bluuebunny/crossref_metadata_2025_split huggingface dataset:
Classification of human tauopathy using blood: Detection of tau isoforms in patients’s blood with a magnetic bead‐based gap sensor
Authors: Kwon SunSang , Yun Mijin , Lee Soo Hyun 
Published: December 2023

AbstractBackgroundTau protein, which is deposited or phosphorylated in the brains of patients with neurodegenerative progression, has six isoforms that include or exclude N‐terminal exons 2 and 3 and Exon 10, which is a microtubule binding region. Especially, 3R‐ and 4R‐tau, which are distinguished by inclusion or exclusion of exon 10, are known to be balanced in normal adults. However, in case of tauopathy such as progressive supranuclear palsy, the balance is disrupted and 4R‐tau becomes dominant in the patient’s brain. In this regard, some tauopathies can be classified through comparison of tau isoforms in the blood or cerebrospinal fluid (CSF) of neurodegenerative patients.MethodFirst, magnetic beads were coated with each antibody that specifically interact with 3R‐ or 4R‐tau protein, respectively. The prepared samples were reacted with patient’s blood samples from 1) healthy control (HC), 2) Alzheimer’s disease (AD), and 3) 4R‐tau dominant tauopathy (4RDT). Samples incubated with 3R‐ and 4R‐tau antibodies, respectively, were placed between two metal electrode arrays surrounded by the SU‐8 well structure and their impedance changes were measured by electrochemical method (Figure 1).ResultIn the case of HC and AD, 3R‐ and 4R‐tau are known to be in balance, but as a result of measuring the impedance change rate, it was found that the impedance change rate of 4R‐tau is larger than that of 3R‐tau. For the 4R‐tau, HC group exhibits a larger impedance change rate than the AD group (Figure 2). The 4RDT group is currently measuring. Based on reference (Acta Neuropathol., 131, 267 (2016)), the impedance change rate of 4R tau in blood will be large, while that of 3R tau is expected to be negligible.ConclusionWe used a magnetic bead‐based gap sensor to detect/compare tau isoforms in blood samples collected from living patients. Although slightly different from the expectation, the HC group showed a larger impedance change rate than the AD group for the 4R‐tau. The 4RDT group data have not yet been included, but are expected to be similar to those from CSF, and blood measurements can be used to classify tauopathies.
Alternative splicing and characterisation of the tauopathy‐induced gene Growth Arrest DNA Damage Induced 45 alpha
Authors: Williamson Kirsten L , Pitera Aleksandra , O'Connor Vincent , Deinhardt Katrin 
Published: December 2023

AbstractBackgroundThe Gadd45 family are a set of 3 genes classically induced by DNA damage. They are also induced by wider stresses such as axonal injury, ischemia and degenerative diseases like ALS. Increased Gadd45 protein staining is observed in AD brains, however their association with pathogenic tau is unknown. The Gadd45 genes undergo alternative splicing to generate 8 functionally distinct proteins, whose significance in neuronal systems are poorly understood. We aim to investigate if the Gadd45 family are upregulated in tauopathies and whether this is accompanied by changes to mRNA splicing of these genes, with a view to understand whether these differentially affect cell health.MethodTransgenic mice (rTg4510) over‐expressing and FTD‐associated mutant tau (TauP301L) were used to investigate tau‐associated upregulation of the Gadd45 genes. Subsequently, we analyse which splice variants are present in primary cortical neurons and express plasmid constructs of these variants to investigate their sub‐cellular localisation and function, using apoptotic cell death as a read‐out.ResultGadd45α, but not β or γ members of the same family, is upregulated in response to pathological tau. Untreated cortical neurones express a single isoform of the Gadd45α gene, however upon cellular stress 2 additional isoforms are induced. The identified variants show distinct sub‐cellular distribution, including changes to nuclear localisation and the development of punctate staining. Furthermore, these differentially affect apoptosis.ConclusionGadd45α is selectively upregulated by tau pathology. The gene undergoes alternative splicing in murine neurones in response to cellular stress, and these variants show evidence for distinct functions. We will next investigate the association of these variants with pathological tau.We thank the Alzheimer’s Society for funding this work.
Cellular and molecular mapping of human adult hippocampal neurogenesis in Alzheimer’s disease
Authors: Tosoni Giorgia , Penning Amber , Ayyildiz Dilara , Snoeck Sarah , Poovathingal Suresh Kumar , Davie Kristofer , Macnair Will , Bryois Julien , Salta Evgenia 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is a progressive, irreversible disorder accounting for 50‐70% of all dementia cases. Given the current lack of disease‐modifying therapies, systematic profiling of the cell type‐ and cell state‐specific molecular signatures of resilience and vulnerability to AD may reveal novel therapeutic avenues. Adult hippocampal neurogenesis (AHN) refers to the birth of new neurons in the neurogenic ‘niche’ of a hippocampal subregion, the dentate gyrus (DG). AHN drops sharply in AD, and positively correlates with ante‐mortem cognition. Our work and previous reports show that boosting AHN in AD mice restores AHN‐related memory. Hence, harnessing AHN in human AD brain may provide novel strategies to prevent or counteract dementia. Insights into the molecular and cellular regulatory networks maintaining homeostasis of the human neurogenic microenvironment are currently missing.MethodHere, we employ single‐nucleus RNA sequencing technology in the human AHN niche to profile cell type specific molecular signatures of AHN and their changes during the course of AD pathology and in resilient brains.ResultWe developed a novel protocol for precise microdissection of the AHN niche in tissue sections of postmortem human brain, which yields high‐quality input material, enriched for niche‐resident cell populations. We employ in silico ‘dissection’ of cellular populations putatively including neurogenic cell types, and lineage trajectories to identify any (rare) bona fide progenitors.ConclusionUsing previously published and our own datasets, we identify species‐conserved and human‐specific markers that could be used for more reliable identification of adult neurogenic populations and of their transcriptional alterations in AD and resilient brains.
Associations between self‐efficacy across adulthood and midlife cognitive function: Evidence from the National Child Development Study (NCDS)
Authors: John Amber , Bartrés‐Faz David , Stott Joshua 
Published: December 2023

AbstractBackgroundPrevious research has shown that self‐efficacy is associated with a range of health outcomes. However, little is known about relationships between self‐efficacy and cognition across the life‐course. The aims of this study were to test (1) whether trajectories of self‐efficacy from age 33 to 50 are associated with midlife cognitive function (age 50); and (2) whether self‐efficacy acts as a path through which the relationship between childhood factors and adult cognition operates.MethodData used were from the National Child Development Study, a longitudinal birth cohort of 17,415 people born during a single week of 1958. Measures of self‐efficacy were available at ages 33, 42, 46, and 50. Measures of immediate and delayed memory, verbal fluency, processing speed, and processing accuracy were available at age 50. Growth mixture models were run to identify longitudinal trajectories of self‐efficacy. Structural equation modes (SEMs) were run to test associations between different trajectories of self‐efficacy and adult cognitive function. Next, mediation models were used to test the direct, indirect and total effects of childhood factors on adult cognitive function, through accumulation of self‐efficacy.ResultAccording to standard indices (AIC, BIC, LRT, class proportions, etc), a 5‐class trajectory model best fitted the data (Figure 1). SEM models showed that compared with persistently high self‐efficacy, being in any other trajectory was significantly associated with poorer immediate and delayed memory, verbal fluency and processing speed. Being in the moderate and decreasing self‐efficacy trajectory was significantly associated with poorer processing accuracy, compared with the high self‐efficacy group. Greater accumulation (number of time points with high self‐efficacy) over time was significantly associated with better cognitive function in all domains. Mediation models showed significant indirect effects of childhood cognition and education on immediate memory through the accumulation of self‐efficacy score, but not for sex or childhood socioeconomic position.ConclusionResults show that in this prospective birth cohort, persistently high self‐efficacy across early adulthood to midlife (age 33 to 50) was significantly associated with higher cognitive function in midlife. This may be one path through which associations between childhood factors (childhood cognition and education) and adult cognitive function may operate.
Head‐to‐head comparisons of cognitive screening tests administered in primary care centers
Authors: Tideman Pontus , Spotorno Nicola , Palmqvist Sebastian , Hansson Oskar 
Published: December 2023

AbstractBackgroundCognitive screening tests are often used in primary care to aid in the decision whether further investigation is needed. The most widely used tests, MMSE and the Clock Drawing Test (CDT), were developed more than 40 years ago and there is a need to update the primary care neuropsychological toolbox. The objective for this pilot study was to examine the diagnostic accuracy of AD for different cognitive tests administered at primary care centers.MethodThe BioFINDER Primary Care Study consecutively recruits patients with cognitive complaints (SCD, MCI, or mild dementia) at different primary care centers in Sweden. Cognitive tests are examined as well as plasma AD‐biomarkers. A test battery including MMSE, MoCA, CDT, Verbal fluency tests, TMT A and B, Symbol Digit Test, ADAS 10‐wordlist and Recall of Picture Test (RPT) are administered to all patients at their respective primary care center. Patients are then referred to a memory clinic where they undergo a full clinical work‐up (including neuropsychological assessment, lumbar puncture or Aβ‐PET, MRI and an examination by a physician specialized in dementia diseases) after which a diagnosis is made (blinded to the tests done in primary care). A clinical diagnosis of AD is supported by CSF or PET findings. The diagnosis of AD, either at the MCI or mild dementia stage, was here used as the dependent variable in logistic regression models with the different cognitive tests as predictors (adjusted for age, sex, education). Comparisons of AUC were performed using DeLong statistics.ResultIn this pilot study the first 276 recruited patients were analyzed (Table 1). Four tests, MMSE (AUC = 0.73, P <0.01), MoCA (AUC = 0.71, P <0.05), ADAS 10‐wordlist (AUC = 0.80, P <0.001) and RPT (AUC = 0.79, P <0.001), performed significantly better than the basic model (age, sex, education) in predicting a diagnosis of AD. Both the ADAS 10‐wordlist and RPT performed significantly better than MMSE (P <0.05). Adding the CDT to MMSE did not improve the AUC (0.73).ConclusionIn a diverse population, as seen at primary care centers, brief tests of memory may provide better accuracy in detecting AD than standard of care tests as MMSE and MoCA.
Is QEEG an effective biomarker in predicting cognitive decline?
Authors: Medici Valentina , Cassini Paola , Rossi Michele , Pettinato Laura , Negro Giulia , Profka Xhulja , Rolandi Elena , Guaita Antonio , Ceroni Mauro , Poloni Tino Emanuele 
Published: December 2023

AbstractBackgroundAlterations in EEG traces are observed in synaptic failure with a reduction in the background α rhythm and an increase in slow frequencies (θ‐δ). The aim of the study is to evaluate whether quantitative EEG (QEEG) can be a reliable biomarker of neuro‐cognitive disorders (NCD), able to identify patients with mild and major‐NCD, and to reflect the clinical course over time.Method63 donors from the Abbiategrasso Brain Bank were included in the study. According to our protocol, the subjects were evaluated longitudinally (2015‐21) through a multidimensional assessment, and divided into 3 groups age and sex matched (NOLD for normal old, mild‐NCD and major‐NCD). A selection of 12 donors was further divided into 3 groups based on the change of the clinical state over time (NOLD>NOLD; NOLD>mild‐NCD and mild‐NCD>major‐NCD). The QEEG analysis was performed considering the relative power distribution (RPD) of band frequency (β, α, θ, δ) and the peak frequency (PF), as synthetic index. The Kruskall Wallis test, with post hoc analysis, and change analysis through one‐way ANOVA were used for the comparison between groups. Kendall’s TAU was used for correlations.ResultThe RPD of the different frequency bands as well as the PF were significantly different in the NOLD, mild‐NCD and major‐NCD groups (p<0.001); α‐RPD and PF decreased, while θ and δ‐RPD increased. NOLDs and mild‐NCDs were always different from major‐NCDs (p<0.001), while NOLDs were statistically different from mild‐NCDs only for θ‐RPD (p = 0.019), b+a‐RPD (p = 0.028) and q+d‐RPD (p = 0.025). A strong correlation between PF and MMSE (p<0.001) was present. Change analysis demonstrated that PF was lower in the NOLD>mild‐NCD group compared to the NOLD>NOLD group (p = 0.049). Interestingly, PF did not present any correlation with depression using CES‐D score (Center Epidemiological Studies‐Depression).ConclusionThe RPD is able to distinguish NOLDs from mild‐ and major‐NCDs. If determined from the initial stages of the disorder, PF may be a promising biomarker for mild‐NCD diagnosis discriminating initial cognitive impairment from depression, and it may be useful to follow the evolution of dementia. PF appears to be a synthetic and simple quantitative index, easily obtained from a standard digital EEG, and widely applicable.
Brain imaging endophenotypes by unsupervised deep learning
Authors: Zhi Degui 
Published: December 2023

AbstractBackgroundUnderstanding the genetic architecture of brain structure and Alzheimer’s disease is challenging, partly due to difficulties in designing robust, non‐biased descriptors of the brain.MethodWe present approaches to derive robust brain imaging phenotypes using unsupervised deep representation learning. Training a 3‐D convolutional autoencoder model with reconstruction loss, we derived a vector representation (termed endophenotype) that captures rich morphological information of the brain. Further, we developed a perturbation‐based decoder interpretation approach that can highlight brain regions that are most relevant to individual endophenotypes.ResultUsing UK Biobank data, we trained the model using over 6,000 UK Biobank (UKBB) participants’ T1 or T2‐FLAIR (T2) brain MRIs. The model is used to derive 128 endophenotypes. The endophenotypes have a mean heritability of 0.3 and the GWAS of which have identified 43 independent loci in the held‐out UKBiobank dataset (discovery n = 22,962/replication n = 12,848), among which 13 loci have not been previously reported by the UK Biobank Big40 study.ConclusionUsing UK Biobank data, we show that, compared to traditional brain image‐derived phenotypes (IDPs), our endophenotypes are more heritable and have higher power for genetic discovery.
Sex differences in the associations between the risk for late‐life Alzheimer’s disease, protective lifestyle factors and cognition in mid‐life: The PREVENT Dementia study.
Authors: Qi Qing , Deng Feng , Ritchie Karen , Muniz‐Terrera Graciela , Koychev Ivan , Malhotra Paresh A , O'Brien John T , Ritchie Craig W , Lawlor Brian , Naci Lorina 
Published: December 2023

AbstractBackgroundIt is now acknowledged that Alzheimer’s Disease (AD) processes are present decades before the symptoms manifest, but whether lifestyle activities can protect against these early AD processes in mid‐life remains poorly understood. Furthermore, the impact of sex as a biological variable on associations between dementia risk, protective lifestyle activities and cognition is unknown. In this study, we aimed to replicate findings from our two recent studies (Deng et al., 2022; Heneghan et al., 2022) on the contribution of mid‐life modifiable activities to cognition in individuals with dementia risk, in a larger independent cohort (N = 461 vs N = 208 used previously). Second, we investigated associations between biological sex, dementia risk, protective lifestyle activities and cognitive performance.MethodCognitively unimpaired middle‐aged participants (40‐59 years; N = 461) completed cognitive and clinical assessments cross‐sectionally. Risk factors (Apolipoprotein E [APOE] ε4 allele status, family history of dementia, and the Cardiovascular Risk Factors Aging and Dementia score [CAIDE]) were assessed and mid‐life activities were measured with the Lifetime of Experiences Questionnaire.ResultReplicating our key previous findings, we found that episodic and relational memory was (a) significantly negatively associated with the CAIDE risk score (Figure 1a), (b) positively associated with stimulating lifestyle activities (Figure 1b), and (c) that females performed significantly better than males in episodic and relational memory (Figure 2a). The key novel finding of this study was that APOE ε4 genotype modulated the association between sex, lifestyle and cognition. Only for APOE ε4+ females, not APOE ε4‐, higher occupational attainment was associated with better episodic and relational memory (Figure 2c, 2d). Conversely, only for APOE ε4+ males, not APOE ε4‐, higher occupational attainment was associated with worse episodic and relational memory (Figure 2c, 2d).ConclusionThese findings suggest that modifiable lifestyle activities offset cognitive decrements due to inherited AD risk in mid‐life and support the targeting of modifiable lifestyle activities for the prevention of AD. Furthermore, these findings suggest an urgent need for targeted research on female‐specific risk factors, to inform personalised strategies for AD prevention and the promotion of female brain health.
Usability experience of remote sleep monitoring in patients with neurodegenerative diseases
Authors: Biswas Bijetri , Gabb Victoria , Li Haoxuan , Morrison Hamish , Blackman Jonathan , Coulthard Elizabeth , Group Remember 
Published: December 2023

AbstractBackgroundSleep disturbances and neurodegenerative disease are prevalent in later life and may worsen life quality. Home sleep monitoring may help allow early recognition of disease progression and offer therapeutic intervention targets. In the Remote Evaluation of Sleep To enhance understanding of Early Dementia (RESTED) study, we explored feasibility and acceptability of digital technologies to characterise sleep in cognitive impaired individuals.MethodRecruitment and data collection is ongoing as of January 2023. We included data from seven RESTED participants who completed an end‐of‐study interview which includes individuals with early Alzheimer’s Dementia (AD) or Lewy Body Dementia (LBD), the prodromal state of Mild Cognitive Impairment (MCI) due to AD or LBD, healthy older adults from memory clinics and databases at the North Bristol NHS Trust. A wrist‐worn actigraph monitored sleep and trial activities were triggered through a mobile application for 8 weeks. During one week in‐depth monitoring included EEG headband worn nightly, overnight oximetry, circadian saliva samples and daily short cognitive tests.ResultsPreliminary data from the interview were analysed using thematic analysis. Participants were asked questions to draw off The Capability, Opportunity, Motivation, Behaviour and Unified theory of acceptance and use of technology model. Overall, Participants were able to use the technologies either independently or with support from a carer or family member. Some participants found it difficult to wear the headband, and doing the cognitive test made them feel anxious and worried about their memory. Using technologies did not negatively impact their relationship with their partner. Carer motivation was a major determinant of data completeness. This study made them aware of the importance of sleep for brain health.ConclusionsFuture research should review the ergonomic design principles by considering the infrastructure to make them more suitable for the targeted population. Our work also demonstrates some challenges in conducting this category of user experience study in healthcare, including time investment from carers, adherence to the continued interview and retrospective biases. This user experience study in dementia suggests remote sleep monitoring is preferred, holds the potential to enhance well‐being, improve participant‐carer relationships, and may provide a means to feel empowered and acquire new skills.
Human iPSC‐microglia expressing TREM2 p.R47H risk variant for Alzheimer’s disease do not show a loss‐of‐function phenotype
Authors: Nonneman Annelies , Swijsen Sofie , Sebrechts Pieterjan , De Bondt An , Wyngaert Ilse Van Den , Bhattacharya Anindya , Ebneth Andreas 
Published: December 2023

AbstractBackgroundThe most common TREM2 variant associated with increased risk to develop Alzheimer’s disease (AD) is p.R47H. This variant has been classified as loss‐of‐function, mostly by comparing p.R47H with the common variant in TREM2 over‐expressing cell lines. Whether this holds true when TREM2 is expressed at physiological levels in a disease‐relevant cell type such as human microglia, has not been fully characterized.MethodWe established and thoroughly characterized human iPSC‐derived microglia endogenously expressing TREM2 to assess the effect of p.R47H on TREM2 cellular distribution, TREM2 signaling and microglial functioning. For this study microglia generated from a set of isogenic gene‐edited iPSC lines homozygous for TREM2 knockout (KO) and TREM2 p.R47H were evaluated and compared to microglia from the parental control iPSC line. In addition, microglia generated from iPSC lines obtained from several p.R47H carriers were compared to microglia from iPSC lines obtained from several healthy control non‐carriers. SNP genotyping confirmed the presence of R47H.ResultThe p.R47H and common variant TREM2 were present at similar levels at the cell surface of iPSC‐derived microglia, whereas no expression of TREM2 was detected in the TREM2 KO microglia. Microarray profiling indicated that the microglial transcriptome is very similar between the common variant and p.R47H yet distinct from TREM2 KO microglia. Biochemical evaluation of TREM2 signaling indicated no reduction in TREM2 downstream signaling activation in the p.R47H variant expressing microglia. Similarly, soluble TREM2 levels were increased in culture medium of p.R47H microglia. Finally, analysis of microglial functioning including phagocytosis of artificial and disease‐relevant substrates showed no difference between the p.R47H variant and the common variant, in contrast to TREM2 KO microglia.ConclusionWe conclude that in cultured human iPSC‐derived microglia, the p.R47H variant shows no evidence of a loss‐of‐function mechanism. Future experiments will determine whether this is also the case in microglia in their natural brain environment. Our long‐term goal is to better understand TREM2 biology to support the development of novel therapeutics for AD and other neurodegenerative diseases characterized by TREM2‐mediated neuroinflammation.