bluuebunny/crossref_metadata_2025_split huggingface dataset:
Variability in working memory performance on mobile devices is sensitive to mild cognitive impairment: Results from the Einstein Aging Study
Authors: Cerino Eric S. , Hyun Jinshil , Hakun Jonathan G. , Roque Nelson A. , Lipton Richard B. , Sliwinski Martin J. 
Published: December 2020

AbstractBackgroundMost prior research on distinguishing cognitive impairment from healthy controls focuses on measuring mean‐level of cognitive performance on one or relatively few assessments, ignoring potentially valuable information about variability. Within‐person variability in cognitive performance is emerging as a promising indicator of mild cognitive impairment (MCI) and dementia. The limited research on this topic, however, typically examines speeded responses and variability transpiring across moments during a single test administration. The current study extends prior work by using ecological momentary assessments (EMA) to examine cognitive status differences in variability across hours and days in three dimensions of working memory (WM): object‐location binding, object‐feature binding, and spatial WM.MethodIn a sample of 243 systematically recruited, community‐dwelling adults age 70+ from the Einstein Aging Study (Mean age=77.46 years, SD=5.13), we identified 68 individuals meeting Jak‐Bondi criteria for MCI and 175 cognitively normal controls (Table 1). All participants performed object‐location binding, object‐feature binding, and spatial WM tasks on a smartphone up to four times daily for 14 days, totaling up to 56 assessments per person. We employed heterogeneous variance models using log‐linear prediction of residual variance to simultaneously assess MCI differences in mean performance and within‐person variability. Models adjusted for linear trends across assessments and study days, as well as age, education, gender, and ethnicity (Table 2; Figure 1).ResultsFor mean performance, individuals with MCI exhibited worse performance than healthy controls in measures of object‐location binding (Est.=0.14, SE=0.02, p<.001), object‐feature binding (Est.=‐0.27, SE=0.04, p<.001), and spatial WM (Est.=0.90, SE=0.20, p<.001). For variability across assessments, individuals with MCI exhibited greater within‐person variability than controls in object‐location binding (Est.=0.89, SE=0.03, p<.001) and object‐feature binding (Est.=0.37, SE=0.03, p<.001) performance. Variability in spatial WM performance did not vary as a function of cognitive status (Est.=0.02, SE=0.03, p=.63).ConclusionResults suggest both mean and variability in performance are sensitive to MCI and exhibit dissociative patterns by WM dimension. Variability in object‐location and object‐feature binding performance may provide specific detection of MCI. The 14‐day smartphone‐based EMA offers novel opportunity to leverage performance variability across frequent assessments for identifying early clinical manifestations of cognitive impairment.
Proteomic analysis of microglia during LPS‐induced acute neuroinflammation
Authors: Cartier Anna , Yeung Bertrand , Moyron‐Quiroz Juan , Gao Qing , Hunag Tse Shun , Nazor Kristopher , Tan Miguel 
Published: December 2020

AbstractBackgroundDysregulation of microglia function is associated with neuroinflammation. A major limitation in understanding microglial contribution to cellular processes and their role in disease has been the lack of tools to specifically distinguish these cells from other myeloid cells.MethodWe generated and validated a rat monoclonal antibody against a highly selective microglia marker P2RY12. We utilized LPS administration as a model for neuroinflammation to assess alterations in P2RY12 expression, a homeostatic protein. To gain better understanding of microglial function, we assessed their proteomic profile using BioLegend’s proprietary technology, TotalSeq™, which allows simultaneous analysis of both the transcriptome and proteome at the single‐cell level.ResultMice were injected with either PBS, low or high dosages of LPS daily for 4 days after which microglia were harvested from the brain. Isolated cells were co‐stained with CD11b, CX3CR1, and P2RY12 as general markers for microglia. Flow cytometric quantification using live cells showed a significant increase in CD11b+ expression in both low and high dose LPS treated mice compared to the control untreated group. Low and high dose LPS injections led to a significant reduction in P2RY12 and CX3CR1 expression in these cells. These data are consistent with a decrease in P2RY12 expression under inflammatory conditions. We utilized a panel of 200 antibody‐oligonucleotide conjugates from our TotalSeq™ platform, including P2RY12, CD11b, CD45, and CX3CR1, to analyze differentially expressed proteins under normal and LPS‐induced inflammation in mice.ConclusionThese studies help elucidate the diversity and physiology of microglia, and potentially aid in the discovery of novel markers in response to neuroinflammation. Our future goal is to extend our studies and use our platform to assess alternations in microglial response in neurodegeneration.
Effect of interferon regulatory factor 5 in LPS‐induced neuro‐inflammation
Authors: Fan Ziqi 
Published: December 2020

AbstractBackgroundActivated microglia plays a central role in neuro‐inflammation in central nervous system (CNS), which is involved in the progress of disease. Interferon regulatory factor 5 (IRF5) has been well established relating to inflammatory responses and is highly expressed in M1 macrophage in periphery, the role of which in the CNS remains elusive.MethodDown‐regulation of IRF5 by siRNA in C57/BL6 mice and BV2 microglial cells was employed. Lipopolysaccharide (LPS) challenge activates the response of neuro‐inflammation, Pro‐inflammatory cytokines were evaluated by ELISA, western blot, and real‐time PCR.ResultLPS induced the activation of microglia, which co‐localized with the significantly increase expression of IRF5. Down‐regulation of IRF5 significantly quenched the pro‐inflammatory responses. The levels of pro‐inflammatory cytokine TNF‐α, IL‐1βand IL‐6 were significantly up‐regulated at 4h after LPS treatment, which were reduced with the down‐regulation of IRF5. However, LPS did not up‐regulate the expression of IRF5 in BV2 microglial cells, indicating that LPS induced inflammation does not involve IRF5 signaling.ConclusionIRF5 plays an important role in the inflammatory responses in the CNS, which might serve as a therapeutic target for CNS inflammatory diseases. BV2 microglia is not an ideal cell line for the studies involves IRF5.
Prediction of clinical diagnosis of Alzheimer’s disease, vascular, mixed, and all‐cause dementia by a polygenic risk score and APOE status in a community‐based cohort prospectively followed over 17 years
Authors: Stocker Hannah , Perna Laura , Weigl Korbinian , Möllers Tobias , Thomsen Hauke , Schöttker Ben , Holleczek Bernd , Rujescu Dan , Brenner Hermann 
Published: December 2020

AbstractBackgroundThe strongest genetic risk factor for Alzheimer’s disease (AD) is the ε4 allele of Apolipoprotein E (APOE4) and recent genome‐wide association (GWA) meta‐analyses have confirmed additional associated genetic loci with smaller effects. The aim of this study was to investigate the ability of an AD polygenic risk score (PRS) and APOE status to predict clinical diagnosis of AD, vascular (VD), mixed (MD), and all‐cause dementia in a community‐based cohort prospectively followed over 17 years and secondarily across age, sex and education strata.MethodA PRS encompassing genetic variants reaching genome‐wide significant associations to AD (excluding APOE) from the most recent genome‐wide association meta‐analysis data was calculated and APOE status was determined in 5 351 participants. During follow‐up, 109, 113, 59, and 366 participants were diagnosed with AD, VD, MD, and all‐cause dementia, respectively. Prediction ability of AD, VD, MD, and all‐cause dementia by the PRS and APOE was assessed by multiple logistic regression and receiver operating characteristic curve analyses.ResultThe PRS per standard deviation increase in score and APOE4 (≥ 1 e4 allele) positivity were significantly associated with greater odds of AD (PRS OR, 95% CI: 1.70, 1.45‐2.03; APOE4 OR, 95% CI: 3.21, 2.14‐4.80) and AD prediction accuracy was significantly improved when adding the PRS to a base model of age, sex and education (ASE) (c‐statistics: ASE, 0.772; ASE+PRS, 0.809).ConclusionThe PRS enriched the ability of APOE4 to discern AD with stronger associations than to VD, MD, or all‐cause dementia in a prospective community‐based cohort.
A brain penetrant progranulin biotherapeutic rescues lysosomal and inflammatory phenotypes in the brain of GRN knockout mice
Authors: Logan Todd , DeVos Sarah , Simon Matthew J. , Davis Sonnet , Wang Junhua , Low Ray , Huang Fen , Rajendra Yashas , Prorok Rachel , Sun Elizabeth , Rana Anil , Hsiao‐Nakamoto Jennifer , Mosesova Sofia , Zhu Yuda , Cherf Gerald M. , Lengerich Bettina , Bhalla Akhil , Kim Do Jin , Chan Darren , Duque Joseph , Tran Hai , Lenser Melina , Nguyen Hoang , Chau Roni , Earr Timothy , Kariolis Mihalis S. , Monroe Kathryn M. , Sanchez Pascal E. , Dennis Mark S. , Henne Kirk R. , Gunasekaran Kannan , Astarita Giuseppe , Watts Ryan J. , Sweeney Zachary K. , Lewcock Joseph W. , Srivastava Ankita , Di Paolo Gilbert 
Published: December 2020

AbstractBackgroundHeterozygous loss of function (LOF) mutations in GRN cause frontotemporal dementia (FTD), a neurodegenerative disorder associated with lysosomal dysfunction, TDP‐43 pathology and inflammation in the CNS. Additionally, homozygous LOF mutations cause neuronal ceroid lipofuscinosis, a lysosomal storage disorder. GRN encodes progranulin (PGRN), a soluble protein that is most abundantly expressed in microglia, where it localizes to lysosomes and can undergo secretion. Although the precise function of PGRN is unknown, growing evidence suggests that it regulates lysosomal function, inflammatory responses and promotes neuronal survival. Accordingly, PGRN LOF models are associated with lysosomal defects, hyperinflammatory responses, and decreased neuronal viability, both in vitro and in vivo. Because GRN‐FTD patients exhibit reduced levels of PGRN in biofluids and tissues, including the brain, a protein replacement therapy analogous to enzyme replacement therapy and capable of crossing the blood brain barrier (BBB) more efficiently may represent a powerful approach to slow or prevent disease progression.MethodHere we describe a novel therapeutic for increasing brain penetrance of PGRN, referred to as Protein Transport Vehicle (PTV):PGRN. PTV:PGRN consists of recombinant human PGRN fused to a modified Fc domain engineered to bind to the human transferrin receptor (huTfR), thus facilitating receptor‐mediated transcytosis across the BBB.ResultWe found that extracellular applications of PTV:PGRN rescue a range of Grn KO cell phenotypes in vitro, including lysosomal proteolysis and alteration in the levels of bis(monoacylglycero)phosphate (BMP), an endolysosomal phospholipid involved in lysosomal lipid catabolism. Intravenously administered PTV:PGRN showed increased acute brain exposure in huTfR knock‐in (TfRmu/hu) mice relative to a regular Fc:PGRN fusion that does not bind to huTfR. Importantly, low doses of PTV:PGRN, but not Fc:PGRN, fully corrected lysosomal lipid alterations, including BMP deficiency, as well as inflammatory markers in the brain of Grn KO x TfRmu/hu mice.ConclusionOur data suggest that PTV:PGRN may represent a viable therapeutic strategy for the treatment of GRN‐FTD and potentially other disorders associated with PGRN deficiency.
Selective targeting of plaque‐associated microglia through systemic dendrimer administration in an Alzheimer’s disease model
Authors: Henningfield Caden M. , Cleland Jeffrey L. , Sharma Rishi , Green Kim N 
Published: December 2020

AbstractBackgroundIn Alzheimer’s disease (AD) microglia surround extracellular plaques and mount a sustained inflammatory response. Microglial elimination studies, as well as targeted microglial gene deletion studies, have suggested that this sustained microglial response to plaques contributes to the pathogenesis of the disease, including in plaque homeostasis, as well as contributing to synaptic and neuronal loss. The ability to specifically target plaque associated microglia would afford a powerful tool and potential therapeutic avenue. To that end, we sought proof of principle to target plaque associated microglia while leaving other microglia unaffected, via systemically administered Cy5 labelled hydroxyl dendrimers.MethodTo specifically target plaque associated microglia, we performed intraperitoneal injections with hydroxyl dendrimers conjugated to a Cy5 fluorophore into 5xFAD mice. Dendrimers are symmetric and highly branched molecules which are selectively endocytosed by reactive cells at sites of inflammation. To test whether we could alter plaque associated microglia phenotypes via peripheral drug administration, we next injected 5xFAD mice intraperitoneally with hydroxyl dendrimers conjugated to N‐acetyl cysteine, OP‐101, which has demonstrated ability to cause normalization of reactive microglia in several animal models.ResultHere, we find that hydroxyl dendrimers are selectively taken up by reactive microglia surrounding plaques in the brain parenchyma of 5xFAD mice. The hydroxyl dendrimers co‐localize with lysosomal (CD68+) puncta in the microglia and do not co‐localize with neurons, astrocytes, or oligodendrocytes. The impact of OP‐101 on microglia in the 5xFAD mouse as measured by RNAseq will also be presented.ConclusionThese data provide evidence that hydroxyl dendrimers are specifically taken up by reactive microglia rather than other central nervous system cells. This study demonstrated that systemic administration of hydroxyl dendrimers is a sufficient tool to target plaque associated microglia, demonstrating the potential for hydroxyl dendrimer‐based therapeutics in AD.
In‐vivo imaging of locus coeruleus integrity at ultra‐high field: A feasibility study
Authors: Pievani Michela , Jelescu Ileana O , Jorge Joao , Reynaud Olivier , Andryszak Paulina , Garibotto Valentina , Jovicich Jorge , Frisoni Giovanni B 
Published: December 2020

AbstractBackgroundIncreasing evidence suggests that neurodegeneration of the locus coeruleus (LC) is an early pathological feature of Alzheimer’s Disease (AD). However, assessment of the LC in‐vivo is hampered by its small size. Here we test the feasibility of characterizing LC’s integrity in‐vivo using ultra‐high field MRI.MethodEight young controls (age: 23+3y, education: 17+2y) and 9 elderly subjects from the Geneva memory clinic cohort (age: 74+7y, education: 16+3y; MMSE: 26+2; diagnosis: 1 cognitively normal, 7 cognitively impaired; biomarker profile: 63% A+, 14% T+) underwent MRI on a 7T Siemens Magnetom scanner, including magnetization transfer (MT; voxel: 0.43x0.43x0.5mm) and diffusion tensor imaging (DTI; voxel: 1.3x1.3x1.4mm). A MT template was generated from all the MT images with the Advanced Normalization Tools software. A LC map was extracted from the template with semi‐automated intensity thresholding. Individual MT and DTI images were warped to the MT template of the LC to measure: LC contrast ratio (CR) on MT; fractional anisotropy (FA) and mean diffusivity (MD) on DTI. These metrics were compared between groups and hemispheres using non‐parametric tests.ResultThe LC volume (MT template) was 62mm3, spanning 15mm rostro‐caudally. Elderly showed higher CR than younger subjects (median [IQR]: 23 [21‐28] vs 15 [12‐19], p=0.008 on Mann Whitney U test). This difference was detected along most of the rostro‐caudal LC axis (significance differences over 77% of the LC axis). In both younger and older subjects, the CR was greater in the left vs. right hemisphere (p=0.018 and p=0.015 respectively, Wilcoxon signed‐rank test). MD was more heterogeneous and overall higher in the LC of elderly compared to younger subjects (median [IQR]: 1.7 [0.7‐2.4] vs 0.94 [0.86‐1.02], p=0.023 on Mann Whitney U test). FA showed neither group nor hemisphere differences.ConclusionThese findings are consistent with previous LC literature at 3T. We confirmed that LC signal increases with age and reported a hemisphere asymmetry in LC signal. Microstructure atrophy with age is suggested by increased diffusivity. Data acquisition is ongoing with the aim to evaluate MT, DTI and fMRI differences across cognitively normal, AD and non‐AD impaired groups. Funding: H2020‐EU.3.1.1 (grant ID:667375), Swiss National Science Foundation (SNF‐320030_169876).
Effects of iron and/or inflammation on regional brain magnetic resonance imaging T1 and T2 in an Alzheimer’s disease mouse model
Authors: Aljuhani Manal , Ashraf Azhaar , Kislitsyna Elena , Anjum Rifah , Hubens Chantal , Parkes Harry , So Po‐Wah 
Published: December 2020

AbstractBackgroundBoth iron dyshomeostasis and neuroinflammation feature in Alzheimer’s disease (AD)1,2, the former thought to induce neuronal death via oxidative stress3,4. Interestingly, iron metabolism can be modulated by neuroinflammation5. Here, we investigate the effects of systemic iron or neuroinflammation (induced by lipopolysaccharide, LPS), and possible synergies in an AD mouse model (5xFAD) using in vivo magnetic resonance imaging (MRI).MethodAD mice were given iron (II) sulphate or saline, with or without LPS pretreatment (see Figure 1). A month after the final iron treatment, brain MRI was performed at 9.4T. MRI‐T1 and ‐T2 values from the hippocampus (ventral and dorsal; Hippven and Hippdor, respectively) and various cortices (prefrontal, somatosensory and motor cortex; PFC, SSC and MC, respectively) were obtained. Group differences were assessed using ANOVA and Tukey’s post‐testing with significance at p<0.05.ResultIron is paramagnetic and lowers MRI‐T26. Iron reduced T2 in the SSC compared to saline but not in other regions, remaining low even with LPS pre‐treatment (Figure 2). While T2 was generally decreased in the PFC, LPS pre‐treatment significantly increased T2, possibly by attenuating iron deposition. Interestingly, LPS reduced T2 in the Hippven and this was alleviated by combined treatment with iron, suggesting increased iron deposition due to microglia activation during inflammation5 which is attenuated by iron‐inhibition of cellular iron importation7. T1 is also reduced by iron although T1 is less sensitive than T26 and relates more to water content, e.g. oedema8. Indeed, iron treatment reduced T1 in the Hippven and PFC but T1 was similar in the other regions (Figure 2). In the Hippven, PFC, SSC and MC, LPS only or iron+LPS treatments increased T1 when compared to the iron only group, suggesting LPS may induce oedema and counteract the iron‐induced T1 reductions.ConclusionChanges in T2 suggests iron deposition in different brain areas with iron or LPS treatment, that is counteracted when LPS and iron treatments are combined. Similarly, selective T1‐changes observed in the hippocampus and cortices are also attenuated by combined LPS and iron treatment. Specific iron‐neuroinflammation interactions occur in different brain regions, not necessarily synergistically and further investigations are needed.
Identification of α4β2 nAChR interaction site with Aβ42 and development of tetrapeptide capable of breaking this interaction
Authors: Barykin Evgeny , Garifulina Alexandra , Adzhubei Alexei , Shelukhina Irina , Kozin Sergey A. , Mitkevich Vladimir , Tsetlin Victor , Makarov Alexander 
Published: December 2020

AbstractBackgroundCholinergic dysfunction in Alzheimer’s disease may arise from selective death of cholinergic neurons caused by the interaction of Aβ peptide with nicotinic acetylcholine receptors (nAChRs). Thereby, compounds that prevent the interaction of Aβ with nAChRs are needed to address the cholinergic deficit. Here, we identify the interaction site between Aβ42 and one of the two most abundant nicotinic receptors ‐ α4β2 nAChR. Further, we propose a tetrapeptide that prevents this interaction and serves as a potential therapeutic to counteract the cholinergic deficit in AD.MethodSequence analysis was used to identify the binding site of Aβ42 to α4β2 nAChR (35HAEE38). Surface plasmon resonance was utilized to evaluate the interaction between HAEE peptide and Aβ16. A complex of human α4β2 nAChR with Aβ42 was modeled with bioinformatics approaches. Human α4β2 nAChR was expressed in X. laevis oocytes. The receptor currents in the presence of Aβ42 and HAEE were studied with a two‐electrode voltage clamp.ResultAnalysis of α4β2 nAChR sequence showed that N‐terminal fragment 35HAEE38 of the α4 subunit is ionic complementary to 11EVHH14 in Aβ, suggesting it to be a potential site of the interaction. Synthetic HAEE peptide demonstrated binding to Aβ16, and molecular modeling confirmed that interaction of Aβ42 with α4β2 nAChR can occur via 11EVHH14:35HAEE38 interface. Pre‐incubation with Aβ42 reduced the amplitude of ACh‐evoked response in α4β2 nAChR‐transfected X. laevis oocytes by 20% and increased the leakage current in oocytes. Co‐incubation of Aβ42 with HAEE tetrapeptide reduced the degree of inhibition. Washout of Aβ42 with HAEE‐containing solution restored the current amplitude and reduced the leakage current.Conclusion35HAEE38 is a potential binding site for Aβ42 on α4β2 nAChR. HAEE tetrapeptide corresponding to this site restores inhibition of α4β2 nAChR by Aβ42 opening a potential therapeutic avenue for cholinergic dysfunction in AD.Supported by RSF grant #19‐74‐30007.
Cortical thickness of parahippocampal gyrus discriminates mild cognitive impairment (MCI) groups with different profiles of CSF biomarkers
Authors: Fernández Miguel Ángel Rivas , Aldrey‐Vázquez Jose M. , Lojo‐Seoane Cristina , Lindín Mónica , Pías‐Peleteiro Juan M. , Vieites Ana Nieto , Zurrón Montserrat , Domínguez‐Vivero Clara , Campos‐Magdaleno Maria , Pereiro Arturo X. , Díaz Fernando 
Published: December 2020

AbstractBackgroundMild cognitive impairment (MCI), clinically considered an intermediate state between the cognitive changes of normal aging and early dementia (Petersen, 2016), progress frequently to Alzheimer´s clinical syndrome. Alzheimer Disease (AD) biomarkers are used to evaluate the etiology and progression of MCI. In this study, we evaluated whether MCI participants with different profiles of CSF biomarkers (proposed by the National Institute on Aging and Alzheimer's Association ‐Jack et al., 2018‐) show differences in cortical thickness measures of the parahippocampal gyrus subregions.MethodSeventy‐eight patients from the Compostela Aging Study diagnosed as MCI according to the Petersen criteria (Petersen, 2004; Albert et al., 2011) underwent neuropsychological assessment, CSF (β‐amyloid, p‐tau and t‐tau), and MRI cortical thickness measures of the parahippocampal gyrus. Subcortical segmentation of T1‐weighted MR images was conducted with FreeSurfer (6.0 version) using the “recon‐all” pipeline to obtain the mean thickness measures of the parahippocampal and the entorhinal cortex of each participant. Participants were classified into four groups according to CSF biomarkers: Group 1: Normal AD with MCI; Group 2: Alzheimer’s pathologic change with MCI; Group 3: Alzheimer’s disease with MCI (Prodromal AD); and Group 4: non‐Alzheimer’s pathologic change with MCI. General lineal models were performed to evaluate Group differences in the cortical thickness measures.ResultsThe MCI Group 1 showed significantly higher cortical thickness than: a) Group 3 in right and left parahippocampal cortex, and b) Group 2 in right entorhinal cortex (Table 1 and Figure 1). No other significant differences were obtained.ConclusionsThe MCI CSF profile groups 3 (“prodromal AD”) and 2 (“Alzheimer´s pathologic change”) showed significant parahippocampal gyrus atrophy compared with MCI group 1 (“normal AD”). These results support MCI profiles proposed by Jack et al. (2018). Moreover, considering the degeneration of medial temporal lobe in AD, the aforementioned changes might have an AD diagnostic and prognostic value for both MCI groups.