bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of blood eQTLs for AD risk loci
Authors: Bradley Joseph , Deming Yuetiva , Li Zeran , Harari Oscar , Saef Benjamin , Budde John P. , Wang Fengxian , Farias Fabiana H.G. , Davenport Richard ,   Alzheimer’s Disease Neuroimaging Initiative (ADNI), Cruchaga Carlos 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) is the sixth leading cause of death in the US and most common form of dementia, affecting an estimated 5 million individuals. Currently there are no publicly available treatments for clinical or pre‐clinical symptoms of AD as well as there is high number of genetic variants involved in the onset and progression of the disease. The Alzheimer’s disease Neuroimaging Initiative (ADNI) aims to determine imaging, clinical and genetic biomarkers for early detection and treatment of AD. The goal of this study was to identify blood eQTLs for the genes located under the GWAS loci for AD risk.MethodThe expression data, collected and RMA normalized by ADNI, was captured by the Affymetrix Human Genome U219 Microarray. The data were normalized, trimmed to 500 genes within known AD risk gene regions, and used with GWAS data in multivariate linear regression of European individuals. These analyses can help to identify the functional variant and gene driving the original association.ResultOur analysis found genome‐wide eQTLs for over 200 genes (∼600 including all isoforms) across the genome.ConclusionThese results suggests that these variants may play a role in the onset and progression of AD; however, further analysis associating these variants with case/control status, age at onset, and differential expression would be necessary to further verify this. We may also speculate from these data that AD risk loci where we could not find eQTLs play a much stronger functional role in AD onset.
AmyloidIQ: An advanced analytical algorithm to quantify amyloid‐PET [18F]NAV4694 scans
Authors: Rizzo Gaia , Whittington Alex , Hesterman Jacob , Gunn Roger N 
Published: December 2020

AbstractBackgroundThe global amyloid‐β (Aβ) burden in Alzheimer’s disease (AD) is routinely quantified from static amyloid PET scans using SUVR. We have previously used AmyloidIQ to analyse over 3000 18F‐Florbetapir, 18F‐Florbetaben and 18F‐Flutemetamol scans. These analyses demonstrated that the outcome measure amyloid load (AβL) derived from AmyloidIQ is more powerful than SUVR in cross‐sectional and longitudinal analyses (Whittington et al. 2018 JNM) as well as having a better agreement with visual reads (Whittington et al. HAI 2019). In this work, we extend the AmyloidIQ methodology to [18F]NAV4694 images downloaded from the Global Alzheimer's Association Interactive Network (GAAIN) website (http://www.gaain.org).MethodAβL is automatically calculated by the AmyloidIQ algorithm from an individual Aβ‐PET scan using voxel‐wise regression with two canonical images that represent non‐displaceable and specific binding signals. The canonical images were derived from 18F‐Florbetapir ADNI data (Whittington et al. 2018 JNM). A composite SUVR was also calculated for each scan. 52 [18F]NAV4694 scans (35 healthy controls, HC, 10 mild cognitive impaired, MCI, and 7 AD) were obtained from GAAIN. The effect sizes (Hedges’ g) between HC and AD patients, and between HC and AD/MCI of AβL and SUVR were compared in [18F]NAV4694 cross‐sectional data.ResultThe AmyloidIQ algorithm was successfully extended to [18F]NAV4694 data with accurate characterization of the data obtained with the previously derived canonical images, now demonstrating its applicability to four different Aβ tracers (Figure 1). In this small sample dataset the cross‐sectional analysis showed that, AβL had similar performance to SUVR (effect size between non‐HC patients and HC was 2.29 for AβL and 2.32 SUVR, and between HC and AD patients was 4.41 for AβL and 4.90 for SUVR). In previous works, AβL has shown better agreement with visual reads than SUVR (Figure 2) and more power in cross‐sectional analysis (Figure 3) with an average increase in effect size of 44% and 21% compared to SUVR for [18F]Florbetapir and [18F]Florbetaben respectively.ConclusionAmyloidIQ is a powerful algorithm that has been successfully applied to four different Aβ tracers and that can be used for stratification. A larger sample is required to determine whether AmyloidIQ is more powerful than SUVR for [18F]NAV4694.
Antineuronal antibody prevalence in Alzheimer dementia
Authors: Koertvelyessy Peter , Teegen Bianca , Stoecker Winfried , Düzel Emrah , Glanz Wenzel , Bittner Daniel , Vielhaber Stefan , Diekaemper Elena , Pruess Harald 
Published: December 2020

AbstractBackgroundThe prevalence of antibodies against neuronal epitopes (nAB) in CSF and serum of Alzheimer dementia (AD) patients is unknown, as is the potential contribution to pathomechanisms influencing the clinical picture parallel to neurodegeneration.MethodWe screened CSF and serum of 164 AD patients and 29 control patients suffering from depression with cognitive impairment. 36 known nAB were examined using cell‐based immunoassays (EUROIMMUN, Germany). Every sample was also examined for as yet undefined nAB using native brain slices of hippocampus and cerebellum. We compared standard CSF parameters and biomarkers of neurodegeneration (commercial ELISA kits, Fujirebio, Ghent, Belgium) between nAB‐positive and negative AD patients and controls. A pathological finding is defined for each nAB reaching or exceeding a predefined, known titer and having a corresponding binding pattern as seen on native hippocampus and/or cerebellum.ResultWe found nAB in 20.1% (33/164) of the AD patients’ serum with 1.8% (3/164) having pathological findings (1*IgG NMDAR, 1*Homer3 and 1*GABAbR antibodies). 2 AD patients had the same nAB in CSF and serum, no nAB was found in CSF alone. Three out of the 29 control patients had nABs but noone had pathological titers.There was no difference between nAB‐positive and nAB‐negative AD and controls regarding the biomarkers and standard CSF parameters in one‐way ANOVA (see Figure 1 for details and Figure 2 as an overview).Clinical records of the 3 nAB‐positive AD patients with pathological findings showed normal CSF parameters and biomarkers without signs of abnormal neurological findings with a mean follow‐up of 37 months (ranging from 14‐54 months).ConclusionThis is the largest study on nAB prevalence in AD using the largest nAB panel so far. In general, prevalence of nABs is high in AD patients. Three patients out of all 193 patients (AD+controls) had pathological nAB findings. Follow‐up of the medical records over more than three years did not reveal aberrant clinical courses. CSF parameters and biomarkers of neurodegeneration did not show any difference between nAB‐positive and ‐negative patients. Patients were not treated with immunosuppressive therapy and therefore the potential impact of the nAB on the clinical picture will require further studies.
Neuroprotective effect of taurine on human neuroblastoma under induced stress
Authors: Rossato Rafaella Carvalho , Pinto Jessica Cristina , de Oliveira Moraes Carlos Dailton Guedes , Salles Geisa Nogueira , Pacheco‐Soares Cristina 
Published: December 2020

AbstractBackgroundHigh concentrations of hydrocortisone is known to cause oxidative stress in neural cell, impairing damage repair and, consequently, triggering cell death. This represents one of the mechanisms of Alzheimer's Disease (AD). To prevent oxidative stress, novel studies have demonstrated neuroprotective effects of taurine in specific concentrations, regulating brain activity, maintaining the integrity of neural membrane and controlling calcium homeostasis, thus preventing cell death by preventing oxidative stress.MethodFirst, SH‐SY5Y (human neuroblastoma) cells were incubated with different concentrations of taurine (0.25 to 1 mg/mL), then, after 24h, cells were exposed to 200 µM of hydrocortisone for another 24h (a stablished concentration that reduces SH‐SY5Y viability and induces oxidative stress). Cell viability was evaluated by crystal violet technique. Cells not exposed to hydrocortisone or taurine were used as control.ResultA concentration curve of taurine was performed (0.25 to 1 mg/mL), demonstrating that the compound stimulates SH‐SY5Y cell growth at 0.5 mg/mL (p = 0.0457) (Figure 1A). This concentration was stablished as protective. To verify the neuroprotective potential, cells were pre‐treated with 0.5 mg/mL of taurine and then exposed to 200 µM of hydrocortisone. Importantly, cytoviability was not only preserved but also statistically improved, compared to the control group (p < 0.0001) (Figure 1B).ConclusionIn high concentration (200 µM), hydrocortisone induces oxidative stress in SH‐SY5Y, an important pathway observed in AD. Once cells are pre‐incubated with 0.5 mg/mL of taurine followed by 200 µM of hydrocortisone exposure, cytoviability is preserved and stimulated, representing a considerable step to further evaluate taurine as a significant neuroprotective tool for AD. (1) Moraes, C.D.G.O. et al. Genotoxic effects of photodynamic therapy in laryngeal cancer cells–An in vitro study. Experimental Biology and Medicine, v. 244, n. 3, p. 262‐271, 2019. (2) Salles, G.N. et al. Prolonged Drug‐Releasing Fibers Attenuate Alzheimer’s Disease‐like Pathogenesis. ACS applied materials & interfaces, v.10, n.43, p.36693‐36702, 2018. (3) Sergeeva, O.A. et al. Taurine‐induced long‐lasting enhancement of synaptic transmission in mice: Role oftransporters. The Journal of physiology, v.550, n.3, p.911‐919, 2003. (4) ROSSATO, R.C. et al. Hydrocortisone cytorestores oxidative stress‐induced neuroblastoma. Alzheimer's & Dementia: The Journal of the Alzheimer's Association, 15(7), p.642, 2019.
Novel small chemical compound with NFAT modulatory properties alleviates synaptic dysfunction and improves cognition in mouse models of amyloid pathology
Authors: Sompol Pradoldej , Gollihue Jenna L. , Cloyd Ryan , Koren Shon , Nation Grant K. , Abisambra Jose F. , Artiushin Irina A. , Kraner Susan D. , Huzian Orsolya , Hackler Laszlo , Puskas Laszlo G. , Norris Christopher M. 
Published: December 2020

AbstractBackgroundHyperactivity of the protein phosphatase calcineurin (CN) in brain directly corresponds to key neuropathological and clinical features of Alzheimer’s disease (AD). While inhibition of CN ameliorates pathophysiologic and cognitive changes in mice with AD‐like pathology, concerns over adverse effects have slowed the transition of common CN‐inhibiting drugs to the clinic for treatment of AD and AD‐related disorders. Targeting substrates of CN, like the nuclear factor of activated T‐cells (NFATs), has been suggested as an alternative, safer approach to CN inhibitors. Here, we investigate a newly developed neuroprotective hydroxyquinoline derivative (Q134R) that modulates NFAT signaling, without inhibiting CN activity.Method
Cell culture studies — Rat cortical astrocyte cultures were treated with a variety of pathogenic factors in the presence of Q134R or the CN inhibitor, cyclosporine. NFAT‐dependent luciferase activity and dephosphorylation of non‐NFAT substrates were assessed. Intact mouse studies — Q134R was delivered (via oral gavage) to APP/PS1 mice at different ages, or to wild type (WT) mice infused with oligomeric amyloid‐beta peptides. Cognition was assessed on a Y maze along with several postmortem measures including NFAT4 activity, glial activation (GFAP and Iba‐1 expression), amyloid deposition, long‐term survival, and synaptic function and plasticity.ResultIn primary astrocytes, Q134R significantly inhibited NFAT activation in a concentration‐dependent manner, but did not inhibit the CN‐dependent dephosphorylation of non‐NFAT substrates in vivo or in vitro. Short‐term treatment of APP/PS1 mice with Q134R inhibited the nuclear translocation of NFAT4 in hippocampal astrocytes while causing a significant drop in GFAP volume, a mild reduction in Iba1, and no change in amyloid pathology. Short‐term treatment with Q134R also improved cognitive function in APP/PS1 mice and amyloid‐infused WT mice. Long‐term oral delivery of Q134R over many months promoted survival in WT mice and improved synaptic function and plasticity in APP/PS1 mice.ConclusionQ134R has novel CN‐independent, NFAT modulatory properties and improves key neurologic function parameters in mouse models of AD‐like pathology. The results suggest that Q134R is a promising drug for treating AD and AD‐related disorders.
Leveraging amino acid sensors as therapeutic targets for tauopathies and related dementias
Authors: Lee Daniel C. , Ma Chao , Morgan Dave , Liang Huimin , Kovalenko Andrii , Sandusky‐Beltran Leslie A. , Calahatian John Ivan , Kallupurackal Mani , Hunt Jerry B , Pandey Shalini , Blazier Danielle , Bickford Paula , Michalski Camilla , Fahnestock Margaret , Pedersen Daniel Sejer , Brauner‐Osborne Hans , Ulven Trond , Selenica Maj‐Linda B. 
Published: December 2020

AbstractBackgroundTauopathies including Alzheimer’s disease (AD) comprise of over 27 neurodegenerative diseases. Our group has uncovered a unique interaction between uncoupling of amino acid sensors and tauopathies. L‐Arginine metabolism impacts multiple processes that seemingly show considerable influence upon tau biology. Several protein sensors have been identified that sense arginine within the lysosomal lumen, cytoplasm and signal to the mechanistic target of rapamycin complex 1 (mTORC1). GPRC6a, g‐protein coupled receptor also senses arginine levels but also signals to mTORC1. We posit that GPRC6a remains tonically active through extracellular arginine. GPRC6a signaling increases during tauopathies and thereby promotes hyper‐mTORC1 activation and impairs autophagy flux.MethodWe performed PCR‐array analysis, biochemical analysis for gene transcripts and protein expression for Alzheimer’s disease brain tissue and aged matched controls. We performed a series of mechanistic studies on GPRC6a and tau biology using siRNA, shRNA, drug pharmacology in cell culture models and (PS19 tau mice) or wild‐type littermates. RNA seq was performed on GPRC6a knockout mice crossed with PS19 mice.ResultOur work indicates dysregulation of gene transcripts for arginine sensors, components of mTORC1 signaling in Alzheimer’s disease (AD) brains and mice with tauopathy. AD brains and tau PS19 mice showed increased GPRC6a, CASTOR1 and SLC38A9 signifying dysfunction in arginine sensing. Tau PS19 mice showed increased total and extracellular arginine in the brain, which further increased with neuronal activity. GPRC6a gene repression or novel allosteric antagonists decreased mTORC1 activation and reduced tau burden. Conversely, GPRC6a overexpression increased mTORC1 and tau accumulation. Knockout mice for GPRC6a crossed with PS19 tau transgenic mice reversed tau‐induced mRNA signatures in the brain via RNA seq. Microglia and neurometabolism were most affected in GPRC6a knockout mice signifying a critical role for arginine sensors in microglia during tau deposition. Importantly, novel allosteric antagonists to GPRC6a increased microglia phagocytosis and index.ConclusionOur work identifies a new pathway activated in AD and models of tauopathy yet provides the discovery of a new class of agents that govern microglia function, autophagy and neurometabolism. These data provide new therapeutic strategies for proteinopathies that exploit nutrient sensing dysfunction in AD.
Integrating human brain proteomes and genome‐wide association results implicates new genes in Alzheimer’s disease
Authors: Wingo Aliza P. , Liu Yue , Gockley Jake , Logsdon Benjamin A. , Duong Duc , Dammer Eric B. , Robins Chloe , Cutler David J. , De Jager Philip L. , Lah James J. , Bennett David A. , Levey Allan I. , Seyfried Nicholas T. , Wingo Thomas S. 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) is the most common type of dementia, and it has a substantial genetic basis. Recent AD genome‐wide association studies (GWAS) continue to expand the number of loci that are significantly associated with AD; however, how those loci confer risk for AD remains unclear. Here, we addressed this problem by integrating 376 deep human brain proteomes and 888 human brain transcriptomes with recent AD GWAS results to identify genes, transcripts, and proteins that likely contribute to AD pathogenesis.MethodsWe inferred the genetically controlled portion of protein abundance using 376 deep human brain proteomes, and these results were integrated with two recent large AD GWAS results that included 455,258 participants (Jansen et al 2019), and 82,771 participants (Kunkle et al 2019), respectively, using the FUSION pipeline (Gusev et al 2016). We performed an analogous analysis using 888 human brain transcriptomes to infer the genetically controlled portion of the transcript abundance and integrated those results with the aforementioned AD GWAS results.ResultsWe identified a total of 15 genes whose genetically regulated brain protein abundances were associated with AD. They are ACE, CARHSP1, CTSH, DOC2A, EPHX2, ICA1L, LACTB, MADD, PITPNC1, PLEKHA1, PVR, RTFDC1, SNX32, STX4, and STX6. At the transcript level, we identified a total of 49 genes whose cis‐regulated mRNA expression levels were associated with AD. Of the 15 genes identified at the protein level, 33% (5 of 15) were also identified at the transcript level. Furthermore, 73% of these 15 genes identified at the protein level were highly expressed in excitatory neurons based on a reference single‐cell RNA‐sequencing dataset from human brain. In an independent replication dataset using single‐shot label‐free proteomes (n = 205), only one of the 15 proteins were measured and imputed (EPHX2). We replicated EPHX2’s association with AD in that dataset.ConclusionTogether, our findings implicate 15 human brain proteins in the pathogenesis of AD and suggest that these proteins are controlled by both transcriptional and post‐transcriptional mechanisms. Our results lay a foundation for future mechanistic studies to develop novel treatments and biomarkers for AD.
Automatic analysis of Alzheimer’s disease: Evaluation of eye movements in natural conversations
Authors: Perez Arlen , Ratté Sylvie 
Published: December 2020

AbstractBackgroundAmong the studies concerned with the description of changes in nonverbal communications, some authors have established a link between eye movement and AD [1]. In this presentation, we introduce a method to automatically analyze and evaluate the performance of AD patients during natural conversations through eye movements. This project was conducted as part of a research program funded by Natural Sciences and Engineering Research Council of Canada ( "Pattern recognition for the detection and monitoring of verbal and non‐verbal alterations in Alzheimer's disease", RGPIN‐2018‐05714).MethodWe analyzed 22 videos in the Carolinas Conversations Collection, a dataset where conversations with elderly people were recorded. These videos have 370 minutes approximately, with 17 subjects, 9 healthy controls (HC), and 8 AD patients. We tracked the eye movements through time in two ways, as a vector [Figure 1] and as landmarks on the eyes [Figure 2]. Then we trained classifiers to distinguish HCs and AD subjects, and performed the experiments using gaze vectors and eye landmarks as features (individually, combined).ResultWe obtain the performance of the classifiers measuring the accuracy, precision, recall, and ROC curve. Our results show that the combination of eye landmarks and gaze vectors features is strongly related with the AD condition. The classification sensitivity (ROC) is 77% performing with gaze vector features, 85% using the eyes landmarks in 3D, and combining both, we obtained 88% sensitivity (HC vs. AD) [Table 1].ConclusionThe automatic analysis of the eye movements could be a useful tool for clinicians and researchers studying early signs of AD. In future work, we will analyze facial expressions in order to study the link between verbal features (related to speech and content) and non‐verbal features (facial expressions, eye movements), and their correlations with AD. [1] Fernández G, Mandolesi P, Rotstein NP, Colombo O, Agamennoni O, Politi LE. Eye movement alterations during reading in patients with early Alzheimer disease. Invest Ophthalmol Vis Sci 2013;54:8345–52. https://doi.org/10.1167/iovs.13‐12877.
Expression of mutant human tau protein drives synaptic loss in Caenorhabditis elegans
Authors: Massengale Molly B. , Gamblin T. Chris , Ackley Brian D. 
Published: December 2020

AbstractBackgroundTau aggregation is associated with many neurodegenerative diseases, and inter‐neuronal neurofibrillary lesions composed of tau are a defining characteristic of various tauopathies, including Alzheimer’s disease. Additionally, mutations in human tau have been linked to several neurodegenerative disorders with varying phenotypic effects. How tau aggregation results in altered neuronal function is complex and not yet fully understood. Animal models are powerful tools to probe tau aggregation‐dependent phenotypes. However, they can take a long time to mature and give phenotypes, are created in different genetic backgrounds and can require death of the animal to visualize outcomes. Thus, new models that can avoid some of these issues can facilitate a better understanding of tauopathies.MethodWe have generated multiple lines of transgenic C. elegans expressing different variants of the longest isoform of human tau (htau40) in neurons to better understand how aggregation might cause subsequent downstream events leading to increased toxicity. We have used synaptic markers to examine the consequences of tau aggregation on synaptic integrity during aging.ResultWhen broadly expressed throughout the nervous system an aggregation prone htau40 variant (3PO) or an FTDP‐17 associated mutation (P301L) resulted in decreased lifespan, as well as a decreased locomotor capability as animals aged. Decreased lifespan, along with cognitive and motor defects, are associated with human tauopathies, suggesting our model is reproducing consequences relevant to human disorders. When we selectively express mutated htau40 in the GABAergic motorneurons, we find an age‐associated decline in the number of GABAergic motor neuron synapses, importantly, in the absence of other indicators of neuronal degeneration, i.e. axons and cell bodies were still intact. We have also begun testing mutations in C. elegans orthologs of known Alzheimer’s risk factors and found that loss of the LAR‐like receptor tyrosine phosphatase enhances the synaptic loss due to mutations in htau40.ConclusionC. elegans models of tauopathies permit an analysis of synaptic phenotypes in living animals. Our model can be used to probe both tau variants and other genetic modifiers to better understand how tau aggregation impacts neuronal homeostasis and function.