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Emerging evidence indicates that high-fat, high carbohydrate diet (HFHC) impacts central pathological features of Alzheimer's disease (AD) across both human incidences and animal models. However, the mechanisms underlying this association are poorly understood. Here, we identify compartment-specific metabolic and inflammatory dysregulations that are induced by HFHC diet in the 5xFAD mouse model of AD pathology. We observe that both male and female 5xFAD mice display exacerbated adiposity, cholesterolemia, and dysregulated insulin signaling. Independent of biological sex, HFHC diet also resulted in altered inflammatory cytokine profiles across the gastrointestinal, circulating, and central nervous systems (CNS) compartments demonstrating region-specific impacts of metabolic inflammation. Interestingly, inhibiting the inflammatory cytokine, soluble tumor necrosis factor (TNF) with the brain-permeant soluble TNF inhibitor XPro1595 was able to restore aspects of HFHC-induced metabolic inflammation, but only in male mice. Targeted transcriptomics of CNS regions revealed that inhibition of soluble TNF was sufficient to alter expression of hippocampal and cortical genes associated with beneficial immune and metabolic responses. Collectively, these results suggest that HFHC diet impairs metabolic and inflammatory pathways in an AD-relevant genotype and that soluble TNF has sex-dependent roles in modulating these pathways across anatomical compartments. Modulation of energy homeostasis and inflammation may provide new therapeutic avenues for AD.

Abstract Purpose The US Food and Drug Administration authorized lecanemab for the therapeutic use of Alzheimer's disease (AD) in January 2023. To assess the effectiveness and safety of lecanemab in treating AD, we thoroughly examined the studies that are currently accessible. Method Preferred Reporting Items for Systematic Reviews and Meta‐Analysis recommendations were followed. In order to find relevant studies on lecanemab, we carried out a thorough literature search utilizing the electronic databases MEDLINE via PubMed, Cochrane, Web of Science, EBSCOhost, and Scopus. Excluding any research using experimental animals, we looked at lecanemab's effectiveness and side effects in treating AD in human clinical trials. Three randomized controlled studies were included. Findings According to studies, lecanemab lessens clinical deterioration and reduces brain amyloid‐beta plaques (difference,.45; 95% confidence interval,.67 to.23; p

Aim: Researchers using herbs and natural products to find new drugs often prefer flavonoids because of their potential as antioxidants and anti-inflammatories. The planned review addressed baicalein research findings in detail. This manuscript provides a complete review of baicalein’s potential pharmacological effects along with several molecular targets for better understanding of its therapeutic activities. Materials and methods: We targeted the review on in vitro and in vivo studies reported on baicalein. For this, the literature is gathered from the database available on search engines like PubMed, ScienceDirect, Scopus, and Google Scholar up to 21 December 2023. The keywords “Scutellaria baicalensis”, “Oroxylum indicum”, “Neuroprotective”, “Cardioprotective”, “Toxicity studies”, and “Baicalein” were used to fetch the content. Results: Baicalein’s molecular receptor binding approach has shown anticancer, antidiabetic, antimicrobial, antiaging, neuroprotective, cardioprotective, respiratory protective, gastroprotective, hepatic protective, and renal protective effects. The synergistic effects of this drug with other selective herbs are also contributed towards significant therapeutic potential. Conclusion: This systematic review article from a contemporary and scientific perspective offers fresh insight into S. baicalensis, O. indicum, and its bioactive component baicalein as a potential complementary medicine. Baicalein may be transformed into more efficacious and acceptable evidence-based medicine. However, we recommend more clinical and mechanistic approaches to confirm safety and efficacy of baicalein.

Strong evidence indicates that amyloid beta (Aβ) inflicts its toxicity in Alzheimers disease (AD) by promoting uncontrolled elevation of cytosolic Ca2+ in neurons. We have previously shown that synthetic Aβ42 oligomers stimulate abnormal intracellular Ca2+ release from the endoplasmic reticulum stores, suggesting that a similar mechanism of Ca2+ toxicity may be common to the endogenous Aβs oligomers. Here, we use human postmortem brain extracts from AD-affected patients and test their ability to trigger Ca2+ fluxes when injected intracellularly into Xenopus oocytes. Immunological characterization of the samples revealed the elevated content of soluble Aβ oligomers only in samples from AD patients. Intracellular injection of brain extracts from control patients failed to trigger detectable changes in intracellular Ca2+. Conversely, brain extracts from AD patients triggered Ca2+ events consisting of local and global Ca2+ fluorescent transients. Pre-incubation with either the conformation-specific OC antiserum or caffeine completely suppressed the brain extracts ability to trigger cytosolic Ca2+ events. Computational modeling suggests that these Ca2+ fluxes may impair cells bioenergetic by affecting ATP and ROS production. These results support the hypothesis that Aβ oligomers contained in neurons of AD-affected brains may represent the toxic agents responsible for neuronal malfunctioning and death associated with the disruption of Ca2+ homeostasis.

Purpose of reviewIntegrative medicine is the practice of combining conventional medical treatments with "alternative" or "complementary" therapies. Integrative psychiatry is a holistic, person-centered approach to neuropsychiatric disorders that emphasizes a person's physical, emotional, interpersonal, behavioral, nutritional, environmental, and spiritual dimensions to achieve well-being. Older adults are more prone to physical injury, interpersonal loss, chronic illnesses, and physical and cognitive decline that can manifest as anxiety, depression, with functional decline and inability to care for self. Additionally, stress of caring for older adults with dementia can adversely affect caregivers' health. Although integrative approaches are perceived as safer and less stigmatizing, it is important to understand the risks and benefits of such therapies for older adults with neurocognitive disorders and their caregivers.Recent findingsHere, we summarize the results of the recent clinical trials and meta-analyses that provide evidence for integrative approaches to treating older adults with cognitive disorders and their caregivers which include the use of diet and supplements, and mind-body therapies. Dietary and mind-body therapies have become increasingly popular and show the strongest evidence of effectiveness for cognitive disorders and caregiver stress. Vitamins and supplements are the most popular integrative intervention, but there is mixed evidence supporting their use and the concern for herb (supplement)-drug interactions. While there is increasing popularity of integrative treatments, information to guide clinicians providing care for older adults remains limited, with variable scientific rigor of the available RCTs for a large number of commonly used integrative interventions particularly for cognitive disorders and caregiver stress and well-being.

Background: An application of artificial intelligence is machine learning, which allows computer programs to learn and create data. Methods: In this work, we aimed to evaluate the performance of the MySLR machine learning platform, which implements the Latent Dirichlet Allocation (LDA) algorithm in the identification and screening of papers present in the literature that focus on mutations of the apolipoprotein E (ApoE) gene in Italian Alzheimer’s Disease patients. Results: MySLR excludes duplicates and creates topics. MySLR was applied to analyze a set of 164 scientific publications. After duplicate removal, the results allowed us to identify 92 papers divided into two relevant topics characterizing the investigated research area. Topic 1 contains 70 papers, and topic 2 contains the remaining 22. Despite the current limitations, the available evidence suggests that articles containing studies on Italian Alzheimer’s Disease (AD) patients were 65.22% (n = 60). Furthermore, the presence of papers about mutations, including single nucleotide polymorphisms (SNPs) ApoE gene, the primary genetic risk factor of AD, for the Italian population was 5.4% (n = 5). Conclusion: The results show that the machine learning platform helped to identify case-control studies on ApoE gene mutations, including SNPs, but not only conducted in Italy.

Abstract Background To assess the effectiveness, safety, and tolerability of anti-Alzheimer agents (memantine, galantamine, rivastigmine, and donepezil) in controlling ADHD symptoms in children, adolescents, and adults. Methods Following the PRISMA guideline, clinical trials assessing the potency of anti-Alzheimer medications in managing ADHD symptoms were imported from PubMed, Web of Science, and Scopus (until February 2023). Screening stages were conducted by two independent researchers. Two independent researchers also extracted data from clinical trials reporting the outcomes as the reduction in scores of ADHD questionnaires. The risk of bias within the included studies was assessed using the Cochrane Collaboration tool, while the certainty of outcomes was evaluated based on the GRADE criteria. Results Of the initial 1597 studies, 11 studies were included. No studies were available for rivastigmine, and only a single study was conducted for galantamine. The results of the other two medications had a slight inconsistency. While both memantine and donepezil were reported to be effective in several studies, they were reported to be ineffective in some other studies. Side effects were mostly reduced appetite and headache. The tolerability of memantine, donepezil, and galantamine was all convincing. Conclusions While galantamine did not demonstrate a promising efficacy in ADHD, memantine and donepezil showed effectiveness. However, future studies are needed to confirm their efficacy in ADHD since there was some inconsistency.

Abstract Citrus fruit essential oil is considered one of the widely studied essential oils while its leaves attract less attention although being rich in nearly the same composition as the peel and flowers. The leaves of bitter orange or sour orange (Citrus aurantium L.) were extracted using three different techniques namely; hydrodistillation (HD), steam distillation (SD), and microwave-assisted distillation (MV) to compare their chemical composition. The three essential oil samples were analyzed through GC/FID and GC/MS analyses. The samples were tested in vitro using different antioxidant techniques (DPPH, ABTS, CUPRAC, FRAP, PBD, and MCA), neuroprotective enzyme inhibitory activities (acetylcholine and butyl choline enzymes), and antidiabetic activities (α-amylase and α-glucosidase). The results showed that thirty-five volatile ingredients were detected and quantified. Monoterpenes represented the most abundant class in the three essential oils followed by sesquiterpenes. C. aurantium essential oil carried potential antioxidant activity where SD exhibited the highest antioxidant activity, with values arranged in the following order: FRAP (200.43 mg TE/g), CUPRAC (138.69 mg TE/g), ABTS (129.49 mg TE/g), and DPPH (51.67 mg TE/g). SD essential oil also presented the most potent α-amylase (0.32) inhibition while the MV essential oil showed the highest α-glucosidase inhibition (2.73 mmol ACAE/g), followed by HD (2.53 mmol ACAE/g), and SD (2.46 mmol ACAE/g). The SD essential oil exhibited the highest BChE and AChE inhibitory activities (3.73 and 2.06 mg GALAE/g), respectively). Thus, bitter orange essential oil can act as a potential source of potent antioxidant, antidiabetic, and neuroprotective activities for future drug leads.

Abstract Alzheimer’s disease (AD) is the major form of dementia prevalent in older adults and with a high incidence in females. Identification of early biomarkers is essential for preventive intervention to delay its progression. Furthermore, due to its multifactorial nature, a multi-target approach could be therapeutically beneficial. Our studies included 4- (pre-pathology) and 11-month (mild-pathology) TgF344-AD rats, a transgenic Alzheimer’s model that exhibits age-dependent AD progression. We identified two potential early biomarker genes for AD, early growth response 2 (EGR2) and histone 1H2AA (HIST1H2AA), in the hippocampus of 4-month females. Out of 17,168 genes analyzed by RNA sequencing, expression of these two genes was significantly altered in 4-month TgF344-AD rats compared to wild-type littermates. We also evaluated co-treatment with diazoxide (DZ), a potassium channel activator, and dibenzoylmethane (DIB), which inhibits eIF2α-P activity, on TgF344-AD and wild-type rats. DZ/DIB-treatment mitigated spatial memory deficits and buildup of hippocampal Aβ plaques and tau PHF in 11-month TgF344-AD rats but had no effect on wild-type littermates. To our knowledge, this preclinical study is the first to report EGR2 and HIST1H2AA as potential AD biomarkers in females, and the benefits of DZ/DIB-treatment in AD. Evaluations across multiple AD-related models is warranted to corroborate our findings.

Alzheimer’s Disease (AD) is characterized by the gradual degeneration and decline of brain cells, leading to irreversible neurological changes. This study investigates advanced image enhancement techniques for improving AD diagnosis using brain MRI. The methods used include CLAHE (Contrast Limited Adaptive Histogram Equalization) to enhance local image contrast and ESRGAN (Enhanced Super-Resolution Generative Adversarial Networks) to improve image resolution. These preprocessing methods improve MRI images and classification accuracy. An ensemble model of MobileNetV2 and DenseNet121, two efficient deep-learning models with feature extraction capabilities, were used as classifiers. This approach addresses challenges in AD diagnosis by leveraging deep learning for more accurate classification of brain tissue images. The model achieved an accuracy of 80.31% for MobileNetV2 and 89.22% for DenseNet121 when no enhancements were utilized. The model achieved accuracies of 92.34% and 89.38% for MobileNetV2 and DenseNet121, respectively, when enhancement methods were utilized, indicating strong dependability with the Kaggle dataset of MRI images. These findings underscore the efficacy of advanced image processing and deep learning in the early and accurate detection of Alzheimer’s disease.

Dementia is a condition that often comes with aging and affects how people think, remember, and behave. Diagnosing dementia early is important because it can greatly improve patients’ lives. This systematic review looks at how deep learning (DL) techniques have been used to diagnose dementia automatically from 2012 to 2023. We explore how different DL methods like Convolutional Neural Networks (CNN), Recurrent Neural Networks (RNN), and Deep Neural Networks (DNN) are used to diagnose types of dementia such as Alzheimer’s, vascular dementia, and Lewy body dementia. We also discuss the difficulties of using DL for diagnosing dementia, like the lack of large and varied datasets and the challenge of applying models to different groups of people. These issues indicate the need for more dependable and understandable models that consider a wide range of patient characteristics and biomarkers. Longitudinal studies are also needed to understand how the disease progresses and how treatments work. Collaboration among researchers, doctors, and data scientists is crucial to ensure DL models are scientifically sound and effective in clinical settings. In summary, DL techniques show promise for automated dementia diagnosis and could improve how accurately and efficiently it is diagnosed in practice. However, further research is needed to address the challenges highlighted in this review.

Abstract Background Combining multimodal lifestyle interventions and disease-modifying drugs (novel or repurposed) could provide novel precision approaches to prevent cognitive impairment. Metformin is a promising candidate in view of the well-established link between type 2 diabetes (T2D) and Alzheimer’s Disease and emerging evidence of its potential neuro-protective effects (e.g. vascular, metabolic, anti-senescence). MET-FINGER aims to test a FINGER 2.0 multimodal intervention, combining an updated FINGER multidomain lifestyle intervention with metformin, where appropriate, in an APOE ε4-enriched population of older adults (60–79 years) at increased risk of dementia. Methods MET-FINGER is an international randomised, controlled, parallel-group, phase-IIb proof-of-concept clinical trial, where metformin is included through a trial-within-trial design. 600 participants will be recruited at three sites (UK, Finland, Sweden). Participants at increased risk of dementia based on vascular risk factors and cognitive screening, will be first randomised to the FINGER 2.0 intervention (lifestyle + metformin if eligible; active arm) or to receive regular health advice (control arm). Participants allocated to the FINGER 2.0 intervention group at risk indicators of T2D will be additionally randomised to receive metformin (2000 mg/day or 1000 mg/day) or placebo. The study duration is 2 years. The changes in global cognition (primary outcome, using a Neuropsychological Test Battery), memory, executive function, and processing speed cognitive domains; functional status; lifestyle, vascular, metabolic, and other dementia-related risk factors (secondary outcomes), will be compared between the FINGER 2.0 intervention and the control arm. The feasibility, potential interaction (between-groups differences in healthy lifestyle changes), and disease-modifying effects of the lifestyle-metformin combination will be exploratory outcomes. The lifestyle intervention is adapted from the original FINGER trial (diet, physical activity, cognitive training, monitoring of cardiovascular/metabolic risk factors, social interaction) to be consistently delivered in three countries. Metformin is administered as Glucophage®XR/SR 500, (500 mg oral tablets). The metformin/placebo treatment will be double blinded. Conclusion MET-FINGER is the first trial combining a multimodal lifestyle intervention with a putative repurposed disease-modifying drug for cognitive impairment prevention. Although preliminary, its findings will provide crucial information for innovative precision prevention strategies and form the basis for a larger phase-III trial design and future research in this field. Trial registration ClinicalTrials.gov (NCT05109169).

The usefulness of Contingent Negative Variation (CNV) potential as a biomarker of neurocognitive disorders due to possible Alzheimer’s disease, is based on its possible physiological correlates. However, its application in the diagnostic evaluation of these disorders is still incipient. The aim of this study is to characterize the patterns of cognitive processing of information in the domain of nonspecific global attention, by recording potential CNV in a group of patients with neurocognitive disorders due to possible Alzheimer’s disease. An experimental study of cases and controls was carried out. The sample included 39 patients classified according to DSM-5 with a neurocognitive disorder subtype possibly due Alzheimer’s disease, and a Control Group of 53 subjects with normal cognitive functions. CNV potential was registered using standard protocol. The analysis of variance obtained significant differences in mean values and confidence intervals of total CNV amplitude between the three study groups. The late CNV segment amplitudes makes it possible to discriminate between the level of mild and major dysfunction in the group of patients. The CNV total amplitudes of potential allows for effective discrimination between normal cognitive functioning and neurocognitive disorders due to possible Alzheimer’s disease.

Objective(s): It is urgent to develop non-pharmacological interventions or multifactor combination approaches to combat Alzheimer’s disease (AD). The effect of exercise (EX) combined with environmental enrichment (EE) on behavioral phenotypes and neurogenesis markers in an Alzheimer-like rat model was investigated. Materials and Methods: The groups consisted of AD, sham-operated, AD+EX, AD+EE, and AD+EX+EE. AD was produced by injection of amyloid-beta (1-42, 6 µg) intrahippocampally, and a daily treadmill for 3 consecutive weeks was used for EX animals. EE was a large cage (50× 50× 50 cm) containing differently shaped objects. Spatial learning and memory were evaluated in the Morris water maze (MWM), and a shuttle box was used to evaluate inhibitory avoidance memory. RT-PCR was performed to assess the expression of early neurogenesis markers, DCX, and Sox2 within the hippocampus.Results: Pretreatment with exercise and EE, both individually and in combination, could provide protection from memory impairments in AD rats. Combined treatment led to a significantly more pronounced improvement in memory deficits of AD rats than either paradigm alone. Combination therapy with exercise and EE could also reverse the passive avoidance memory impairment and hippocampal DCX expression of AD rats to the control levels.Conclusion: These data suggest that exercise in combination with cognitive engagement can provide a non-pharmacological and multidomain policy that may prevent or delay AD symptoms.

The disruption of cell membranes by tau and amylin oligomers is linked to amyloid diseases such as Alzheimer’s and diabetes, respectively. The recent studies suggest that misfolded tau and amylin can form neurotoxic hetero-oligomers that are structurally different from homo-oligomers. However, the molecular interactions of these hetero-oligomers with the neuronal membranes remain unclear. Using MD simulations, we have investigated the binding behaviors, membrane disruption, and protein folding of hetero-oligomers on a raft membrane containing phase-separated lipid nanodomains like those found in neurons. We discovered that the hetero-oligomers bind to the liquid-order and liquid-disorder phase boundaries of the raft membrane. The major lipid-binding sites of these interactions include the L16 and I26 residues of amylin and the N-terminal of tau. Strong disruptions of the raft domain size by the hetero-tetramer were detected. Furthermore, the hetero-dimer disrupted the saturated phospholipid orientational order to a greater extent than the individual tau or amylin monomer. In addition, the constituent tau more strongly promoted the alpha-helix to the beta-sheet transition of the constituent amylin within the hetero-dimer when compared with the amylin monomer alone. Our results provide new molecular insights into understanding the neurotoxicity of the hetero-oligomers associated with the cross-talk between amyloid diseases.

Background and Aim: Alzheimer’s is a chronic disease that causes cognitive disabilities, thinking, personality changes and disruptions in daily activities. Due to these disorders, patients need long-term care. Most care for Alzheimer’s patients is done at home by family members, which makes home caregivers mentally, physically, emotionally, socially and financially vulnerable. Health personnel have a key role to play in providing information and guidance and helping the family control these conditions. The purpose of this study was to examines the level of knowledge and attitude of health workers and determines the related factors. Materials and Methods: This research is a cross-sectional study to evaluate the level of knowledge and attitude of health workers about Alzheimer’s disease and its related factors. All 260 health workers of Gorgan and Kordkuy districts were studied by census method to assess their knowledge and attitude about Alzheimer’s disease and its related factors. ANOVA and T-tests were used to determine the relationship between the independent variables and the dependent variable. Variables whose significant level of correlation with response variable was less than 0.2 in bivariate analysis were entered into the regression model and finally multiple linear regression was used to determine the factors related to level of knowledge and attitude. Results: The mean level of knowledge was 46.73% (95% CI, 45.46 to 48.16) and the mean level of attitude was 55.61% (95% CI, 54.63 to 56.74). The results show that those with a history of previous education, a history of caring for Alzheimer’s patients, a higher level of work experience in the health care system, and having a female gender and be married have higher levels of knowledge and those with a history of previous education and Sistani descent had a higher attitude. Conclusion: In general, the mean level of knowledge was 46.73(0-100) and the mean level of attitude was 55.61(0-100). Factors such as: gender, work history in the health system, history of participating in educational workshops, history of caring for sick patients, and marital status were related to the level of knowledge and factors such as ethnicity and history of participating in the training workshop were related to the level of attitude of the health care providers.

Behavioral experiments have demonstrated that long-term physical exercise can be beneficial for learning and memory dysfunction caused by neuroinflammation in Alzheimer's disease (AD). However, the molecular mechanism remains poorly understood due to a lack of sufficient pertinent biochemical evidence. We investigated the potential effect of long-term physical exercise on cognition and hippocampal gene and protein expression changes in a transgenic AD mouse model. Following twenty weeks of treadmill exercise, transgenic AD mice showed improvement in cognitive functions and downregulation of Nod-like receptor protein 3 (NLRP3) (p ​

BackgroundLewy body (LB) dementias have limited clinical diagnostic accuracy because of frequent copathologies contributing to clinical heterogeneity. Although sex differences in clinical prevalence and frequency of pure LB pathology were shown, differences for clinicopathological correlations are less known.ObjectiveThe aim of this study was to determine sex differences for clinical associations of Alzheimer's disease (AD) copathology in those with LB pathology.MethodsData were from National Alzheimer's Coordinating Center for 223 women and 468 men with limbic or neocortical LB, separated into two groups as those with high likelihood and low/intermediate likelihood for LB clinical phenotype based on pathology. Clinical associations of sex and interaction of sex and pathology for the clinical phenotype were analyzed.ResultsMore severe AD copathology was associated with worse cognitive decline and lower likelihood of LB disease clinical phenotype. Women with more severe AD copathology and tau had worse cognitive decline and higher likelihood of AD clinical phenotype than men. Men with more severe AD copathology had lower likelihood of LB clinical phenotype than women. Interaction of sex and pathology was more pronounced in those aged between 70 and 80 years.ConclusionsAD copathology reduces the likelihood of LB clinical phenotype for both women and men; however, men may be at higher risk for LB disease underdiagnosis and women at higher risk for dementia. The use of both LB and AD biomarkers, even when LB or AD pathology is not clinically expected, is necessary for the accurate clinical diagnosis of both LB diseases and AD. © 2022 International Parkinson and Movement Disorder Society.

ObjectiveThere are minimal data directly comparing plasma neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) in aging and neurodegenerative disease research. We evaluated associations of plasma NfL and plasma GFAP with brain volume and cognition in two independent cohorts of older adults diagnosed as clinically normal (CN), mild cognitive impairment (MCI), or Alzheimer's dementia.MethodsWe studied 121 total participants (Cohort 1: n = 50, age 71.6 ± 6.9 years, 78% CN, 22% MCI; Cohort 2: n = 71, age 72.2 ± 9.2 years, 45% CN, 25% MCI, 30% dementia). Gray and white matter volumes were obtained for total brain and broad subregions of interest (ROIs). Neuropsychological testing evaluated memory, executive functioning, language, and visuospatial abilities. Plasma samples were analyzed in duplicate for NfL and GFAP using single molecule array assays (Quanterix Simoa). Linear regression models with structural MRI and cognitive outcomes included plasma NfL and GFAP simultaneously along with relevant covariates.ResultsHigher plasma GFAP was associated with lower white matter volume in both cohorts for temporal (Cohort 1: β = -0.33, p = .002; Cohort 2: β = -0.36, p = .03) and parietal ROIs (Cohort 1: β = -0.31, p = .01; Cohort 2: β = -0.35, p = .04). No consistent findings emerged for gray matter volumes. Higher plasma GFAP was associated with lower executive function scores (Cohort 1: β = -0.38, p = .01; Cohort 2: β = -0.36, p = .007). Plasma NfL was not associated with gray or white matter volumes, or cognition after adjusting for plasma GFAP.ConclusionsPlasma GFAP may be more sensitive to white matter and cognitive changes than plasma NfL. Biomarkers reflecting astroglial pathophysiology may capture complex dynamics of aging and neurodegenerative disease.

In microscopy-based drug screens, fluorescent markers carry critical information on how compounds affect different biological processes. However, practical considerations, such as the labor and preparation formats needed to produce different image channels, hinders the use of certain fluorescent markers. Consequently, completed screens may lack biologically informative but experimentally impractical markers. Here, we present a deep learning method for overcoming these limitations. We accurately generated predicted fluorescent signals from other related markers and validated this new machine learning (ML) method on two biologically distinct datasets. We used the ML method to improve the selection of biologically active compounds for Alzheimer's disease (AD) from a completed high-content high-throughput screen (HCS) that had only contained the original markers. The ML method identified novel compounds that effectively blocked tau aggregation, which had been missed by traditional screening approaches unguided by ML. The method improved triaging efficiency of compound rankings over conventional rankings by raw image channels. We reproduced this ML pipeline on a biologically independent cancer-based dataset, demonstrating its generalizability. The approach is disease-agnostic and applicable across diverse fluorescence microscopy datasets.

Alzheimer's disease (AD) is the major form of dementia prevalent in older adults and with a high incidence in females. Identification of early biomarkers is essential for preventive intervention to delay its progression. Furthermore, due to its multifactorial nature, a multi-target approach could be therapeutically beneficial. Our studies included 4- (pre-pathology) and 11-month (mild-pathology) TgF344-AD rats, a transgenic Alzheimer's model that exhibits age-dependent AD progression. We identified two potential early biomarker genes for AD, early growth response 2 (EGR2) and histone 1H2AA (HIST1H2AA), in the hippocampus of 4-month females. Out of 17,168 genes analyzed by RNA sequencing, expression of these two genes was significantly altered in 4-month TgF344-AD rats compared to wild-type littermates. We also evaluated co-treatment with diazoxide (DZ), a potassium channel activator, and dibenzoylmethane (DIB), which inhibits eIF2α-P activity, on TgF344-AD and wild-type rats. DZ/DIB-treatment mitigated spatial memory deficits and buildup of hippocampal Aβ plaques and tau PHF in 11-month TgF344-AD rats but had no effect on wild-type littermates. To our knowledge, this preclinical study is the first to report EGR2 and HIST1H2AA as potential AD biomarkers in females, and the benefits of DZ/DIB-treatment in AD. Evaluations across multiple AD-related models is warranted to corroborate our findings. [ABSTRACT FROM AUTHOR]

Background: To assess the effectiveness, safety, and tolerability of anti-Alzheimer agents (memantine, galantamine, rivastigmine, and donepezil) in controlling ADHD symptoms in children, adolescents, and adults. Methods: Following the PRISMA guideline, clinical trials assessing the potency of anti-Alzheimer medications in managing ADHD symptoms were imported from PubMed, Web of Science, and Scopus (until February 2023). Screening stages were conducted by two independent researchers. Two independent researchers also extracted data from clinical trials reporting the outcomes as the reduction in scores of ADHD questionnaires. The risk of bias within the included studies was assessed using the Cochrane Collaboration tool, while the certainty of outcomes was evaluated based on the GRADE criteria. Results: Of the initial 1597 studies, 11 studies were included. No studies were available for rivastigmine, and only a single study was conducted for galantamine. The results of the other two medications had a slight inconsistency. While both memantine and donepezil were reported to be effective in several studies, they were reported to be ineffective in some other studies. Side effects were mostly reduced appetite and headache. The tolerability of memantine, donepezil, and galantamine was all convincing. Conclusions: While galantamine did not demonstrate a promising efficacy in ADHD, memantine and donepezil showed effectiveness. However, future studies are needed to confirm their efficacy in ADHD since there was some inconsistency. [ABSTRACT FROM AUTHOR]

\nCONTRIBUTION TO THE FIELDMusic interventions show promise to support critical areas of decline for those living with dementia. There is a gap in identifying the skills and experiences necessary to facilitate the music activities in such an intervention. This pilot research creates an understanding of the characteristics and experiences of adolescent musicians who facilitated a digital, intergenerational music intervention. The research team conducted in-depth interviews with the adolescent participants and used descriptive phenomenological methodology. Eight adolescent musicians participated in the study, ranging from 14 to 18 years old. For characteristics, adolescents reported prior experience in music and key social supports. For experiences, adolescents reported decreased performance anxiety and increase in human connection and understanding of Alzheimer’s disease and dementia. There is potential for researchers to explore if adolescents who facilitate such a music intervention experience less performance anxiety as well as more empathy for those living with dementia. Demonstrates the potential that facilitating an intergenerational music intervention can have positive effects on adolescents’ music skills and social well-being, informing future pilot studies.Provides an understanding about the promise of adolescent musicians to facilitate an intergenerational music intervention for adults living with dementia, suggesting mutual benefits and scalability of this intergenerational design.Describes the characteristics of the adolescent musicians, informing future research studies and community programs of the qualities of adolescents for recruitment.Demonstrates the potential that facilitating an intergenerational music intervention can have positive effects on adolescents’ music skills and social well-being, informing future pilot studies.Provides an understanding about the promise of adolescent musicians to facilitate an intergenerational music intervention for adults living with dementia, suggesting mutual benefits and scalability of this intergenerational design.Describes the characteristics of the adolescent musicians, informing future research studies and community programs of the qualities of adolescents for recruitment. [ABSTRACT FROM AUTHOR]

The usefulness of Contingent Negative Variation (CNV) potential as a biomarker of neurocognitive disorders due to possible Alzheimer's disease, is based on its possible physiological correlates. However, its application in the diagnostic evaluation of these disorders is still incipient. The aim of this study is to characterize the patterns of cognitive processing of information in the domain of nonspecific global attention, by recording potential CNV in a group of patients with neurocognitive disorders due to possible Alzheimer's disease. An experimental study of cases and controls was carried out. The sample included 39 patients classified according to DSM-5 with a neurocognitive disorder subtype possibly due Alzheimer's disease, and a Control Group of 53 subjects with normal cognitive functions. CNV potential was registered using standard protocol. The analysis of variance obtained significant differences in mean values and confidence intervals of total CNV amplitude between the three study groups. The late CNV segment amplitudes makes it possible to discriminate between the level of mild and major dysfunction in the group of patients. The CNV total amplitudes of potential allows for effective discrimination between normal cognitive functioning and neurocognitive disorders due to possible Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Proteinaceous aggregates accumulate in neurodegenerative diseases such as Alzheimer's Disease (AD), inducing cellular defense mechanisms and altering the redox status. S100 pro-inflammatory cytokines, particularly S100B, are activated during AD, but recent findings reveal an unconventional molecular chaperone role for S100B in hindering Aβ aggregation and toxicity. This suggests a potential protective role for S100B at the onset of Aβ proteotoxicity, occurring in a complex biochemical environment prone to oxidative damage. Herein, we report an investigation in which extracellular oxidative conditions are mimicked to test if the susceptibility of S100B to oxidation influences its protective activities. Resorting to mild oxidation of S100B, we observed methionine oxidation as inferred from mass spectrometry, but no cysteine-mediated crosslinking. Structural analysis showed that the folding, structure, and stability of oxidized S100B were not affected, and nor was its quaternary structure. However, studies on Aβ aggregation kinetics indicated that oxidized S100B was more effective in preventing aggregation, potentially linked to the oxidation of Met residues within the S100:Aβ binding cleft that favors interactions. Using a cell culture model to analyze the S100B functions in a highly oxidative milieu, as in AD, we observed that Aβ toxicity is rescued by the co-administration of oxidized S100B to a greater extent than by S100B. Additionally, results suggest a disrupted positive feedback loop involving S100B which is caused by its oxidation, leading to the downstream regulation of IL-17 and IFN-α2 expression as mediated by S100B. [ABSTRACT FROM AUTHOR]

Citrus fruit essential oil is considered one of the widely studied essential oils while its leaves attract less attention although being rich in nearly the same composition as the peel and flowers. The leaves of bitter orange or sour orange (Citrus aurantium L.) were extracted using three different techniques namely; hydrodistillation (HD), steam distillation (SD), and microwave-assisted distillation (MV) to compare their chemical composition. The three essential oil samples were analyzed through GC/FID and GC/MS analyses. The samples were tested in vitro using different antioxidant techniques (DPPH, ABTS, CUPRAC, FRAP, PBD, and MCA), neuroprotective enzyme inhibitory activities (acetylcholine and butyl choline enzymes), and antidiabetic activities (α-amylase and α-glucosidase). The results showed that thirty-five volatile ingredients were detected and quantified. Monoterpenes represented the most abundant class in the three essential oils followed by sesquiterpenes. C. aurantium essential oil carried potential antioxidant activity where SD exhibited the highest antioxidant activity, with values arranged in the following order: FRAP (200.43 mg TE/g), CUPRAC (138.69 mg TE/g), ABTS (129.49 mg TE/g), and DPPH (51.67 mg TE/g). SD essential oil also presented the most potent α-amylase (0.32) inhibition while the MV essential oil showed the highest α-glucosidase inhibition (2.73 mmol ACAE/g), followed by HD (2.53 mmol ACAE/g), and SD (2.46 mmol ACAE/g). The SD essential oil exhibited the highest BChE and AChE inhibitory activities (3.73 and 2.06 mg GALAE/g), respectively). Thus, bitter orange essential oil can act as a potential source of potent antioxidant, antidiabetic, and neuroprotective activities for future drug leads. [ABSTRACT FROM AUTHOR]

The US Food and Drug Administration's approval of anti-amyloid therapies for the treatment of Alzheimer's dementia has resulted in a proliferation of publications reporting and conveying rapidly changing information. Unfortunately for the clinician, this information is surfacing in a variety of places and formats without a unifying consensus or clear guidance. [ABSTRACT FROM AUTHOR]

Purpose of Review: This comprehensive review delves into the intricate interplay between Alzheimer's disease (AD) and osteoporosis, two prevalent conditions with significant implications for individuals' quality of life. The purpose is to explore their bidirectional association, underpinned by common pathological processes such as aging, genetic factors, inflammation, and estrogen deficiency. Recent Findings: Recent advances have shown promise in treating both Alzheimer's disease (AD) and osteoporosis by targeting disease-specific proteins and bone metabolism regulators. Monoclonal antibodies against beta-amyloid and tau for AD, as well as RANKL and sclerostin for osteoporosis, have displayed therapeutic potential. Additionally, ongoing research has identified neuroinflammatory genes shared between AD and osteoporosis, offering insight into the interconnected inflammatory mechanisms. This knowledge opens avenues for innovative dual-purpose therapies that could address both conditions, potentially revolutionizing treatment approaches for AD and osteoporosis simultaneously. Summary: This review underscores the potential for groundbreaking advancements in early diagnosis and treatment by unraveling the intricate connection between AD and bone health. It advocates for a holistic, patient-centered approach to medical care that considers both cognitive and bone health, ultimately aiming to enhance the overall well-being of individuals affected by these conditions. This review article is part of a series of multiple manuscripts designed to determine the utility of using artificial intelligence for writing scientific reviews. [ABSTRACT FROM AUTHOR]

Background: Combining multimodal lifestyle interventions and disease-modifying drugs (novel or repurposed) could provide novel precision approaches to prevent cognitive impairment. Metformin is a promising candidate in view of the well-established link between type 2 diabetes (T2D) and Alzheimer's Disease and emerging evidence of its potential neuro-protective effects (e.g. vascular, metabolic, anti-senescence). MET-FINGER aims to test a FINGER 2.0 multimodal intervention, combining an updated FINGER multidomain lifestyle intervention with metformin, where appropriate, in an APOE ε4-enriched population of older adults (60–79 years) at increased risk of dementia. Methods: MET-FINGER is an international randomised, controlled, parallel-group, phase-IIb proof-of-concept clinical trial, where metformin is included through a trial-within-trial design. 600 participants will be recruited at three sites (UK, Finland, Sweden). Participants at increased risk of dementia based on vascular risk factors and cognitive screening, will be first randomised to the FINGER 2.0 intervention (lifestyle + metformin if eligible; active arm) or to receive regular health advice (control arm). Participants allocated to the FINGER 2.0 intervention group at risk indicators of T2D will be additionally randomised to receive metformin (2000 mg/day or 1000 mg/day) or placebo. The study duration is 2 years. The changes in global cognition (primary outcome, using a Neuropsychological Test Battery), memory, executive function, and processing speed cognitive domains; functional status; lifestyle, vascular, metabolic, and other dementia-related risk factors (secondary outcomes), will be compared between the FINGER 2.0 intervention and the control arm. The feasibility, potential interaction (between-groups differences in healthy lifestyle changes), and disease-modifying effects of the lifestyle-metformin combination will be exploratory outcomes. The lifestyle intervention is adapted from the original FINGER trial (diet, physical activity, cognitive training, monitoring of cardiovascular/metabolic risk factors, social interaction) to be consistently delivered in three countries. Metformin is administered as Glucophage®XR/SR 500, (500 mg oral tablets). The metformin/placebo treatment will be double blinded. Conclusion: MET-FINGER is the first trial combining a multimodal lifestyle intervention with a putative repurposed disease-modifying drug for cognitive impairment prevention. Although preliminary, its findings will provide crucial information for innovative precision prevention strategies and form the basis for a larger phase-III trial design and future research in this field. Trial registration: ClinicalTrials.gov (NCT05109169). [ABSTRACT FROM AUTHOR]

Introduction: Caring for people with Alzheimer's disease (AD) is burdensome, especially when family members act as caregivers. This multicenter survey first aimed to investigate caregivers' mental states as well as its influencing factors in caring for people with different severities of AD in China. Methods: People with AD and their caregivers from 30 provincial regions in mainland China were enrolled from October 2020 to December 2020 to be surveyed for caregivers' mental states and living conditions, as well as caregivers' attitudes toward treatment and caring. Logistic regression was used to explore the factors that influence the positive and negative states of caregivers who care for people with different stages of AD. Results: A total of 1,966 valid questionnaires were analyzed (mild AD: 795, moderate AD: 521, severe AD: 650). A total of 73.6% of caregivers maintained normal states (mild group: 71.9%, moderate group: 73.9%, severe group: 75.2%; X2 = 2.023, p = 0.364), and the proportions of caregivers with positive and negative states were 26.3% (mild group: 38.4%, moderate group: 24.6%, severe group: 13.1%; X2 = 119.000, p < 0.001) and 36.5% (mild group: 25.2%, moderate group: 36.9%, severe group: 50.2%; X2 = 96.417, p < 0.001), respectively. The major factors that both influenced caregivers' positive and negative states were the severity of AD, perceived efficacy of treatment, safety issues after AD dementia diagnosis and perceived social support (p < 0.005), while neuropsychiatric symptoms causing stress in caregivers (p < 0.001) only affected the negative states of caregivers. The results of further analysis according to disease severity showed that safety issues after AD dementia diagnosis (p < 0.005) only made significant differences in the mild-to-moderate group. Conclusion: To reduce negative states and promote positive states among caregivers, flexible and sensitive caregiving support could be built on caregivers' demands in caring for people with different stages of AD. The support of emotion, social functioning and nursing skills is one of the significant ways for health workers to enhance caregivers' competency. [ABSTRACT FROM AUTHOR]

ZCCHC17 is a putativemaster regulator of synaptic gene dysfunction in Alzheimer's disease (AD), and ZCCHC17 protein declines early in AD brain tissue, before significant gliosis or neuronal loss. Here, we investigate the function of ZCCHC17 and its role in AD pathogenesis using data fromhuman autopsy tissue (consisting of males and females) and female human cell lines. Co-immunoprecipitation (co-IP) of ZCCHC17 followed by mass spectrometry analysis in human iPSC-derived neurons reveals that ZCCHC17's binding partners are enriched for RNA-splicing proteins. ZCCHC17 knockdown results in widespread RNA-splicing changes that significantly overlap with splicing changes found in AD brain tissue, with synaptic genes commonly affected. ZCCHC17 expression correlates with cognitive resilience in AD patients, and we uncover an APOE4-dependent negative correlation of ZCCHC17 expression with tangle burden. Furthermore, amajority of ZCCHC17 interactors also co-IP with known tau interactors, and we find a significant overlap between alternatively spliced genes in ZCCHC17 knockdown and tau overexpression neurons. These results demonstrate ZCCHC17's role in neuronal RNA processing and its interaction with pathology and cognitive resilience in AD, and suggest that the maintenance of ZCCHC17 function may be a therapeutic strategy for preserving cognitive function in the setting of AD pathology. [ABSTRACT FROM AUTHOR]

The world's population is in a demographical transition, with an increase in the number of older adults and prevalence of diseases related to aging. This study evaluated in vitro the potential of using Durvillaea incurvata extract (extracted using ultrasound-assisted extraction) to inhibit key enzymes associated with the development of age-related diseases. Our results show that an extract extracted via ultrasound-assisted extracted, as well as an extract conventional extracted from Durvillaea incurvata, presented antidiabetes potential by exhibiting inhibitory activity against α-glucosidase (91.8 ± 1.0% and 93.8 ± 0.3%, respectively, at 500 µg/mL) and α-amylase (42.2 ± 1.4% and 61.9 ± 0.9%, respectively, at 1500 µg/mL) enzymes related to starch digestion and postprandial glycemic response. Also, the extracts showed inhibitory activity against the enzymes acetylcholinesterase (51.5% and 50.8%, respectively, at 500 µg/mL) and butyrylcholinesterase (32.8% and 34.4%, respectively, at 0.5 mg/mL), the biomarkers associated with Alzheimer's disease, and angiotensin-converting enzyme (98.7 ± 7.4% and 93.0 ± 3.4%, respectively, at 2.0 mg/mL), which is key in the regulation of vascular tone and blood pressure and helps to prevent the development of hypertension. In conclusion, the extract of Durvillaea incurvata obtained from ultrasound-assisted extraction has the potential to prevent the development of age-related pathologies such as diabetes, Alzheimer's disease, and hypertension. [ABSTRACT FROM AUTHOR]

α-Synuclein is an important drug target for the treatment of Parkinson’s disease (PD), but it is an intrinsically disordered protein lacking typical small-molecule binding pockets. In contrast, the encoding SNCA mRNA has regions of ordered structure in its 5′ untranslated region (UTR). Here, we present an integrated approach to identify small molecules that bind this structured region and inhibit α-synuclein translation. A drug-like, RNA-focused compound collection was studied for binding to the 5′ UTR of SNCA mRNA, affording Synucleozid-2.0, a drug-like small molecule that decreases α-synuclein levels by inhibiting ribosomes from assembling onto SNCA mRNA. This RNA-binding small molecule was converted into a ribonuclease-targeting chimera (RiboTAC) to degrade cellular SNCA mRNA. RNA-seq and proteomics studies demonstrated that the RiboTAC (Syn-RiboTAC) selectively degraded SNCA mRNA to reduce its protein levels, affording a fivefold enhancement of cytoprotective effects as compared to Synucleozid-2.0. As observed in many diseases, transcriptome-wide changes in RNA expression are observed in PD. Syn-RiboTAC also rescued the expression of ~50% of genes that were abnormally expressed in dopaminergic neurons differentiated from PD patient–derived iPSCs. These studies demonstrate that the druggability of the proteome can be expanded greatly by targeting the encoding mRNAs with both small molecule binders and RiboTAC degraders. [ABSTRACT FROM AUTHOR]

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Astrocyte-derived extracellular vesicles (ADEVs) have garnered attention as a fundamental mechanism of intercellular communication in health and disease. In the context of neurological diseases, for which prodromal diagnosis would be advantageous, ADEVs are also being explored for their potential utility as biomarkers. In this review, we provide the current state of data supporting our understanding on the manifold roles of ADEVs in several common neurological disorders. We also discuss these findings from a unique emerging perspective that ADEVs represent a means by which the central nervous system may broadcast influence over other systems in the body to affect neuroinflammatory processes, with both dual potential to either propagate illness or restore health and homeostasis. [ABSTRACT FROM AUTHOR]

Objectives: This article examines a novel theoretical framework, which we term Home Triad, for research and practice involving people living with dementia (PLWD). Background: Most of the existing home-related research on PLWD focuses on interior modifications, home care interventions and models, place attachment, and/or institutional homelike environments. However, limited studies have examined the meaning of home from PLWD's perspective, and even fewer have simultaneously considered the individual experience of PLWD, the external power (e.g., the role of design), and their interaction dynamics in the meaning-making process. Methods: We developed home triad based on Lefebvre's spatial triad. Inspired by Chaudhury's home story structure, we conducted a life story analysis of a person living with dementia, "Kai," under four contexts—childhood home, neighborhood and city, daily routine, and attachment—within home triad. Results: Home triad abstracts "home" with a dialectically interconnected relationship of the conceived, perceived, and lived home. Through PLWD's everyday life, the essence of home is primarily shaped by the interaction between their lived and perceived homes. However, a person's experiences of and participation in home living activities are also planned and/or regulated by different groups of people (caregivers, designers, and policymakers), who play important roles in the conceived home. Critically examining how PLWD's lived and perceived home is constrained or enabled through the conceived home deserves greater future research efforts. Conclusion: A systematic examination of the essence of home for PLWD using home triad can facilitate subsequent research and practice that promote PLWD's health, well-being, and quality of life. [ABSTRACT FROM AUTHOR]

Liver transplant (LT) recipients have a high burden of cognitive impairment risk factors identified in other populations, yet little work has explored cognition in the United States LT population. We characterized prevalence of cognitive impairment (CI) in LT recipients pre‐LT and ≥3 months post‐LT. Adult LT recipients with cirrhosis but without active pre‐LT hepatic encephalopathy (HE) were screened for CI using the Montreal Cognitive Assessment (MoCA) for CI (MoCA <24) both pre‐LT and ≥3 months post‐LT. The association between cognitive performance and recipient characteristics was assessed using logistic regression. Of 107 LT recipients, 36% had pre‐LT CI and 27% had post‐LT CI [median (Q1–Q3) MoCA 26 (23–28)]. Each 1‐point increase in pre‐LT MoCA was associated with 26% lower odds of post‐LT cognitive impairment (aOR.74, 95% CI.63–.87, p <.001), after adjusting for recipient age, history of HE, and time since LT. In this study of cirrhosis recipients without active pre‐LT HE, cognitive impairment was prevalent before LT and remained prevalent ≥3 months after LT (27%), long after effects of portal hypertension on cognition would be expected to have resolved. Our data expose an urgent need for more comprehensive neurologic examination of LT recipients to better identify, characterize, and address predictors of post‐LT cognitive impairment. [ABSTRACT FROM AUTHOR]

The present work analyzes the repercussion of the nontoxic engraving technique Collagraph, in people with Early Alzheimer's Dementia, in the artistic education program "Retales de una vida". The objective is to connect the participants with programs of a cultural nature to encourage communication and interaction between participants. The experience was carried out at the State Reference Center for people with Alzheimer's and other Dementias of Salamanca (CREA). Once the methodology of the workshop has been adapted to the personal and health characteristics of people with Alzheimer's disease, it is considered that the use of engraving generates important benefits in the participants, related to the increase in crystallized intelligence, prosocial behavior and positive assessment. of themselves, favoring social and family inclusion. Likewise, the use of engraving can offer support for individual and cooperative therapeutic help to the participants, develop functional, social and cognitive skills, expanding their emotional resources and enjoying the experience. In turn, they strengthen their self-esteem and security in the face of their ability and worth. Finally, we propose a series of guidelines for the planning and implementation of this artistic process so that it serves as a reference for health professionals. [ABSTRACT FROM AUTHOR]

Swertia species are common ingredients in numerous herbal remedies. It is also used to treat a wide range of illnesses and possess diverse therapeutic activities. The aim of the study is to elucidate the comprehensive metabolomics profile of Swertia chirayita and the role of various extraction methods in the phytochemical compositions of the extracts of S. chirayita, and their antioxidant and enzyme inhibitory activities. Extraction of the stems, leaves, and flowering tops of S. chirayita was performed by maceration, infusion, and soxhlation using methanol and water as solvent. Extracts were subjected to phytochemical profiling by a liquid‐chromatographic system. Antioxidant and enzyme inhibitory activity was carried out. The metabolomics profiling showed that a diverse range of specialized metabolites were present in the stems and leaves & flowering tops of the plant. All the extracts showed substantial antioxidant and enzyme inhibitory activities further confirmed by molecular docking studies. This study appraised the use of S. chirayita aerial parts as a potential antioxidant and its therapeutic application in various chronic illnesses including Alzheimer's disease, diabetes, and other skin‐related disorders. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease (AD) stands as the most prevalent form of dementia affecting elderly individuals and ranks as the sixth leading cause of death globally. The pathological hallmarks of AD involve the formation of beta-amyloid plaques and neurofibrillary tangles in the brains of affected individuals, contributing to progressive brain degradation. This study aimed to utilize molecular modeling methods as a theoretical approach to explore the inhibition of beta-amyloid plaques and neurofibrillary tangles. Beta-amyloid and tau receptors were employed to carry out molecular docking with the ligands, including curcumin, memantine, nicotine, and caffeine. The selected compounds demonstrated minimum binding affinity and interactions with the active sites of the receptors while docking studies were performed. Notably, molecular interactions of the receptor complexes with curcumin compounds exhibited prominence in number. Curcumin, known for its antioxidant, anti-inflammatory, and lipophilic properties, has shown promise in enhancing cognitive function in AD patients. The findings of this study highlight the potential for further research aimed at developing improved drugs based on curcumin for the treatment of AD. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Alzheimer's disease studies often lack ethnic diversity. METHODS: We evaluated associations between plasma biomarkers commonly studied in Alzheimer's (p‐tau181, GFAP, and NfL), clinical diagnosis (clinically normal, amnestic MCI, amnestic dementia, or non‐amnestic MCI/dementia), and Aβ‐PET in Hispanic and non‐Hispanic older adults. Hispanics were predominantly of Cuban or South American ancestry. RESULTS: Three‐hundred seventy nine participants underwent blood draw (71.9 ± 7.8 years old, 60.2% female, 57% Hispanic of which 88% were Cuban or South American) and 240 completed Aβ‐PET. P‐tau181 was higher in amnestic MCI (p = 0.004, d = 0.53) and dementia (p < 0.001, d = 0.97) than in clinically normal participants and discriminated Aβ‐PET[+] and Aβ‐PET[‐] (AUC = 0.86). P‐tau181 outperformed GFAP and NfL. There were no significant interactions with ethnicity. Among amnestic MCI, Hispanics had lower odds of elevated p‐tau181 than non‐Hispanic (OR = 0.41, p = 0.006). DISCUSSION: Plasma p‐tau181 informs etiological diagnosis of cognitively impaired Hispanic and non‐Hispanic older adults. Hispanic ethnicity may relate to greater likelihood of non‐Alzheimer's contributions to memory loss. Highlights: Alzheimer's biomarkers were measured in Hispanic and non‐Hispanic older adults.Plasma p‐tau181 related to amnestic cognitive decline and brain amyloid burden.AD biomarker associations did not differ between Hispanic and non‐Hispanic ethnicity.Hispanic individuals may be more likely to have non‐Alzheimer causes of memory loss. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Down syndrome (DS) is a genetic cause of early‐onset Alzheimer's disease (AD). The National Institute on Aging–Alzheimer's Association AT(N) Research Framework is a staging model for AD biomarkers but has not been assessed in DS. METHOD: Data are from the Alzheimer's Biomarker Consortium–Down Syndrome. Positron emission tomography (PET) amyloid beta (Aβ; 15 mCi of [11C]Pittsburgh compound B) and tau (10 mCi of [18F]AV‐1451) were used to classify amyloid (A) –/+ and tau (T) +/–. Hippocampal volume classified neurodegeneration (N) –/+. The modified Cued Recall Test assessed episodic memory. RESULTS: Analyses included 162 adults with DS (aged M = 38.84 years, standard deviation = 8.41). Overall, 69.8% of participants were classified as A–/T–/(N)–, 11.1% were A+/T–/(N)–, 5.6% were A+/T+/(N)–, and 9.3% were A+/T+/(N)+. Participants deemed cognitively stable were most likely to be A–T–(N)– and A+T–(N)–. Tau PET (T+) most closely aligning with memory impairment and AD clinical status. DISCUSSION: Findings add to understanding of AT(N) biomarker profiles in DS. Highlights: Overall, 69.8% of adults with Down syndrome (DS) aged 25 to 61 years were classified as amyloid (A)–/tau (T)–/neurodegeneration (N)–, 11.1% were A+/T–/(N)–, 5.6% were A+/T+/(N)–, and 9.3% were A+/T+/(N)+.The AT(N) profiles were associated with clinical Alzheimer's disease (AD) status and with memory performance, with the presence of T+ aligned with AD clinical symptomology.Findings inform models for predicting the transition to the prodromal stage of AD in DS. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Alzheimer's disease (AD) and AD‐related dementias (ADRD) are leading causes of death among older adults in the United States. Efforts to understand risk factors for prevention are needed. METHODS: Participants (n = 146,166) enrolled in the Women's Health Initiative without AD at baseline were included. Diabetes status was ascertained from self‐reported questionnaires and deaths attributed to AD/ADRD from hospital, autopsy, and death records. Competing risk regression models were used to estimate the cause‐specific hazard ratios (HRs) and 95% confidence intervals (CIs) for the prospective association of type 2 diabetes mellitus (T2DM) with AD/ADRD and non‐AD/ADRD mortality. RESULTS: There were 29,393 treated T2DM cases and 8628 AD/ADRD deaths during 21.6 (14.0–23.5) median (IQR) years of follow‐up. Fully adjusted HRs (95% CIs) of the association with T2DM were 2.94 (2.76–3.12) for AD/ADRD and 2.65 (2.60–2.71) for the competing risk of non‐AD/ADRD mortality. DISCUSSION: T2DM is associated with AD/ADRD and non‐AD/ADRD mortality. Highlights: Type 2 diabetes mellitus is more strongly associated with Alzheimer's disease (AD)/AD and related dementias (ADRD) mortality compared to the competing risk of non‐AD/ADRD mortality among postmenopausal women.This relationship was consistent for AD and ADRD, respectively.This association is strongest among participants without obesity or hypertension and with younger age at baseline, higher diet quality, higher physical activity, higher alcohol consumption, and older age at the time of diagnosis of type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Surface-enhanced Raman spectroscopy (SERS) has recently emerged as a potent analytical technique with significant potential in the field of brain research. This review explores the applications and innovations of SERS in understanding the pathophysiological basis and diagnosis of brain disorders. SERS holds significant advantages over conventional Raman spectroscopy, particularly in terms of sensitivity and stability. The integration of label-free SERS presents promising opportunities for the rapid, reliable, and non-invasive diagnosis of brain-associated diseases, particularly when combined with advanced computational methods such as machine learning. SERS has potential to deepen our understanding of brain diseases, enhancing diagnosis, monitoring, and therapeutic interventions. Such advancements could significantly enhance the accuracy of clinical diagnosis and further our understanding of brain-related processes and diseases. This review assesses the utility of SERS in diagnosing and understanding the pathophysiological basis of brain disorders such as Alzheimer's and Parkinson's diseases, stroke, and brain cancer. Recent technological advances in SERS instrumentation and techniques are discussed, including innovations in nanoparticle design, substrate materials, and imaging technologies. We also explore prospects and emerging trends, offering insights into new technologies, while also addressing various challenges and limitations associated with SERS in brain research. [ABSTRACT FROM AUTHOR]

Introduction: The exclusion of affected populations from Alzheimer's disease (AD) clinical research limits our understanding of disease heterogeneity and its impact on clinical care. While micro sampling with dried plasma spots (DPS) can promote inclusivity by enabling sample collection in remote areas, current techniques lack the sensitivity required for the quantification of phosphorylated tau at Thr181 (pTau‐181) in DPS extracts. Methods: We developed an assay for pTau‐181 with reduced bead count and improved bead read efficiency (BRE) using a prototype Simoa instrument. This novel assay's performance was evaluated against standard pTau‐181 assays on two Simoa platforms, and DPS extracts were tested for pTau‐181 quantification feasibility. Results: The novel assay quantifies pTau‐181 at concentrations up to 16x lower than traditional pTau‐181 assays on HD‐X and SR‐X platforms. DPS extracts tested with our low‐bead assay were quantified considerably above the lower limit of quantification (LLOQ), indicating the suitability of this assay for future DPS extract measurements. Discussion: Implementing DPS sampling and pTau‐181 quantification could increase participation from underrepresented groups in AD research. However, additional assay optimization and an in‐depth study of preanalytical sample stability are essential for the transition to clinical applicability. [ABSTRACT FROM AUTHOR]