bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plasma P‐tau181 levels predict amyloid pathology in cognitively unimpaired individuals after 10 years
Authors: den Braber Anouk , Verberk Inge M.W. , Den Dulk Ben , Tomassen Jori , Dage Jeffrey L , Stoops Erik , Willemsen Gonneke , Nivard Michel G. , Van Berckel Bart N.M. , Scheltens Philip , Visser Pieter Jelle , de Geus Eco J.C. , Teunissen Charlotte E. 
Published: December 2021

AbstractBackgroundPlasma levels of phosphorylated‐tau (P‐tau) are able to identify core Alzheimer’s Disease (AD) pathologies, but its value in cognitively unimpaired individuals needs further study. We aimed to investigate the value of plasma P‐tau at threonine‐181 (P‐tau181) for predicting amyloid pathology in cognitively unimpaired individuals followed over 10 years.MethodFrom the EMIF‐AD PreclinAD study we selected 74 individuals, aged 60 years and older (Table 1) with normal cognition, that had plasma samples available that were collected at time of amyloid status assessment, as well as 10 years earlier (median (IQR) = ‐9.7 (2)). Amyloid status was defined using visual read of dynamic [18F]flutemetamol‐PET images or CSF amyloid‐β1‐42/1‐40<0.065 (Euroimmun). Simoa assays were applied to measure plasma P‐tau181 levels (Eli Lilly). ROC curve analysis was used to determine the value of plasma P‐tau181 in predicting amyloid status. Further, linear mixed models, adjusted for age and sex, were applied to assess longitudinal change in plasma P‐tau181, using time and the interaction between time and amyloid status as a predictor.ResultAmyloid‐positive individuals had higher plasma P‐tau181 levels compared to amyloid‐negative individuals, both at time of amyloid status assessment and 10 years earlier. Plasma P‐tau181 obtained 10 years prior to amyloid status assessment was able to discriminate amyloid status with similar high Area Under Curve, sensitivity and specificity as plasma P‐tau181 obtained at time of amyloid status assessment (Figure 1). Longitudinally, we observed a general increase in plasma P‐tau181 levels over time (β=0.10, p<.001). Interestingly, amyloid‐positive individuals showed a steeper increase in plasma P‐tau181 levels over 10 years compared to amyloid‐negative individuals (time*amyloid‐β‐interaction: β=0.16, p=.005 (Figure 2)).ConclusionOur data suggest that plasma P‐tau181 can be used to predict AD pathology in cognitively unimpaired individuals. The high discriminative value observed, even using plasma P‐tau181 collected 10 years prior to amyloid status assessment, indicates the potential of this marker as an early amyloid pathology pre‐screening tool in the normal aging population. The observed amyloid dependent longitudinal increases in plasma P‐tau181 levels indicates this marker to be eligible for disease monitoring.
Memory impairments in Tg19959 and APP/PS1 AD model mice are alleviated by eEF2K inhibitor A‐484954
Authors: Kasica Nicole P , Yang Wenzhong , Zhou Xueyan , Ma Tao 
Published: December 2021

AbstractBackgroundMounting evidence indicates synaptic failure as an early and key event in Alzheimer’s Disease (AD) pathophysiology. Maintenance of long‐term memory and synaptic plasticity requires de novo protein synthesis. Phosphorylation of mRNA translation factor eukaryotic elongation factor 2 (eEF2) by its kinase eEF2K results in inhibition of general protein synthesis. Previous studies have shown elevated levels of eEF2 phosphorylation in post mortem AD human brain tissue and in AD mouse models. Here we investigated whether suppression of eEF2 phosphorylation via eEF2K inhibitor A‐484954 can alleviate AD‐associated synaptic failure and memory impairmentsMethodAged Tg19959 mice (6‐9 months), APP/PS1 (12‐16 months) and age‐matched controls were treated with a subcutaneous pellet containing A‐484954 or vehicle. The pellet continuously releases treatment over 30 days. Starting two weeks after pellet placement, the mice underwent cognitive assessment via the Novel Object Recognition (NOR) and Morris Water Maze (MWM) tasks. Golgi‐Cox Stain, Amyloid Beta immunohistochemistry, Western blots, SUnSET Assays, and a variety of other experiments were performed on the mice after sacrifice.ResultWe found that cognitive impairments displayed in aged Tg19959 and APP/PS1 mice were alleviated with treatment of A‐484954. Brain tissue from these mice also underwent high performance liquid chromatography (HPLC) to assess drug concentration. In addition, Golgi‐Cox stain was done to assess dendritic spine density and morphology. Spine analysis indicates a rescue in levels of mature spines in the CA1 region of the hippocampus in APP/PS1 mice treated with A‐484954.ConclusionTaken together, our results suggest that treatment with a eEF2K inhibitor, A‐484954, alleviates cognitive impairments and restores synaptic morphology in two mouse models of AD.
Single‐particle characterization of tau oligomers in solution
Authors: Awasthi Saurabh , Mayer Michael 
Published: December 2021

AbstractBackgroundProtein aggregation is the hallmark of neurodegenerative disorders such as Alzheimer’s disease (AD), and oligomeric species of microtubule‐associated protein Tau are implicated as neurotoxic species as well as promising biomarkers. The size and shape of the oligomers are critical to their toxicity. Currently existing, sensitive immunoassays for biomarker detection do, however, not provide information on the size‐ or shape‐distribution of Tau aggregates. This limitation reduces the information content from tau analyses since specific sizes and shapes of oligomeric Tau aggregates are more toxic than others. Hence, a novel approach that reveals the size‐, and the shape‐distribution of Tau oligomers rapidly in solution would be ideal.MethodHere, we use resistive‐pulse sensing with solid‐state nanopores to detect and characterize Tau oligomers on a single particle basis in solution with respect to their size and shape.ResultThe nanopore‐based approach facilitates single‐particle detection and fingerprinting of tau oligomers with regard to their size and shapes. We can determine the heterogeneity among oligomers with respect to their sizes and shapes, which is usually overlooked by averaging. We follow and compare the aggregation kinetics of wild type and AD‐associated variants of Tau.ConclusionResistive‐pulse sensing using nanopores allows rapid fingerprinting Tau oligomers in solution in a label‐free manner. The size and shape information of oligomeric species can improve the general understanding of their toxicity and facilitate the development of new prevention strategies.
Neural correlates of cognitive resilience differ between experiences of bilingualism and education: A cortical surface‐based morphometry study in dementia
Authors: Alladi Suvarna , Arshad Faheem , Kenchaih Raghavendra , Surampudi Bapiraju , Paplikar Avanthi , Varghese Feba Anna , Ramakrishnan Subasree , Saini Jitender , SrInivasan Narayanan , Khokhar Sunil , Bak Thomas H 
Published: December 2021

AbstractBackgroundLife‐course experiences such as education and bilingualism can be protective against dementia. The cognitive effects of bilingualism are specific while education has a more pervasive effect on general cognitive abilities, indicating that there is a likelihood of a variability in mechanisms underlying resilience. India is characterised by educational diversity and bilingualism. Importantly, bilingualism is not always associated with confounding effects of education, socioeconomic class or immigration. This makes the population uniquely suited for the study of resilience and opens up the possibility to disentangle the independent effects of bilingualism and education. Recent evidence indicates that surface‐based morphometric features of the cortical thickness and surface area are significantly modulated by life course experiences. Therefore, in this study, the independent influence of bilingualism and education on cortical thickness and surface area in dementia were studied to investigate the mechanisms that underlie resilience.MethodForty‐five patients with Frontotemporal dementia (FTD) were enrolled. 27 bilinguals were matched with 18 monolinguals for demographic factors and clinical severity. We examined the independent associations of bilingualism and education with cortical thickness and surface area using a surface based morphometric approach.ResultBilinguals with FTD had greater cortical thickness and reduced surface area in bilateral dorsolateral and medial frontal areas, and right parietotemporal cortex, regions associated with executive control. Bilinguals also demonstrated lesser cortical thickness in the language processing areas of left superior temporal, inferior parietal and lateral occipital regions compared to monolinguals. On the other hand, higher education was associated with decreased cortical thickness and increased surface area in bilateral frontal, medial temporal, parietal, occipital, and left temporal regions.ConclusionThis study explores for the first‐time, associations of two different proxies of resilience with cortical thickness and surface area in FTD. Our findings indicate that the neural substrate underlying the protective effects of bilingualism differ from education in FTD, and can be related to their differential effects on cognition. Results indicate specific neural correlates of resilience for different life‐course experiences.
The Critical Path for Alzheimer’s Disease (CPAD) Consortium: A platform for pre‐competitive data sharing, standardization, and analysis to support quantitative tools for AD drug development
Authors: Sivakumaran Sudhir , Hanan Nathan J , Cui Zihan , Burton Jackson , Lang Patrick , Priest Eileen , White Hazel , Romero Klaus , Karten Yashmin 
Published: December 2021

AbstractBackgroundThe primary objective of the Critical Path for Alzheimer’s Disease (CPAD) consortium, a pre‐competitive consortium of the Critical Path Institute, is to promote, support, and manage pre‐competitive data and knowledge sharing from Alzheimer disease (AD) drug development stakeholders. Since 2019, CPAD has embarked on a new data sharing initiative to acquire fluid and imaging biomarker‐rich data sources for development of novel tools to quantify Alzheimer’s Disease progression across the AD continuum.MethodPatient‐level data from contemporary Phase2/Phase3 AD clinical trials and observational studies is acquired through formal data contribution agreements within CPAD, curated in collaboration with data contributors, standardized to common structure and terminology, and input into a relational data model (RDM) tool to generate analysis subsets. Data standardization is being accomplished using Clinical Data Interchange Standards Consortium (CDISC) standards. The RDM was developed using the open‐source software R and converts CDISC structure to analysis ready files for quantitative analyses through user defined primary keys, i.e. unique identifying variables for extracting information. The RDM includes a front‐end data interrogator that provides users with versatile capabilities to visualize and tabulate the data.ResultAs of October 2020, CPAD’s database (https://codr.c‐path.org/) contains 41 studies, standardized to the AD CDISC standards, of which three datasets were used to generate analysis subsets. Four additional datasets were recently acquired and are being standardized. Execution of Data Contribution Agreements (DCAs) is in progress for two contemporary datasets rich in key fluid and imaging biomarkers. Nine additional prioritized datasets are targeted for acquisition. The RDM is currently being used to transform the CDISC standardized data into analysis ready subsets containing patient demographics (age, sex), fluid biomarker information (Aβ 40/42), and clinical outcome assessments (Clinical Dementia Rating Scale – Sum of Boxes).ConclusionThe data acquisition and analysis platform developed is stimulating pre‐competitive efforts to generate quantitative tools for advancing AD drug development. Previously developed tools, including a regulatory endorsed clinical trial simulation tool, help optimize trial design and advance drug development in AD.
Quantitative electroencephalography features of dysexecutive Alzheimer's disease
Authors: Li Wentao , Varatharajah Yogatheesan , Barnard Leland R. , Allen Kay S. , Brinkmann Benjamin H. , Worrell Gregory A. , Jones David T. 
Published: December 2021

AbstractBackgroundProgressive dysexecutive syndrome (dAD) is an atypical presentation of early onset Alzheimer’s disease (AD) with increased frontal and parietal region hypometabolism on FDG‐PET imaging compared to classic amnestic AD. We compared electroencephalogram (EEG) and FDG‐PET in dAD patients to determine if there was a correlation between EEG spectral activity and standard uptake value ratios (SUVR) in those regions.MethodFDG‐PET and resting state scalp EEG were obtained on AD‐biomarker confirmed, behavioral neurologist diagnosed cases of dAD (n = 11). We isolated awake‐eyes‐closed segments (mean duration: 113s, median:118s, range: 58‐138s) of each EEG and calculated the relative power of delta, theta, alpha, beta, and gamma bands within a wideband of 0.5‐40 Hz. In bilateral frontal and parietal regions, we averaged select channels across 6 to 14 10‐second windows per subject (fig.1). We evaluated the correlation between relative band powers and SUVRs of the regions by linear regression analysis.ResultThere is a strong negative correlation (R2 = 0.54, p < 0.01) between alpha band relative power and SUVR in bilateral frontal regions (fig 2). Delta band relative power showed a strong positive correlation (R2 = 0.54, p < 0.05) with SUVR in the left frontal region. A positive trend was noted in the delta band in the right frontal region but did not reach statistical significance. Beta band relative power was negatively correlated with frontal region SUVR bilaterally, but only the left side reached statistical significance. These findings remained significant after multiple comparisons correction. No statistically significant correlations were noted in the parietal regions. Exploratory analysis revealed negative correlations between alpha bands and temporal region SUVRs bilaterally.ConclusionIn this small sample of selected individuals with dysexecutive AD, we report a strong correlation between EEG relative spectral power and PET regional SUVR in multiple EEG frequency bands and brain regions. In the bilateral frontal regions, slower delta frequencies and faster alpha and beta frequencies were associated with lower FDG‐PET signal. Future studies are needed to determine if this spectral power pattern and other EEG properties of dAD differ from other clinical dementia phenotypes and its clinical significance.
Using academic detailing to enhance the knowledge, skills and attitudes of clinicians caring for patients with behavioral and psychological symptoms of dementia
Authors: Walaszek Art , Schroeder Molly , Albrecht Tammi , LeCaire Tamara , Carlsson Cynthia M 
Published: December 2021

AbstractIntroduction: Approximately 90% of persons with dementia experience behavioral and psychological symptoms of dementia (BPSD) over the course of their illness. Primary care clinicians often provide care as specialty geriatric‐medicine or ‐psychiatry consultation may be difficult to obtain. Academic detailing (AD) is an evidence‐based educational approach for engaging and persuading healthcare professionals to make changes in their practice (Avorn 2017). We sought to enhance the knowledge, skills and attitudes of providers’ care of patients with BPSD using the AD model in primary care.MethodsWe implemented AD in an urban clinic serving a largely Black community and a rural clinic serving a large, White community. Each AD visit included didactic content, case discussion, and consultation regarding patients with BPSD. Eleven visits over 18 months are planned for each site. Outcome measures include a 10‐item multiple‐choice assessment of knowledge and an adaptation of the General Practitioners Attitude and Confidence Scale for Dementia (GPACS‐D) (Mason et al. 2019) at baseline before training, and 6 and 18 months, and Likert‐scale measurement of acceptability at 6 and 18 months, all self‐report.ResultsWe present interim data. Five urban and 14 rural providers completed baseline assessments. Providers were mostly White (95%) and Non‐Hispanic (100%); 47% were female. Urban and rural providers had similar baseline BPSD knowledge (mean (SD) of correct answers, 5.4 (1.7) for rural, and 5.0 (2.6) for urban). The adapted GPACS‐D, where higher score indicates more confidence, showed less confidence (mean score 11.4 versus 16.6, p=0.01) in urban versus rural providers. The overall attitudes score indicate there may be more confidence in treating BPSD at baseline among the slightly older rural providers as compared to their urban colleagues. Thus far, eight of 22 planned AD visits have been completed; 6‐month assessments are forthcoming and will be presented.DiscussionAcademic detailing may be a feasible and effective way of increasing self‐reported knowledge and skills and improving self‐reported attitude of primary care providers responsible for the care of patients with BPSD. The pilot data collected in this study will inform the design of a larger study to measure the impact of AD on patient outcomes.
Analytical validation of plasma amyloid β measuring system by immunoprecipitation‐mass spectrometry
Authors: Yoda Ritsuko , Kaneko Naoki , Korenaga Akihito , Funatsu Shinji , Sakashita Nanami , Nishikaze Takashi , Ohashi Yuko , Honda Mamoru , Hioki Yusaku , Sekiya Sadanori , Ogata Koretsugu , Iwamoto Shinichi , Tsujino Kazushige , Tanaka Koichi 
Published: December 2021

AbstractBackgroundWith the increasing number of patients with Alzheimer's disease, construction of inspection system for blood biomarkers to replace or complement amyloid PET and CSF biomarkers has been required. Since our first report in 2014 (Kaneko et al., Proc Jpn Acad Ser B Phys Biol Sci. 2014), we have been focusing on three amyloid peptides, Aβ1‐40, Aβ1‐42, and APP669‐711 in human plasma, and found that the combination of peptide ratios APP669‐711/Aβ1‐42 and Aβ1‐40/Aβ1‐42 became a biomarker for amyloid peptide accumulation in human brain (Nakamura et al., Nature 2018). Here we describe the analytical validation of plasma amyloid β measuring system by immunoprecipitation‐matrix‐assisted laser desorption ionization time‐of‐flight mass spectrometry (IP‐MALDI‐MS).MethodCommercially available human plasma and artificial plasma were immunoprecipitated with anti‐Aβ antibody (clone 6E10) covalently bound to the magnetic beads, then measured by MALDI‐TOF‐MS. The peak intensity of the Aβ‐related peptides was normalized by the internal standard peak, and biomarker values were calculated from those intensities. A method validation including experiments of calibration range, sensitivity, specificity, reproducibility, interfering substances, dilution linearity, recovery, and stability was performed.ResultThe system showed good linearity over the range from 15 to 150 pM for Aβ1‐40, and 3 to 15 pM for Aβ1‐42 and APP669‐711. The trueness was within 100 ± 25% at the lower limit of quantification and within 100 ± 20% at all other concentrations. The precision of the intra‐ and inter‐assay was 1% to 13% as a CV value. Recovery from spiked human plasma ranged from 83% to 101% at low, middle, and high concentrations. Stability testing has shown that the antibody beads are stable for up to 6 months in the refrigerator so far. The addition of the interfering substances, such as anticoagulants, Alzheimer's disease drugs, etc., had only a slight effect on the biomarker values showing 10% or less difference relative to the control. Further results will be reported in the presentation.ConclusionThe results demonstrate that the plasma amyloid β measuring system by IP‐MALDI‐MS is an accurate, reliable, and robust assay that would be most suitable for screening subjects in clinical trials.
Economic burden of dementia studies in low‐ and middle‐ income countries (LMICs): A systematic review
Authors: Mattap Siti Maisarah , Mohan Devi , McGrattan Andrea , Allotey Pascale , Stephan Blossom CM , Reidpath Daniel , Siervo Mario , Robinson Louise , Chaiyakunapruk Nathorn 
Published: December 2021

AbstractBackgroundMore than two thirds of people with dementia are living in the low‐ and middle‐ income countries (LMICs). The growing dementia prevalence will result in significant economic burden in these countries. This systematic review aimed to summarise the evidence on the economic burden of dementia in LMICs.MethodSeven databases (EconLit, EMBASE, PubMed, Cochrane Review (DARE), ERIC, PsycINFO and CINAHL) were searched from inception to September 2020 for original research articles reporting the economic burden or cost of illness for all‐cause dementia and/or its subtypes e.g., Alzheimer’s disease (AD), from any LMICs as defined by the World Bank. Two independent reviewers assessed studies for eligibility. Data on the location, study characteristics, cost estimation methods and estimated costs were extracted. The national level total, direct and indirect costs inflated to 2019, were expressed as a percentage of each country’s Gross Domestic Product (GDP) and were summarised using mean percentage of GDP. Study quality was assessed using the Larg and Moss method.ResultThe literature search identified 14092 articles, of which 22 studies met the eligibility criteria. The national cost of dementia was reported in 64% of the studies (from 120 countries). The remaining studies reported only patient level cost. Majority of the studies had low risk of bias. The average national dementia cost estimated as proportion of GDP was 0.42%. Informal care or indirect costs on average accounted for 62% of the total cost of dementia, while 38% was due to the direct cost.ConclusionDementia is a major cause of economic burden in LMICs. Cost of informal care or indirect cost is the major contributor of this cost. The cost of dementia in LMIC has doubled since first reported in the World Alzheimer Report in 2015 (0.2% of GDP).Acknowledgement: This research was funded by the National Institute for Health Research (NIHR) (16/137/62 ‐ Dementia Prevention and Enhanced Care (DePEC), Newcastle University, United Kingdom), using UK aid from the UK Government to support global health research. The views expressed in this publication are those of the author(s) and not necessarily those of the NIHR or the UK Department of Health and Social Care.