bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fully automated ApoE4 assay in plasma and the estimation of the APOE polymorphism
Authors: Yuri Tatsushi , Sato Hideo , Nakazawa Takuya , Kamada Jo , Kaneko Atsushi , Aoyagi Katsumi , Nojima Hisashi 
Published: December 2023

AbstractBackgroundApolipoprotein E (ApoE) is a major cholesterol carrier that supports lipid transport and injury repair in the brain. APOE polymorphic alleles are the main genetic determinants of Alzheimer disease (AD) risk: individuals carrying the ε4 allele are at increased risk of AD compared with those carrying the more common ε3 allele, whereas the ε2 allele decreases risk. Moreover, it has been reported that the APOE4 haplotype has a dose‐dependent association with an increased risk of amyloid‐related imaging abnormalities (ARIA) in individuals receiving disease‐modifying therapy (DMT) for AD. Therefore, the importance of APOE genotyping or phenotyping and its expanding clinical role in dementia field has been highlighted. Here, we developed fully automated chemiluminescence enzyme‐immunoassay (CLEIA) kits for ApoE4 and pan‐ApoE, and evaluated its diagnostic concordance with the APOE genotyping.MethodApoE4 and pan‐ApoE assays for fully automated platform, LUMIPULSE, are a two‐step sandwich CLEIA with a specific treatment process to extract the antigen from the lipid surface in plasma samples during the 1st immunoreaction. The turnaround time for each reaction is within 30 minutes. Healthy volunteers’ samples were used for the measurement of ApoE4 and pan‐ApoE with CLEIA or the PCR‐Restriction fragment length polymorphism (PCR‐RFLP) analysis for the APOE polymorphism. The study design was approved by the ethics committee at H.U. Group Holdings, Inc in the 2022 fiscal year (22‐012‐01).ResultThe ApoE4 kit specifically detected the ApoE4 concentration in plasma samples, and could distinguish ApoE polymorphism. Moreover, the polymorphism could be classified clearly by the ratio of ApoE4 and Pan‐ApoE amount in plasma.ConclusionThe new CLEIA ApoE4 and pan‐ApoE assay robustly distinguishes among APOE4 carrier status in plasma. Assessing ApoE isoform by CLEIA may help not only clarify ApoE metabolism, but also ARIA risk.
Altered patterns of brain activity during a fMRI memory task in cognitively normal adults carrying the APOE ε4 allele
Authors: Corbo Daniele , Quattrini Giulia , Saglia Silvia , Agnelli Giancarlo , Mega Anna , Marizzoni Moira , D'Aprile Ilari , Cattaneo Annamaria , Bortoletto Marta , Gasparotti Roberto , Pievani Michela 
Published: December 2023

AbstractBackgroundThe ε4 allele of the Apolipoprotein E gene (APOE) is a well‐established risk factor for Alzheimer’s disease (AD), ε4 carriers showing earlier onset and more severe memory impairment than non‐carriers. Neuroimaging evidence suggests that APOEε4 may modulate neural activity in AD since early stages. The purpose of this study was to determine whether APOEε4 influences brain activity in the memory circuit in older cognitively unimpaired individuals.MethodThirty cognitively unimpaired participants (n = 10 APOEε4 heterozygous carriers, age = 65± 5 years, 50% females, MMSE score = 29±1; n = 20 APOEε4 non‐carriers, age = 68±5 years, 35% females, MMSE score = 30±1) were recruited and underwent multidomain (i.e., memory, visuospatial abilities, language, attention) neuropsychological exams and functional MRI scan during an associative memory task, which consisted of two phases: (i) encoding of face‐name associations; (ii) recognition of the name associated to each face. Image preprocessing and voxel‐wise comparisons were conducted using the Statistical Parametric Mapping (SPM, v12). Clusters were considered significant at an uncorrected threshold of p<0.001.ResultParticipants were comparable for demographic and cognitive features (p>0.10) and performed similarly on the in‐scanner face‐name association memory task (p>0.10). Compared to ε4 non‐carriers, carriers showed (i) greater activation during the encoding task in the left temporo‐occipital cortex/fusiform gyrus, (ii) greater activation during the recognition task in the middle temporal gyrus/temporo‐occipital cortex bilaterally and in the right cerebellum, and (iii) lower activation during the recognition task in the medial supplementary motor area.ConclusionThese preliminary results confirm that the APOE ε4 allele is associated with a different pattern of brain functional activity during an associative memory task in cognitively unimpaired older. Given the similar cognitive performance between groups, higher activation in temporo‐occipital regions might reflect a compensatory process in regions vulnerable to AD pathology.
Digital biomarker co‐design with people with preclinical or prodromal dementia
Authors: Köhler Stefanie , Teipel Stefan 
Published: December 2023

AbstractBackgroundLanguage markers can serve screening and early detection in Alzheimer’s disease (AD). Using artificial intelligence (AI) approaches enables automated assessment and analysis of speech biomarkes using chatbot technology. Reliable digital speech biomarkers require an easy‐to‐use chatbot which is adopted to the users’ needs. Currently, chatbots often are unsuitable for people with cognitive impairment and rather frustrating for their users. Here, we implemented a user centred design approach to iteratively evaluate usability of a chatbot system for automated speech assessments for people with prodromal or preclinical dementia.MethodWithin the study PROSPECT‐AD, participants (n = 53 by January 2023, 300 planned) are automatically called for six times every three months by our chatbot “Mili”. Each call takes about 15 minutes and consists of three cognitive tasks (Wordlist, Semantic Verbal Fluency, Story Telling). We applied a six stage usability check to improve Mili iteratively (see Figure 1). For deeper insights, we conduct semi‐structured interviews (n = 20). During the interviews, we focus on affinity for technology, usability, and participants’ attitude towards chatbots and artificial intelligence in medicine.ResultsTo date, Mili has completed 54 assessments (see Figure 2). Drop‐outs (11.3%) occcur around the first assessment. Reasons were e.g., lack of accessibility of participants, excessive demands through cognitive tasks or through Mili. Participants reported problems due to Mili’s high speaking pace and hangs of Mili. Additionally, Mili struggled in automatically retrieving appointments and missed calling. All problems were quickly resolved. The speaking pace was reduced and the time‐out time extented by 2 seconds. Results of the system usability scale revealed a high user‐friendliness of the calls (see Table 1). Participants (n = 6) evaluated the calls as quick to learn and easy to use. Two participants wished for more technical support for the calls. Two participants felt uncomfortable in using Mili.ConclusionOur results revealed a high usability and feasibility of the automated phone calls by Mili. Due to close colaboration, problems with Mili were solved qickly and further drop‐outs prevented. This underlines the benefit of close cooperation between participants, scientists, and IT specialists. Interviews are needed for further improvement of Mili and to understand uncertainty with Mili.
Remote Caring Guidelines: An innovative protocol for dementia caregivers
Authors: Manola Panayiota , Makri Marina , Tsolaki Magda 
Published: December 2023

AbstractVarious technological innovations have emerged which allow for remote caring of people with dementia by their informal caregivers. Lack of access and social isolation have negatively impacted people with dementia and caregivers experience intensification of stress and burden. Currently, there is no widely accepted dementia protocol on remote care for caregivers. A partnership of five European institutions which specialise in mental health and dementia is preparing a protocol based on non‐formal education (NFE) which aims at training caregivers to provide better support and enhanced care even when physical presence is not possible. The NFE is designed to educate the caregivers on five major topics; recognising the symptoms of dementia, dementia prevention, potential activities for early and advanced dementia aimed at improving social interaction and the mental/physical wellbeing of people with dementia and on how to create support groups. Three piloting activities involving a minimum of 75 participants, caregivers of people with dementia, and ten case studies of successful support groups will be conducted in order to assess and refine the NFE. It is expected that; the social interaction between people suffering from dementia and their caregivers will be improved by using innovative devices and will allow for enhanced caring and assistance conditions for caregivers and the stigma which surrounds people will be diminished through the creation of support groups and the extensive use of new technologies. These findings will have a strong impact on the provision of everyday dementia care from informal caregivers and may lead to a more future‐proof dementia care. Moreover, upon the successful implementation of the protocol in dementia caregivers, the protocol could be adapted to serve as a protocol for mental and physical health caregiving.
Synergistic interaction between Cu overload and Aβ peptide promotes pro‐inflammatory response of microglia
Authors: Zubillaga Marlene , Calaf Xenia Abadin , Colell Anna , Bellini María José , Arnal Nathalie 
Published: December 2023

AbstractBackgroundChanges in copper (Cu) homeostasis have been consistently linked to Alzheimer’s disease (AD). Cu can bind to amyloid beta (Ab) and enhance neurotoxicity through the generation of reactive oxygen species.Furthermore, Cu possesses both pro‐ and anti‐inflammatory properties mediated by its proximity to amyloid plaques. A key pro‐inflammatory pathway reported induced in AD is the NLRP3 inflammasome that leads to the activation of inflammatory caspases, mainly caspase‐1, and the processing of interleukin‐1b (IL‐1b) into its active form. This work aimed to assess the synergistic interaction between Cu overload and the Aβ‐induced inflammatory response on microglia and evaluate the underlying mechanisms.MethodUsing immortalized mouse microglia (SIM‐A9) exposed to 1 uM Ab and subtoxic doses of Cu (50, 100 and 200 uM) for 24 h, we assessed ROS by fluorometry using Dihydroethidium (DHE), expression levels of inflammasome‐related proteins by western blot and RT‐PCR selfie, and phagocytosis of microglia by confocal microscopy using fluorescent microbeads (1µm). To assess inflammasome assembly, cells were transfected with the pLEX‐MSC‐ASC‐GFP vector and ASC speckle formation was analyzed by confocal microscopy.ResultsCu treatment induced IL‐1b and Nlrp3 expression, which was further enhanced when combined with Aβ. While untreated cells showed homogeneously distributed ASCs in the cytosol, we found “speckles” of ASCs in those treated with Cu and Cu plus Aβ, in the vicinity of the nucleus, indicating involvement of the inflammasome. Cu treatment increased total cholesterol (Cho) and mitochondrial Cho levels and was accompanied by a significant decrease in mitochondrial GSH levels. Accordingly, ROS levels increased significantly with the combination of Cu and Aβ. Oxidative stress was prevented by glutathione ester (GSHee) treatment and the use of mitochondrial antioxidant agents (MitoTEMPO and MitoQ). In parallel, we analyzed microglia phagocytosis by confocal microscopy. Microbead uptake was significantly impaired after Cu overload but was partially restored by pretreatment with GSHee, which recovered mitochondrial GSH and reduced oxidative stressConclusionHigh Cu levels regulate the microglial response to Aβ by boosting mitochondrial oxidative stress, resulting in inflammasome activation with the release of pro‐inflammatory cytokines such as IL‐1b) and decreased phagocytic capacity, which may contribute to the accumulation and formation of Aβ deposits.
The molar ratio between PAI‐1 and BDNF is increased in Alzheimer’s disease patients with full dementia and negatively correlates with MMSE score
Authors: Angelucci Francesco , Veverova Katerina , Katonova Alzbeta , Jurasova Vanesa , Vyhnalek Martin , Andel Ross , Hort Jakub , Sheardova Katerina 
Published: December 2023

AbstractBackgroundIn a previous study, we demonstrated that the enzyme plasminogen activator inhibitor‐1 (PAI‐1), which inhibits plasmin synthesis in the central nervous system (CNS), is increased in the serum of patients with Alzheimer’s disease (AD). In addition to reducing the accumulation of Ab, plasmin in the CNS regulates the synthesis of the trophic factor brain‐derived neurotrophic factor (BDNF) which appears to be altered in the brain of patients with AD. We investigated whether BDNF serum levels in AD and amnestic mild cognitive impairment (aMCI) patients are altered compared to cognitively healthy controls. Moreover, we examined the PAI‐1/BDNF ratio in these patient groups and correlated with cognitive scores as measured by Mini‐Mental State Examination (MMSE).Method40 AD, 40 aMCI and 10 healthy controls were recruited. Venous blood was collected and BDNF serum concentration were quantified by sandwich ELISAs. Comparisons among the experimental groups (AD dementia, aMCI patients, and cognitively healthy controls) on BDNF serum levels were performed using univariate analyses of variance (ANOVA). Pearson correlation coefficients were calculated to explore relationships between biochemical and clinical data. The level of statistical significance was set at p<0.05.ResultThe results showed that BDNF serum levels are decreased in AD as compared to aMCI patients (p < .05). In addition, there was a positive correlation between PAI‐1 and BDNF serum levels (r = .190, p < .05). Furthermore, PAI‐1/BDNF ratio was significantly increased in AD patients as compared to aMCI (p < .001) and controls (p < .001). Lastly, PAI‐1/BDNF ratio negatively correlated with MMSE score (r = ‐.508, p < .001).ConclusionThese data suggest that in AD a reduction of plasmin caused by PAI‐1 may negatively affect the production of BDNF and promote disease progression. Our results also demonstrate that the PAI‐1/BDNF ratio is increased in AD patients compared with aMCI and controls. They also suggest that this ratio could be used as a marker of AD in a state of overt cognitive impairment, as supported by the strong negative correlation between PAI‐1/BDNF ratio and MMSE.
Single‐nuclei spatiotemporal transcriptomics reveal an APOE4‐associated specific oligodendrocyte signature
Authors: Qin Wei , Xu Lingzhi , Li Bingqiu , Wei Yiping , Jia Jianping 
Published: December 2023

AbstractBackgroundThe APOE4 gene is a strong risk factor for Alzheimer’s disease (AD). However, an understanding of the APOE4 genotype‐associated cellular and molecular processes in the brains remains unclear.MethodTo clarify the APOE4‐related pathogenic pathways in AD, we performed single‐nuclei RNA‐sequencing and spatial enhanced resolution omics sequencing on the brains of aging human APOE3‐knockin mice and APOE4 knock‐in mice. We also investigated the relationship between different cell types and AD‐related pathology in APOE knock‐in mice using immunostaining. We conducted amplification‐based single molecule in situ hybridization to validate the characteristics of the APOE4‐specific subcluster. To substantiate the APOE knock‐in mice analyses, we also re‐analyzed a published single‐nuclei RNA‐seq dataset containing postmortem prefrontal cortex tissue samples from patients with AD and controls.ResultWe identified seven distinct cell types in brains from APOE‐knockin mice, and observed oligodendrocytes with most unique differentially expressed genes (Figure 1). And we found significantly increased Alzheimer’s disease‐related pathologies (including intracellular beta‐amyloid and phosphorylated tau) in oligodendrocytes in the hippocampus of APOE4‐KI mice compared to APOE3‐KI mice. Furthermore, an APOE4‐specific oligodendrocyte subcluster was identified. This subcluster had a dysregulated autophagy flux signature, which may affect neuronal oxidative stress and synaptic function (Figure 2). Both excitatory and inhibitory neurons presented dysregulation of genes related to synapse plasticity. Additionally, the oligodendrocyte subcluster significantly correlated with neuronal loss, beta‐amyloid deposition and tau phosphorylation in the brain tissues examined. We also found a similar oligodendrocyte subcluster in post‐mortem brains from AD patients.ConclusionAltogether, this study suggests the specific oligodendrocyte subcluster is related to the susceptibility of APOE4 to AD, and targeting autophagy changes in oligodendrocyte may be a novel therapeutic intervention approach in APOE4 carriers.
Psychometric evaluation of the German version of the Mild Behavioural Impairment Checklist (MBI‐C)
Authors: Grothe Jessica , Luppa Melanie , Pabst Alexander , Röhr Susanne , Riedel‐Heller Steffi G. 
Published: December 2023

AbstractBackgroundNeuropsychiatric symptoms (NPS) are common in pre‐dementia state and are associated with an increased risk of dementia. The concept of Mild Behavioral Impairment (MBI) addresses this circumstance. However, to date, instruments that measure MBI in a standardized method are lacking. Therefore, the Mild Behavioral Impairment Checklist (MBI‐C) was developed on the basis of the MBI diagnostic criteria. Our aim was to psychometrically evaluate the German version of the MBI‐C.MethodWe interviewed 86 dyads of individuals with either subjective cognitive impairment (SCD), mild cognitive impairment (MCI), or cognitively healthy individuals, paired each of them with a relative and test the reliability, validity and acceptance of the MBI‐C.ResultThe internal consistency of both MBI‐C versions were at a questionable to acceptable level (α = 0.64‐0.86) and the interrater reliability was good to excellent (patients: ICC = 0.94, CI [0.91–0.96]; informants: ICC = 0.86, CI [0.79–0.90]). Informant‐rated MBI‐C correlated strongly with the Neuropsychiatric Inventory (NPI) total score (r = 0.51; p ≤.001). All participants found the MBI‐C acceptable.ConclusionThe German MBI‐C is an instrument to assess MBI in healthy individuals, individuals with SCD, and those with MCI. It has acceptable psychometric properties. Further studies should address a larger sample of individuals in a pre‐dementia state to confirm the findings of our study. Moreover, the factor structure should be investigated.
The progression from Mild Cognitive Impairment to dementia in a community older population from São Paulo, Brazil
Authors: Lopes Marcos A , Nassar Silvia M , Barcelos‐Ferreira Ricardo , Folquitto Jefferson C , Litvoc Julio 
Published: December 2023

AbstractBackgroundMild Cognitive Impairment (MCI) is a cognitive condition greatly studied around the world, considering its potential to precede dementia, but it is little investigated in Brazilian community population. This study aimed to estimate the progression from MCI to dementia in a community‐dwelling older population from São Paulo city, Brazil.MethodA two‐phase prospective cohort study evaluated a representative cluster sample of 1,370 individuals aged 60 years old and over from three different socioeconomic levels. The diagnosis of dementia was made according to DSM IV criteria. MCI was assessed at baseline, using Mini Mental State Examination (MMSE), Fuld Object Memory Evaluation (FOME) and Bayer‐Activities of Daily Living scale (B‐ADL), and classified into three subtypes: amnestic MCI (FOME < 35 and B‐ADL scale ≤ 3.19); non‐amnestic MCI‐multiple domains (MMSE < cut‐offs according to four levels of education and FOME ≥ 35 and B‐ADL scale ≤ 3.19); non‐amnestic MCI‐specific domain (executive function)(FOME ≥ 35 and verbal fluency for animals <11 and B‐ADL scale ≤ 3.19).ResultAmong 489 subjects that completed the evaluation, 42 were diagnosed with dementia. Considering the population completely evaluated, at baseline 76, 87 and 35 subjects were classified as amnestic‐MCI, non‐amnestic MCI‐multiple domains and non‐amnestic MCI‐specific domain (executive function), respectively. The rates of conversion to dementia from non‐amnestic‐multiple domains and non‐amnestic MCI‐specific domain (executive function), compared to non‐MCI, were 6.9%% (vs 5.1%) and 2.9% (vs 5.7%), respectively (no significative difference between groups). The rate of conversion to dementia from amnestic‐MCI was 23.7% (vs 5.7%)(p <0.001; OR: 5.1, 95%CI: 2.6‐10.1); specifically for amnestic‐MCI with depressive syndrome, it was 66.7% (vs 5.1%)(p <0.001; OR: 37.0, 95%CI: 6.3‐214.2).ConclusionThe findings reinforced the role of amnestic‐MCI in the progression to dementia and Alzheimer’s Disease and exhibited an additional effect of depression on this process.
The eye as a window to the brain: hyperspectral retinal imaging as a biomarker for Alzheimer’s disease
Authors: Dahdouh‐Guebas Yasmin , Kulenovic Hana , Christinaki Eirini , Van Eijgen Jan , Lemmens Sophie , Ceccarini Jenny , Rousseau Frederic , Schymkowitz Joost , Vandenbulcke Mathieu , Vandenberghe Wim , Vandenberghe Rik , De Strooper Bart , Jayapala Murali , Blaschko Matthew , Moons Lieve , Stalmans Ingeborg , De Groef Lies 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is a neurodegenerative disorder that is the leading cause of dementia, affecting more than 50 million people worldwide. In the search for new biomarkers, increasing attention has been dedicated to the retina. As part of the central nervous system, the retina manifests many of the characteristic pathological processes that occur in the AD brain. Moreover, it can be imaged at low‐cost and non‐invasively at high resolution, and therefore it may be used for AD diagnosis and monitoring. In this context, emerging evidence suggests the potential of in vivo hyperspectral retinal imaging (HSRI) as a potential biomarker for brain amyloid‐β accumulation. Therefore, this project aims at studying HSRI as a novel biomarker that could lead to inexpensive population screening, thereby removing one of the principal bottlenecks to therapeutic advances in AD.MethodIn this study, we seek to define the molecular basis, sensitivity, and specificity of the HSRI signal of AD, and whether it can distinguish AD from other dementias in a translational pre‐clinical and clinical research project. We perform HSRI of synthetic protein aggregates, and different cell and mouse models of neurodegenerative proteinopathies, and correlate these data with molecular biology assays, to study the molecular basis and pathological correlates of HSRI signals. In a parallel clinical study, we assess the correlation between amyloid status and HSRI and evaluate whether the diagnostic power of HSRI can be increased via a multimodal imaging approach.ResultOur preliminary results demonstrate that HSRI can be used to quantify retinal amyloid in AD animal models and post‐mortem tissues as well as discriminate between AD patients and controls, with improvement in classification accuracy by including optical coherence tomography (OCT) data.ConclusionThis research study covers out‐of‐the‐box thinking to transform the detection of AD. It collects evidence of the specificity and molecular basis of HSRI which is essential for its rational clinical use as an AD imaging biomarker.