bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evolutionary neurotoxicology of manganese (Mn) and its implications for Mn‐induced mixed dementia
Authors: Hernandez Raul B. ,   Laboratory of Bioinorganic and Environmental Toxicology
Published: December 2020

AbstractBackgroundManganese (Mn) is an essential element for all living systems, involved in several biological processes, but chronic and/or acute exposure for this metal can lead to adverse outcome pathways, especially neurotoxicity. In this manner; we hypothesized that if these alterations are conserved cross‐species, this must improve the understanding of the toxicological mechanisms of this metal. Thus, this study aimed to investigate the evolutionary neurotoxicology mechanisms of the manganese.MethodsDifferent biological models (Saccharomyces cerevisiae ‐ yeast, Danio rerio ‐ zebrafish, Mus musculus ‐ cerebellar granular neurons and Homo sapiens ‐ human neuroblastoma SH‐SY5Y cell line) were exposed for chmical species of Mn and studied through different bioanalytical approaches such as cell viability‐MTT‐assay; sensitivity‐gene‐screening assay; b‐galactosidase assay; ribosome profiles; translation protein efficiency assay; semi‐quantitative proteomics ‐ tandem mass tag; metallomics; transcriptomics (human gene expression microarray kit and qRT‐PCR); bioinformatics (gene ontology and prediction of protein‐protein interaction, which were conducted at the String database and the comparative toxicogenomic database respectively. The results were expressed as mean ± SEM of at least 3 experiments; LC50 and statistically significant differences were estimated by ANOVA (analysis of variance followed by Bonferroni’s tests), using the GraphPad Prism 4.0 Software Inc, San Diego, CA, USAResultWe revealed that chemical species of Mn2+ (0.001‐1.5 mM) disrupt metal homeostasis (K, Ca, Fe and Cu); protein metabolism, including translation, post‐translation, and protein degradation as well as associated pathways such as those involved in energetics, cell signaling, cell cycle and neurotransmitter metabolism, in a suite of organisms, from yeast to mammalian. Collectively these cross‐talking alteration of cell pathways potentially can explain with more precision the mechanism of neurotoxicity of this metal. Additionally, analysis in the comparative toxicogenomic database suggested that Mn‐induced neurotoxicity shares mechanism with neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease; but sometimes involving different genes or proteins, which needs to be considered before drawing comparisons to humans.ConclusionThe evolutionary neurotoxicology of the manganese showed in this study represent a new paradigm for Mn‐induced neurotoxicity and neurodegeneration and open a new avenue to study the role of other essential trace elements in similar pathogenic processes.
Sex differences in CSF biomarkers for neurodegeneration and blood‐brain barrier integrity
Authors: Skillback Tobias , Blennow Kaj , Zetterberg Henrik , Shams Sara , Machado Alejandra , Pereira Joana B. , Lindberg Olof , Mielke Michelle M. , Zettergren Anna , Rydén Lina , Westman Eric , Wahlund Lars‐Olof , Skoog Ingmar , Kern Silke 
Published: December 2020

AbstractBackgroundCSF neurofilament light protein (NfL) is an important biomarker in several neurologic diseases. CSF NfL concentrations are known to increase with age, but sex differences have been less examined. The CSF/serum albumin ratio (QAlb) is a biomarker for blood‐brain barrier integrity, which has previously been found to be higher in men. As NfL and QAlb are used in clinical routine, the impact of demographic factors on these biomarkers is important to understand.MethodParticipants were derived from two samples. The first was a population‐based cohort of 308 70‐year olds from the Gothenburg H70 Birth Cohort Study, Sweden. The second data set comprised CSF NfL and QAlb results from 8995 and 39252 subjects respectively, generated in clinical practice between 2005‐2012 in Gothenburg, Sweden. In the population‐based study, QAlb and NfL concentrations were examined in relation to sex, cardiovascular risk factors, and MRI signs of cerebral white matter lesions. In the clinical routine cohort, sex differences in QAlb and NfL were tested in relation to age.ResultIn the population‐based sample, men had higher QAlb and NfL concentrations than women. NfL was not related to cerebral vascular pathology, but QAlb correlated positively with several measures of white matter lesions. In the clinical routine cohort, men also had higher QAlb and NfL concentrations from adolescence and throughout life.ConclusionQAlb ratios and CSF NfL levels are higher in men throughout life. The CSF NfL sex difference could not be explained by vascular pathology. Future studies should consider using different reference limits for men and women.
Web‐based requisitioning, tracking and laboratory result reporting system for clinical trials using a central laboratory
Authors: Figurski Michal J. , Berlas Shaila , Korecka Magdalena , Foroud Tatiana M. , Galasko Doug R. , Shaw Leslie M. 
Published: December 2020

AbstractBackgroundChemical biomarkers are increasingly important in clinical trials. Many multi‐center trials use single core laboratory to process biomarkers, to ensure comparability of results. Sample shipment is accompanied by transmission of data between centers, core lab, and other entities. Often physical forms are used: transmitted via email, fax, or as paper forms. Consequently, flow of information about samples is restricted. Core laboratories receive inquiries about sample receipt on a daily basis. The process of information look‐up is a substantial burden on the lab personnel, more so when paper forms are involved, and especially when samples were not actually received.MethodTo alleviate the issues that arise in this setting, we created a secure web‐based system that integrates information about sample, shipment and test results. The application (“R3+ system” for Requisitioning, Tracking and Result Reporting) allows participating centers to enter information about samples being shipped (Requisitioning), track shipment and the progress of the sample as it’s received and analysed by the core laboratory (Tracking), and see results of analyses, along with full Audit Trail and automated timestamping of all steps (Result Reporting). Records, both current and past, can be retrieved at any time.ResultThe first project using the application is BioSTAC: a multi‐center trial evaluating biomarkers Abeta42, Tau and p‐Tau, in CSF samples shipped overnight at ambient temperature. Participating centers received no training in using R3+ except instruction on registering an account. Within the first 2 months of operation, 14 users from 11 centers registered their accounts. 24 samples have been requested and reported via this application to 6 centers. No usability or security issues were reported. BioSTAC users have requested to utilize the app in other projects, thus two other projects are now actively using this platform.ConclusionImplementation of the web‐based system for storage and transmission of data about the samples in clinical trials has proven to be easy to use and an efficient means of communication, as it replaces email, fax and paper forms, and eliminates the need for querying paper records. Users typically report high satisfaction using this system, while core laboratory personnel save time on administrative tasks.
A portable brainwave technology in detecting functional brain changes in aging and dementia: A pilot study on feasibility of the application in residential care older adults
Authors: Arvan Tara , Sepheri Kattie , Hajra Sujoy Ghosh , Pawlowski Gabriela , Fickling Shaun , D’arcy Ryan C.N. , Song Xiaowei 
Published: December 2020

AbstractBackgroundA portable brainwave technology based on electroencephalography (EEG) / event‐related potential (ERP) has been established; i.e., the so called Brain Vital Signs ‐ BVS. Previous studies reported the development of the BVS framework and the characterization of BVS features in healthy younger adults. In the present study, we investigated the feasibility of application of this novel brainwave technology in older adult residents in long‐term care, and analyzed the relationship of the BVS scores in relation to age and dementia diagnosis.MethodFifty‐one residents in long‐term care (mean age=81.4±9.5 years; range =56‐98; 66% female) with or without dementia (31:20) participated in the study. Each participant was tested, in their residence facility, at baseline and followed for up to 12 months during which two more tests were conducted. At each test time, participants were scanned twice using the BVS device, with which the electrodes placed on the frontal, central, and posterior sites along the midline of the head. Three ERP components, N100 (perception), P300 (attention), and N400 (cognition) were identified and converted into normalized comparative scores, based on which BVS sub‐scores assessing the amplitude, latency, and the area under the curve of each component were computed. The BVS total score was generated based on the sub‐scores applying a weighted algorithm. Inter‐rater reliability was examined using Intraclass Correlation Coefficient. The BVS scores were correlated with age, and compared for dementia and cognitive status.ResultData were consistently collected from residential‐care older adults at each of the three time points with 100% success rate, suggesting the feasible application of the portably brainwave technology. Inter‐rater reliability rate was as high as 0.991‐1.000. The BVS total scores and several of the component scores were moderately related to age; e.g., Spearman correlation coefficient r=.262, p=.027 for P300 amplitude and r=‐.286, p=.016 for N400 latency. Some of the component scores differed by dementia status (e.g., t=‐2.03, p‐value= .046 for P300 latency).ConclusionThe study suggests that BVS can be feasibly applied in studying older residents in long‐term care. Ongoing analysis effort is to better understand age‐ and dementia‐ associated changes of the BVS scores for practical result interpretation.
Relationship between regional atrophy and amyloid‐β load in Alzheimer’s disease and mild cognitive impairment
Authors: Bao Yiwen , Cheung Eva YW , Chau Anson CM , Zhang Huiqin , Zhang H , Chiu Patrick Ka‐Chun , Shea Yat Fung , Kwan Joseph SK , Mak Henry 
Published: December 2020

AbstractBackgroundMild cognitive impairment (MCI) is a transition stage between cognitively unimpaired and Alzheimer’s Disease (AD). Accumulation of amyloid‐β (Aβ) is considered as upstream event in the development of AD, while grey matter (GM) atrophy occurs in the late stage (Jack et al., 2010). In the cognitive continuum from MCI to AD, the correlation between two biomarkers are still not clearly known. From neuropathological perspective, the regional relationship between Aβ and GM atrophy is deficient.MethodAβ deposition was assessed by 18F‐Flutemetamol‐positron emission tomography (PET) and magnetic resonance imaging (MRI) was used to estimate grey matter volume (GMV). 17 AD subjects and 28 MCI subjects were recruited in our study and underwent both MRI and PET scanning. Based on fused MRI and PET images, Statistical parametric mapping (SPM) and voxel‐based morphometry (VBM) were used to obtain 18F‐Flutemetamol Standardized uptake value ratio (SUVR) and GMV respectively in 8 paired standardized region‐of‐interests and at global level. The correlations were assessed by partial correlation test controlling for age and sex.ResultThe mean differences of Aβ‐SUVR between AD and MCI were significant (p<0.0001) in most region‐of‐interests (ROIs) and globally. Compared to MCI group, AD group had significantly smaller GMV in hippocampus and mesial temporal lobe (p<0.0001) as well as globally(p<0.01) and in lateral temporal lobe (p<0.05). In AD group, GMV was negatively correlated with Aβ burden in left sensorimotor region (r=‐0.617, p<0.05), while positively correlated in mesial temporal lobe (left: r=0.682, p<0.0; right: r=0.522, p<0.05) and left hippocampus (r=0.548, p<0.05). For MCI group, GMV was negatively correlated with Aβ burden in right precuneus/posterior cingulate only (r=‐0.481, p<0.05).ConclusionOur result indicates that the relationship of amyloid deposition and neurodegeneration might vary during the cognitive continuum. In MCI stage, Aβ burden may lead to severe atrophy in right precuneus/posterior cingulate, early site where Aβ deposition occurs. However, in AD stage, Aβ accumulation might lead to sensorimotor (left) atrophy and compensatory increase in GMV in mesial temporal lobe sites and left hippocampus where Aβ builds up relatively late.
Efficacy of Serious exerGame in Alzheimer’s disease and related disorders: Results of the AZgame multicenter study
Authors: Philippe Robert , Derreumaux Alexandre , Albrengues Claire , Foulon Pierre , Fabre Roxanne , Mercier Gégoire , Manera Valeria 
Published: December 2020

AbstractBackgroundSerious exerGames (SeG) promotes cognitive simulation with physical activity in a positive emotional context. Results of the first pilot usability study with X‐Torp (Bensadoun & al, JAD, 2016) suggest that this SeG represents a usable as enriched environments, for healthy subjects and persons with MCI and Alzheimer's Disease. The aim of the AZgame multicenter study using X‐Torp is to evaluate the efficacy and the cost‐utility in patients suffering from Alzheimer’s disease in comparison to the usual management.MethodX‐Torp use the Microsoft® Kinect™. The scenario mode combines action game dynamics, with exploration of open environments fin order to stimulate motor activities and mini‐games in order to stimulate cognitive activities. (full description available here: http://www.innovation-alzheimer.fr/azgame-eco-2/). 91 subjects (mean age 81.7 years, mean Minimental state Examination MMSE 18.3 sd 3.6) with a DSM 5 diagnosis of minor (n = 26) or major (n = 65) Neurocognitive disorders were recruited in 16 centres including memory consultation, day care center, nursing home. Center were randomised in Intervention (using XTorp) and control center with regular care.In the intervention group patients used Xtorp for 12 weeks, 2 sessions of 30 mn per week. Patients underwent cognitive (MMSE), functional (EQ5D) and behavioural assessment (NPI and Apathy Inventory) at base line, at the end of the intervention (Week 12) and 12 weeks after the intervention (W 24).ResultWhen comparing cognitive, functional and behavioural scores between base line W12 and W24 mixed model analysis (time x group interaction) indicated no significant interaction for the MMSE and the EQ5D. On the behavioural point of view patients of the Intervention XTorp group showed an improvement at the NPI total score and at the apathy Inventory. Mixed analysis (time BL, W12, W24 x group) indicated a significant interaction for the NPI total score (p value = 0.03) apathy inventory score (p value = 0.008) with a significant increase in apathy in the non‐active subjects.ConclusionAccording to these results use of X‐Torp, a therapeutic video game with motion capture improved neuropsychiatric symptoms and most particularly apathy. This effect is also observed 12 weeks after the end of the intervention.
Relationship between carotid atherosclerosis and plasma Aβ levels in patients with high risk of stroke
Authors: Wang Anqi , Gao Ling , Wei Shan , Dang Liangjun , Shang Suhang , Chen Chen , Wang Jin , Huo Kang , Deng Meiying , Wang Jingyi , Qu Qiumin 
Published: December 2020

AbstractBackgroundGrowing evidence indicated that vascular factors contributed to the pathogenesis of Alzheimer’s disease (AD), but the relationship of atherosclerosis and AD is unclear. As Amyloid‐β (Aβ) deposition in the brain is a main pathophysiology of AD and plasma Aβ is closely related to Aβ deposition in the brain. In present study, we investigated the relationship between carotid atherosclerosis and plasma Aβ levels.MethodPatients with high risk of stroke were from community stroke screening in Qubao Village, Xi'an. Carotid ultrasound was used to detect carotid atherosclerosis. Venous blood was collected on an empty stomach in the morning. Plasma Aβ1‐40 and Aβ1‐42 levels were measured by ELISA. Univariate and multivariate analysis were used to investigated carotid atherosclerosis and plasma Aβ1‐40 and Aβ1‐42 levels.ResultAmong 222 participants underwent carotid ultrasound, 149 had carotid atherosclerosis (49.01%). Univariate analysis showed that plasma Aβ1‐40 level and Aβ1‐42 level had no significant differences between carotid atherosclerosis group and non‐carotid atherosclerosis group (53.15 ± 8.77 vs. 50.96 ± 8.79 pg/ml, P=0.083; 41.07 ± 6.51 vs. 39.95 ± 5.93 pg/ml, P=0.217). Multivariate linear regression analysis showed that plasma Aβ1‐40 (b=1.832, p = 0.213), plasma Aβ1‐42 (b=1.605, P=0.131) and plasma Aβ1‐40/Aβ1‐42 ratio (b=‐0.012, P = 0.829) had no significant difference between two groups in the total population. However, in the non‐hypertensive population, plasma Aβ1‐40 and Aβ1‐42 were significantly higher in the carotid atherosclerosis group than those in the non‐carotid atherosclerosis group (b=6.774, 95% CI: 2.691‐10.858 pg/ml, P =0.001; b=3.408, 95% CI: 0.309‐6.508 pg/ml, P=0.032).ConclusionAmong patients with high risk of stroke, carotid atherosclerosis was associated with higher plasma Aβ levels in non‐hypertension group. These indicated that atherosclerosis may be related to AD, and the relationships may be confounded by hypertension.
Disease progression and costs at two‐year follow‐up of GERAS‐US: A three‐year study of mild cognitive impairment and mild dementia due to Alzheimer’s disease in the United States
Authors: Chandler Julie , Zagar Anthony , Kim Yongin , Zimmer Jennifer A , Rentz Dorene M , Schwartz Ronald L , Fillit Howard M 
Published: December 2020

AbstractBackgroundGERAS‐US is a 36‐month study that aims to understand long‐term clinical and economic outcomes of Alzheimer’s disease (AD). Changes in total costs at 1 and 2 years post‐baseline in beta‐amyloid‐positive [+] patients with mild cognitive impairment (MCI) and mild dementia (MILD) are reported.MethodsPatients aged 55 to 85 years (N=617) were enrolled from 30 October 2016 through 09 October 2017. Mean 30‐day total societal costs (direct and indirect using opportunity costs [Figure 1]) were captured. Opportunity cost sums lost productive hours multiplied by national average annual gross hourly wage for workers and by lost leisure time for nonworkers (35% of hourly wage for workers). Costs are presented as mean (95% confidence interval [CI]) at baseline and at 1 and 2 years for the overall population and stratified by baseline severity (MCI vs MILD). Mean (95% CI) changes from baseline at 1 and 2 years are presented. A repeated measures model was used. Comparisons were conducted at 5% significance level.ResultsAt baseline, patient mean age was 70.3 years for MCI and 71.7 years for MILD; overall, 52.7% were females. Analyses at 1 and 2 years post‐baseline included 483 (78.3%) and 388 (62.9%) patients, respectively. For amyloid[+] patients, mean change from baseline in Cognitive Function Index (study partner version) and Mini‐Mental State Examination scores demonstrated worsening at 1 and 2 years (Table 1). Mean estimated total societal costs for overall population decreased at 1 ($2343; p<0.001) and 2 years ($2641; p=0.026) vs baseline ($3033). Neither direct medical nor direct nonmedical costs changed over the 2‐year period for MILD patients, but direct medical costs increased significantly at Year 2 vs Year 1 for MCI patients (p=0.024; Table 2). Direct costs for study partners did not change over a 2‐year period; however, indirect costs were significantly higher for MILD vs MCI cohort at Years 1 and 2 (p£0.001).ConclusionsBoth function and cognition declined over 2‐year period for AD patients. In amyloid[+] MCI AD patients, direct medical costs increased from Year 1 to Year 2. Understanding why costs did not increase for MILD AD patients, despite clinical progression, requires further study.
The attitudes of physicians and the general public toward prognostic disclosure of different serious illnesses: A nationwide survey
Authors: Oh Sinae , Yun Young Ho , Kim Young Ae , Kim Yu Jung , Shim Hyun‐Jeong , Song Eun‐Kee , Kang Jung Hun , Kwon Jung Hye , Lee Jung Lim , Lee Soon Nam , Maeng Chi Hoon , Kang Eun Joo , Do Young Rok , Yun Hwan‐Jung , Jung Kyung Hae 
Published: December 2020

AbstractBackgroundAlthough international guidelines recommend palliative care approaches for many serious illnesses, the palliative needs of patients with serious illnesses other than cancer are often unmet, mainly due to insufficient prognosis‐related discussion. We investigated physicians’ and the general public’s respective attitudes toward prognostic disclosure for several serious illnesses.MethodWe conducted a survey of 928 physicians, sourced from 12 hospitals and the Korean Medical Association, and 1005 members of the general public, sourced from 17 major cities and provinces.ResultFor most illnesses, most physicians (adjusted proportions – end‐organ failure: 99.0%; incurable genetic or neurologic disease: 98.5%; acquired immune deficiency syndrome: 98.4%; stroke or Parkinson’s disease: 96.0%; and dementia: 89.6%) and members of the general public (end‐organ failure: 92.0%; incurable genetic or neurologic disease: 92.5%; acquired immune deficiency syndrome: 91.5%; stroke or Parkinson’s disease: 92.1%; and dementia: 86.9%) wanted to be informed if they had a terminal prognosis. For physicians and the general public, the primary factor to consider when disclosing terminal status was “the patient’s right to know his/her condition” (31.0%). Meanwhile, for the general public the main reason for not disclosing prognosis was “psychological burden such as anxiety and depression” (35.8%), while for the physicians it was “disclosure would have no beneficial effect” (42.4%).ConclusionPhysicians and the general public strongly agree that disclosure of a terminal prognosis respects patient autonomy in several serious illnesses.
Clinical development of tricaprilin, a ketogenic drug for Alzheimer's disease
Authors: Walker Judith Anne , Nelleman Lars , Henderson Samuel T , Morimoto Bruce 
Published: December 2020

AbstractBackgroundCerebral glucose hypometabolism in posterior cingulate, parietal, temporal, and prefrontal cortex is an early feature of Alzheimer’s disease (AD). Cells in these regions which exhibit a defect in glucose metabolism have been shown to preserve the ability to metabolise ketones. We report on an approach to induce ketosis and treat AD with a new drug formulation of a semi‐synthetic triglyceride, tricaprilin.MethodNovel formulations of tricaprilin were developed and tested in vitro, in vivo, and in human studies to assess pharmacokinetics, safety, and tolerability. The clinical studies were conducted in healthy human Caucasian and Asian volunteers and in a variety of food conditions.ResultTwo new formulations of tricaprilin showed desirable PK characteristics, leading to generation of ketones and excellent safety and tolerability, when administered in doses of 20g after a meal, in both Caucasians and Asians.ConclusionThe selected formulation will be moved forward in drug development with an ascending dose study in healthy elderly subjects and a Phase 3 study in mild to moderate Alzheimer's disease.