bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of the instrument protocol to verify the effects of the iSupport‐Brasil program for caregivers of people living with dementia
Authors: Ferreira Camila Rafael , Ottaviani Ana Carolina , Monteiro Diana Quirino , Cardoso Anabel Machado , Barbosa Gustavo Carrijo , Correa Larissa , Rocha Luana Aparecida , Maciel Luiza Barros , Barham Elizabeth Joan , Monteiro Diana Q , de Cruz Keila Cristianne Trindade , Pavarini Sofia Cristina Iost , Monteiro Diana Q , Oliveira Déborah 
Published: December 2023

AbstractBackgroundThe World Health Organization (WHO) developed iSupport, an online, psychoeducational program for informal caregivers who assist someone who lives with dementia. The iSupport program is being adapted for use in many countries, and in Brazil, we now need to evaluate the effects of this program. However, there are no Brazilian versions of instruments needed to evaluate some of the expected outcomes (self‐efficacy, mastery, and positive aspects of caregiving) and there are no online versions of the instruments. The objective of this study was to evaluate an online protocol to evaluate the effects of the iSupport program, in Brazil.MethodAn online data‐collection form was developed for use in Brazil, based on the protocol suggested by the WHO and considering protocols being used in other countries. Caregivers who were eligible for using the program were accompanied while completing this protocol, to identify their doubts and difficulties. There were seven participants, in two subgroups, so issues identified by one group could be resolved before testing the protocol with the next. Problems were discussed in research team meetings, and solutions were developed.ResultCaregivers indicated problems that resulted in the exclusion of instruments that had similar objectives, the modification of response alternatives to better reflect the diversity of people who are informal caregivers, and wording changes to improve the clarity of instructions or items.ConclusionThis study was important for maximizing the acceptability of the protocol and the usability of the response form we developed for evaluating the Brazilian version of the iSupport program. Thus, community participation in the development of research protocols should help maximize participation rates and the validity of the information gathered, which, in this case, involves the mental health and wellbeing of informal caregivers who assist people living with dementia. Furthermore, this process enabled us to work on cultural and format adaptations of the instruments needed for evaluating the effects of the iSupport‐Brasil program, so that our protocol will be aligned with those being used in other countries to evaluate the effects of the iSupport program.
Study of microRNAs and their targets in exosome from Alzheimer’s and Frontotemporal Dementia patients
Authors: Gerlando Rosalinda Di , Garofalo Maria , Busacca Maria , Francesca Dragoni , Matteo Bordoni , Scarian Eveljn , Perini Giulia , Ramusino Matteo Cotta , Costa Alfredo , Pansarasa Orietta , Gagliardi Stella 
Published: December 2023

AbstractBackgroundA central role of RNA metabolism and non‐coding RNAs biogenesis has emerged in Alzheimer’s disease (AD) and Frontotemporal Dementia (FTD). We investigated miRNA cargo of Small Extracellular Vesicles (SEVs) derived from plasma of FTD and AD patients, and Healthy Controls (HC). The purpose was to evaluate deregulated miRNAs in patients to identify new peripheral biomarkers and to determine mRNA targets involved in FTD and AD pathogenesis.MethodSEVs were isolated from plasma of 13 FTD patients, 20 AD and 20 HC by differential centrifugation and characterized by Nanosight and Western Blot. MicroRNA libraries were generated using Small RNA Seq Library Prep Kit (Lexogen) and sequenced on a NextSeq 500 (Illumina). Interaction prediction was carried out on TarBase v.8 database.ResultWe found a total of 339 Differentially Expressed (DE) microRNAs in FTD, and 291 DE microRNAs in AD compared to controls. Interestingly, 74 miRNAs were commonly deregulated: 38 had the same trend and 36 had an opposite trend. In order to find a miRNA biomarker able to discern FTD and AD, we selected 8 DE miRNAs with opposite trend based on fold changes difference and targets. In fact these miRNAs were found to have validated mRNAs target that may be of interest for molecular study of dementia, such as APP and PTEN.ConclusionOur data highlight the importance of miRNAs cargo examination in EVs of FTD and AD patients. In fact, their potential is exploitable both for biomarkers discovery and for study of gene expression alteration in dementia pathogenesis.
Neurons and astrocytes derived from human iPSCs to model Alzheimer´s disease
Authors: Palomo Laura Caceres , Trujillo‐Estrada Laura , Oliva Elba Lopez , Vitorica Javier , Gutierrez Antonia , Leon Juan Antonio Garcia 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is characterized by presenting a complex pathology, not fully resolved yet. This fact, together with the lack of reliable models, has impeded the development of effective therapies. Recently, several studies have shown that functional glial cell defects have a key role in the pathology of AD. However, this glial dysfunction, currently, cannot be correctly modeled using the available animal models, so we hypothesized that cells derived from Alzheimer’s patients can serve as a better platform for studying the disease. In this sense, human pluripotent stem cells (hPSC) allow the generation of different types of neural cells, which can be used for disease modeling, identification of new targets and drugs development.MethodWe have a collection of hiPSCs derived from patients with sporadic forms of AD stratified based on APOE genotype. We have differentiated these cells towards neural cells and mature them to neurons or astrocytes using a serum‐free approach, to assess intrinsic differences between those derived from AD patients or healthy controls.ResultWe have implemented a serum‐free approach and generated neural precursors and astrocytes from all the lines tested. We observe differences at the phenotypic level and a reduced capacity to differentiate towards neural lineage in those lines derived from APOE4 carriers.ConclusionOur preliminary data suggest intrinsic differences in the neural differentiation capacity between cell lines derived from APOE4 or APOE3 carrier subjects. Further experiments would contribute to elucidate novel pathogenic pathways associated with neurodegeneration and susceptible of therapeutic modulation, likely contributing to the development of new effective drugs against AD.Acknowledgments: This study was supported by Instituto de Salud Carlos III (ISCiii) of Spain, co‐financed by FEDER funds from European Union, through grants PI21/00915 (to AG) and PI21/00914 (to JV); by Junta de Andalucia through Consejería de Economía y Conocimiento grants UMA20‐FEDERJA‐048 (to JAGL), PY18‐RT‐2233 (to AG) and US‐1262734 (to JV) co‐financed by Programa Operativo FEDER 2014‐2020, University of Malaga (B1‐2020_04) to JAGL and Programa Operativo de Empleo Juvenil SNGJ4‐11 to LCP.
Nanobodies: a promising tool to perturb ApoE4 activity in Alzheimer’s disease pathology
Authors: Vandevelde Laure , Zwaenepoel Olivier , Gettemans Jan , Braeckmans Kevin 
Published: December 2023

AbstractBackgroundThe APOE‐ε4 allele encoding for apolipoprotein (apo) E4, an isoform of the APOE gene, is the strongest genetic risk factor for Alzheimer’s disease (AD). The exact mechanism by which apoE4 increases this risk is not fully understood. However, apoE4 has a very different structure than the other isoforms, apoE2 and apoE3, and it is suggested that this different structure contributes to the development of AD1. More efforts are still needed to further understand how apoE4 contributes to AD pathogenesis. Single domain antibodies or nanobodies are versatile tools to reveal new information on apoE4 and its pathological effects in AD.MethodsNanobodies are routinely obtained from immunized camelids, or from naïve libraries. Nanobodies need to be characterized by i.e. immunoprecipitation with apoE2, apoE3 and apoE4 and their affinity can be determined via an Octet device. Via laser‐induced photoporation, nanobodies can be delivered into living induced pluripotent stem cell derived APOE‐ε4 homozygous neurons. Nanobodies can be tagged with a fluorophore via click chemistry and derivates can be made by equipping them with a degradation or delocalization tag (cloning).ResultsLlama immunization will lead to a set of ApoE‐targeting nanobodies which will be further reduced to a couple of nanobodies after their further characterization (specificity and affinity). Given the high similarity between apoE isoforms, it is to be expected that some nanobodies will cross‐react with different isoforms. Because nanobodies recognize conformational epitopes it is likely that ApoE4 nanobodies can be generated.Delivery of the nanobodies into apoE4 expressing neurons allows to manipulate endogenous apoE4 and as such our approach does not require expression modulation of the target: the protein can be degraded or it can be trapped/relocated to different regions or organelles in cells. We aim to perturb apoE4 in a way that typical AD pathologies seen in AD neurons are ameliorated and as such gain more insight about the pathophysiology of apoE4 effects in AD.ConclusionNanobodies are excellent tools to uncover new biological information concerning apoE4.References:1 Najm, R., Jones, E. A., & Huang, Y. (2019). Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease. Molecular neurodegeneration, 14(1), 1‐13.
Unpuzzling the relationship between hypertension, stroke, and Alzheimer’s disease – an observation from the Australian Imaging Biomarkers and Lifestyle Study
Authors: Ma Liwei , Chu Chenyin , Zhuo Yuanhao , Sun Jiaqi , Masters Colin L , Jin Liang , Pan Yijun 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD), hypertension and stroke are common diseases in elderly people, but whether they are intrinsically linked with each other remains uncertain. The aim of this study was to investigate the risks of people who have hypertension and stroke to develop mild cognitive impairment (MCI) and AD, and if hypertension and stroke are risk factors for AD.MethodThe longitudinal data was retrieved from the Australian Imaging Biomarkers and Lifestyle Study (AIBL). The prevalence of hypertension and stroke was compared between cognitively normal (CN) participants, participants who were CN but subsequently diagnosed with MCI/AD during the study (refer to as participants exhibited cognitive decline), and participants with AD confirmed at recruitment.ResultThe prevalence of hypertension (odds ratio [OR] = 1.37, 95% confidence interval [CI] = 1.05 ‐ 1.77, p = 0.018) was significantly higher in participants exhibited cognitive decline than CN participants. Interestingly, the prevalence of hypertension (OR = 0.88, 95% CI = 0.70 ‐ 1.11, p = 0.287) was comparable between CN and AD participants. This observation suggested that hypertension is a risk factor for the progression of cognitive decline. The prevalence of stroke was significantly higher in participants exhibited cognitive decline (OR = 2.04, 95% CI = 1.10 ‐ 3.79, p = 0.024) and AD participants (OR = 3.43, 95% CI = 2.09 – 5.64, p<0.001) than CN participants. This observation suggested that stroke is a risk factor for the progression of cognitive decline and AD.ConclusionThis preliminary study demonstrated that hypertension and stroke are risk factors for the progression of cognitive decline, and stroke is a risk factor for AD. Given the elevated risk in cognitive decline, the cognitive function of elderly people with hypertension or history of stroke should be monitored for timely detection of MCI and AD.
Bidirectional associations between quality of life and cognitive function over 17 years: Evidence from the English Longitudinal Study of Ageing (ELSA)
Authors: John Amber , Desai Roopal , Marchant Natalie L , Woodward‐Carlton Barbara , Saunders Rob , Bell Georgia , Gonzalez Aida , Gaysina Darya , Richards Marcus , Stott Joshua 
Published: December 2023

AbstractBackgroundDepression and anxiety are well recognised as risk factors for dementia and poorer cognitive outcomes. However, considerably less is known about the relationship between quality of life and cognitive function over time. Quality of life is not simply the absence of mental health problems, but instead is a related but distinct construct. In particular, it is unclear whether poorer quality of life precedes cognitive decline, or vice versa or whether there is a bidirectional relationship. This is of import because understanding directionality allows us to start to plan interventions around dementia risk reduction. The aim of this study was to test bidirectionality between quality of life and memory in a large, nationally representative sample of people aged 50+ without cognitive impairment.MethodData were used from the English Longitudinal Study of Ageing (ELSA), a longitudinal cohort comprising 12,099 people over the age of 50 and their partners. Repeated measures of quality of life and memory (immediate and delayed) were available nine times over a 17‐year period. Cross‐lagged models were fitted to test for bidirectionality between quality of life and memory function.ResultThe fully adjusted model revealed that higher quality of life was significantly associated with higher subsequent immediate memory scores at all time‐points, and with higher subsequent delayed memory scores at all except the final time‐point. There was no consistent evidence that memory was significantly associated with subsequent quality of life.ConclusionThese results extend previous research by providing evidence for the temporal association between quality of life and memory in a population‐based sample of people aged 50+. Specifically, results suggest that quality of life is consistently associated with later memory function over nearly two decades, though the study did not provide evidence that the association operates in the opposite direction. The lack of consistent evidence for a relationship between cognitive function and subsequent quality of life may be due to the exclusion of people with cognitive impairment and adjustment for depressive symptoms. Better quality of life may act as a protective factor in retaining memory function from middle to later adulthood.
Developing a classifier to screen for mild cognitive impairment and Alzheimer’s disease using machine learning approaches
Authors: Chu Chenyin , Ma Liwei , Zhuo Yuanhao , Sun Jiaqi , Masters Colin L , Goudey Benjamin , Jin Liang , Pan Yijun 
Published: December 2023

AbstractBackgroundMachine learning classifier is a powerful tool that has been recently applied to datasets of Alzheimer’s disease (AD). The majority of approaches developed to classify people with mild cognitive impairment (MCI) and Alzheimer’s disease (AD) from cognitively normal (CN) people have made use of expensive or invasive measurements, discouraging the clinical use of these tools. In the current study, we aimed to develop a classifier to screen for MCI and AD using data that can be routinely collected at low cost (e.g. blood pressure, ApoE genotype).MethodDatabase of the Australian Imaging Biomarkers and Lifestyle Study of Ageing (AIBL) was used (n = 14553 data entries). Dataset was split into two parts: training (80%) and testing (20%). A decision tree was first employed to screen for factors (i.e. clinical parameters) that can effectively discriminate CN, MCI, and AD (Step 1). To further refine factor selection, the association between the factors (from screening) and health status (CN, MCI, AD) were assessed using linear and logistic regression methods. Factors that were rejected by the hypothesis test (i.e. non‐obvious relationship with MCI or AD) and those require high cost for collection were removed (Step 2). The remaining factors were used for the construction of the classifier, where decision tree, Gaussian Naïve Bayes and second‐order polynomial approaches were employed.ResultsThe selected factors for classifier construction were ApoE genotype (p<0.001), medical history of stroke (p<0.001 AD, p = 0.223 MCI), diabetes (p<0.001) and depression (p<0.001), and systolic blood pressure (p<0.001). Three models were used to construct the classifier, and the differential accuracy ranges between 74.1 – 84.2% for CN, 25.3 – 50.2% for MCI, and 47.8 – 73.4% for AD (Table 1). Accuracy from second‐order polynomial model was lower than that from the decision tree and Gaussian Naïve Bayes model.ConclusionThe classifier developed in the current study is yet to be optimized, especially for MCI. In future study, the performance of our classifier will be evaluated using other AD datasets for generalizability. This classifier can potentially be used by the clinicians as an MCI/AD screening tool for at‐risk population prior to requesting costly diagnostic tests.
Automatic assessment of classical Alzheimer’s disease biomarkers in paired cerebrospinal fluid and plasma samples
Authors: Bellomo Giovanni , Megaro Alfredo , Toja Andrea , Nardi Giovanna , Wojdala Anna , Filidei Marta , Paoletti Federico Paolini , Gaetani Lorenzo , Parnetti Lucilla 
Published: December 2023

AbstractBackgroundA/T/(N) cerebrospinal fluid (CSF) biomarkers, i.e., amyloid‐β 1‐42 and 1‐40 ratio (Aβ42/Aβ40, A), tau phosphorylated at threonine 181 (p‐T181‐tau, T), and total tau (N), define molecular diagnosis of Alzheimer’s disease (AD). Automated platforms have brought a significant achievement in reducing the pre‐analytical variability. Measuring such biomarkers in blood might allow longitudinal sampling for disease monitoring, in view of disease‐modifying therapies. Along with this premise, to test the agreement between CSF and plasma measurements, we assessed Aβ42, Aβ40 and p‐T181‐tau with Lumipulse® G600II automated platform in paired CSF and plasma samples from 224 patients.MethodWe selected 224 plasma samples collected from subjects with different clinical diagnosis (see Table 1), for whom CSF measurements were performed between 2018 and 2021. Both plasma and CSF were collected at the time of lumbar puncture following international guidelines. ATN CSF profiles have been defined according to cutoff values measured in our lab. One‐way analysis of variance with post‐hoc Tukey test was applied to determine statistically significant differences among groups, linear regression and correlation analysis were applied to determine degree of agreement between CSF and plasma biomarkers, and ROC analysis was applied to test the ability to differentiate AD‐like CSF profiles (A+/T+) from normal CSF profiles (A‐/T‐).ResultDistributions of Aβ42/Aβ40 ratio and p‐T181‐tau for the different A/T groups are shown in Figure 1. Plasma Aβ42/Aβ40 ratio was found to be significantly decreased in A+/T‐ and A+/T+ subjects as compared with A‐/T‐ and A‐/T+; p‐T181‐tau was found to be significantly increased in A+/T+ subjects as compared with all the other A/T profiles. Plasma Aβ42/Aβ40 ratio and p‐T181‐tau showed moderate correlation with their CSF equivalents (r = 0.62 and 0.60, p << 0.001, respectively). Both biomarkers could detect AD‐like CSF profiles (A+/T+) with an area under the ROC curve > 0.8 (see Figure 2).ConclusionThe automated assessment of Aβ42/Aβ40 and p‐T181‐tau in plasma can satisfactorily reflect the CSF A+T+ status. Larger cohorts are needed to verify the concordance of plasma with CSF biomarkers
Genome‐Wide Mediation Analysis Reveals the Genetic Underpinnings of the Neuromorphometric Endophenotypes of Alzheimer’s Disease
Authors: Shen Li 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is a common neurodegenerative disorder. AD has high heritability, estimated to be 58%‐79% from twin studies. The strong genetic basis motivates the investigation of AD etiology. AD progression can be captured, in part, by brain volumetric variations, quantified by magnetic resonance imaging (MRI). Brain volumetric variations have been used to capture in vivo imaging biomarkers of AD. Advances in recent brain imaging genetics studies provide an opportunity to elucidate the neuropathogenesis of AD.MethodWe performed a genome‐wide mediation study (GWMS) investigating genetic effects on AD classification that are mediated by regional brain volumes. Specifically, we downloaded the genotyping and raw T1‐weighted brain MRI data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. We extracted 145 regions of interest (ROIs) using a multi‐atlas parcellation method (MUSE) from voxel‐wise regional volumetric maps (RAVENS) generated from the MRI scans. We downloaded, integrated, aligned, imputed, and annotated the genotyping data from ADNI 1, GO, 2, and 3 studies. After quality control that excluded low‐quality SNP variants and genetically similar subjects, we performed a genome‐wide association study (GWAS) on 18,366,758 variants and 145 ROI‐level volumetric QTs with 1,382 individuals adjusted for age, sex, and population structure. We prioritized 12,733 significant SNP‐ROI GWAS signals and performed GWMS of AD on those prioritized SNPs with ROIs as mediators.ResultWe found that 35 unique SNPs significantly influenced AD classification mediated by 13 ROI‐level volumetric QTs after false discovery rate correction – in total 218 significant mediation signals. Among all the significant mediation signals, there were 214 partial mediations and 4 full mediations. Chromosome 19 showed the most significant mediation signals. The hippocampus and amygdala in both hemispheres had the most (n = 30) mediation signals, followed by the left entorhinal area with 28 signals (Figure 1).ConclusionOur GWMS of AD identified various SNP variants influencing AD classification via the mediation of ROI‐level volumetric QTs. Complementary to the traditional GWAS analyses, the GWMS analyses can help to explain the genetic underpinnings of the neuromorphometric endophenotypes of AD and provide valuable guidance for AD precision medicine.