bluuebunny/crossref_metadata_2025_split huggingface dataset:
‘Guttmann Cognitest®’, preliminary validation of an app to test cognitive performance
Authors: Cattaneo Gabriele , Solana Javier , García‐Zafra Edgar , Alviarez‐Schulze Vanessa , Opisso Eloy , Lopez‐Carballo Jaume , García‐Molina Alberto , Tormos‐Muñoz Josep Mª , Bartres‐Faz David , Pascual‐Leone Alvaro 
Published: December 2020

AbstractBackgroundThanks to technological advances the administration of cognitive assessments via computers, tablets or smartphones continues to increase, both in research and clinical practice. Several systems are commercially available and have been validated. However, there are limited tools that provide a baseline assessment and guide a personalized training program with the seamless integration of follow‐up evaluations. The “Guttmann Cognitest”® app has been specifically designed as a smartphone or tablet app to be eventually integrated as an assessment module of the “Guttmann, NeuroPersonalTrainer”® (Solana et al., 2014), a tele‐cognitive rehabilitation platform.MethodIn the context of the Barcelona Brain Health Initiative (BBHI, Cattaneo et al., 2018) 57 healthy subjects (28 women, mean age= 56.1±7, age range 42‐65, years of education= 16.1±3.6) underwent an extensive paper‐and‐pencil classical neuropsychological assessment and a cognitive assessment via the mobile app. The two cognitive assessments were completed on different days and their order was counterbalanced across subjects. The “Guttmann Cognitest”® app includes 6 tests designed to assess main cognitive functions and be completed in about 17 minutes (range 9‐30).ResultsFactorial analysis confirmed that the app measured the intended 6 different cognitive domains. Internal consistency was good (α=0.71) and convergent validity analysis demonstrated that performance in each of the 6 tests in the app correlated with the a priori defined correspondent gold standard paper and pencil test. We found no gender effects, and an expected correlation with age in 5 out of 7 tests.ConclusionsCognitive assessment with a mobile phone is feasible and useful. Preliminary results reveal that the “Guttmann Cognitest”® app has good psychometric properties and is suitable to test cognitive performance in large samples. Once integrated within the “Guttmann NeuroPersonalTrainer”® platform, it will enable automatically screening and effectively monitoring patient’s cognitive capacities over time while undergoing personalized cognitive training and allowing automatic adjustment of treatments in intensity and difficulty according to performance.
Mining gene expression omnibus metadata to unravel key genes entwined with pathogenesis and prognosis of Alzheimer’s disease: A comprehensive bioinformatics approach
Authors: Sree G.N.S Hema , Rajalekshmi Saraswathy Ganesan , Burri Raghunath R. 
Published: December 2020

AbstractBackgroundGene expression analysis has become a valuable resource to derive new hypotheses in exploring genetic background of neurodegenerative disorders. Dearth in break through Alzheimer’s disease research to unravel i) genetic predisposition, and ii) disease specific druggable targets, prompted us to initiate and frame this project.MethodGene Expression Omnibus (GEO) database was screened with a set of prescribed inclusion and exclusion criterion. Datasets evaluated in Homosapiens containing controls and patient samples describing the genetic source and diagnostic criteria were selected for the study. Datasets evaluated in cell lines, animals, mutational studies and methylation status were excluded. Shortlisted datasets were analysed individually to retrieve Differentially Expressed Genes (DEGs) by considering False Discovery Rate (FDR) and log Fold Change (FC) through GEO2R tool. Different permutation and combinations were tried between FDR p‐value and log FC (FDR p‐value < 0.05 and log FC >2; FDR p‐value < 0.05 and log FC >1.5; FDR p‐value < 0.05 and log FC >1; and FDR p‐value <0.01 and log FC >1) to retrieve common DEGs from 70% of the datasets satisfying any of the above criteria between control and disease groups. Protein‐Protein Interactions (PPI) of common DEGs with Literature Derived Genes (LDGs) (retrieved from NCBI) was constructed to identify potential AD specific target proteins.ResultAround 32 datasets were identified from GEO database meeting the prescribed criteria. Each dataset was analysed individually and DEGs were retrieved. Amongst the different combinations applied between FDR p‐value and log FC, FDR p‐value <0.01 and log FC >1 was considered suitable and this ultimately resulted in 6 datasets which were found to satisfy the fixed criteria in up‐regulated and down‐regulated DEGs as well. Amid the 6 datasets, common DEGs were found in 4 datasets (about 70%) ‐ SLC5A3 and SERPINA3 from up‐regulated DEGs; SST, RGS4, CRYM, NPTX2, RTN3, BDNF and ENC1 from down‐regulated DEGs. PPI analysis revealed significant interactions of SERPINA3, SST, RGS4, BDNF and RTN3 with LDGs.ConclusionThe above analysis identified the genetic potential of SERPINA3, SST, RGS4, BDNF and RTN3 to underpin AD pathogenesis.
The anti‐amyloid treatment in asymptomatic Alzheimer’s disease (A4) study: Report of screening and recruitment characteristics of the Melbourne composite site
Authors: Zisis Georgios , Mastwyk Maree , Huynh Andrew , Yates Paul A. , Langford Oliver , Raman Rema , Donohue Michael C. , Aisen Paul S. , Robertson Joanne S. , Fowler Christopher J. , Mitchell Natasha L. , Barac Alex M. , Rowe Christopher C. , Sperling Reisa A. , Masters Colin L. 
Published: December 2020

AbstractBackgroundSecondary prevention trials in cognitively‐normal older people with brain amyloid beta (Aβ) accumulation are emerging as the next frontier in dementia therapy. The A4 Study is an international randomised placebo controlled trial of immunotherapy against Aβ, a hallmark contributing factor to Alzheimer’s disease (AD). Here we report the screening characteristics and common reasons for participation and screen failure for the Melbourne Composite Site (MCS).MethodAn advertising campaign was conducted over three years. Individuals who expressed interest were phone screened for initial eligibility and invited to the MCS for full assessment. Cognitively normal [CDR=0; Logical Memory Index II (LMII) score 6 to 18; MMSE ≥25] individuals underwent Aβ‐PET imaging using Florbetapir and were classified as Aβ+ (eligible), or Aβ‐ (not eligible) according to study protocol. Participants also provided responses to the Concerns about AD (CAD) and Views and Perceptions of Amyloid Imaging (VPAI) questionnaires.ResultScience media was our main recruitment source (Mastwyk M et al, International Psychogeriatric Association 2019, DOI: https://doi.org/10.1017/S1041610219000474). 689 individuals were invited to be screened for eligibility and 674 were enrolled. 51% were female and median education level was 16 years (IQR: 12 – 18); 336/517 (65.0%) reported a family history of dementia. 446/524 (85%) wanted to know if they would develop AD (CAD). 452/523 (87%) desired to contribute to AD research (VPAI). The main screen fail reasons in 580 participants were: classified as Aβ‐ (56%); CDR and/or LMII (11%); unstable medical condition (8%); MMSE <25 (4%); PET scans were acquired in 431 participants; 94 Aβ+ participants were randomised [median age 70 (IQR: 67 – 73)]. Aβ‐ participants were more likely to be ≤70 years old.ConclusionIntervention trials in preclinical AD present a unique opportunity to reduce the impact of dementia for the future. Individual choice to participate in this sample was motivated by a desire to contribute to AD research and to find out their likelihood of developing AD.
Exploring the role of BIN1 in Alzheimer’s disease
Authors: Gabriele Rebecca , Glennon Elizabeth , Wray Selina , Lines Georgie 
Published: December 2020

AbstractBackgroundBridging integrator 1 (BIN1) is a major risk factor for Alzheimer’s disease (AD). In the brain BIN1 is expressed by neurons and glial cells with each cell type expressing specific isoforms. Interestingly, previous studies have shown that BIN1 expression is altered in AD brains. However, little is known on how each individual isoform is affected and how BIN1 contributes to AD pathogenesis. Our preliminary data suggests that the neuronal isoforms of BIN1 (nBIN1) may modulate the unfolded protein response (UPR), an endoplasmic reticulum stress triggered mechanism. The UPR consists of three different signalling pathways regulated by: PERK, IRE1 and the transcription factor ATF6, which is cleaved into an active form which translocates to the nucleus. Interestingly, the UPR is thought to play a role in AD pathogenesis. This study examines the role of BIN1 in AD as UPR modulator.MethodEffects of BIN1 expression on UPR activation was investigated by means of western blot and immunocytochemistry in SH‐SY5Y cells expressing nBIN1 or an empty vector. To detect the ATF6 fragment, western blot was carried out on HEK cells expressing BIN1 or an empty vector co‐transfected with an ATF6‐GFP construct. Effects of BIN1 downregulation was explored by luciferase assay and immunocytochemistry in N2a cells transfected with BIN1 or control siRNAResultIncreased expression of BIN1 showed a significant decrease in full‐length ATF6, an increase in the cleaved fragment of ATF6, an increase in the ATF6 target gene Bip and a significant increase in ATF6 nuclear translocation compared to control, suggesting a selective activation of the ATF6 arm of the UPR. Interestingly, downregulation of BIN1 in N2a shows a selective inhibition of the ATF6 pathway.ConclusionUPR dysregulation is a salient feature in AD; we explored the involvement of BIN1 in the regulation of the UPR and found that altered levels of BIN1 can selectively modulate the ATF6 pathway. Future studies to dissect the relationship between BIN1 and ATF6 and better understand the underlying mechanisms might offer an insight into future therapeutic targets.
Alteration of metabolic profile and potential biomarkers in the plasma of Alzheimer's disease
Authors: Le Weidong 
Published: December 2020

AbstractBackgroundThe expending of elderly population worldwide leads to a dramatical rising in the incidence of chronic diseases including Alzheimer’s Disease (AD) in the elderly. The inadequate understanding of the mechanisms underlying AD is deemed the greatest stumbling block against progress in definitive diagnosis and curative intervention of this disease. Efforts have been made towards the discovery of reliable AD biomarkers, but they are either invasive based on neuropathological markers in cerebrospinal fluid (CSF) or expensive using emission tomography scanning or magnetic resonance imaging techniques. With the emergence of high‐throughput technology that could detect and catalogue larger numbers of small metabolites, metabolomics offers hope for a better understanding of AD and subsequent identification of biomarkers.MethodHerein, using untargeted ultra‐performance liquid chromatography‐mass spectrometry we firstly measured concentrations of plasma metabolites in a cohort of AD subjects (n=44) and cognitively normal controls (Ctrl, n=94).ResultWe found remarkable reductions of polyunsaturated fatty acids (PUFAs), acyl‐carnitines, tryptophan degradation related metabolites and elevated levels of bile acids in AD compared to Ctrl. Followed by repeated validation in an independent cohort including AD (n=30), mild cognitive impairment (MCI, n=13), Ctrl (n=43) and non‐AD neurological disease controls (NDC, n=31), we further identified a metabolite panel consisting of five metabolites including cholic acid, chenodeoxycholic acid, allocholic acid, indolelactic acid and tryptophan that can distinguish AD from both Ctrl and NDC with satisfactory sensitivity and specificity.ConclusionNotably, the concentrations of these metabolites are significantly correlated with disease severity. Our results also suggested the altered bile acid profiles in AD and MCI might provide clues for early risk of AD. Following further validation in larger cohorts, these findings are expected to provide new approaches for diagnosis of AD and offer novel insights into AD pathogenesis.
CLK inhibition alters tau splicing and has a neuroprotective effect in vitro
Authors: Alalwany Roaa H. , Donaldson Lucy F. , Morgan Kevin , Hawtrey Tom J. , Morris Jonathan C. , Bates David O. 
Published: December 2020

AbstractBackgroundMicrotubule‐associated protein tau (MAPT) undergoes alternative splicing at exon 10 which encodes one of its four microtubule‐binding repeats. Exon 10 inclusion gives rise to tau isoforms with all four repeats (4R) whilst exon 10 exclusion leads to isoforms with three repeats (3R). The 1:1 ratio between 3R and 4R isoforms is tightly regulated by splicing machinery and crucial to normal function. Kinases such as CLKs regulate the activity of splicing factors and their interaction with target transcripts, including MAPT. Disruption to this balance leads to the formation of neurofibrillary tangles (NFTs) and neurodegeneration but the mechanism of this is not yet wholly understood.MethodsDifferentiated Neuro2a and SH‐SY5Y cells were used as neuronal models as these cell lines show an imbalance of MAPT isoforms with bias towards 4R and 3R respectively. Splicing factor SRSF1 was transiently knocked down to confirm its role in MAPT splicing. Novel kinase inhibitors were used to reduce the activity of CLKs and determine the effect on MAPT splicing. The expression ratio of 4R and 3R isoforms was measured by RT‐PCR. Okadaic acid (OA) was used to produce a neurotoxic model and investigate the use of kinase inhibitors for neuronal protection. As a functional measure β3‐tubulin fluorescent marker was used to quantify OA dependent reduction in neurite outgrowth.Results4R:3R tau expression significantly decreased by 65% in Neuro2a cells with knockdown of SRSF1 (students t‐test, p<0.001). CLK inhibition increased 4R:3R by 50% in SH‐SY5Y cells compared to control (one‐way ANOVA, p<0.05). SHSY5Y cells neurite outgrowth was significantly reduced by 60% and 85% with 1nM and 5nM OA treatment respectively, demonstrating a concentration dependent effect (one‐way ANOVA, p<0.001). At 1nM OA, neurite outgrowth was rescued by co‐treatment with a novel CLK inhibitor (two‐way ANOVA, p<0.0001).ConclusionsNovel CLK inhibitors can modulate the expression of MAPT splicing isoforms and exert a functional effect on neurite outgrowth. This suggests these compounds could have a therapeutic effect by rectifying the balance of 4R:3R tau expression.
Vafidemstat in mild to moderate Alzheimer’s disease: The ETHERAL study European cohort interim analysis
Authors: Bullock Roger Alan , Ropacki Michael T. , Gutierrez Sonia , Xaus Jordi , Maes Tamara , Buesa Carlos 
Published: December 2020

AbstractBackgroundETHERAL is a global, multicentre, 12‐month, randomized, Phase IIa safety study of vafidemstat in mild to moderate AD. The study includes a 6‐month, placebo‐controlled, 3‐arm period followed by a 6‐month, 2‐arm active treatment period where participants remain blinded to dose. Vafidemstat is the first epigenetic compound to be studied in clinical trials in CNS disorders. The primary endpoint is safety though data on cognition, behaviour and function and extensive CSF biomarker data was collected at 0, 6 and 12 months. The CSF biomarkers include amyloid and tau and the pro‐inflammatory biomarker S100A9, which is one of the top ten upregulated genes in late onset AD. This paper presents the first unblinded analysis of the data at the end of the first 6‐month period for the EU cohort.Method117 participants comprise the EU cohort recruited from sites in Spain, France and the UK. They were randomised to two doses of vafidemstat and placebo; with the placebo participants subsequently randomised to one of the two doses for the second half of the study. Unblinding will occur in February 2020 and randomised results will be presented on safety, cognition, behaviour and function, along with biomarker changes and correlations with clinical efficacy.ResultBaseline data has shown that all participants meet the amyloid and tau requirements for a diagnosis of AD and S100A9 levels were elevated across groups, as expected. Safety data to‐date supports that vafidemstat has been safe and well‐tolerated, and there has been a low drop‐out rate.ConclusionThis first analysis presentation will provide data analyses from the EU cohort of randomized, double‐blind 6‐month period of ETHERAL, examine safety data, and correlate clinical data with biomarker changes in CSF. While we may assume the sample size is likely not powered for the clinical efficacy outcomes, the study will demonstrate: a) that an epigenetic compound (vafidemstat, an LSD1 inhibitor) can be developed for CNS disorders, b) that vafidemstat is generally safe and well tolerated, especially in this frail population, and c) that initial efficacy of vafidemstat will provide further knowledge on how to design the confirmatory studies.
Vascular risk and neuroimaging profile of MCI patients in the FINOMAIN Study
Authors: Guevarra Anne Cristine Deocariza , De Guzman Maria Fe Payno , Galvez Francy Joy , Rodriguez Anthony , Citron Raphael Louis B , Yu Justine Megan F , Rivamonte Vladimir , Phung Thien Kieu Thi , Dominguez Jacqueline C 
Published: December 2020

AbstractBackgroundThe Asian population has been found to be at a higher risk of developing dementia compared to other races due to the high prevalence of vascular risk factors. Utilization of different modalities that manage these vascular risk factors is the focus of this study in order to prevent progression of dementia among senior citizens with mild cognitive impairment.MethodCommunity‐based participants with MCI were recruited to join the FINOMAIN Study. They were divided into control and intervention groups, to which INDAK (dance therapy) shall be given. Both groups shall receive health education, management of non‐communicable diseases, and nutrition management. 72 participants shall undergo neuroimaging. Hypertension, diabetes mellitus type 2, and dyslipidemia were derived from clinical data and ancillary procedures. Small vessel disease markers (white matter hyperintensity, chronic lacunes, enlarged perivascular spaces, global atrophy, medial temporal lobe atrophy, frontotemporal atrophy, and posterior cortical atrophy) were documented through T1W, T2W, and FLAIR sequences on MRI and with the use scales like Fazekas, modified Staal’s score, and atrophy scores. All MRI assessments were performed by a single neurologist blinded to the clinical and cognitive measures. Cognitive measures had been done including tests for global cognition (MMSE‐P and MoCA‐P). Independent t‐test was used to show descriptive results of both groups.Result42 subjects had completed MRI as of this writing (18 control group, 24 intervention group) with a mean age of 70 and mean years of education 9.48 years. Only 12% of the subpopulation are males. Markers of noncommunicable diseases did not show significant differences between groups. SVD burden measured through modified Staal’s score showed 2.50+0.985 for the control group and 2.33+0.917 for the intervention group (with a maximum score of 3 points) Fazekas scores for both groups showed moderate WMH burden (2.17+0.786 vs. 2.29+0.859; p = 0.125). MTA scores did not exceed the score of 2 in both groups (1.56+0.784 vs. 1.50+0.590; p = 0.794).ConclusionThe subsample of the FINOMAIN study shows comparable demographics, clinical, and neuroimaging findings which is considered as a good pre‐intervention data. Small vessel disease burden in the neuroimaging is quite high in both study groups.
Neurofilament‐light chain in murine models of neurodegenerative and rare diseases
Authors: Schilcher Irene , Loeffler Tina , Flunkert Stefanie , Hutter‐Paier Birgit 
Published: December 2020

AbstractBackgroundNeurofilament‐light chain (NF‐L) is known as biomarker of many neurodegenerative diseases and their progression. By analyzing amyotrophic lateral sclerosis (ALS) patients CSF or plasma progression of NF‐L levels can forecast conversion from the presymptomatic to symptomatic stage and the time of survival. So far, detailed analyses of NF‐L expression in neurodegenerative disease patient’s samples were performed, while NF‐L levels of preclinical mouse models of ALS, Alzheimer’s and Parkinson’s disease as well as lysosomal storage diseases are still unknown.MethodWe therefore evaluated NF‐L levels in the plasma of the ALS models SOD1‐G93A low expressor and TAR6/6 mice, the Alzheimer’s disease model 5xFAD, the Parkinson’s disease model Line 61 and the Gaucher disease model 4L/PS‐NA and the CSF of selected models using a commercially available ELISA kit from UmanDiagnostics.ResultOur results show that NF‐L levels are highly increased in the plasma of ALS, Alzheimer’s and Gaucher disease mouse models, while in the analyzed PD model NF‐L plasma levels barely changed. Most of the analyzed models show a progressive increase of NF‐L levels over age.ConclusionNF‐L measurements in the plasma of the neurodegenerative disease mouse models of ALS and Alzheimer’s disease are thus a good tool to evaluate disease progression. Compared to analyses in human tissues, our results suggest that murine NF‐L levels and their progression have a high translation value. Furthermore, our data indicate that NF‐L might also be a good biomarker for diseases that are not classical neurodegenerative diseases but disorders with a neuronal component like some lysosomal storage diseases.
Stakeholders’ views around the concept and diagnosis of mild cognitive impairment and their understanding of dementia prevention: A qualitative study
Authors: Poppe Michaela , Mansour Hassan , Rapaport Penny , Palomo Marina , Burton Alexandra , Morgan‐Trimmer Sarah , Carter Christine , Roche Moise , Higgs Paul , Walker Zuzana , Aguirre Elisa , Bass Nicholas , Huntley Jonathan D , Wenborn Jennifer , Cooper Claudia 
Published: December 2020

AbstractBackgroundMany people live with an awareness of mild cognitive changes and an associated dementia risk. Previous authors describe the uncertainties of this liminal state between cognitive health and dementia. The interface of this group with health services is growing, driven by early dementia diagnosis campaigns and research about the preventative potential of health promotion. This brings both preventative opportunities and risks of medicalisation, which have not previously been qualitatively explored from the perspectives of professionals, clients and their family members. We ask how services respond to people with memory concerns currently, and how future dementia prevention interventions for people with memory concerns should be structured.MethodWe conducted qualitative interviews with 18 people aged 60+ with subjective or objective memory problems, six family members, 10 health and social care professionals and 11 third sector workers. Interviews were audio‐recorded, transcribed and analysed using an inductive thematic approach. Interviews were conducted as part of the APPLE‐Tree (Active Prevention in People at risk of dementia: Lifestyle, bEhaviour change and Technology to REducE cognitive and functional decline) programme, which is an international collaboration run in the UK.ResultThree main themes were identified: 1) acknowledging the liminal state, compounded by current, discordant health service responses, which medicalise memory concerns yet situate responsibilities for their management with patients and families; 2) challenges of enabling change in contexts of physical and cognitive frailty and social disengagement, and 3) building on existing values, cultures and routines to facilitate the process of implementing and maintaining behavioural and lifestyle changes.ConclusionThis study extends our understanding of the complex liminal position of people with memory concerns seeking help. Effective dementia prevention must empower individuals within challenging contexts and acknowledge their existing values. This cannot be realised within current memory service responses. Our findings further feed into a dementia prevention intervention which is currently being developed as part of the APPLE‐Tree programme.