bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association between patterns of multiple chronic conditions and cognitive impairment in community‐dwelling older adults in Taiwan
Authors: Hsieh Pei‐Iun , Chen Yen‐Ching , Chiou Jeng‐Min , Chen Ta‐Fu , Yeh Su‐Ling , Chen Jen‐Hau 
Published: December 2021

AbstractBackgroundPrevious studies mainly explored the effect of single chronic disease on cognition. However, limited focuses have been put on the co‐existence of diseases, symptoms, and functional impairments and how their combinations affect older adults. This study aimed to identify sex‐specific patterns of multiple chronic conditions (MCC) and to relate them with cognitive impairment in a six‐year cohort study.MethodWe included 516 non‐demented older adults at baseline (2011‐2013) from the ongoing Taiwan Initiative for Geriatric Epidemiological Research, with three biennially follow‐ups. The global and domain‐specific (memory, attention, executive function, and language) cognition were assessed using the Taiwanese version of Montreal Cognitive Assessment and a battery of neuropsychological tests. Exploratory factor analysis was utilized to identify patterns of 33 self‐reported chronic conditions. For each pattern, the factor score of each participant was calculated by summing up the product of the status of a specific condition and its corresponding factor loadings. The generalized linear mixed model was utilized to examine the association between MCC patterns and cognitive performance adjusted for age, years of education, apolipoprotein E ε4 status, cigarette smoking, alcohol consumption, and years of follow‐up.ResultThree MCC patterns were identified for each sex, which included (1) Mental‐Exhaustion, (2) Cancer‐Thyroid, and (3) Frailty‐Cardiometabolic patterns in females; and (1) Mental‐Skeletal, (2) Cardiometabolic‐Renal, and (3) Thyroid‐Prostate patterns in males. Among females, higher factor scores of the Mental‐Exhaustion and Frailty‐Cardiometabolic patterns were significantly associated with poor performance of global cognition (β: ‐0.16), logical memory (β:‐0.11 to ‐0.07) and executive function (β:‐0.32). Among males, higher factor scores of the Mental‐Skeletal and Thyroid‐Prostate patterns were significantly associated with poor performance of memory (β:‐0.11) and attention (β:‐0.13). In contrast, a protective effect was observed between Cancer‐Thyroid pattern and memory (β:0.12 to 0.13) or attention (β:0.16), as well as between Cardiometabolic‐Renal pattern and verbal fluency (β:0.15).ConclusionMCC patterns identified in this Asian population were different from those observed in western countries, and these patterns were associated with poor global or domain‐specific cognition. Further research was required to validate our findings and to clarify the underlying mechanism between MCC and cognitive impairment.
Hal, do I have memory problems? A pilot study investigating a voice recognition cognitive screening tool for detection of neuropsychological changes
Authors: Rosen Jay , Alasantro Lori Haase , Wagner Gabrielle , Sahagian Gregory , Vignisson Vidar 
Published: December 2021

AbstractBackgroundThe prevalence of mild, age‐advanced changes in cognition, defined as mild cognitive impairment, is spiking as the baby boomer population ages. Early and accurate detection of age‐advanced changes in thinking abilities leads to proper care, efficient use of resources, and promotion of research. Indeed, government based health care systems and insurance programs incentivize routine neurocognitive assessment. Brief, paper and pencil cognitive screeners such as the MMSE and MOCA are widely utilized in clinical settings. Such screeners lack sensitivity to subtle cognitive change and specificity related to the cause of decline. Moreover, administration and interpretation of these screeners is time consuming in a busy, clinical setting. Prior research has determined that electronic‐based testing is effective in detecting cognitive change (Zygouris & Tsolaki, 2014). This pilot study aimed to investigate a convenient, platform agnostic, voice‐recognition screening tool for detection of mild, age‐advanced neurocognitive problems.MethodParticipants (n=16) were recruited from a large community‐based neurology practice, who underwent a comprehensive neuropsychological (NP) evaluation as part of their standard of care. Participants were administered an auditory list learning/recall test and a verbal fluency test (F/A/S and animals) via a voice recognition cognitive screening tool. Pearson correlations were conducted to examine the concurrent validity between the standard NP measures and those obtained using the current screening tool.ResultPreliminary data suggests a positive correlation between standard NP measures and those obtained using voice recording and speech recognition technologies; language: F/A/S (r = .716, p < .005), animals (r .810, p < .005); memory: delayed recall (r = .515, p < .05).ConclusionThis pilot study demonstrated concurrent validity between standard NP measures of memory and verbal fluency and those obtained using a novel, voice recording and speech recognition screening tool. These initial data provide support for the efficacy of a computerized based screening tool for older adults. Such a screening too has the potential to maximize utilization across multiple settings (e.g., medical office, hospital, in‐home) and improve early detection of cognitive decline.
Learning vector quantization model for prediction of cerebral Aβ in non‐demented individuals using plasma biomarkers
Authors: Ko Hyunwoong 
Published: December 2021

AbstractBackgroundCerebral Aβ is the hallmark of the AD in the early therapeutic intervention as well as diagnosis of the disease. Detecting in‐vivo Aβ deposition, however, still have limited accessibility. In this respect, the current study aims to identify plasma markers related to cerebral Aβ status via simple machine learning approach.MethodsPredictability of the candidate plasma markers for cerebral Aβ burden was examined by analyzing 303 non‐demented participants those who had rules based medicine (RMB) and amyloid PET data from the ADNI cohort at baseline visit (83 control and 220 with MCI). Demographic variables (age, gender, education, and APOE status), and 146 of 190 plasma analytes passed quality check were selected as input in learning vector quantization (LVQ) model. The cerebral Aβ burden was measured using PiB PET images. Predictability and importance of variable were calculated using LVQ model.ResultsLVQ model with 10‐cross validation predicted cerebral Aβ status with the 90.67% accuracy (balanced accuracy: 93.14%) in non‐demented people. Based on variable importance analysis, Top‐10 variables above importance ratio above 60 after rescaling were selected: APOE carrier status (100.00), Angiotensin‐Converting Enzyme (ACE, 92.77), Eotaxin‐3 (89.74), Chromogranin A (CgA, 83.61), Brain Natriuretic Peptide (BNP, 79.61), Creatine Kinase‐MB (CK‐MB, 69.61), Monokine Induced by Gamma Interferon (68.26), T Lymphocyte‐Secreted Protein I‐309 (I‐309, 66.89), Matrix Metalloproteinase‐9 (MMP‐9, 64.52), Matrix Metalloproteinase‐9 total (MMP‐9 total, 60.90).ConclusionsOur findings demonstrated that plasma based analytes can predict the cerebral Aβ positivity in non‐demented people. More specifically, ACE is can be a candidate marker for early detection of Aβ deposition in the asymptomatic stage of dementia. Plus, Eoxatain, and CgA can also play a role in AD pathology. To this end, this research was supported by the MSIT (Ministry of Science and ICT), Korea, under the ITRC (Information Technology Research Center) support program(IITP‐2021‐2017‐0‐01630) supervised by the IITP (Institute for Information & communications Technology Promotion).
The effect of plasmalogen precursor supplementation on blood plasmalogen and C‐reactive protein levels and cognition in cognitively impaired persons
Authors: Goodenowe Dayan B , Haroon Jonathan , Zielinski Margaret A , Mahdavi Kennedy D , Habelhah Barshen , Jordan Sheldon E 
Published: December 2021

AbstractBackgroundDecreased blood and brain plasmalogens levels are associated with decreased cognition in humans. 1‐O‐alkyl‐2,3‐diacylglycerol (ADG) plasmalogen precursors containing docosahexaenoic acid (DHA) at the sn‐2 position have been shown to increase blood plasmalogens and to be neuroprotective in animal models of neurodegeneration. The goal of this study was to evaluate the effect of dietary DHA‐ADG supplementation on blood plasmalogen and C‐Reactive Protein (CRP) levels and cognition in cognitively impaired persons.MethodTwenty persons (9M/11F), aged 37‐81 (average = 68) with mild to moderate cognitive impairment [CDR: 13(0.5); 3(1); 4(2)] were administered an escalating dose of DHA‐ADG [1.0ml/day for 30 days; 2.0ml/day for 60 days; 4.0ml for 30 days]. Blood plasmalogen and CRP levels and cognitive status were measured at baseline and the end of each month. Cognitive status was determined using the Quick Dementia Rating System (QDRS), which was used to derive the participant’s Clinical Dementia Rating (CDR).ResultOverall, maximum average DHA ethanolamine plasmalogen levels were achieved by the end of the 2nd month [224% of baseline, 95%CI = 173‐273%] and this level of elevation was sustained for the duration of the study. Of the 20 participants, 14 (70%) exhibited robust and sustained plasmalogen elevations (>150%, >2 months, ADG Responder). Of the 14 ADG responders, 10 exhibited improvements on QDRS and 6 of these 10 exhibited improvements of at least one CDR level. Of the 14 ADG responders, 4 had baseline CRP levels >1.0. In each of these 4 subjects, CRP levels decreased by >0.5 by the end of the 4th month. DHA‐ADG was well tolerated at all dosages and no adverse reactions were observed. No cognitive improvement was observed in any of the ADG non‐responders.ConclusionDHA‐ADG was effective at elevating blood plasmalogen levels at the dosages studied. 10/14 (71%) of cognitively impaired persons experienced improved levels of cognition when blood DHA‐plasmalogens were elevated by >150%. In all persons with elevated baseline CRP levels, DHA‐plasmalogen elevation was associated with a decrease in blood CRP. This analysis suggests that DHA‐ADG supplementation may be beneficial for patients with mild to moderate cognitive impairment.
Plasma complement C3 levels in Alzheimer's disease
Authors: Wang Lijun , Liu Jun 
Published: December 2021

AbstractBackgroundAlzheimer's disease (AD) is closely related to the loss of synapses. It has been shown that the complement system is involved in the process of synaptic elimination. We investigated whether the levels of plasma complement C3 could be a probable biomarker for the prodromal and demented AD.MethodParticipants included 58 cognitively normal (CN) subjects, 395 patients with late mild cognitive impairment (LMCI), and 112 AD patients enrolled in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database in the current study.ResultThe results showed that plasma complement C3 levels were significantly increased in AD patients compared to LMCI and CN subjects. Negative correlations between plasma complement C3 and education, MMSE were observed in all subjects.ConclusionOur findings indicate that plasma complement C3 levels may not be a valuable biomarker for the diagnosis of AD in the prodromal and dementia stages. Further studies are needed to explore the diagnostic value of plasma complement C3 based on longitudinal population.
Lithium chloride inhibits phosphorylation of tau protein
Authors: Asano Rei , Hamano Tadanori , Yen Shu‐Hui , Sasaki Hirohito , Yamaguchi Tomohisa , Endo Yoshinori , Enomoto Soichi , Shirafuji Norimichi , Ikawa Masamichi , Yamamura Osamu , Nakamoto Yasunari 
Published: December 2021

AbstractBackgroundPathological hallmarks of Alzheimer's disease (AD) are senile plaques (SPs) and neurofibrillary tangles (NFTs), which are formed from highly phosphorylated tau. Lithium chloride (LiCl) has been shown to inhibit phosphorylated tau by inhibiting glycogen synthase kinase‐3β (GSK‐3β). In addition, autophagy lysosome system (Hamano et al., Eur J Neurosci 27; 1119, 2008) and proteasome (J Neurochem 2000) are known to play an important role as tau degradation pathways. We investigated the decrease of phosphorylated tau by LiCl by using cell culture model expressing wild‐type tau via TetOff induction system.MethodsTen to 50mM of LiCl treatment (24 hours) was performed to neuroblastoma cells (M1C) expressing wild‐type tau protein (4R0N) via TetOff induction. Total and phosphorylated tau (PHF‐1) levels and autophagy activation were examined by Western blot (WB) analysis.ResultsReduction of total tau (Tau5) and phosphorylated tau (PHF‐1, and CP13) with LiCl treatment was detected by WB analysis. C‐terminal truncated tau species detected by TauC3 was decreased by LiCl, too. In addition, increase of LC3Ⅱ/I, and decrease of P62 suggesting autophagy activation was observed. Major Tau kinase GSK3β was inactivated by LiCl.ConclusionsThese results imply that LiCl may decrease the phosphorylated tau through suppression of tau phosphokinase and activation of autophagy.
A structured brain‐wide and genome‐wide association study using ADNI PET images
Authors: Li Yanming , Nan Bin , Zhu Ji 
Published: December 2021

AbstractBackgroundDetecting association signals between the brain and the genome using ultrahigh‐dimensional PET neuroimaging scans and GWAS SNP dataMethodA multi‐stage variable selection method is introduced for detecting association signals in structured brain‐wide and genome‐wide association studies (brain‐GWAS). Validity of the proposed approach is demonstrated by both theoretical investigation and numerical simulations. We apply our proposed method to a brain‐GWAS using ADNI PET imaging and genomic data.ResultWe confirm previously reported association signals (e.g. IL8RB and COLEC12 genes) and also uncover several novel SNPs and genes (e.g. GALNT4 and RIN2 genes) that either are associated with brain glucose metabolism or have their association significantly modified by Alzheimer's disease status.ConclusionCompared to conventional single‐voxel‐to‐single‐SNP methods, our approach is more efficient and powerful in selecting the important signals by integrating anatomic and gene grouping structures in the brain and the genome, respectively. It avoids resorting to large number of multiple comparisons while effectively controlling the false discoveries.
Development and analytical performance testing of a novel sTREM2 ELISA method to support drug development
Authors: Stoops Erik , Demeyer Leentje , Francois Cindy , Engelborghs Sebastiaan , Bjerke Maria , Dage Jeffrey L. , Wang Hong 
Published: December 2021

AbstractBackgroundThe triggering receptor expressed on myeloid cells 2 (TREM2) is a cell surface receptor of microglia cells in the central nerve system and is associated with neuroinflammation. sTREM2 can be used as pharmacodynamic biomarker for inflammation or microglial activation in therapeutic development programs. There is a need for well characterized assays that are suitable for measurement of neuroinflammatory biomarkers in pre‐clinical and clinical drug development. This abstract describes the characterization of a new robust sTREM2 prototype immunoassay based on monoclonal recombinant rabbit antibodies(mAbs).MethodA colorimetric sandwich ELISA was developed using capture mAb B02 (code ADx601) and detector mAb C10 (code ADx602) reactive towards the sTREM2 extracellular ectodomain (aa 19‐172). The analytical assay performance will be reported: the repeatability and reproducibility was determined using a neat CSF based QC panel (n=3; 6 test runs; duplicate testing). Accuracy was assessed by testing parallelism and calibrator point back calculated concentrations. Passing Bablok regression analysis was used to demonstrate consistency of sample testing results (43 samples; duplicate testing; 3 test runs). Finally clinical routine CSF samples were analysed (19 patients diagnosed with AD and 20 controls based upon biomarker profile).ResultA prototype sTREM2 ELISA assay was used to generate the assay characterization data: The %CV for repeatability respectively reproducibility were <12.2% and 15.4%. Accuracy: a slope value of 0.992 was obtained after Deming regression between the theoretical and experimentally obtained levels of 8 samples diluted over the measuring range (25‐3500 pg/mL) while the accuracy of the calibrator points was between 0 and 12.6% difference in back calculated concentration over 6 runs. Testing of the lot consistency (Figure 1) resulted in a slope and intercept value of respectively 1.07 (95%CI: 0.90‐1.17) and ‐80.9 (95%CI: ‐294.70‐154.30).Testing of clinical samples showed an increased sTREM2 concentration in AD versus controls (p<0.01).ConclusionA novel CSF prototype ELISA for sTREM2 was developed and characterized including lot consistency, precision, accuracy and others. The generated data indicate a robust sTREM2 immunoassay for use in drug development programs. The next step is the transfer to a manufacturing environment to make the assay available as a commercial test kit (RUO).
Clinical relevance of three‐range cutpoints in Alzheimer’s disease CSF biomarkers
Authors: Brum Wagner Scheeren , Bastiani Marco Antônio , Therriault Joseph , Bieger Andrei , Ferrari‐Souza João Pedro , Benedet Andréa Lessa , Pascoal Tharick A. , Saha‐Chaudhuri Paramita , Rosa‐Neto Pedro , Zimmer Eduardo R. 
Published: December 2021

AbstractBackgroundAlzheimer’s disease (AD) was biologically defined by the 2018 NIA‐AA Research Framework (RF), which recommends dichotomously categorizing biomarker status as normal or abnormal using single cutpoints. Nevertheless, the RF also states a three‐range approach might be useful in AD research. However, this potentially relevant strategy remains mostly unexplored in the field. We hereby propose a three‐range cutpoint system to interpret CSF biomarker measurements. We hypothesized the intermediate group would have a different cognitive trajectory than negative/positive groups and that three‐range models would prognostically outperform binary models.MethodWe included 1278 non‐demented individuals (CU: n=575; MCI: n=703) from the ADNI with baseline CSF Elecsys® biomarkers. 20% of these individuals (who had baseline [18F]AV45 Aβ‐PET) were randomly allocated to a “training set” to define three‐range cutpoints – which were later evaluated in a “test set” comprising the remainder 80% participants. Three‐range cutpoints were defined with two‐graph receiver operating characteristics (TGROC) for each CSF biomarker (Aβ1‐42, p‐tau, t‐tau, p‐tau/Aβ1‐42, t‐tau/Aβ1‐42). Cutpoints were generated with 100,000 bootstraps, combining conventional or earlier‐centiloid [18F]AV45 thresholds to cognition in five different schemes for each biomarker. Linear mixed‐effects models (LMM) were employed to choose the best three‐range scheme and also to main analyses. The primary outcome of LMMs was the mPACC composite and participants were followed for up to 6 years. Three‐range models were compared within themselves, to binary and to continuous models based on AIC, BIC, log‐likelihood and R2.ResultLMMs indicated all three‐range approaches outperformed models with binarized or linear‐continuous form of biomarkers and, interestingly, were closer in information metrics to more sophisticate spline‐continuous models, with p‐tau/Aβ1‐42 being the best three‐range predictor (Table 1). For the latter model (Figure 1), slope‐contrast analyses indicated the intermediate group had a faster rate of decline than the negative (β‐estimate: 2.04, t=4.88, p= 3.5x10‐6) but slower than the positive group (β‐estimate: 4.68, t=10.4, p=1x10‐14).ConclusionOur findings demonstrate that the proposed three‐range system for interpreting CSF biomarkers in AD prognostically outperforms binary cutpoints for all evaluated biomarkers, supporting the existence of an intermediate zone beyond the current normal/abnormal paradigm. This approach has clear potential applications to clinical trial recruitment and to clinical practice.
Cortical arousal is differently related with resting‐state electroencephalographic delta rhythms in healthy seniors and in patients with dementia due to Alzheimer’s disease
Authors: Lopez Susanna , Babiloni Claudio , Ferri Raffaele , Noce Giuseppe , Lizio Roberta , Soricelli Andrea , Nobili Flavio Mariano , Giubilei Franco , Marizzoni Moira , Güntekin Bahar , Yener Gorsev , Frisoni Giovanni B , Del Percio Claudio 
Published: December 2021

AbstractBackgroundKeeping in mind Başar’s theory of event‐related EEG oscillations, here we hypothesize that transient increases in delta rhythms in quiet wakefulness may enhance global cortical arousal as revealed by the desynchronization of alpha rhythms in normal (Nold) seniors with some derangement in Alzheimer’s disease dementia (ADD).MethodClinical and EEG datasets in 100 ADD and 100 Nold individuals matched as demography, education, and gender were taken from an international archive. Standard delta (< 4 Hz) and alpha1 (8‐10.5 Hz) bands were used for the main analysis, while alpha2 (10.5‐13 Hz), theta (4‐8 Hz), beta1 (13‐20 Hz), beta2 (20‐35 Hz), and gamma (35‐40 Hz) served as controls. In the interpretation, the higher the alpha1 power (density), the lower that arousal.ResultAs expected, when compared to the Nold group, the ADD group showed higher global (scalp) power density at the delta‐theta band and lower global power density at the alpha‐beta bands. As novel findings, we observed that: (1) in the Nold group, the global delta and alpha1‐2 power were negatively and linearly correlated; (2) in the ADD group, this correlation was just marginal; and (3) in both Nold and AD groups, the EEG epochs with the highest delta power (median value for stratification) were associated with the lowest voxel‐based eLORETA solutions at the alpha1 band (i.e., eLORETA alpha1 current density at 8‐10.5 Hz). In the Nold group, the maximum t values of the differences between DELTA+ and DELTA‐ were localized in the occipital Brodmann area (BA) 18 at the Talairach coordinates X = 0, Y = −100, and Z = 5 (p < 0.05 corrected; Figure 1). In the ADD group, those maximum t values were instead localized more anteriorly, namely in the central BA 6 at the Talairach coordinates X = 40, Y = −10, and Z = 45 (p < 0.05 corrected; Figure 2).ConclusionThese results suggest that even in quiet wakefulness, delta and alpha rhythms are related to each other, and ADD partially affects this cross‐band neurophysiological mechanism.