompanied by significant inconvenience, risk, and cost. Thus, a better understanding of the risk factors and pathophysiology of AD is needed to develop novel prevention and treatment strategies. Aging is the most important risk factor for AD. Elucidating molecular mechanisms of aging may suggest novel therapeutic targets. While aging is inevitable, it may be accelerated by caloric excess and slowed by caloric restriction (CR) or intermittent fasting. As such, CR may slow aging and reduce the risk of all diseases of aging, including dementia due to AD. The literature on CR, intermittent fasting, and treatment with polyphenols such as resveratrol-a pharmacologic CR-mimetic-supports this hypothesis based on clinical outcomes as well as biomarkers of aging and AD. More studies exploring the role of CR in regulating aging and AD progression in man are needed to fill gaps in our understanding and develop safer and more effective strategies for the prevention and treatment of AD.},
}

@article {pmid38645691,
year = {2024},
author = {Eugenín, J and Richerson, GB},
title = {Editorial: Alternative and expanding views on central respiratory chemoreception in health and disease.},
journal = {Frontiers in physiology},
volume = {15},
number = {},
pages = {1403768},
pmid = {38645691},
issn = {1664-042X},
}

@article {pmid38645663,
year = {2024},
author = {Sun, J and Xie, Z and Sun, Y and Shen, A and Li, R and Yuan, X and Lu, B and Li, Y},
title = {Precise prediction of cerebrospinal fluid amyloid beta protein for early Alzheimer's disease detection using multimodal data.},
journal = {MedComm},
volume = {5},
number = {5},
pages = {e532},
pmid = {38645663},
issn = {2688-2663},
abstract = {Alzheimer's disease (AD) constitutes a neurodegenerative disorder marked by a progressive decline in cognitive function and memory capacity. The accurate diagnosis of this condition predominantly relies on cerebrospinal fluid (CSF) markers, notwithstanding the associated burdens of pain and substantial financial costs endured by patients. This study encompasses subjects exhibiting varying degrees of cognitive impairment, encompassing individuals with subjective cognitive decline, mild cognitive impairment, and dementia, constituting a total sample size of 82 participants. The primary objective of this investigation is to explore the relationships among brain atrophy measurements derived from magnetic resonance imaging, atypical electroencephalography (EEG) patterns, behavioral assessment scales, and amyloid β-protein (Aβ) indicators. The findings of this research reveal that individuals displaying reduced Aβ1-42/Aβ-40 levels exhibit significant atrophy in the frontotemporal lobe, alongside irregularities in various parameters related to EEG frequency characteristics, signal complexity, inter-regional information exchange, and microstates. The study additionally endeavors to estimate Aβ1-42/Aβ-40 content through the application of a random forest algorithm, amalgamating structural data, electrophysiological features, and clinical scales, achieving a remarkable predictive precision of 91.6%. In summary, this study proposes a cost-effective methodology for acquiring CSF markers, thereby offering a valuable tool for the early detection of AD.},
}

@article {pmid38645585,
year = {2024},
author = {Lee, K and Park, TY and Lee, W and Kim, H},
title = {A review of functional neuromodulation in humans using low-intensity transcranial focused ultrasound.},
journal = {Biomedical engineering letters},
volume = {14},
number = {3},
pages = {407-438},
pmid = {38645585},
issn = {2093-985X},
abstract = {Transcranial ultrasonic neuromodulation is a rapidly burgeoning field where low-intensity transcranial focused ultrasound (tFUS), with exquisite spatial resolution and deep tissue penetration, is used to non-invasively activate or suppress neural activity in specific brain regions. Over the past decade, there has been a rapid increase of tFUS neuromodulation studies in healthy humans and subjects with central nervous system (CNS) disease conditions, including a recent surge of clinical investigations in patients. This narrative review summarized the findings of human neuromodulation studies using either tFUS or unfocused transcranial ultrasound (TUS) reported from 2013 to 2023. The studies were categorized into two separate sections: healthy human research and clinical studies. A total of 42 healthy human investigations were reviewed as grouped by targeted brain regions, including various cortical, subcortical, and deep brain areas including the thalamus. For clinical research, a total of 22 articles were reviewed for each studied CNS disease condition, including chronic pain, disorder of consciousness, Alzheimer's disease, Parkinson's disease, depression, schizophrenia, anxiety disorders, substance use disorder, drug-resistant epilepsy, and stroke. Detailed information on subjects/cohorts, target brain regions, sonication parameters, outcome readouts, and stimulatory efficacies were tabulated for each study. In later sections, considerations for planning tFUS neuromodulation in humans were also concisely discussed. With an excellent safety profile to date, the rapid growth of human tFUS research underscores the increasing interest and recognition of its significant potential in the field of non-invasive brain stimulation (NIBS), offering theranostic potential for neurological and psychiatric disease conditions and neuroscientific tools for functional brain mapping.},
}

@article {pmid38645567,
year = {2024},
author = {Ji, X and Walczak, P and Boltze, J},
title = {Mitigating the impact of mechanisms causing neuronal degeneration.},
journal = {Neuroprotection},
volume = {2},
number = {1},
pages = {1-3},
pmid = {38645567},
issn = {2770-730X},
}

@article {pmid38645276,
year = {2024},
author = {Okafor, M and Champomier, O and Raibaut, L and Ozkan, S and El Kholti, N and Ory, S and Chasserot-Golaz, S and Gasman, S and Hureau, C and Faller, P and Vitale, N},
title = {Restoring cellular copper homeostasis in Alzheimer disease: a novel peptide shuttle is internalized by an ATP-dependent endocytosis pathway involving Rab5- and Rab14-endosomes.},
journal = {Frontiers in molecular biosciences},
volume = {11},
number = {},
pages = {1355963},
pmid = {38645276},
issn = {2296-889X},
abstract = {CPPs, or Cell-Penetrating Peptides, offer invaluable utility in disease treatment due to their ability to transport various therapeutic molecules across cellular membranes. Their unique characteristics, such as biocompatibility and low immunogenicity, make them ideal candidates for delivering drugs, genes, or imaging agents directly into cells. This targeted delivery enhances treatment efficacy while minimizing systemic side effects. CPPs exhibit versatility, crossing biological barriers and reaching intracellular targets that conventional drugs struggle to access. This capability holds promise in treating a wide array of diseases, including cancer, neurodegenerative disorders, and infectious diseases, offering a potent avenue for innovative and targeted therapies, yet their precise mechanism of cell entry is far from being fully understood. In order to correct Cu dysregulation found in various pathologies such as Alzheimer disease, we have recently conceived a peptide Cu(II) shuttle, based on the αR5W4 CPP, which, when bound to Cu(II), is able to readily enter a neurosecretory cell model, and release bioavailable Cu in cells. Furthermore, this shuttle has the capacity to protect cells in culture against oxidative stress-induced damage which occurs when Cu binds to the Aβ peptide. The aim of this study was therefore to characterize the cell entry route used by this shuttle and determine in which compartment Cu is released. Pharmacological treatments, siRNA silencing and colocalization experiments with GFP-Rab fusion proteins, indicate that the shuttle is internalized by an ATP-dependent endocytosis pathway involving both Rab5 and Rab14 endosomes route and suggest an early release of Cu from the shuttle.},
}

@article {pmid38645255,
year = {2024},
author = {Sanati, M and Bayat, S and Panahi, MM and Khodadadi, A and Rezaee, S and Ghasimi, M and Besharat, S and Fooladi, ZM and Dooghaee, MA and Taheri, MS and Dickerson, BC and Goldberg, A and Rezaii, N},
title = {Impaired language in Alzheimer's disease: A comparison between English and Persian implicates content-word frequency rather than the noun-verb distinction.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.04.09.24305534},
pmid = {38645255},
abstract = {This study challenges the conventional psycholinguistic view that the distinction between nouns and verbs is pivotal in understanding language impairments in neurological disorders. Traditional views link frontal brain region damage with verb processing deficits and posterior temporoparietal damage with noun difficulties. However, this perspective is contested by findings from patients with Alzheimer's disease (pwAD), who show impairments in both word classes despite their typical temporoparietal atrophy. Notably, pwAD tend to use semantically lighter verbs in their speech than healthy individuals. By examining English-speaking pwAD and comparing them with Persian-speaking pwAD, this research aims to demonstrate that language impairments in Alzheimer's disease (AD) stem from the distributional properties of words within a language rather than distinct neural processing networks for nouns and verbs. We propose that the primary deficit in AD language production is an overreliance on high-frequency words. English has a set of particularly high-frequency verbs that surpass most nouns in usage frequency. Since pwAD tend to use high-frequency words, the byproduct of this word distribution in the English language would be an over-usage of high-frequency verbs. In contrast, Persian features complex verbs with an overall distribution lacking extremely high-frequency verbs like those found in English. As a result, we hypothesize that Persian-speaking pwAD would not have a bias toward the overuse of high-frequency verbs. We analyzed language samples from 95 English-speaking pwAD and 91 healthy controls, along with 27 Persian-speaking pwAD and 27 healthy controls. Employing uniform automated natural language processing methods, we measured the usage rates of nouns, verbs, and word frequencies across both cohorts. Our findings showed that English-speaking pwAD use higher-frequency verbs than healthy individuals, a pattern not mirrored by Persian-speaking pwAD. Crucially, we found a significant interaction between the frequencies of verbs used by English and Persian speakers with and without AD. Moreover, regression models that treated noun and verb frequencies as separate predictors did not outperform models that considered overall word frequency alone in classifying AD. In conclusion, this study suggests that language abnormalities among English-speaking pwAD reflect the unique distributional properties of words in English rather than a universal noun-verb class distinction. Beyond offering a new understanding of language abnormalities in AD, the study highlights the critical need for further investigation across diverse languages to deepen our insight into the mechanisms of language impairments in neurological disorders.},
}

@article {pmid38645244,
year = {2024},
author = {Alcantara-Gonzalez, D and Kennedy, M and Criscuolo, C and Botterill, J and Scharfman, HE},
title = {Increased excitability of dentate gyrus mossy cells occurs early in life in the Tg2576 model of Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.02.09.579729},
pmid = {38645244},
abstract = {INTRODUCTION: Hyperexcitability in Alzheimer's disease (AD) emerge early and contribute to disease progression. The dentate gyrus (DG) is implicated in hyperexcitability in AD. We hypothesized that mossy cells (MCs), regulators of DG excitability, contribute to early hyperexcitability in AD. Indeed, MCs generate hyperexcitability in epilepsy.

METHODS: Using the Tg2576 model and WT mice (∼1month-old), we compared MCs electrophysiologically, assessed c-Fos activity marker, Aβ expression and mice performance in a hippocampal-dependent memory task.

RESULTS: Tg2576 MCs exhibit increased spontaneous excitatory events and decreased inhibitory currents, increasing the charge transfer excitation/inhibition ratio. Tg2576 MC intrinsic excitability was enhanced, and showed higher c-Fos, intracellular Aβ expression, and axon sprouting. Granule cells only showed changes in synaptic properties, without intrinsic changes. The effects occurred before a memory task is affected.

DISCUSSION: Early electrophysiological and morphological alterations in Tg2576 MCs are consistent with enhanced excitability, suggesting an early role in DG hyperexcitability and AD pathophysiology.

HIGHLIGHTS: ∘ MCs from 1 month-old Tg2576 mice had increased spontaneous excitatory synaptic input. ∘ Tg2576 MCs had reduced spontaneous inhibitory synaptic input. ∘ Several intrinsic properties were abnormal in Tg2576 MCs. ∘ Tg2576 GCs had enhanced synaptic excitation but no changes in intrinsic properties. ∘ Tg2576 MCs exhibited high c-Fos expression, soluble Aβ and axonal sprouting.},
}

@article {pmid38645234,
year = {2024},
author = {Heavener, K and Kabra, K and Yidenk, M and Bradshaw, E},
title = {IL-1RA Disrupts ATP Activation of P2RX7 in Human Monocyte-Derived Microglia-like Cells.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.04.08.588607},
pmid = {38645234},
abstract = {The immune system has a dynamic role in neurodegenerative diseases, and purinergic receptors allow immune cells to recognize neuronal signaling, cell injury, or stress. Purinergic Receptor 7 (P2RX7) can modulate inflammatory cascades and its expression is upregulated in Alzheimer's disease (AD) brain tissue. P2RX7 expression is enriched in microglia, and elevated levels are found in microglia surrounding amyloid-beta plaques in the brain. While P2RX7 is thought to play a role in neurodegenerative diseases, how it modulates pathology and disease progression is not well understood. Here, we utilize a human monocyte-derived microglia-like cell (MDMi) model to interrogate P2RX7 activation and downstream consequences on microglia function. By using MDMi derived from human donors, we can examine how human donor variation impacts microglia function. We assessed P2RX7-driven IL1β and IL18 production and amyloid-beta peptide 1-42 (Aβ1-42) uptake levels. Our results show that ATP-stimulation of MDMi triggers upregulation of IL1β and IL18 expression. This upregulation of cytokine gene expression is blocked with the A740003 P2RX7 antagonist. We find that high extracellular ATP conditions also reduced MDMi capacity for Aβ1-42 uptake, and this loss of function is prevented through A740003 inhibition of P2RX7. In addition, pretreatment of MDMi with IL-1RA limited ATP-driven IL1β and IL18 gene expression upregulation, indicating that ATP immunomodulation of P2RX7 is IL-1R dependent. Aβ1-42 uptake was higher with IL-1RA pretreatment compared to ATP treatment alone, suggesting P2RX7 regulates phagocytic engulfment through IL-1 signaling. Overall, our results demonstrate that P2RX7 is a key response protein for high extracellular ATP in human microglia-like cells, and its function can be modulated by IL-1 signaling. This work opens the door to future studies examining anti-IL-1 biologics to increase the clearance of amyloid-beta.},
}

@article {pmid38645146,
year = {2024},
author = {Dando, O and McGeachan, R and McQueen, J and Baxter, P and Rockley, N and McAlister, H and Prasad, A and He, X and King, D and Rose, J and Jones, PB and Tulloch, J and Chandran, S and Smith, C and Hardingham, G and Spires-Jones, TL},
title = {Synaptic gene expression changes in frontotemporal dementia due to the MAPT 10+16 mutation.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.04.09.24305501},
pmid = {38645146},
abstract = {Mutations in the MAPT gene encoding tau protein can cause autosomal dominant neurodegenerative tauopathies including frontotemporal dementia (often with Parkinsonism). In Alzheimer's disease, the most common tauopathy, synapse loss is the strongest pathological correlate of cognitive decline. Recently, PET imaging with synaptic tracers revealed clinically relevant loss of synapses in primary tauopathies; however, the molecular mechanisms leading to synapse degeneration in primary tauopathies remain largely unknown. In this study, we examined post-mortem brain tissue from people who died with frontotemporal dementia with tau pathology (FTDtau) caused by the MAPT intronic exon 10+16 mutation, which increases splice variants containing exon 10 resulting in higher levels of tau with four microtubule binding domains. We used RNA sequencing and histopathology to examine temporal cortex and visual cortex, to look for molecular phenotypes compared to age, sex, and RNA integrity matched participants who died without neurological disease (n=12 per group). Bulk tissue RNA sequencing reveals substantial downregulation of gene expression associated with synaptic function. Upregulated biological pathways in human MAPT 10+16 brain included those involved in transcriptional regulation, DNA damage response, and neuroinflammation. Histopathology confirmed increased pathological tau accumulation in FTDtau cortex as well as a loss of presynaptic protein staining, and region-specific increased colocalization of phospho-tau with synapses in temporal cortex. Our data indicate that synaptic pathology likely contributes to pathogenesis in FTDtau caused by the MAPT 10+16 mutation.},
}

@article {pmid38645131,
year = {2024},
author = {Bischof, GN and Jaeger, E and Giehl, K and Jessen, F and Onur, OA and O'Bryant, S and Kara, E and Weiss, PH and Drzezga, A},
title = {Cortical Tau Aggregation Patterns associated with Apraxia in Alzheimer's Disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.04.09.24305535},
pmid = {38645131},
abstract = {OBJECTIVES: Apraxia is a core feature of Alzheimer's disease, but the pathomechanism of this characteristic symptom is not well understood. Here, we systematically investigated apraxia profiles in a well-defined group of patients with Alzheimer's disease (AD; N=32) who additionally underwent PET imaging with the second-generation tau PET tracer [18F]PI-2620. We hypothesized that specific patterns of tau pathology might be related to apraxic deficits.

METHODS: Patients (N=32) with a biomarker-confirmed diagnosis of Alzheimer's disease were recruited in addition to a sample cognitively unimpaired controls (CU 1 ; N=41). Both groups underwent in-depth neuropsychological assessment of apraxia (Dementia Apraxia Screening Test; DATE and the Cologne Apraxia Screening; KAS). In addition, static PET imaging with [18F]PI-2620 was performed to assess tau pathology in the AD patients. To specifically investigate the association of apraxia with regional tau-pathology, we compared the PET-data from this group with an independent sample of amyloid-negative cognitively intact participants (CU 2; N=54) by generation of z-score-deviation maps as well as voxel- based multiple regression analyses.

RESULTS: We identified significant clusters of tau-aggregation in praxis-related regions (e.g., supramarginal gyrus, angular gyrus, temporal, parietal and occipital regions) that were associated with apraxia. These regions were similar between the two apraxia assessments. No correlations between tau-tracer uptake in primary motor cortical or subcortical brain regions and apraxia were observed.

CONCLUSIONS: These results suggest that tau deposition in specific cortical brain regions may induce local neuronal dysfunction leading to a dose-dependent functional decline in praxis performance.},
}

@article {pmid38645120,
year = {2024},
author = {Li, H and Khang, TF},
title = {SIEVE: One-stop differential expression, variability, and skewness analyses using RNA-Seq data.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.04.09.588804},
pmid = {38645120},
abstract = {MOTIVATION: RNA-Seq data analysis is commonly biased towards detecting differentially expressed genes and insufficiently conveys the complexity of gene expression changes between biological conditions. This bias arises because discrete models of RNA-Seq count data cannot fully characterize the mean, variance, and skewness of gene expression distribution using independent model parameters. A unified framework that simultaneously tests for differential expression, variability, and skewness is needed to realize the full potential of RNA-Seq data analysis in a systems biology context.

RESULTS: We present SIEVE, a statistical methodology that provides the desired unified framework. SIEVE embraces a compositional data analysis framework that transforms discrete RNA-Seq counts to a continuous form with a distribution that is well-fitted by a skew-normal distribution. Simulation results show that SIEVE controls the false discovery rate and probability of Type II error better than existing methods for differential expression analysis. Analysis of the Mayo RNA-Seq dataset for Alzheimer's disease using SIEVE reveals that a gene set with significant expression difference in mean, standard deviation and skewness between the control and the Alzheimer's disease group strongly predicts a subject's disease state. Furthermore, functional enrichment analysis shows that relying solely on differentially expressed genes detects only a segment of a much broader spectrum of biological aspects associated with Alzheimer's disease. The latter aspects can only be revealed using genes that show differential variability and skewness. Thus, SIEVE enables fresh perspectives for understanding the intricate changes in gene expression that occur in complex diseases.

AVAILABILITY: The SIEVE R package and source codes are available at https://github.com/Divo-Lee/SIEVE .},
}

@article {pmid38645114,
year = {2024},
author = {Griswold, AJ and Rajabli, F and Gu, T and Arvizu, J and Golightly, CG and Whitehead, PL and Hamilton-Nelson, KL and Adams, LD and Sanchez, JJ and Mena, PR and Starks, TD and Illanes-Manrique, M and Silva, C and Bush, WS and Cuccaro, ML and Vance, JM and Cornejo-Olivas, MR and Feliciano-Astacio, BE and Byrd, GS and Beecham, GW and Haines, JL and Pericak-Vance, MA},
title = {Generalizability of Tau and Amyloid Plasma Biomarkers in Alzheimer's Disease Cohorts of Diverse Genetic Ancestries.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.04.10.24305617},
pmid = {38645114},
abstract = {INTRODUCTION: Plasma phosphorylated threonine-181 of Tau and amyloid beta are biomarkers for differential diagnosis and preclinical detection of Alzheimer disease (AD). Given differences in AD risk across diverse populations, generalizability of existing biomarker data is not assured.

METHODS: In 2,086 individuals of diverse genetic ancestries (African American, Caribbean Hispanic, and Peruvians) we measured plasma pTau-181 and Aβ42/Aβ40. Differences in biomarkers between cohorts and clinical diagnosis groups and the potential discriminative performance of the two biomarkers were assessed.

RESULTS: pTau-181 and Aβ42/Aβ40 were consistent across cohorts. Higher levels of pTau181 were associated with AD while Aβ42/Aβ40 had minimal differences. Correspondingly, pTau-181 had greater predictive value than Aβ42/Aβ40, however, the area under the curve differed between cohorts.

DISCUSSION: pTau-181 as a plasma biomarker for clinical AD is generalizable across genetic ancestries, but predictive value may differ. Combining genomic and biomarker data from diverse individuals will increase understanding of genetic risk and refine clinical diagnoses.},
}

@article {pmid38645082,
year = {2024},
author = {Katdare, KA and Kjar, A and O'Brown, NM and Neal, EH and Sorets, AG and Shostak, A and Romero-Fernandez, W and Kwiatkowski, AJ and Mlouk, K and Kim, H and Cowell, RP and Schwensen, KR and Horner, KB and Wilson, JT and Schrag, MS and Megason, SG and Lippmann, ES},
title = {IQGAP2 regulates blood-brain barrier immune dynamics.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2023.02.07.527394},
pmid = {38645082},
abstract = {Brain endothelial cells (BECs) play an important role in maintaining central nervous system (CNS) homeostasis through blood-brain barrier (BBB) functions. BECs express low baseline levels of adhesion receptors, which limits entry of leukocytes. However, the molecular mediators governing this phenotype remain mostly unclear. Here, we explored how infiltration of immune cells across the BBB is influenced by the scaffold protein IQ motif containing GTPase activating protein 2 (IQGAP2). In mice and zebrafish, we demonstrate that loss of Iqgap2 increases infiltration of peripheral leukocytes into the CNS under homeostatic and inflammatory conditions. Using single-cell RNA sequencing and immunohistology, we further show that BECs from mice lacking Iqgap2 exhibit a profound inflammatory signature, including extensive upregulation of adhesion receptors and antigen-processing machinery. Human tissue analyses also reveal that Alzheimer's disease is associated with reduced hippocampal IQGAP2. Overall, our results implicate IQGAP2 as an essential regulator of BBB immune privilege and immune cell entry into the CNS.},
}

@article {pmid38645027,
year = {2024},
author = {Wiesman, AI and Gallego-Rudolf, J and Villeneuve, S and Baillet, S and Wilson, TW and , },
title = {Alignments between cortical neurochemical systems, proteinopathy and neurophysiological alterations along the Alzheimer's disease continuum.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.04.13.24305551},
pmid = {38645027},
abstract = {Two neuropathological hallmarks of Alzheimer's disease (AD) are the accumulation of amyloid-β (Aβ) proteins and alterations in cortical neurophysiological signaling. Despite parallel research indicating disruption of multiple neurotransmitter systems in AD, it has been unclear whether these two phenomena are related to the neurochemical organization of the cortex. We leveraged task-free magnetoencephalography and positron emission tomography, with a cortical atlas of 19 neurotransmitters to study the alignment and interactions between alterations of neurophysiological signaling, Aβ deposition, and the neurochemical gradients of the human cortex. In patients with amnestic mild cognitive impairment (N = 18) and probable AD (N = 20), we found that changes in rhythmic, but not arrhythmic, cortical neurophysiological signaling relative to healthy controls (N = 20) are topographically aligned with cholinergic, serotonergic, and dopaminergic neurochemical systems. These neuro-physio-chemical alignments are related to the severity of cognitive and behavioral impairments. We also found that cortical Aβ plaques are preferentially deposited along neurochemical boundaries, and mediate how beta-band rhythmic cortical activity maps align with muscarinic acetylcholine receptors. Finally, we show in an independent dataset that many of these alignments manifest in the asymptomatic stages of cortical Aβ accumulation (N = 33; N = 71 healthy controls), particularly the Aβ-neurochemical alignments (57.1%) and neuro-physio-chemical alignments in the alpha frequency band (62.5%). Overall, the present study demonstrates that the expression of pathology in pre-clinical and clinical AD aligns topographically with the cortical distribution of chemical neuromodulator systems, scaling with clinical severity and with implications for potential pharmacotherapeutic pathways.},
}

@article {pmid38644999,
year = {2024},
author = {Hulse, J and Maphis, N and Peabody, J and Chackerian, B and Bhaskar, K},
title = {Virus-like particle (VLP)-based vaccine targeting tau phosphorylated at Ser396/Ser404 (PHF1) site outperforms phosphorylated S199/S202 (AT8) site in reducing tau pathology and restoring cognitive deficits in the rTg4510 mouse model of tauopathy.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.04.05.588338},
pmid = {38644999},
abstract = {Tauopathies, including Alzheimer's disease (AD) and Frontotemporal Dementia (FTD), are histopathologically defined by the aggregation of hyperphosphorylated pathological tau (pTau) as neurofibrillary tangles in the brain. Site-specific phosphorylation of tau occurs early in the disease process and correlates with progressive cognitive decline, thus serving as targetable pathological epitopes for immunotherapeutic development. Previously, we developed a vaccine (Qβ-pT181) displaying phosphorylated Thr181 tau peptides on the surface of a Qβ bacteriophage virus-like particle (VLP) that induced robust antibody responses, cleared pathological tau, and rescued memory deficits in a transgenic mouse model of tauopathy. Here we report the characterization and comparison of two additional Qβ VLP-based vaccines targeting the dual phosphorylation sites Ser199/Ser202 (Qβ-AT8) and Ser396/Ser404 (Qβ-PHF1). Both Qβ-AT8 and Qβ-PHF1 vaccines elicited high-titer antibody responses against their pTau epitopes. However, only Qβ-PHF1 rescued cognitive deficits, reduced soluble and insoluble pathological tau, and reactive microgliosis in a 4-month rTg4510 model of FTD. Both sera from Qβ-AT8 and Qβ-PHF1 vaccinated mice were specifically reactive to tau pathology in human AD post-mortem brain sections. These studies further support the use of VLP-based immunotherapies to target pTau in AD and related tauopathies and provide potential insight into the clinical efficacy of various pTau epitopes in the development of immunotherapeutics.},
}

@article {pmid38644932,
year = {2024},
author = {Kreutzer, AG and Malonis, RJ and Parrocha, CMT and Tong, K and Guaglianone, G and Nguyen, JT and Diab, MN and Lai, JR and Nowick, JS},
title = {Generation and Study of Antibodies against Two Triangular Trimers Derived from Aβ.},
journal = {Peptide science (Hoboken, N.J.)},
volume = {116},
number = {2},
pages = {},
pmid = {38644932},
issn = {2475-8817},
abstract = {Monoclonal antibodies (mAbs) that target the P-amyloid peptide (Aβ) are important Alzheimer's disease research tools and are now being used as Alzheimer's disease therapies. Conformation-specific mAbs that target oligomeric and fibrillar Aβ assemblies are of particular interest, as these assemblies are associated with Alzheimer's disease pathogenesis and progression. This paper reports the generation of rabbit mAbs against two different triangular trimers derived from Aβ. These antibodies are the first mAbs generated against Aβ oligomer mimics in which the high-resolution structures of the oligomers are known. We describe the isolation of the mAbs using single B-cell sorting of peripheral blood mononuclear cells (PBMCs) from immunized rabbits, the selectivity of the mAbs for the triangular trimers, the immunoreactivity of the mAbs with aggregated Aβ42, and the immunoreactivity of the mAbs in brain tissue from the 5xFAD Alzheimer's disease mouse model. The characterization of these mAbs against structurally defined trimers derived from Aβ enhances understanding of antibody-amyloid recognition and may benefit the development of diagnostics and immunotherapies in Alzheimer's disease.},
}

@article {pmid38644883,
year = {2024},
author = {Yin, KF and Gu, XJ and Su, WM and Chen, T and Long, J and Gong, L and Ying, ZY and Dou, M and Jiang, Z and Duan, QQ and Cao, B and Gao, X and Chi, LY and Chen, YP},
title = {Causal association and mediating effect of blood biochemical metabolic traits and brain image-derived endophenotypes on Alzheimer's disease.},
journal = {Heliyon},
volume = {10},
number = {8},
pages = {e27422},
pmid = {38644883},
issn = {2405-8440},
abstract = {BACKGROUND: Recent genetic evidence supports that circulating biochemical and metabolic traits (BMTs) play a causal role in Alzheimer's disease (AD), which might be mediated by changes in brain structure. Here, we leveraged publicly available genome-wide association study data to investigate the intrinsic causal relationship between blood BMTs, brain image-derived phenotypes (IDPs) and AD.

METHODS: Utilizing the genetic variants associated with 760 blood BMTs and 172 brain IDPs as the exposure and the latest AD summary statistics as the outcome, we analyzed the causal relationship between blood BMTs and brain IDPs and AD by using a two-sample Mendelian randomization (MR) method. Additionally, we used two-step/mediation MR to study the mediating effect of brain IDPs between blood BMTs and AD.

RESULTS: Twenty-five traits for genetic evidence supporting a causal association with AD were identified, including 12 blood BMTs and 13 brain IDPs. For BMTs, glutamine consistently reduced the risk of AD in 3 datasets. For IDPs, specific alterations of cortical thickness (atrophy in frontal pole and insular lobe, and incrassation in superior parietal lobe) and subcortical volume (atrophy in hippocampus and its subgroups, left accumbens and left choroid plexus, and expansion in cerebral white matter) are vulnerable to AD. In the two-step/mediation MR analysis, superior parietal lobe, right hippocampal fissure and left accumbens were identified to play a potential mediating role among three blood BMTs and AD.

CONCLUSIONS: The results obtained in our study suggest that 12 circulating BMTs and 13 brain IDPs play a causal role in AD. Importantly, a subset of BMTs exhibit shared genetic architecture and potentially causal relationships with brain structure, which may contribute to the alteration of brain IDPs in AD.},
}

@article {pmid38644855,
year = {2024},
author = {Ul Rehman, S and Tarek, N and Magdy, C and Kamel, M and Abdelhalim, M and Melek, A and N Mahmoud, L and Sadek, I},
title = {AI-based tool for early detection of Alzheimer's disease.},
journal = {Heliyon},
volume = {10},
number = {8},
pages = {e29375},
pmid = {38644855},
issn = {2405-8440},
abstract = {In the context of Alzheimer's disease (AD), timely identification is paramount for effective management, acknowledging its chronic and irreversible nature, where medications can only impede its progression. Our study introduces a holistic solution, leveraging the hippocampus and the VGG16 model with transfer learning for early AD detection. The hippocampus, a pivotal early affected region linked to memory, plays a central role in classifying patients into three categories: cognitively normal (CN), representing individuals without cognitive impairment; mild cognitive impairment (MCI), indicative of a subtle decline in cognitive abilities; and AD, denoting Alzheimer's disease. Employing the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset, our model undergoes training enriched by advanced image preprocessing techniques, achieving outstanding accuracy (testing 98.17 %, validation 97.52 %, training 99.62 %). The strategic use of transfer learning fortifies our competitive edge, incorporating the hippocampus approach and, notably, a progressive data augmentation technique. This innovative augmentation strategy gradually introduces augmentation factors during training, significantly elevating accuracy and enhancing the model's generalization ability. The study emphasizes practical application with a user-friendly website, empowering radiologists to predict class probabilities, track disease progression, and visualize patient images in both 2D and 3D formats, contributing significantly to the advancement of early AD detection.},
}

@article {pmid38644825,
year = {2024},
author = {Patil, N and Dhariwal, R and Mohammed, A and Wei, LS and Jain, M},
title = {Network pharmacology-based approach to elucidate the pharmacologic mechanisms of natural compounds from Dictyostelium discoideum for Alzheimer's disease treatment.},
journal = {Heliyon},
volume = {10},
number = {8},
pages = {e28852},
pmid = {38644825},
issn = {2405-8440},
abstract = {Alzheimer's disease (AD) is increasingly becoming a major public health concern in our society. While many studies have explored the use of natural polyketides, alkaloids, and other chemical components in AD treatment, there is an urgent need to clarify the concept of multi-target treatment for AD. This study focuses on using network pharmacology approach to elucidate how secondary metabolites from Dictyostelium discoideum affect AD through multi-target or indirect mechanisms. The secondary metabolites produced by D. discoideum during their development were obtained from literature sources and PubChem. Disease targets were selected using GeneCards, DisGeNET, and CTD databases, while compound-based targets were identified through Swiss target prediction and Venn diagrams were used to find intersections between these targets. A network depicting the interplay among disease, drugs, active ingredients, and key target proteins (PPI network) was formed utilizing the STRING (Protein-Protein Interaction Networks Functional Enrichment Analysis) database. To anticipate the function and mechanism of the screened compounds, GO and KEGG enrichment analyses were conducted and visually presented using graphs and bubble charts. After the screening phase, the top interacting targets in the PPI network and the compound with the most active target were chosen for subsequent molecular docking and molecular dynamic simulation studies. This study identified nearly 50 potential targeting genes for each of the screened compounds and revealed multiple signaling pathways. Among these pathways, the inflammatory pathway stood out. COX-2, a receptor associated with neuroinflammation, showed differential expression in various stages of AD, particularly in pyramidal neurons during the early stages of the disease. This increase in COX-2 expression is likely induce by higher levels of IL-1, which is associated with neuritic plaques and microglial cells in AD. Molecular docking investigations demonstrated a strong binding interaction between the terpene compound PQA-11 and the neuroinflammatory receptor COX2, with a substantial binding affinity of -8.4 kcal/mol. Subsequently, a thorough analysis of the docked complex (COX2-PQA11) through Molecular Dynamics Simulation showed lower RMSD, minimal RMSF fluctuations, and a reduced total energy of -291.35 kJ/mol compared to the standard drug. These findings suggest that the therapeutic effect of PQA-11 operates through the inflammatory pathway, laying the groundwork for further in-depth research into the role of secondary metabolites in AD treatment.},
}

@article {pmid38644711,
year = {2024},
author = {Shanaida, M and Lysiuk, R and Mykhailenko, O and Hudz, N and Abdulsalam, A and Gontova, T and Oleshchuk, O and Ivankiv, Y and Shanaida, V and Lytkin, D and Bjørklund, G},
title = {Alpha-lipoic Acid: An Antioxidant with Anti-Aging Properties for Disease Therapy.},
journal = {Current medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0109298673300496240416114827},
pmid = {38644711},
issn = {1875-533X},
abstract = {The anti-aging effects of alpha-lipoic acid (αLA), a natural antioxidant synthesized in human tissues, have attracted a growing interest in recent years. αLA is a short- -chain sulfur-containing fatty acid occurring in the mitochondria of all kinds of eukaryotic cells. Both the oxidized disulfide of αLA and its reduced form (dihydrolipoic acid, DHLA) exhibit prominent antioxidant function. The amount of αLA inside the human body gradually decreases with age resulting in various health disorders. Its lack can be compensated by supplying from external sources such as dietary supplements or medicinal dosage forms. The primary objectives of this study were the analysis of updated information on the latest two-decade research regarding the use of αLA from an anti-aging perspective. The information was collected from PubMed, Wiley Online Library, Scopus, ScienceDirect, SpringerLink, Google Scholar, and clinicaltrials.gov. Numerous in silico, in vitro, in vivo, and clinical studies revealed that αLA shows a protective role in biological systems by direct or indirect reactive oxygen/nitrogen species quenching. αLA demonstrated beneficial properties in the prevention and treatment of many age-related disorders such as neurodegeneration, metabolic disorders, different cancers, nephropathy, infertility, and skin senescence. Its preventive effects in case of Alzheimer's and Parkinson's diseases are of particular interest. Further mechanistic and clinical studies are highly recommended to evaluate the wide spectrum of αLA therapeutic potential that could optimize its dietary intake for prevention and alleviation disorders related to aging.},
}

@article {pmid38644708,
year = {2024},
author = {Patwekar, M and Patwekar, F and Khan, S and Sharma, R and Kumar, D},
title = {Navigating the Alzheimer's Treatment Landscape: Unraveling Amyloid-Beta Complexities and Pioneering Precision Medicine Approaches.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115680266295495240415114919},
pmid = {38644708},
issn = {1873-4294},
abstract = {A variety of cutting-edge methods and good knowledge of the illness's complex causes are causing a sea change in the field of Alzheimer's Disease (A.D.) research and treatment. Precision medicine is at the vanguard of this change, where individualized treatment plans based on genetic and biomarker profiles give a ray of hope for customized therapeutics. Combination therapies are becoming increasingly popular as a way to address the multifaceted pathology of Alzheimer's by simultaneously attacking Aβ plaques, tau tangles, neuroinflammation, and other factors. The article covers several therapeutic design efforts, including BACE inhibitors, gamma- secretase modulators, monoclonal antibodies (e.g., Aducanumab and Lecanemab), and anti- Aβ vaccinations. While these techniques appear promising, clinical development faces safety concerns and uneven efficacy. To address the complicated Aβ pathology in Alzheimer's disease, a multimodal approach is necessary. The statement emphasizes the continued importance of clinical trials in addressing safety and efficacy concerns. Looking ahead, it suggests that future treatments may take into account genetic and biomarker traits in order to provide more personalized care. Therapies targeting Aβ, tau tangles, neuroinflammation, and novel drug delivery modalities are planned. Nanoparticles and gene therapies are only two examples of novel drug delivery methods that have the potential to deliver treatments more effectively, with fewer side effects, and with better therapeutic results. In addition, medicines that target tau proteins in addition to Aβ are in the works. Early intervention, based on precise biomarkers, is a linchpin of Alzheimer's care, emphasizing the critical need for detecting the disease at its earliest stages. Lifestyle interventions, encompassing diet, exercise, cognitive training, and social engagement, are emerging as key components in the fight against cognitive decline. Data analytics and art are gaining prominence as strategies to mitigate the brain's inflammatory responses. To pool knowledge and resources in the fight against Alzheimer's, international cooperation between scientists, doctors, and pharmaceutical companies is still essential. In essence, a complex, individualized, and collaborative strategy will characterize Alzheimer's research and therapy in the future. Despite obstacles, these encouraging possibilities show the ongoing commitment of the scientific and medical communities to combat A.D. head-on, providing a glimmer of hope to the countless people and families touched by this savage sickness.},
}

@article {pmid38644684,
year = {2024},
author = {Meyer, N and Torrent, J and Balme, S},
title = {Characterizing Prion-Like Protein Aggregation: Emerging Nanopore-Based Approaches.},
journal = {Small methods},
volume = {},
number = {},
pages = {e2400058},
doi = {10.1002/smtd.202400058},
pmid = {38644684},
issn = {2366-9608},
support = {ANR-19-CE42-0006//Agence Nationale de la Recherche/ ; },
abstract = {Prion-like protein aggregation is characteristic of numerous neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. This process involves the formation of aggregates ranging from small and potentially neurotoxic oligomers to highly structured self-propagating amyloid fibrils. Various approaches are used to study protein aggregation, but they do not always provide continuous information on the polymorphic, transient, and heterogeneous species formed. This review provides an updated state-of-the-art approach to the detection and characterization of a wide range of protein aggregates using nanopore technology. For each type of nanopore, biological, solid-state polymer, and nanopipette, discuss the main achievements for the detection of protein aggregates as well as the significant contributions to the understanding of protein aggregation and diagnostics.},
}

@article {pmid38644682,
year = {2024},
author = {Cousins, KAQ and Phillips, JS and Das, SR and O'Brien, K and Tropea, TF and Chen-Plotkin, A and Shaw, LM and Nasrallah, IM and Mechanic-Hamilton, D and McMillan, CT and Irwin, DJ and Lee, EB and Wolk, DA},
title = {Pathologic and cognitive correlates of plasma biomarkers in neurodegenerative disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {},
number = {},
pages = {},
doi = {10.1002/alz.13777},
pmid = {38644682},
issn = {1552-5279},
support = {R01-NS082265/NS/NINDS NIH HHS/United States ; R01-NS115139/NS/NINDS NIH HHS/United States ; },
abstract = {INTRODUCTION: We investigate pathological correlates of plasma phosphorylated tau 181 (p-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) across a clinically diverse spectrum of neurodegenerative disease, including normal cognition (NormCog) and impaired cognition (ImpCog).

METHODS: Participants were NormCog (n = 132) and ImpCog (n = 461), with confirmed β-amyloid (Aβ+/-) status (cerebrospinal fluid, positron emission tomography, autopsy) and single molecule array plasma measurements. Logistic regression and receiver operating characteristic (ROC) area under the curve (AUC) tested how combining plasma analytes discriminated Aβ+ from Aβ-. Survival analyses tested time to clinical dementia rating (global CDR) progression.

RESULTS: Multivariable models (p-tau+GFAP+NfL) had the best performance to detect Aβ+ in NormCog (ROCAUC = 0.87) and ImpCog (ROCAUC = 0.87). Survival analyses demonstrated that higher NfL best predicted faster CDR progression for both Aβ+ (hazard ratio [HR] = 2.94; p = 8.1e-06) and Aβ- individuals (HR = 3.11; p = 2.6e-09).

DISCUSSION: Combining plasma biomarkers can optimize detection of Alzheimer's disease (AD) pathology across cognitively normal and clinically diverse neurodegenerative disease.

HIGHLIGHTS: Participants were clinically heterogeneous, with autopsy- or biomarker-confirmed Aβ. Combining plasma p-tau181, GFAP, and NfL improved diagnostic accuracy for Aβ status. Diagnosis by plasma biomarkers is more accurate in amnestic AD than nonamnestic AD. Plasma analytes show independent associations with tau PET and post mortem Aβ/tau. Plasma NfL predicted longitudinal cognitive decline in both Aβ+ and Aβ- individuals.},
}

@article {pmid38644660,
year = {2024},
author = {Aranha, MR and Montal, V and van den Brink, H and Pegueroles, J and Carmona-Iragui, M and Videla, L and Maure Blesa, L and Benejam, B and Arranz, J and Valldeneu, S and Barroeta, I and Fernández, S and Ribas, L and Alcolea, D and González-Ortiz, S and Bargalló, N and Biessels, GJ and Blesa, R and Lleó, A and Coutinho, AM and Leite, CC and Bejanin, A and Fortea, J},
title = {Cortical microinfarcts in adults with Down syndrome assessed with 3T-MRI.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {},
number = {},
pages = {},
doi = {10.1002/alz.13797},
pmid = {38644660},
issn = {1552-5279},
support = {1R01AG056850-01A1/NH/NIH HHS/United States ; 3RF1AG056850-01S1/NH/NIH HHS/United States ; AG056850/NH/NIH HHS/United States ; R21AG056974/NH/NIH HHS/United States ; R01AG061566/NH/NIH HHS/United States ; AARG-22-923680/ALZ/Alzheimer's Association/United States ; },
abstract = {BACKGROUND: Cortical microinfarcts (CMI) were attributed to cerebrovascular disease and cerebral amyloid angiopathy (CAA). CAA is frequent in Down syndrome (DS) while hypertension is rare, yet no studies have assessed CMI in DS.

METHODS: We included 195 adults with DS, 63 with symptomatic sporadic Alzheimer's disease (AD), and 106 controls with 3T magnetic resonance imaging. We assessed CMI prevalence in each group and CMI association with age, AD clinical continuum, vascular risk factors, vascular neuroimaging findings, amyloid/tau/neurodegeneration biomarkers, and cognition in DS.

RESULTS: CMI prevalence was 11.8% in DS, 4.7% in controls, and 17.5% in sporadic AD. In DS, CMI increased in prevalence with age and the AD clinical continuum, was clustered in the parietal lobes, and was associated with lacunes and cortico-subcortical infarcts, but not hemorrhagic lesions.

DISCUSSION: In DS, CMI are posteriorly distributed and related to ischemic but not hemorrhagic findings suggesting they might be associated with a specific ischemic CAA phenotype.

HIGHLIGHTS: This is the first study to assess cortical microinfarcts (assessed with 3T magnetic resonance imaging) in adults with Down syndrome (DS). We studied the prevalence of cortical microinfarcts in DS and its relationship with age, the Alzheimer's disease (AD) clinical continuum, vascular risk factors, vascular neuroimaging findings, amyloid/tau/neurodegeneration biomarkers, and cognition. The prevalence of cortical microinfarcts was 11.8% in DS and increased with age and along the AD clinical continuum. Cortical microinfarcts were clustered in the parietal lobes, and were associated with lacunes and cortico-subcortical infarcts, but not hemorrhagic lesions. In DS, cortical microinfarcts are posteriorly distributed and related to ischemic but not hemorrhagic findings suggesting they might be associated with a specific ischemic phenotype of cerebral amyloid angiopathy.},
}

@article {pmid38644649,
year = {2024},
author = {Finch, CE and Thorwald, MA},
title = {Inhaled pollutants of the Gero-Exposome and later life health.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/gerona/glae107},
pmid = {38644649},
issn = {1758-535X},
abstract = {Inhaled air pollutants (AirP) comprise extraordinarily diverse particles, volatiles, and gases from traffic, wildfire, cigarette smoke, dust, and various other sources. These pollutants contain numerous toxic components which collectively differ in relative levels of components, but broadly share chemical classes. Exposure and health outcomes from AirP are complex, depending on pollutant source, duration of exposure, and socioeconomic status. We discuss examples in the current literature on organ responses to AirP, with a focus on lung, arteries, and brain. Some transcriptional responses are shared. It is well accepted that AirP contributes to Alzheimer's disease and other neurodegenerative conditions in the Gero-Exposome. However, we do not know which chemical compounds initiate these changes and how activation of these transcriptional pathways is further modified by genetics and prenatal development.},
}

@article {pmid38644578,
year = {2024},
author = {Yao, Q and Long, C and Yi, P and Zhang, G and Wan, W and Rao, X and Ying, J and Liang, W and Hua, F},
title = {C/EBPβ: A transcription factor associated with the irreversible progression of Alzheimer's disease.},
journal = {CNS neuroscience & therapeutics},
volume = {30},
number = {4},
pages = {e14721},
doi = {10.1111/cns.14721},
pmid = {38644578},
issn = {1755-5949},
support = {jxsq2019201023//Jiangxi Province "Double Thousand Plan"/ ; 82060219//National Natural Science Foundation of China/ ; 82271234//National Natural Science Foundation of China/ ; 20212ACB216009//Natural Science Foundation of Jiangxi Province/ ; 20212BAB216048//Natural Science Foundation of Jiangxi Province/ ; 2019YNTD12003//Youth Team Project of the Second Affiliated Hospital of Nanchang University/ ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder distinguished by a swift cognitive deterioration accompanied by distinctive pathological hallmarks such as extracellular Aβ (β-amyloid) peptides, neuronal neurofibrillary tangles (NFTs), sustained neuroinflammation, and synaptic degeneration. The elevated frequency of AD cases and its proclivity to manifest at a younger age present a pressing challenge in the quest for novel therapeutic interventions. Numerous investigations have substantiated the involvement of C/EBPβ in the progression of AD pathology, thus indicating its potential as a therapeutic target for AD treatment.

AIMS: Several studies have demonstrated an elevation in the expression level of C/EBPβ among individuals afflicted with AD. Consequently, this review predominantly delves into the association between C/EBPβ expression and the pathological progression of Alzheimer's disease, elucidating its underlying molecular mechanism, and pointing out the possibility that C/EBPβ can be a new therapeutic target for AD.

METHODS: A systematic literature search was performed across multiple databases, including PubMed, Google Scholar, and so on, utilizing predetermined keywords and MeSH terms, without temporal constraints. The inclusion criteria encompassed diverse study designs, such as experimental, case-control, and cohort studies, restricted to publications in the English language, while conference abstracts and unpublished sources were excluded.

RESULTS: Overexpression of C/EBPβ exacerbates the pathological features of AD, primarily by promoting neuroinflammation and mediating the transcriptional regulation of key molecular pathways, including δ-secretase, apolipoprotein E4 (APOE4), acidic leucine-rich nuclear phosphoprotein-32A (ANP32A), transient receptor potential channel 1 (TRPC1), and Forkhead BoxO (FOXO).

DISCUSSION: The correlation between overexpression of C/EBPβ and the pathological development of AD, along with its molecular mechanisms, is evident. Investigating the pathways through which C/EBPβ regulates the development of AD reveals numerous multiple vicious cycle pathways exacerbating the pathological progression of the disease. Furthermore, the exacerbation of pathological progression due to C/EBPβ overexpression and its molecular mechanism is not limited to AD but also extends to other neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and multiple sclerosis (MS).

CONCLUSION: The overexpression of C/EBPβ accelerates the irreversible progression of AD pathophysiology. Additionally, C/EBPβ plays a crucial role in mediating multiple pathways linked to AD pathology, some of which engender vicious cycles, leading to the establishment of feedback mechanisms. To sum up, targeting C/EBPβ could hold promise as a therapeutic strategy not only for AD but also for other degenerative diseases.},
}

@article {pmid38643971,
year = {2024},
author = {Urbanski, DP and Wolf, JM and Langworthy, BW and Parikh, RR and Jutkowitz, E and Shippee, TP},
title = {Reported Unmet Hearing Aid Need in Older People With Dementia: The US National Core Indicators Survey.},
journal = {Journal of the American Medical Directors Association},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jamda.2024.03.107},
pmid = {38643971},
issn = {1538-9375},
abstract = {OBJECTIVES: Hearing aids have important health benefits for older adults with Alzheimer disease and related dementias (ADRD); however, hearing aid adoption in this group is low. This study aimed to determine where to target hearing aid interventions for American long-term care recipients with ADRD by examining the association of ADRD and residence type with respondent-reported unmet hearing aid need.

This cross-sectional study used data from the United States National Core Indicators-Aging and Disabilities survey (2015-2019) for long-term care recipients aged ≥65 years.

METHODS: We used multivariable logistic regression to model the likelihood of reporting unmet hearing aid need conditional on ADRD status and residence type (own/family house or apartment, residential care, or nursing facility/home), adjusting for sociodemographic factors and response type (self vs proxy).

RESULTS: Of the 25,492 respondents [median (IQR) age, 77 (71, 84) years; 7074 (27.8%) male], 5442 (21.4%) had ADRD and 3659 (14.4%) owned hearing aids. Residence types were 17,004 (66.8%) own/family house or apartment, 4966 (19.5%) residential care, and 3522 (13.8%) nursing home. Among non-hearing aid owners, ADRD [adjusted odds ratio (AOR) 0.90, 95% CI 0.80-1.0] and residence type were associated with respondent-reported unmet hearing aid need. Compared to the nursing home reference group, respondents in their own/family home (AOR 1.85, 95% CI 1.61-2.13) and residential care (AOR 1.30, 95% CI 1.10-1.53) were more likely to report unmet hearing aid need. This pattern was significantly more pronounced in people with ADRD than in those without, stemming from an interaction between ADRD and residence type.

CONCLUSIONS AND IMPLICATIONS: American long-term care recipients with ADRD living in their own/family home are more likely to report unmet hearing aid need than those with ADRD in institutional and congregate settings. This information can inform the design and delivery of hearing interventions for older adults with ADRD.},
}

@article {pmid38643861,
year = {2024},
author = {Lemche, E and Killick, R and Mitchell, J and Caton, PW and Choudhary, P and Howard, JK},
title = {Molecular mechanisms linking type 2 diabetes mellitus and late-onset Alzheimer's disease: A systematic review and qualitative meta-analysis.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {106485},
doi = {10.1016/j.nbd.2024.106485},
pmid = {38643861},
issn = {1095-953X},
abstract = {Research evidence indicating common metabolic mechanisms through which type 2 diabetes mellitus (T2DM) increases risk of late-onset Alzheimer's dementia (LOAD) has accumulated over recent decades. The aim of this systematic review is to provide a comprehensive review of common mechanisms, which have hitherto been discussed in separate perspectives, and to assemble and evaluate candidate loci and epigenetic modifications contributing to polygenic risk linkages between T2DM and LOAD. For the systematic review on pathophysiological mechanisms, both human and animal studies up to December 2023 are included. For the qualitative meta-analysis of genomic bases, human association studies were examined; for epigenetic mechanisms, data from human studies and animal models were accepted. Papers describing pathophysiological studies were identified in databases, and further literature gathered from cited work. For genomic and epigenomic studies, literature mining was conducted by formalised search codes using Boolean operators in search engines, and augmented by GeneRif citations in Entrez Gene, and other sources (WikiGenes, etc.). For the systematic review of pathophysiological mechanisms, 923 publications were evaluated, and 138 gene loci extracted for testing candidate risk linkages. 3 57 publications were evaluated for genomic association and descriptions of epigenomic modifications. Overall accumulated results highlight insulin signalling, inflammation and inflammasome pathways, proteolysis, gluconeogenesis and glycolysis, glycosylation, lipoprotein metabolism and oxidation, cell cycle regulation or survival, autophagic-lysosomal pathways, and energy. Documented findings suggest interplay between brain insulin resistance, neuroinflammation, insult compensatory mechanisms, and peripheral metabolic dysregulation in T2DM and LOAD linkage. The results allow for more streamlined longitudinal studies of T2DM-LOAD risk linkages.},
}

@article {pmid38643666,
year = {2024},
author = {Tian, X and Zhao, Y and Zhu, Y and Cui, M},
title = {Association between elevated blood-brain barrier permeability and the risk of progressive cognitive decline: A longitudinal study.},
journal = {Archives of gerontology and geriatrics},
volume = {124},
number = {},
pages = {105441},
doi = {10.1016/j.archger.2024.105441},
pmid = {38643666},
issn = {1872-6976},
abstract = {BACKGROUND: The breakdown of the blood-brain barrier (BBB) is intricately linked to the onset and advancement of cognitive impairment and dementia. This investigation explores the correlation between blood-brain barrier permeability, assessed through the cerebrospinal fluid/serum albumin ratio (QAlb), in a clinical cohort and the evolution of cognitive decline.

METHODS: This prospective observational cohort study included 295 participants. Cognitive decline progression was characterized by an escalation in the overall deterioration scale and/or clinical dementia rating scores. The investigation delves into the correlation between blood-brain barrier permeability and the advancement of cognitive impairment among patients.

RESULTS: The APOE 4 allele and diabetes mellitus among individuals exhibited increased BBB permeability (P < 0.05). Moreover, AD patients exhibited the highest QAlb levels, signifying elevated BBB permeability compared to individuals with MCI and SCD (P < 0.05). After mean 17 months following up, 117 patients (51.31 %) were identified as experiencing cognitive decline progression, and we found that only AD diagnosis, CDR, and QAlb (All P < 0.05) were significant predictors of cognitive decline progression.

CONCLUSION: Our study emphasizes the clinical relevance of QAlb in detecting individuals with an elevated risk of cognitive decline. It suggests that heightened BBB permeability could contribute to clinical deterioration and serves as a plausible therapeutic target.},
}

@article {pmid38643565,
year = {2024},
author = {Cai, Z and Yang, Z and Li, H and Fang, Y},
title = {Research progress of PROTACs for neurodegenerative diseases therapy.},
journal = {Bioorganic chemistry},
volume = {147},
number = {},
pages = {107386},
doi = {10.1016/j.bioorg.2024.107386},
pmid = {38643565},
issn = {1090-2120},
abstract = {Neurodegenerative diseases (NDD) are characterized by the gradual deterioration of neuronal function and integrity, resulting in an overall decline in brain function. The existing therapeutic options for NDD, including Alzheimer's disease, Parkinson's disease, and Huntington's disease, fall short of meeting the clinical demand. A prominent pathological hallmark observed in numerous neurodegenerative disorders is the aggregation and misfolding of proteins both within and outside neurons. These abnormal proteins play a pivotal role in the pathogenesis of neurodegenerative diseases. Targeted degradation of irregular proteins offers a promising avenue for NDD treatment. Proteolysis-targeting chimeras (PROTACs) function via the ubiquitin-proteasome system and have emerged as a novel and efficacious approach in drug discovery. PROTACs can catalytically degrade "undruggable" proteins even at exceptionally low concentrations, allowing for precise quantitative control of aberrant protein levels. In this review, we present a compilation of reported PROTAC structures and their corresponding biological activities aimed at addressing NDD. Spanning from 2016 to present, this review provides an up-to-date overview of PROTAC-based therapeutic interventions. Currently, most protein degraders intended for NDD treatment remain in the preclinical research phase. Overcoming several challenges is imperative, including enhancing oral bioavailability and permeability across the blood-brain barrier, before these compounds can progress to clinical research or eventually reach the market. However, armed with an enhanced comprehension of the underlying pathological mechanisms and the emergence of innovative scaffolds for protein degraders, along with further structural optimization, we are confident that PROTAC possesses the potential to make substantial breakthroughs in the field of neurodegenerative diseases.},
}

@article {pmid38643562,
year = {2024},
author = {Sharma, V and Chander Sharma, P and Reang, J and Yadav, V and Kumar Tonk, R and Majeed, J and Sharma, K},
title = {Impact of GSK-3β and CK-1δ on Wnt signaling pathway in alzheimer disease: A dual target approach.},
journal = {Bioorganic chemistry},
volume = {147},
number = {},
pages = {107378},
doi = {10.1016/j.bioorg.2024.107378},
pmid = {38643562},
issn = {1090-2120},
abstract = {Alzheimer's disease (AD) is an enigmatic neurological illness that offers few treatment options. Recent exploration has highlighted the crucial connection of the Wnt signaling pathway in AD pathogenesis, shedding light on potential therapeutic targets. The present study focuses on the dual targeting of glycogen synthase kinase-3β (GSK-3β) and casein kinase-1δ (CK-1δ) within the framework of the Wnt signaling pathway as a possible technique for AD intervention. GSK-3β and CK-1δ are multifunctional kinases known for their roles in tau hyperphosphorylation, amyloid processing, and synaptic dysfunction, all of which are major hallmarks of Alzheimer's disease. They are intricately linked to Wnt signaling, which plays a pivotal part in sustaining neuronal function and synaptic plasticity. Dysregulation of the Wnt pathway in AD contributes to cognitive decline and neurodegeneration. This review delves into the molecular mechanisms by which GSK-3β and CK-1δ impact the Wnt signaling pathway, elucidating their roles in AD pathogenesis. We discuss the potential of small-molecule inhibitors along with their SAR studies along with the multi-targetd approach targeting GSK-3β and CK-1δ to modulate Wnt signaling and mitigate AD-related pathology. In summary, the dual targeting of GSK-3β and CK-1δ within the framework of the Wnt signaling pathway presents an innovative and promising avenue for future AD therapies, offering new hope for patients and caregivers in the quest to combat this challenging condition.},
}

@article {pmid38643445,
year = {2024},
author = {Zamboni, G and Maramotti, R and Salemme, S and Tondelli, M and Adani, G and Vinceti, G and Carbone, C and Filippini, T and Vinceti, M and Pagnoni, G and Chiari, A},
title = {Age-specific prevalence of the different clinical presentations of AD and FTD in young-onset dementia.},
journal = {Journal of neurology},
volume = {},
number = {},
pages = {},
pmid = {38643445},
issn = {1432-1459},
support = {101042625//HORIZON EUROPE European Research Council/ ; Dipartimenti di eccellenza 2018-2022//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; },
abstract = {BACKGROUND: Studies have shown that the prevalence of all-variants Alzheimer's disease (AD) and frontotemporal dementia (FTD) both increase with age, even before the age of 65. However, it is not known whether their different clinical presentations all increase in prevalence with age in the same way.

METHODS: We studied the prevalence of the different clinical presentations of young-onset AD and FTD by 5-year age groups in a population-based study identifying all dementia patients with a diagnosis of AD and FTD and symptoms onset before age 65 in the Modena province, Italy. By using regression models of cumulative occurrences, we also estimated age-specific prevalence and compared the growth curves of the clinical presentations.

RESULTS: The prevalence of all-variants AD increased with age, from 18/1,000,000 in the 40-44 age group to 1411/1,000,000 in the 60-64 age group. The prevalence of all-variants FTD also increased with age, from 18/1,000,000 to 866/1,000,000. An estimation of age-specific prevalence functions of each clinical presentation showed that atypical non-amnestic AD and aphasic FTD grew the most in early ages, followed by the behavioural variant of FTD (bvFTD). Then, around the age of 60, amnestic AD took over and its age-specific prevalence continued to increase disproportionally compared to all the other clinical variants of AD and FTD, which, instead, started to decrease in prevalence.

CONCLUSIONS: Amnestic AD is the clinical presentation that increases the most with advancing age, followed by bvFTD, suggesting that there is a differential vulnerability to the effect of ageing within the same neurodegenerative disease.},
}

@article {pmid38643387,
year = {2024},
author = {},
title = {Critical Alzheimer's disease legislation advances in Congress.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {20},
number = {4},
pages = {3141-3142},
doi = {10.1002/alz.13831},
pmid = {38643387},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease ; },
}

Humans
*Alzheimer Disease

@article {pmid38643230,
year = {2024},
author = {Jing, X and Wang, L and Song, M and Geng, H and Li, W and Huo, Y and Huang, A and Wang, X and An, C},
title = {Serum neurofilament light chain and inflammatory cytokines as biomarkers for early detection of mild cognitive impairment.},
journal = {Scientific reports},
volume = {14},
number = {1},
pages = {9072},
pmid = {38643230},
issn = {2045-2322},
support = {ZF2024136//The government funded clinical medicine excellent talents training project of Hebei Province/ ; 199477138G//the Special Fund Project of the Central Government to Guide the Local Science and Technology Development of Hebei Province/ ; SG2021189//Science and Technology Program of Hebei Province/ ; },
mesh = {Humans ; Cross-Sectional Studies ; Intermediate Filaments ; *Alzheimer Disease ; Neurofilament Proteins ; *Cognitive Dysfunction/diagnosis ; Biomarkers ; tau Proteins ; Amyloid beta-Peptides ; },
abstract = {To investigate the association between serum neurofilament light chain (NfL) levels, inflammatory cytokines, and cognitive function to assess their utility in the early detection of mild cognitive impairment (MCI). We conducted a cross-sectional study involving 157 community-dwelling individuals aged 55 years and above, categorized into healthy controls, MCI, and probable Alzheimer's disease (AD). Serum levels of NfL, inflammatory cytokines, and AD pathology markers were measured using enzyme-linked immunosorbent assay (ELISA). Correlations between these biomarkers and cognitive function were analyzed, and the diagnostic performance of the cognitive assessment scales and serum biomarker concentrations was evaluated using receiver operating characteristic (ROC) curve analysis. Serum NfL levels were significantly elevated in MCI and probable AD groups compared to healthy controls. Positive correlations were found between serum NfL and inflammatory cytokines IL-1β, IL-6, and Aβ40. Combining serum NfL with p-tau217 and the Boston Naming Test significantly enhanced the predictive accuracy for MCI. However, combining serum NfL with inflammatory markers did not improve MCI prediction accuracy. Elevated serum NfL is associated with cognitive impairment and inflammatory markers, suggesting its potential as a peripheral serum biomarker for MCI detection. The combination of serum NfL with p-tau217 and cognitive tests could offer a more accurate prediction of MCI, providing new insights for AD treatment strategies.},
}

Humans
Cross-Sectional Studies
Intermediate Filaments
*Alzheimer Disease
Neurofilament Proteins
*Cognitive Dysfunction/diagnosis
Biomarkers
tau Proteins
Amyloid beta-Peptides

@article {pmid38643113,
year = {2024},
author = {Hans, S and Stanton, JE and Sauer, AK and Shiels, K and Saha, SK and Lordan, R and Tsoupras, A and Zabetakis, I and Grabrucker, AM},
title = {Polar lipids modify Alzheimer's Disease pathology by reducing astrocyte pro-inflammatory signaling through platelet-activating factor receptor (PTAFR) modulation.},
journal = {Lipids in health and disease},
volume = {23},
number = {1},
pages = {113},
pmid = {38643113},
issn = {1476-511X},
mesh = {Animals ; *Alzheimer Disease/pathology ; Amyloid beta-Peptides/metabolism ; Astrocytes/metabolism ; Reactive Oxygen Species/metabolism ; Lipids ; },
abstract = {BACKGROUND: Pro-inflammatory processes triggered by the accumulation of extracellular amyloid beta (Aβ) peptides are a well-described pathology in Alzheimer's disease (AD). Activated astrocytes surrounding Aβ plaques contribute to inflammation by secreting proinflammatory factors. While astrocytes may phagocytize Aβ and contribute to Aβ clearance, reactive astrocytes may also increase Aβ production. Therefore, identifying factors that can attenuate astrocyte activation and neuroinflammation and how these factors influence pro-inflammatory pathways is important for developing therapeutic and preventive strategies in AD. Here, we identify the platelet-activating factor receptor (PTAFR) pathway as a key mediator of astrocyte activation. Intriguingly, several polar lipids (PLs) have exhibited anti-inflammatory protective properties outside the central nervous system through their inhibitory effect on the PTAFR pathway. Thus, we additionally investigated whether different PLs also exert inhibitory effects on the PAF pathway in astrocytes and whether their presence influences astrocytic pro-inflammatory signaling and known AD pathologies in vitro.

METHODS: PLs from salmon and yogurt were extracted using novel food-grade techniques and their fatty acid profile was determined using LC/MS. The effect of PLs on parameters such as astrocyte activation and generation of oxygen species (ROS) was assessed. Additionally, effects of the secretome of astrocytes treated with these polar lipids on aged neurons was measured.

RESULTS: We show that PLs obtained from salmon and yogurt lower astrocyte activation, the generation of reactive oxygen species (ROS), and extracellular Aβ accumulation. Cell health of neurons exposed to the secretome of astrocytes treated with salmon-derived PLs and Aβ was less affected than those treated with astrocytes exposed to Aβ only.

CONCLUSION: Our results highlight a novel underlying mechanism, why consuming PL-rich foods such as fish and dairy may reduce the risk of developing dementia and associated disorders.},
}

Animals
*Alzheimer Disease/pathology
Amyloid beta-Peptides/metabolism
Astrocytes/metabolism
Reactive Oxygen Species/metabolism
Lipids

@article {pmid38643014,
year = {2024},
author = {Sugg, E and Gleeson, E and Baker, SN and Li, P and Gao, C and Mueller, A and Deng, H and Shen, S and Franco-Garcia, E and Saxena, R and Musiek, ES and Akeju, O and Xie, Z and Hu, K and Gao, L},
title = {Sleep and circadian biomarkers of postoperative delirium (SLEEP-POD): protocol for a prospective and observational cohort study.},
journal = {BMJ open},
volume = {14},
number = {4},
pages = {e080796},
doi = {10.1136/bmjopen-2023-080796},
pmid = {38643014},
issn = {2044-6055},
mesh = {Humans ; *Emergence Delirium ; Prospective Studies ; *Delirium/diagnosis/etiology ; Postoperative Complications/diagnosis ; Cohort Studies ; Sleep ; Biomarkers ; Observational Studies as Topic ; },
abstract = {INTRODUCTION: Surgical patients over 70 experience postoperative delirium (POD) complications in up to 50% of procedures. Sleep/circadian disruption has emerged as a potential risk factor for POD in epidemiological studies. This protocol presents a single-site, prospective observational study designed to examine the relationship between sleep/circadian regulation and POD and how this association could be moderated or mediated by Alzheimer's disease (AD) pathology and genetic risk for AD.

METHODS AND ANALYSIS: Study staff members will screen for eligible patients (age ≥70) seeking joint replacement or spinal surgery at Massachusetts General Hospital (MGH). At the inclusion visit, patients will be asked a series of questionnaires related to sleep and cognition, conduct a four-lead ECG recording and be fitted for an actigraphy watch to wear for 7 days before surgery. Blood samples will be collected preoperatively and postoperatively and will be used to gather information about AD variant genes (APOE-ε4) and AD-related pathology (total and phosphorylated tau). Confusion Assessment Method-Scale and Montreal Cognitive Assessment will be completed twice daily for 3 days after surgery. Seven-day actigraphy assessments and Patient-Reported Outcomes Measurement Information System questionnaires will be performed 1, 3 and 12 months after surgery. Relevant patient clinical data will be monitored and recorded throughout the study.

ETHICS AND DISSEMINATION: This study is approved by the IRB at MGH, Boston, and it is registered with the US National Institutes of Health on ClinicalTrials.gov (NCT06052397). Plans for dissemination include conference presentations at a variety of scientific institutions. Results from this study are intended to be published in peer-reviewed journals. Relevant updates will be made available on ClinicalTrials.gov.

TRIAL REGISTRATION NUMBER: NCT06052397.},
}

Humans
*Emergence Delirium
Prospective Studies
*Delirium/diagnosis/etiology
Postoperative Complications/diagnosis
Cohort Studies
Sleep
Biomarkers
Observational Studies as Topic

@article {pmid38642804,
year = {2024},
author = {Sulatsky, MI and Stepanenko, OV and Stepanenko, OV and Povarova, OI and Kuznetsova, IM and Turoverov, KK and Sulatskaya, AI},
title = {Broken but not beaten: Challenge of reducing the amyloids pathogenicity by degradation.},
journal = {Journal of advanced research},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jare.2024.04.018},
pmid = {38642804},
issn = {2090-1224},
abstract = {BACKGROUND: The accumulation of ordered protein aggregates, amyloid fibrils, accompanies various neurodegenerative diseases (such as Parkinson's, Huntington's, Alzheimer's, etc.) and causes a wide range of systemic and local amyloidoses (such as insulin, hemodialysis amyloidosis, etc.). Such pathologies are usually diagnosed when the disease is already irreversible and a large amount of amyloid plaques have accumulated. In recent years, new drugs aimed at reducing amyloid levels have been actively developed. However, although clinical trials have demonstrated a reduction in amyloid plaque size with these drugs, their effect on disease progression has been controversial and associated with significant side effects, the reasons of which are not fully understood.

AIM OF REVIEW: The purpose of this review is to summarize extensive array of data on the effect of exogenous and endogenous factors (physico-mechanical effects, chemical effects of low molecular weight compounds, macromolecules and their complexes) on the structure and pathogenicity of mature amyloids for proposing future directions of the development of effective and safe anti-amyloid therapeutics.

Our analysis show that destruction of amyloids is in most cases incomplete and degradation products often retain the properties of amyloids (including high and sometimes higher than fibrils, cytotoxicity), accelerate amyloidogenesis and promote the propagation of amyloids between cells. Probably, the appearance of protein aggregates, polymorphic in structure and properties (such as amorphous aggregates, fibril fragments, amyloid oligomers, etc.), formed because of uncontrolled degradation of amyloids, may be one of the reasons for the ambiguous effectiveness and serious side effects of the anti-amyloid drugs. This means that all medications that are supposed to be used both for degradation and slow down the fibrillogenesis must first be tested on mature fibrils: the mechanism of drug action and cytotoxic, seeding, and infectious activity of the degradation products must be analyzed.},
}

@article {pmid38642789,
year = {2024},
author = {McClarty, BM and Rodriguez, G and Dong, H},
title = {Class 1 histone deacetylases differentially modulate memory and synaptic genes in a spatial and temporal manner in aged and APP/PS1 mice.},
journal = {Brain research},
volume = {},
number = {},
pages = {148951},
doi = {10.1016/j.brainres.2024.148951},
pmid = {38642789},
issn = {1872-6240},
abstract = {Epigenetics plays a vital role in aging and Alzheimer's disease (AD); however, whether epigenetic alterations during aging can initiate AD and exacerbate AD progression remains unclear. In this study, 3-, 12- and 18- month-old APP/PS1 mice and WT littermates underwent memory tests, then synapse-related gene expression, class 1 histone deacetylases (HDACs) abundance, and H3K9ac levels at target gene promoters, were evaluated in the hippocampus and prefrontal cortex (PFC). Our results showed recognition and long-term spatial memory impaired in 18-month-old WT mice and recognition, short-term working, and long-term spatial reference memory deficits in 12-and 18- month-old APP/PS1 mice. The memory impairments are associated with synapse-related gene nr2a, glur1, glur2, psd95 expression, HDAC abundance, and H3K9ac regulation. More specifically, HDAC 2 modulated synapse-related gene expression through H3K9ac at the gene promoters during aging and AD progression in the hippocampus. Conversely, HDAC 3 modulated synapse-related gene expression through H3K9ac at the gene promoters during AD progression in the PFC. These findings suggest a differential HDAC modulation of synapse-related gene expression in aging and AD.},
}

@article {pmid38642716,
year = {2024},
author = {Yadav, K and Vijayalakshmi, R and Kumar Sahu, K and Sure, P and Chahal, K and Yadav, R and Sucheta, and Dubey, A and Jha, M and Pradhan, M},
title = {Exosome-Based Macromolecular neurotherapeutic drug delivery approaches in overcoming the Blood-Brain barrier for treating brain disorders.},
journal = {European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V},
volume = {},
number = {},
pages = {114298},
doi = {10.1016/j.ejpb.2024.114298},
pmid = {38642716},
issn = {1873-3441},
abstract = {Delivering drugs to the brain is a complex challenge in medical research, particularly for disorders like Alzheimer's and Parkinson's. The blood-brain barrier restricts the entry of many therapeutic molecules, hindering their effectiveness. Nanoparticles, a potential solution, face issues like toxicity and limited approvals. A new avenue explores the use of small extracellular vesicles (sEVs), i.e., exosomes, as natural carriers for drug delivery. sEVs, tiny structures below 150 nm, show promise due to their minimal immune response and ability to precisely deliver drugs. This review focuses on the potential of sEVs-based drug delivery systems for treating neurological disorders, brain cancers, and other brain-related issues. Notably, bioengineered sEVs-carrying therapeutic compounds exhibit promise in early studies. The unique features of sEVs, such as their small size and natural properties, position them as candidates to overcome challenges in drug delivery to the brain. Ongoing clinical trials and research into sEVs behavior within the body further highlight their potential for revolutionizing drug delivery and addressing complex brain conditions.},
}

@article {pmid38642715,
year = {2024},
author = {Tong, B and Ba, Y and Li, Z and Yang, C and Su, K and Qi, H and Zhang, D and Liu, X and Wu, Y and Chen, Y and Ling, J and Zhang, J and Yu, P and Yin, X},
title = {Targeting dysregulated lipid metabolism for the treatment of Alzheimer's disease and Parkinson's disease: Current advancements and future prospects.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {106505},
doi = {10.1016/j.nbd.2024.106505},
pmid = {38642715},
issn = {1095-953X},
abstract = {Alzheimer's and Parkinson's diseases are two of the most frequent neurological diseases. The clinical features of AD are memory decline and cognitive dysfunction, while PD mainly manifests as motor dysfunction such as limb tremors, muscle rigidity abnormalities, and slow gait. Abnormalities in cholesterol, sphingolipid, and glycerophospholipid metabolism have been demonstrated to directly exacerbate the progression of AD by stimulating Aβ deposition and tau protein tangles. Indirectly, abnormal lipids can increase the burden on brain vasculature, induce insulin resistance, and affect the structure of neuronal cell membranes. Abnormal lipid metabolism leads to PD through inducing accumulation of α-syn, dysfunction of mitochondria and endoplasmic reticulum, and ferroptosis. Great progress has been made in targeting lipid metabolism abnormalities for the treatment of AD and PD in recent years, like metformin, insulin, peroxisome proliferator-activated receptors (PPARs) agonists, and monoclonal antibodies targeting apolipoprotein E (ApoE). This review comprehensively summarizes the involvement of dysregulated lipid metabolism in the pathogenesis of AD and PD, the application of Lipid Monitoring, and emerging lipid regulatory drug targets. A better understanding of the lipidological bases of AD and PD may pave the way for developing effective prevention and treatment methods for neurodegenerative disorders.},
}

@article {pmid38642702,
year = {2024},
author = {Cheng, J and Liang, T and Xie, XQ and Feng, Z and Meng, L},
title = {A new era of antibody discovery: an in-depth review of AI-driven approaches.},
journal = {Drug discovery today},
volume = {},
number = {},
pages = {103984},
doi = {10.1016/j.drudis.2024.103984},
pmid = {38642702},
issn = {1878-5832},
abstract = {Given their high affinity and specificity for a range of macromolecules, antibodies are widely used in the treatment of autoimmune diseases, cancers, inflammatory diseases, and Alzheimer's disease (AD). Traditional experimental methods are time-consuming, expensive, and labor-intensive. Recent advances in artificial intelligence (AI) technologies provide complementary methods that can reduce the time and costs required for antibody design by minimizing failures and increasing the success rate of experimental tests. In this review, we scrutinize the plethora of AI-driven methodologies that have been deployed over the past 4 years for modeling antibody structures, predicting antibody-antigen interactions, optimizing antibody affinity, and generating novel antibody candidates. We also briefly address the challenges faced in integrating AI-based models with traditional antibody discovery pipelines and highlight the potential future directions in this burgeoning field.},
}

@article {pmid38642602,
year = {2024},
author = {Stephens, GS and Park, J and Eagle, A and You, J and Silva-Pérez, M and Fu, CH and Choi, S and Romain, CPS and Sugimoto, C and Buffington, SA and Zheng, Y and Costa-Mattioli, M and Liu, Y and Robison, AJ and Chin, J},
title = {Persistent ∆FosB expression limits recurrent seizure activity and provides neuroprotection in the dentate gyrus of APP mice.},
journal = {Progress in neurobiology},
volume = {},
number = {},
pages = {102612},
doi = {10.1016/j.pneurobio.2024.102612},
pmid = {38642602},
issn = {1873-5118},
abstract = {Recurrent seizures lead to accumulation of the activity-dependent transcription factor ∆FosB in hippocampal dentate granule cells in both mouse models of epilepsy and mouse models of Alzheimer's disease (AD), which is also associated with increased incidence of seizures. In patients with AD and related mouse models, the degree of ∆FosB accumulation corresponds with increasing severity of cognitive deficits. We previously found that ∆FosB impairs spatial memory in mice by epigenetically regulating expression of target genes such as calbindin that are involved in synaptic plasticity. However, the suppression of calbindin in conditions of neuronal hyperexcitability has been demonstrated to provide neuroprotection to dentate granule cells, indicating that ∆FosB may act over long timescales to coordinate neuroprotective pathways. To test this hypothesis, we used viral-mediated expression of ∆JunD to interfere with ∆FosB signaling over the course of several months in transgenic mice expressing mutant human amyloid precursor protein (APP), which exhibit spontaneous seizures and develop AD-related neuropathology and cognitive deficits. Our results demonstrate that persistent ∆FosB activity acts through discrete modes of hippocampal target gene regulation to modulate neuronal excitability, limit recurrent seizure activity, and provide neuroprotection to hippocampal dentate granule cells in APP mice.},
}

@article {pmid38642588,
year = {2024},
author = {Corbett, A and Williams, G and Creese, B and Hampshire, A and Palmer, A and Brooker, H and Ballard, C},
title = {Impact of Short-Term Computerized Cognitive Training on Cognition in Older Adults With and Without Genetic Risk of Alzheimer's Disease: Outcomes From the START Randomized Controlled Trial.},
journal = {Journal of the American Medical Directors Association},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jamda.2024.03.008},
pmid = {38642588},
issn = {1538-9375},
abstract = {OBJECTIVES: To establish the impact of a 3-minute computerized cognitive training program (START) on cognition in older adults with and without genetic risk of Alzheimer's disease.

DESIGN: Two-arm randomized controlled trial of the START program.

SETTING AND PARTICIPANTS: Remote online trial in adults older than 50 taking part from home.

METHODS: The trial compared the START program with placebo in 6544 people older than 50. Primary outcome was executive function measured through Trailmaking B, with other secondary cognitive measures. Genetic risk profile and ApoE4 status were determined by Illumina Array.

RESULTS: START conferred benefit to executive function, attention, memory, and a composite measure, including in people with the ApoE4 genotype.

CONCLUSIONS AND IMPLICATIONS: The 3-minute START task offers a means of supporting cognitive health in older adults and could be used at scale and within a precision medicine approach to reduce risk of cognitive decline in a targeted way.},
}

@article {pmid38642449,
year = {2024},
author = {Souza, ID and Lanças, FM and Hallak, JEC and Queiroz, MEC},
title = {Fiber-in-tube SPME-CapLC-MS/MS method to determine Aβ peptides in cerebrospinal fluid obtained from Alzheimer's patients.},
journal = {Journal of chromatography. A},
volume = {1723},
number = {},
pages = {464913},
doi = {10.1016/j.chroma.2024.464913},
pmid = {38642449},
issn = {1873-3778},
abstract = {Mass spectrometry is characterized by its high sensitivity, ability to measure very low analyte concentrations, specificity to distinguish between closely related compounds, availability to generate high-throughput methods for screening, and high multiplexing capacity. This technique has been used as a platform to analyze fluid biomarkers for Alzheimer's disease. However, more effective sample preparation procedures, preferably antibody-independent, and more automated mass spectrometry platforms with improved sensitivity, chromatographic separation, and high throughput are needed for this purpose. This short communication discusses the development of a fiber-in-tube SPME-CapLC-MS/MS method to determine Aβ peptides in cerebrospinal fluid obtained from Alzheimer's disease patients. To obtain the fiber-in-tube SPME capillary, we longitudinally packed 22 nitinol fibers coated with a zwitterionic polymeric ionic liquid into the same length of the PEEK tube. In addition, this communication compares this fiber-in-tube SPME method with the conventional HPLC scale (HPLC-MS/MS) and when directly coupled to CapESI-MS/MS without chromatographic separation, and, as a case study, discusses the benefits and challenges inherent in miniaturizing the flow scale of the sample preparation technique (fiber-in-tube SPME) to the CapLC-MS/MS system. Fiber-in-tube SPME-CapLC-MS/MS provided LLOQ ranging from 0.09 to 0.10 ng mL[-1], accuracy ranging from 91 to 117 % (recovery), and reproducibility of less than 18 % (RSD). Analysis of the cerebrospinal fluid samples obtained from Alzheimer's disease patients evidenced that the method is robust. At the capillary scale (10 µL min[-1]), this innovative method presented higher analytical sensitivity than the conventional HPLC-MS/MS scale. Although fiber-in-tube SPME directly coupled to CapESI-MS/MS offers advantages in terms of high throughput, the sample was dispersed and non-quantitatively desorbed from the capillary at low flow rate. These results highlighted that chromatographic separation is important to decrease the matrix effect and to achieve higher detectability, which is indispensable for bioanalysis.},
}

@article {pmid38642407,
year = {2024},
author = {Freedman, VA and Cornman, JC},
title = {Dementia Prevalence, Incidence and Mortality Trends Among US Adults Ages 72 and Older, 2011-2021.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/gerona/glae105},
pmid = {38642407},
issn = {1758-535X},
abstract = {BACKGROUND: U.S.-focused studies have reported decreasing dementia prevalence in recent decades, but have not yet focused on the implications of the COVID-19 pandemic for trends.

METHODS: We use the 2011-2021 National Health and Aging Trends Study (N=48,065) to examine dementia prevalence, incidence and mortality trends among adults ages 72 and older, and the contribution to prevalence trends of changes in the distribution of characteristics of the older population ("compositional shifts") during the full and pre-pandemic periods. To minimize classification error, individuals must meet dementia criteria for two consecutive rounds.

RESULTS: The prevalence of probable dementia declined from 11.9% in 2011 to 9.2% in 2019 and 8.2% in 2021 (3.1% average annual decline). Declines over the 2011-2021 period were concentrated among those ages 80-89 and non-Hispanic White individuals. Declines in dementia incidence were stronger for the 2011-2021 period than for the pre-pandemic period while mortality among those with dementia rose sharply with the onset of the COVID-19 pandemic. Shifts in the composition of the older population accounted for a smaller fraction of the decline over the full period (28%) than over the pre-pandemic period (45%).

CONCLUSIONS: Declines in dementia prevalence continued into years marked by onset of the COVID-19 pandemic, along with declines in incidence and sharp increases in mortality among those with dementia. However, declines are no longer largely attributable to compositional changes in the older population. Continued tracking of dementia prevalence, incidence and mortality among those with and without dementia is needed to understand long-run consequences of the pandemic.},
}

@article {pmid38642387,
year = {2024},
author = {Balbim, GM and Falck, RS and Boa Sorte Silva, NC and Kramer, AF and Voss, M and Liu-Ambrose, T},
title = {The association of the 24-hour activity cycle profiles with cognition in older adults with mild cognitive impairment: A cross-sectional study.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/gerona/glae099},
pmid = {38642387},
issn = {1758-535X},
abstract = {BACKGROUND: The relationship of cognition and the 24-hour activity cycles (24-HAC), encompassing physical activity, sedentary behaviour, and sleep, in older adults with mild cognitive impairment (MCI) remains uncertain. Distinct combinations of 24-HAC behaviours can characterize unique activity profiles and influence cognition. We aimed to characterize 24-HAC activity profiles in older adults with MCI and assess whether differences in cognition exist across profiles.

METHODS: We conducted a cross-sectional analysis utilizing baseline data from three randomized controlled trials involving 253 community-dwelling older adults (55+ years) with MCI (no functional impairment, dementia diagnosis, and Montreal Cognitive Assessment score <26/30). Using MotionWatch8© wrist-worn actigraphy (+5 days), we captured the 24-HAC. Cognition was indexed by the Alzheimer's Disease Assessment Scale Cognitive Plus (ADAS-Cog-Plus). Compositional data and latent profile analyses identified distinct 24-HAC activity profiles. Analysis of covariance examined whether 24-HAC activity profiles differed in cognition.

RESULTS: Four distinct activity profiles were identified. Profile 1 ("Average 24-HAC," n=108) engaged in all 24-HAC behaviours around the sample average. Profile 2 ("Active Chillers," n=64) depicted lower-than-average engagement in physical activity and higher-than-average sedentary behaviour. Profile 3 ("Physical Activity Masters," n=56) were the most active and the least sedentary. Profile 4 ("Sedentary Savants," n=25) were the least active and the most sedentary. Sleep was similar across profiles. There were no significant differences in ADAS-Cog-Plus scores between 24-HAC activity profiles (p>0.05).

CONCLUSION: Older adults with MCI exhibited four 24-HAC activity profiles conforming to recommended physical activity and sleep guidelines. Nonetheless, cognition was similar across these profiles.},
}