bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrative analysis identifies copy number variations and their controlled causal molecular networks in Alzheimer’s disease
Authors: Zhang Bin 
Published: December 2020

AbstractBackgroundThe pathogenic mechanism of late‐onset Alzheimer’s disease (LOAD) remains elusive despite intensive studies in the past few decades. Even though ‐27 AD risk loci have been identified through genome‐wide association studies, they explain only a small fraction of the heritability of LOAD. LOAD is such a complex disease that more types of genetic variations need to be studied. Copy number variation (CNV), as one primary type of genomic variation, has been found to play a significant role in many neurological diseases such as Parkinson’s disease, schizophrenia, mental retardation, and AD. A systematic functional study of CNVs through omics‐levels can provide valuable insights into the mechanism of LOAD.MethodIn this study, we employed four complementary CNV calling approaches including CNVnator, Pindel, MetaSV and Delly2 to comprehensively identify CNVs in the WGS data from 1,662 individuals (including 827 LOAD, 330 mild cognitive impairment, and 505 control subjects) across three LOAD cohorts including the Mount Sinai/JJ Peters VA Medical Center Brain Bank (MSBB) AD cohort, the ROSMAP cohort, and the Mayo Clinic cohort. Integrative analysis of the identified CNVs and the matched transcriptomic, proteomic, clinical and pathological data was then performed to determine the functional impacts of these CNVs.ResultGenes associated with CNVs at the transcriptomic level in seven different brain regions were consistently enriched for glutathione metabolism and antigen processing and presentation pathways. The mRNA and protein expression levels of two genes (ACOT2, and GSTM1) in the frontal pole were significantly correlated with cis‐regulatory CNVs in AD cases. Rare LOAD specific CNVs were involved in axonogenesis and neurite morphogenesis. The LOAD cases had a higher disease‐specific CNV burden compared with the normal controls. Moreover, the causal networks based on the integration of CNV, transcriptomic, proteomic, and clinicopathological data demonstrated brain region‐specificity.ConclusionTo our knowledge, this is the first genomic CNV study focused on LOAD by integrating genomic, transcriptomic, proteomic, and clinicopathologic data. The identified CNVs and their downstream molecular networks provide a blueprint for studying the pathogenic mechanisms of LOAD.
Extracellular complex of beta‐amyloid with glyceraldehyde‐3‐phosphate dehydrogenase contributes to neurodegeneration in Alzheimer’s disease
Authors: Kozin Sergey A. , Lazarev Vladimir , Tsolaki Magda , Mikhailova Elena , Benken Konstantin , Shevtsov Maxim , Nikotina Alina , Mitkevich Vladimir , Makarov Alexander , Margulis Boris , Guzhova Irina 
Published: December 2020

AbstractBackgroundThe discovery of migrating protein complexes armed with β‐amyloid (Aβ) and acting as the driving force of Alzheimer’s disease (AD) mechanism led us to suggest that besides the pathogenic peptide some other proteins may cooperate with the latter and enhance its cytotoxicity and intercellular propagation. One of such proteins was suggested to be glyceraldehyde‐3‐phosphatedehydrogenase (GAPDH), enzyme that in normal conditions maintains cellular glycolysis and under action of oxidative stress is converted to monomers and dimers and forms tight, insoluble complexes with aggregation‐prone polypeptides.MethodCSF samples were collected from patients of both genders. The cohort comprised four patient groups: (1) mild cognitive impairment (MCI) n = 21; (2) mild AD‐type dementia (‘Mild’), n = 58; (3) moderate AD‐type dementia (‘Moderate’) n = 57; and (4) severe AD‐type dementia (‘Severe’), n = 56. The diagnosis was established according to the NINCDS‐ARDRA criteria for AD and the Petersen criteria for MCI. Patients were assigned to severity subgroups based on their scores on the Mini‐Mental State Examination (MMSE). Two animal models of AD were used in this study: (1) “chemical” model in rats and (2) transgenic 5XFAD mice.ResultGAPDH is present in cerebrospinal fluid samples of AD patients as covalent complex with Aβ, and the heavier the stage of the disease, the higher is the level of such complexes. The increase of constitutional GAPDH level in AD animal models results in aggravation of cognitive and brain deficits linked to AD progression.ConclusionThe findings imply a potential role of GAPDH as biomarker and prerequisite of massive neuronal death on the late stages of Alzheimer’s disease Supported by RSF grant #19‐74‐30007.
High‐resolution, genome‐wide, promoter‐focused Capture C in astrocytes implicates causal genes for Alzheimer’s disease
Authors: Burton Elizabeth , Argenziano Mariana , Lu Sumei , Su Chun , Leonard Michelle E. , Hodge Kenyaita M. , Manduchi Elisabetta , Schellenberg Gerard D. , Wang Li‐San , Johnson Matthew E. , Pippin James A. , Brown Christopher D. , Wells Andrew D. , Grant Struan F.A. , Chesi Alessandra 
Published: December 2020

AbstractBackgroundPrevious studies of Alzheimer’s Disease (AD) have primarily implicated neurons and microglia as disease‐conferring cell types due to obvious links with degeneration and inflammation, respectively. However, astrocytes may also play a role in AD pathogenesis, but have been less studied in this context. Indeed, genome‐wide association studies (GWAS) have identified multiple genomic variants that reside near genes with astrocyte‐related functions, such as lipid processing and synaptic function. However, GWAS only reports genomic variants associated with a given trait and not necessarily the precise localization of culprit genes. High resolution chromatin conformation capture‐based techniques detect 3D genomic interactions between GWAS‐implicated signals and their effector genes, and allow for the characterization of non‐coding variants in the context of their regulatory activity.MethodTo improve on the low resolution of available Hi‐C data, we employed a high resolution DpnII‐based Capture‐C method to simultaneously characterize the physical genome‐wide interactions of 36,691 baited regions covering human promoters genome‐wide (including non‐coding transcripts) ‐ which we applied to a human primary astrocyte line (NHA, Lonza). Following sequencing, we investigated significant interactions at two different resolutions (1‐fragment and 4‐fragment resolutions; median fragment size = 265bp and 1,441bp, respectively). In parallel, we generated ATAC‐seq open chromatin maps to filter for informative (r2>0.7) proxy single nucleotide polymorphisms (SNPs) for each of the 45 AD independent signals reported to date.ResultATAC‐seq fine‐mapping yielded 100 candidate SNPs in open chromatin for 30 of these loci. By further constraining on our promoter Capture C data in astrocytes, at both one and four DpnII fragment resolution (median distance between interacting regions 9kb and 71kb, respectively), we observed contacts to “open” promoters for 6 putative target genes, corresponding to 6 of the original GWAS loci. These included PICALM, FERMT2, CASS4, and CLU.
ConclusionWe observed informative contacts between proxy SNPs and putative effector genes in the human astrocyte context for ∼13% of AD GWAS loci. Further efforts in other relevant cell types, where many of the other loci may in fact be principally operating, should shed light on additional signals. Follow‐up functional studies are warranted to validate these findings.
Design, synthesis and neuroprotective potency of self‐assembling memantine‐docosahexaenoic acid conjugate nanomedicine for the effective treatment of Alzheimer’s disease
Authors: Krishna Kowthavarapu Venkata , Dubey Sunil Kumar , Saha Ranendra Narayan 
Published: December 2020

AbstractBackgroundAlzheimer’s Disease (AD) is the most common type of dementia characterized with progressive neurodegeneration and seems to be irreversible, progressive and presently untreatable. Memantine (MEM), a N‐methyl‐D‐aspartate receptor antagonist has been approved by FDA for symptomatic relief in neurodegenerative disorders. Docosahexaenoic acid (DHA) is a brain essential omega‐3 fatty acid that has a vital role in functional development and growth of the brain in infants. It has been reported that the presence of DHA in the diet helps in cognitive enhancement. Hypothesizing the co‐delivery of MEM and DHA for the effective treatment of AD, herein our aim was to design and develop a novel self‐assembling MEM‐DHA conjugate nanomedicine and to investigate its neuroprotective potency on SH‐SY5Y cells. Furthermore, the efficacy of these nanoparticles was assessed in intracerebroventricular‐β‐amyloid1‐42 induced cognitive deficits rats. To the best of our knowledge, this is the first report on self‐assembling nanomedicine of MEM.MethodMEM‐DHA was synthesized by amide coupling reaction and thoroughly characterized by 1H NMR, 13C NMR and HR‐MS. The synthesized conjugate was self‐assembled into nanoparticles by using nanoprecipitation method and morphological characterization was performed by using dynamic light scattering technique and by FE‐SEM analysis. The neuroprotective activity was performed on human neuroblastoma SH‐SY5Y cells against oxidative stress induced by H2O2. Animals were injected with β‐amyloid1‐42 through intracerebroventricular route and dosage administered for a period of 28 days in separate groups viz control, disease control, MEM, MEM‐DHA conjugate and MEM‐DHA nanoparticles. Learning, behavior, memory assessment and biochemical parameters were estimated.ResultThe formation of MEM‐DHA conjugate was confirmed by 1H NMR, 13C NMR and HR‐MS. MEM‐DHA conjugate has a property to self‐assemble into nanoparticles due to its amphiphilic nature. The average hydrodynamic size of the self‐assembled nanoparticles was found to be 144.30 ± 3.91 nm with a polydispersity index 0.181 ± 0.02 and zeta potential was ‐6.82 ± 0.51 (Fig.1.). Cell culture and animal studies revealed MEM‐DHA conjugate nanoparticles are having strong potential as a therapeutic delivery to restore memory impairment in AD.ConclusionThe MEM‐DHA conjugate nanomedicine was successfully prepared, thoroughly characterized and has shown improved neuroprotective efficacy in cognitive induced rats.
Effect of L‐type calcium channel blocking drugs on microglia during inflammation and amyloid pathology
Authors: Hopp Sarah C. , Wickline Jessica , Smith Sabrina 
Published: December 2020

AbstractBackgroundDuring Alzheimer’s Disease (AD), microglia accumulate near amyloid plaques where they acquire a non‐homeostatic phenotype, lose essential neuroprotective functions, and take on an “activated’ phenotype that can induce neurotoxicity. Microglia intracellular calcium orchestrates these functions including cytokine production and formation of neurotoxic reactive oxygen species. Notably, other groups have demonstrated that activated, non‐homeostatic microglia in mouse models of AD display dysregulated intracellular calcium that may mediate their dysfunction. Epidemiological evidence suggests that using calcium channel blocker (CCB) drugs is associated with a reduced incidence of neurodegenerative diseases such as AD. However, the mechanism by which CCBs reduce AD risk is currently unknown. We hypothesize that CCBs reduce AD risk via modulation of microglia, the immune cells of the brain.MethodUsing cultured microglia in vitro, we tested whether CCBs that target L‐type voltage‐dependent calcium channels (L‐VDCCs) could prevent microglia activation in response to lipopolysaccharide (LPS), as measured by cytokine production. We also use the calcium indicator Fluo‐8 to measure directly whether L‐VDCCs could prevent LPS‐induced calcium flux. We then tested whether one of the CCBs, isradipine, could prevent microglia response to LPS in vivo in wild‐type animals. Finally, we used the 5xFAD mouse model of AD to examine whether isradipine could alter microglia phenotype in the presence of amyloid pathology in vivo.ResultWe found that L‐VDCC antagonist CCBs significantly reduce gene expression of inducible nitric oxide synthetase, interleukin 1β (IL‐1β), and tumor necrosis factor α (TNFα) in response to LPS in vitro, regardless of the structural class of the CCB, suggesting these drugs do target microglia L‐VDCCs. We also found that during microglia activation, microglia upregulate gene expression of the L‐VDCC subunits Cav1.2. Similarly, isradipine was able to reduce microglia activation in vivo.ConclusionOverall these data suggest that the reduced incidence of AD in humans treated with L‐VDCC‐targeting CCBs may be via their modulation of microglia. However, further work is required to understand how these drugs may be utilized as an intervention for AD.
Combined treatment with the microdose lithium formulation NP03 and S‐adenosylmethionine reduces cognitive decline and Alzheimer’s‐like amyloid pathology in Mcgill‐R‐Thy1‐APP rats
Authors: Carmo Sonia Do , Emmerson Joshua T. , Foret Morgan K. , Welikovitch Lindsay A. , Cuello A. Claudio 
Published: December 2020

AbstractBackgroundBy engaging several targets simultaneously, combination therapeutics hold promise for the prevention and treatment of complex conditions such as Alzheimer’s disease. We have previously shown that monotherapy using either NP03, a microemulsion formulation of lithium, which can reach the CNS when applied on mucosae, or S‐adenosylmethionine (SAM), a global methyl donor, can blunt amyloid‐driven pathology and cognitive impairment. Here, we explored the potential therapeutic value of a combination of NP03 and SAM in pre‐plaque McGill‐R‐Thy1‐APP transgenic (Tg) rats.MethodWe administered NP03 (rectal administration; 40 ug Li/Kg; 5 days per week), SAM (orally; 20 mg/Kg; 3 days per week), a combination of NP03‐SAM, or vehicle to 3‐month‐old Tg and non‐Tg control rats for 12 weeks. Behavioral testing and tissue harvest were performed 3 weeks after ceasing treatment.ResultsCombined NP03‐SAM treatment had a greater impact in reversing cognitive impairments in the auditory fear‐conditioning task compared with either the NP03 or SAM treatment alone. Moreover, NP03‐SAM‐treated McGill‐APP rats exhibited lower abundance of amyloid‐β peptides. Beneficial effects of NP03‐SAM treatment also included a reduction in neuroinflammation, BACE 1 expression and activity, and global DNA demethylation. Furthermore, combined treatment amplified the rescue of neurogenesis already observed in NP03‐treated rats.ConclusionOur findings provide preclinical evidence suggesting that combined treatment with NP03 and SAM may be of therapeutic value in the early stages of Alzheimer’s disease.
Early dementia diagnosis from spoken language using a transformer approach
Authors: Wahlforss Alfred , Jonasson Alexander Aslaksen 
Published: December 2020

AbstractBackgroundDiagnosing dementia early is a critical factor in order to apply ameliorating factors. Currently, it is both difficult and costly to make an accurate diagnosis of early dementia. We present an approach where an accurate diagnosis is achieved using a machine learning model that analyses the spoken language of patients describing the cookie‐theft picture.MethodThe dataset used is Dementia Bank, which is the largest public dataset of spoken word dementia diagnostics. The experiments were carried out on the cookie‐theft section of the DementiaBank Pitt Corpus, which is a dataset containing audio and transcripts of patient interviews in which the patients perform the cookie‐theft test, a commonly used tool for diagnostics. The dataset consists of 243 control samples and 309 samples from patients with dementia. Although the dataset includes transcripts along with parts‐of‐speech tags produced by linguists, the goal of this study was to automate the process of diagnosis. As such, automatic speech recognition (ASR) was used to generate text transcripts from the audio files. The generated transcripts were split into two sets; one training set consisting of 70% of the original transcripts, and a test set containing the remaining 30%. The training set transcripts were then used as input to various transformer models, including BERT and ROBERTA. These models were then trained on the training set to fine‐tune their parameters. During evaluation, the transcripts from the test set are fed into the transformer model, which then classify the transcript as either belonging to the control group or the dementia group. Accuracy is used as an evaluation metric.ResultWe achieve an accuracy of 90% on the Dementia Bank dataset using the transformer model BERT, which according to a review study by Lyu, Gang (2018) is state‐of‐the‐art when using the entire dataset.ConclusionThese results give the possibility to introduce a cost‐effective screening method for signs of early dementia. These results give the possibility to introduce a cost‐effective screening method for signs of early dementia. Hopefully, our approach could put an end to the current subjective diagnostics which is expensive and has varied results.
Pre‐fall prognostics, prevention and management of frailty in geriatrics: A personalized intelligent system approach (ALL‐FrAAgile)
Authors: Marinescu Mihaela , Bartolome Inaki , Marzan Mircea , Mashayekhi Kaveh , Spiru Luiza 
Published: December 2020

AbstractContextFrailty is a clinical state in which there is an increase in an individual’s vulnerability for developing an increased dependency and/or mortality when exposed to a stressor”. Frailty can occur in 15% of adults aged 65 years and over as the result of a variety of medical and socio‐demographic conditions such as living alone, depression, polypharmacy, malnutrition or sedentary lifestyle, etc. Even small stressors may increase the risk of developing significant health complications such as falls, dependency and hospitalizations. Nevertheless this state can be reversed through personalized intervention. So screening, evaluation and management are highly important.ObjectivesFrailty detection and prevention.MethodsThe FrAAgile is an ICT based personalized Ambient Assisted Living (ALL) intelligent system aimed at pre‐fall prognostics, identification, prevention and management of physical and mental frailty and multimorbidity and transition to robust health status. A personalized intelligent role‐based service is offered to access and improve the physical and the mental state of the individual through physical and cognition‐enhancing games based exercises. Intelligent system applications accessing the individual’s behavior, cognition, mood, agility, onset/lack of outside activities, balance, gate etc. to define a personalized role for that particular person to improve his/her physical and mental condition avoiding fall incidents due to frailty. This approach can be implemented and offered as a service directly to an individual user or to his/her informal and formal caregivers.ResultsDuring the CO‐creation phase, more than ninety End‐Users in Cyprus, Spain, Switzerland and Romania sites are identified and started to be recruited since Jan 2020. The ICT architecture of the project has been defined, considering required hardware, web‐connection, cloud database, data collection modules, video, and game applications and libraries.ConclusionThe mild cognitive impairment individuals (MCI) would be accompanied across three phases of pre‐trial pilot lab‐testing, adaptation, and optimization, which leads finally to field trails. The main focus of the role‐based intervention aims to prevent clinical frailty and falls incidence through augmenting physical and mental health condition considering a holistic personalized view of the individual lifestyle and condition (EU AAL‐frAAgiLe project, Active Assisted Living, Ageing Well in the Digital World, aal‐2018‐5‐152‐CP).
Quantification of tau phosphorylated at threonine 217 using a novel ultrasensitive immunoassay distinguishes Alzheimer’s disease from healthy controls
Authors: Kvartsberg Hlin , Hanes Jozef , Benedet Andréa Lessa , Ashton Nicholas J , Pascoal Tharick A. , Rosa‐Neto Pedro , Hansson Oskar , Zetterberg Henrik , Zilka Norbert , Blennow Kaj 
Published: December 2020

AbstractBackgroundOne of the major neuropathological hallmarks of a brain affected by Alzheimer’s disease (AD) is neurofibrillary tangles (NFTs), which are composed of aggregated, and sometimes truncated, hyperphosphorylated tau protein. Clinical diagnosis of AD is often aided by the use of biomarkers. One of the three core cerebrospinal fluid (CSF) biomarkers for AD, tau phosphorylated at amino acid 181 (p‐tauT181), shows quite a high sensitivity and specificity for AD but there is also a relatively large overlap between AD non‐demented subjects. Recently, tau species phosphorylated at amino acid 217 (p‐tauT217) quantified by mass spectrometry was shown to correlate with amyloid and tau lesions in the brain and clinical disease progression, and thus seem to be a new potential AD biomarker. Here, we present a novel immunoassay used to quantify p‐tauT217 in CSF and show that it outperforms the classical AD biomarkers.MethodCSF samples from AD, healthy controls (Co) (cohort1 [Lund University] and cohort2 [TRIAD cohort, McGill University]), frontotemporal dementia (FTD) and mild cognitive impairment (MCI) (cohort2) were analysed by a novel ultrasensitive immunoassay on the Single molecule array (Simoa) platform. The Simoa assay was based on two in‐house generated monoclonal antibodies.ResultCSF levels of p‐tauT217 were significantly increased in AD compared with Co in both cohort1 (p<0.0001, 4.3‐fold increase) and cohort2 (p=0.0003, 3.5‐fold increase). In cohort2, p‐tauT217 was also increased in AD compared with FTD (p=0.0059) and amyloid PET‐negative MCI (p=0.0203, 4.8‐fold increase), and in amyloid PET‐positive MCI compared with Co (p<0.0001, 3.9‐fold increase), amyloid PET‐negative MCI (p=0.0035, 5.2‐fold increase) and FTD (p=0.0011).ConclusionWe present performance data on a novel ultrasensitive immunoassay capable of quantifying p‐tauT217 in CSF. There was much less overlap between AD patients and healthy controls, as well as between amyloid PET‐positive and ‐negative MCI when using p‐tauT217 compared with p‐tauT181 in both cohorts, thus indicating that p‐tauT217 reflects the presence of AD pathology better. In conclusion, p‐tauT217 is a very promising new biomarker for AD, which potentially could be used to aid clinical diagnosis, even at pre‐dementia stages of the disease.