bluuebunny/crossref_metadata_2025_split huggingface dataset:
African and European local ancestry surrounding Apolipoprotein E has a differential biological effect upon acute amyloid beta exposure in iPSC‐differentiated astrocytes
Authors: Oron Oded , Maddy Krisna S. , Celis Katrina , Cukier Holly N. , Pericak‐Vance Margaret A. , Young Juan , Blurton‐Jones Mathew , Griswold Anthony J. , Vance Jeffery M. , Dykxhoorn Derek M. 
Published: December 2020

AbstractBackgroundStudies have shown that the lower risk associated with the ε4 allele for African ancestry is associated with the local ancestry (LA) surrounding the ApoE gene. Previous studies have shown differences between ApoE3 and ApoE4 alleles in isogenic induced pluripotent stem cell (iPSC) models when exposed to Aβ. We hypothesized that ApoE4 individuals with African LA would respond differently to Aβ compared to European ApoE3 and European ApoE4 LA lines. However, as we cannot produce isogenic lines to test LA, we used RNA expression changes to Aβ exposure to increase our sensitivity to potential differences.MethodWe differentiated European LA ε4/ε4 and African LA ε4/ε4 allele astrocytes from iPSC lines. Astrocytes were exposed to exogenous Aβ and RNA was obtained at 0 and 24 hours. We performed bioinformatic analyses with the STAR algorithm and differential expression calculation using linear models implemented in edgeR. Pathway enrichment analysis for Gene Ontology Biological Processes, KEGG and Reactome pathways was performed using Metascape.ResultTwenty‐four hours following Aβ exposure, 524 and 671 genes were deferentially expressed from baseline in African and European LA lines respectively. Analysis of the unregulated genes in the two different ancestries revealed markedly different pathways. The unregulated genes in African LA astrocytes were enriched for Ribosome Biogenesis and RNA modification processes while the upregulated genes in the European LA astrocytes were enriched for Cell Cycle and DNA modification processes. In the European LA astrocytes, downregulated genes were enriched for Synaptic Assembly and Kainate Receptor Activity while in the African LA astrocytes downregulated genes enriched for Extracellular Matrix‐related processes.ConclusionOur initial results suggest that the two ancestries respond differently to Aβ exposure. Whether this is due to global or local ancestry differences is unclear. Further studies including astrocytes bearing African LA ε3/ε3 are needed to clarify that question. Both ribosomal dysfunction and astrocyte‐neuronal and astrocyte‐microglia synaptic assembly have been implicated in Aβ clearance and/or AD. A potential link between LA and the regulation of these processes due to Aβ exposure could pave the path to a better understanding of LOAD pathology.
Evaluation of amyloid and tau PET quantitation methods using a 3D‐printed anatomically accurate brain phantom
Authors: Minhas Davneet S , Ghodadra Anish , Yu Zheming , Royse Sarah K , Aizenstein Howard J , Cohen Ann , Tudorascu Dana L , Lopresti Brian J , Mathis Chester , Klunk William E , Laymon Charles M 
Published: December 2020

AbstractBackgroundA potential source of error in quantifying longitudinal changes in amyloid and tau imaging is the spatial resolution of PET. Partial volume correction (PVC) methods have been developed to account for this, but there remains a lack of consensus in the Alzheimer’s field on their use due to a lack of method evaluation relative to ground truth. The aim of this work was to evaluate various reconstruction and image‐based PVC techniques using an anatomically accurate 3D‐printed PET phantom with physiologically relevant radiotracer distributions.MethodsA lateral temporal phantom (Figure 1) with six fillable, thin‐walled (1.0 mm) chambers corresponding to inferior, middle, and superior temporal gray matter (GM) and white matter (WM) regions was constructed via 3D‐printing (Formlabs Form 3) using the FreeSurfer v5.3 segmented sample subject “bert” as a pattern. Inferior and superior temporal GM regions were filled with a 3.0 kBq/cc concentration of F‐18 solution and WM regions with 1.5 kBq/cc, simulating a high amyloid‐burden subject with a GM‐to‐WM radioactivity ratio of 2:1. The phantom was scanned on a Siemens Biograph mCT and reconstructed using three techniques: FBP; OSEM; and TrueX, an iterative method with system matrix modeling using a spatially variant point spread function. Image‐based geometric transfer matrix (GTM) PVC was applied to the FBP and OSEM images. Regional uncorrected and PVC radioactivity concentrations were compared to known ground truth.ResultsFBP, OSEM, and TrueX PET images are presented in Figure 2. Inferior and superior temporal GM and WM radioactivity concentrations for each of the reconstructions, uncorrected and PVC, are presented in Figure 3.ConclusionGTM PVC resulted in more accurate regional quantification relative to uncorrected data, regardless of reconstruction method. TrueX, which accounts for the system resolution during reconstruction, did not result in improved quantitative accuracy despite apparent differences in image quality. Optimization of TrueX parameters may result in improved quantitation accuracy. This study adhered to one fundamental assumption of the GTM technique: radioactivity uniformity within a region. This assumption may be violated in human imaging. Future studies will address this and will examine varying levels of amyloid and tau burden and cortical atrophy.
Rationally designed antibodies selective for pathogenic tau aggregates
Authors: Roman Andrei , Hsueh Shawn Ching‐Chung , Kaplan Johanne , Gibbs Ebrima , Adekunle Aina , Plotkin Steven S. , Cashman Neil R. 
Published: December 2020

AbstractBackgroundTauopathies are neurodegenerative disorders characterized by the abnormal aggregation of tau protein in the brain. Soluble toxic tau aggregates have the ability to transfer from cell‐to‐cell and to induce newly formed aggregates in recipient cells, thereby propagating tau pathology across the brain in a prion‐like manner. We used computational modeling to identify conformational “disease‐specific” epitopes predicted to become exposed on misfolded tau aggregates. Selectivity of antibodies for tau pathogenic species, as opposed to pan‐tau reactivity, is needed both in order to preserve normal tau function and to minimize the diversion of active antibody from the target through unproductive binding to more abundant non‐toxic forms of the protein.MethodThe ability of predicted disease‐associated conformational peptide epitopes to induce tau aggregation on their own was tested in a Thioflavin‐T fluorescence(ThT)‐based seeding assay. Mouse monoclonal antibodies raised against selected epitopes were screened by surface plasmon resonance (SPR) for binding to synthetic tau monomers, toxic oligomers, and soluble pre‐formed fibrils (PFFs). Recognition of naturally occurring tau species in Alzheimer’s disease (AD) brain was also confirmed by SPR. The ability of selected antibodies to inhibit induction of tau aggregation by AD brain seeds was assessed in a seeding assay using TauRD P301S FRET Biosensor Cells expressing tau constructs with different fluorescent labels producing a FRET signal when aggregated.ResultPredicted conformational peptide epitopes capable of seeding activity in the ThT assay were used to immunize mice. SPR screening of hybridoma supernatants was used to identify antibody clones with the desired profile of preferential binding to a preparation of toxic tau oligomers vs non‐toxic tau monomers. A majority of these antibodies also bound soluble tau PFFs, a species believed to play a role in propagation of disease. Antibodies selected for further testing were found to recognize tau from AD brain extract by SPR and to inhibit seeding activity in a FRET assay.ConclusionComputational modeling for identification of predicted disease‐associated epitopes together with in vitro screening methods allowed for the generation of monoclonal antibodies with selectivity and activity against pathogenic, aggregated species of tau.
Therapeutic potential of oxytocin receptor signaling in vascular dementia
Authors: Counts Scott E. , Manfredsson Fredric P. , Sandoval Ivette , Paulson Henry L. , Lieberman Andrew P. , McKay Erin C. 
Published: December 2020

AbstractBackgroundWe recently demonstrated a de novo upregulation of the oxytocin receptor (OXTR) in astrocytes located in the peri‐infarct regions of subjects who died with vascular dementia (multi‐infarct subtype). OXTR activation has been linked to antioxidant, anti‐inflammatory, and angiogenic signaling, suggesting that OXTR upregulation is a novel protective target for vascular dementia, mixed dementias, and perhaps even cerebrovascular accidents. To test this hypothesis, we modeled OXTR upregulation in a novel rat model of vascular dementia.MethodFour month‐old spontaneously hypertensive, stroke prone rats are being randomized to receive cortical injections of adeno‐associated virus (AAV, serotype 6) bearing either OXTR or green fluorescent protein (GFP) cDNA under control of the astroglial‐specific GFAP promoter, followed by randomization to receive cortical injections of the vasoconstrictor endothelin‐1 (ET‐1) or saline vehicle (n = 16/group, balanced for sex). Following behavioral testing, rats are being analyzed postmortem for infarction lesion size, cerebrovascular pathology, and several mechanistic indices including markers for cell death, inflammation, and oxidative stress.ResultPreliminary results (n = 6‐8/group) showed that rats receiving AAV‐OXTR and ET‐1 displayed a nonsignificant 40% reduction in mean latency time to target on the Barnes maze compared to rats receiving AAV‐GFP and ET‐1 (p = 0.7). Similarly, OXTR/ET‐1‐treated rats showed a 110% increase in the mean ratio of time spent exploring novel vs. familiar objects on the Novel Object Task compared to GFP/ET‐1‐treated rats (p = 0.08). Postmortem histological analysis revealed a nonsignificant 60% reduction in infarct size in OXTR/ET‐1 compared to GFP/ET‐1 rats (p = 0.08).ConclusionPreliminary data are trending to support the concept that astrocytic OXTR signaling may have a therapeutic benefit for dementia resulting from cerebrovascular accidents.
Development and validation of composite scores for language and visuospatial functioning in ADNI
Authors: Choi Seo‐Eun , Mukherjee Shubhabrata , Gibbons Laura E , Sanders R. Elizabeth , Jones Richard N. , Tommet Douglas , Mez Jesse , Trittschuh Emily H , Saykin Andrew J. , Lamar Melissa , Rabin Laura , Foldi Nancy , Sikkes Sietske A.M. , Jutten Roos J. , Grandoit Evan , MacDonald Christine , Risacher Shannon L. , Groot Colin , Ossenkoppele Rik , Crane Paul K. ,   Alzheimer's Disease Neuroimaging Initiative
Published: December 2020

AbstractBackgroundComposite scores may be useful to summarize overall language or visuospatial functioning. We generated composite scores for these domains from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and evaluated their validity.MethodWe used item response theory to derive composite measures for language (ADNI‐Lan) and visuospatial functioning (ADNI‐VS). We performed multiple validation analyses comparing ADNI‐Lan and ADNI‐VS to individual test and global scores among participants with normal cognition (NC), mild cognitive impairment (MCI), and Alzheimer’s disease (AD). We evaluated ability to detect change, strength of association with a priori selected structural brain imaging findings, association with risk of AD conversion for people with MCI, and differences in intercepts and slopes for people with MCI with vs. without the CSF AD biomarker signature.ResultThere were 1,913 people with imaging data and age ³60. Single factor IRT models fit the data well for both composites. ADNI‐Lan outperformed MMSE language items, ADAS‐Cog language items, the Boston Naming Test (BNT), and fluency items in detecting change for MCI and AD. The clock score was modestly better than ADNI‐VS at detecting change for MCI and AD. ADNI Lan was the best at predicting MCI to AD conversion, while the clock score did slightly better than ADNI‐VS. Strength of association of language scores with structural MRI findings are shown in Table 1. ADNI‐Lan and the BNT had stronger associations than other scores for MCI in ADNI1, and also in ADNI2/ADNIGO except for BNT/temporal pole. For AD, ADNI‐Lan had strong associations with each region, similar to other scores except MMSE. Strength of association of visuospatial scores with structural MRI findings are shown in Table 2. ADNI‐VS and the clock had similar strong associations for most regions. People with MCI with the CSF AD biomarker signature had lower language intercepts, captured best by ADNI‐Lan, and more rapid decline, also captured best by ADNI‐Lan. Intercepts were not different for either visuospatial score, and ADNI‐VS and the clock score had similar slope terms.ConclusionADNI‐Lang and ADNI‐VS had good evidence of validity and may be useful composites for language and visuospatial functioning in ADNI.
Heart rate and blood pressure decreases after a motor task in pre‐symptomatic AD
Authors: Rochart Roger , Liu Quanying , Doyle John C , Arechavala Rebecca Johnson , Kloner Robert , Kleinman Michael T , Harrington Michael G , Arakaki Xianghong 
Published: December 2020

AbstractBackgroundUnderstanding how cardiovascular health affects the early Alzheimer’s disease (AD) pathology is challenging because several variables can contribute to significant changes in blood pressure (BP) and heart rate (HR). Previous studies have suggested an association between Alzheimer's disease and HR. Little association is known about pre‐symptomatic AD. We aim to explore the HR and BP changes before and after a motor task in a cognitive healthy population.MethodParticipants (age ranged 61‐95 years old) were recruited from the local community, including cognitively healthy (CH) individuals who were further subdivided based on cerebrospinal fluid (CSF) classification: those with a normal amyloid/tau ratio (CH‐NAT, n = 11) or a pathological amyloid/tau ratio (CH‐PAT, n = 8). Two groups were age, gender, BMI, and education matched. Participants were asked to use a steering wheel to follow a moving line presented on the monitor. Practice session were followed by three task‐identical sessions, 90 seconds per session. Each session consisted of 3 repeated blocks, 30 seconds per block: bump, trail, and bump & trail. Systolic pressure (SP), diastolic pressure (DP), pulse pressure (PP), and HR were measured before and after completing the whole task.ResultNo differences in BP and HR were found between CH‐NATs and CH‐PATs. We found a significant decrease in SP for both CH‐NATs (pre‐task 135.2±24.2, post‐task 127.2±18.8, reduced by 8±9.7, p = 0.0208) and CH‐PATs (pre‐task: 146.1±20.6, post‐task: 134.8±19.6, reduced by 11.3±5.2, p = 0.0004). Furthermore, CH‐PATs have a significant drop in HR (pre‐task: 71.4±10.7, post‐task: 66.3±8.2, reduced by 5.1±4.1 beats, p = 0.0098) compared to CH‐NATs (pre‐task: 70.8±11.8, post‐task: 69.2±13.3, reduced by 1.5±6.2 beats, p = 0.4302). CH‐PATs has decreased HR*SP (pre‐task: 10464±2375.6, post‐task: 8941.1±1843.1, reduced by 1522.9±775.8, p = 0.0009), compared to CH‐NATs (pre‐task: 9537.2±2098.3, post‐task: 8765.2±1769.2, reduced by 772.0±1153.5, p=0.0507). No significant change was found in DP for either CH‐NATs or CH‐PATs.ConclusionPre‐symptomatic AD participants have a significant drop of HR, SP, and SP*HR compared to CH‐NATs, indicating reduced sympathetic responses after motor task. These changes in HR and SP may provide evidence of compromised cardiovascular health and autonomic regulation in pre‐symptomatic AD.
Lifetime brain structural trajectories in TAUPS2APP mouse model of Alzheimer's disease
Authors: Blūma Marina , Micotti Edoardo , Devenyi Gabriel A. , Tolomeo Daniele , Cupo Lani , Forloni Gianluigi , Chakravarty M. Mallar , Babiloni Claudio 
Published: December 2020

AbstractBackgroundThe TAUPS2APP Alzheimer’s disease (AD) mouse model expresses mutant APPSWE, PSEN2N141I and TAUP301L mutations and displays age‐dependent accumulation of Aβ plaques and neurofibrillary tangles. In humans, abnormal protein accumulation and spreading are related to neurodegenerative processes, most stereotypically in the hippocampus and medial temporal lobe. Prior reports in different AD models have demonstrated various brain structural phenotypes (Grandjean et al.,2016). Here we assess neuroanatomical trajectories in the TAUPS2APP model of AD using longitudinal MRIs.MethodThirteen C67BL/6 (11f/2m) and seventeen TAUPS2APP (10f/7m) mice underwent T2‐weighted MRI (voxel size 117x147x147 μm, matrix 256x102x120, FoV 3x1.5x1.5 cm, TR=2500 ms TE=50 ms) at 4,9,13,18, and 24 months of age. Data were analyzed following two‐level deformation‐based morphometry pipeline that uses ANTs SyN nonlinear registration. At the first level within subjects’ minimum deformation averages are created and estimates of volume change are computed (log Jacobian determinants). Next, a second level average is created out of unbiased within‐subject averages and the Jacobians are resampled into the common spaceResultA linear mixed‐effect model with subject as random effect (second order spline fit, sex as a covariate) revealed significant differences in interaction between age and genotype in neuroanatomical trajectory (absolute Jacobian) of bilateral hippocampus, lateral septal area (LSA) and isocortical areas (at False Discovery Rate of 5%, fig.1). TAUPS2APP showed an accelerated overgrowth of hippocampus at young age but larger volumetric decline with age in comparison to non‐TG animals (fig.2a). A similar pattern was observed in LSA (fig.2b). On the contrary in the isocortex, where non‐TG declined with age, TAUPS2APP mice showed volume enlargement (fig. 3c).ConclusionThese data suggest that TAUPS2APP model is characterized by abnormal neuroanatomical trajectory throughout its lifespan relative to controls. While hippocampal atrophy recapitulates clinical markers of late‐onset AD, enlarged cortex that had been reported earlier in some AD mouse models (TgCRND8, APP/J20 and PSAPP) does not. It was suggested that elevated APP levels may affect the rate of local region growth in adult mice ‐ due to space occupancy by amyloidosis and astrogliosis. In line with this Maheswaran et al. had reported a link between transgene expression, age, and volume increase over time (Maheswaran et al., 2009).
Retinal amyloid deposits found in association with Alzheimer’s disease compared with those in age‐related macular degeneration
Authors: Neathway Peter A.C. , Campbell Melanie C.W. , Redekop Rachel , Kitor Monika , Hirsch‐Reinshagen Veronica , Hsiung Ging‐Yuek Robin , Mackenzie Ian R. 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) and age‐related macular degeneration (AMD), both associated with ageing, share common underlying pathology, in that both have been shown to be associated with retinal amyloid deposits. However, amyloid in association with AD has been found in more anterior retinal layers, while amyloid in AMD is typically found in association with drusen, in posterior retinal layers. Here, we compare amyloid deposits found in anterior and posterior layers of the retina.MethodEyes were obtained from donors, including those with an intermediate (n=2) or high likelihood of AD (n=10). The severity of AD was assessed from brain pathology. Retinas were stained with 0.1% Thioflavin‐S, counter‐stained with DAPI and flat mounted. Retinal deposits were imaged using a fluorescence microscope fitted with a polarimeter. For each deposit, retinal layer was recorded (anterior, n=264; posterior, n=65). From 16 polarimetric images, interactions with polarized light were derived and image texture was assessed via multifractal analysis (MFA). 15 MFA properties were calculated. Using principal component analysis, the polarimetric and MFA variables which explain most of the variance within each group of deposits (anterior and posterior) were determined. These variables were then input into a non‐parametric discriminatory analysis to separate and classify deposits by retinal location (anterior or posterior).ResultFollowing principal component analysis, 12 polarimetric and 7 MFA properties were retained. Using the 5 nearest neighbours, a non‐parametric discriminate analysis was able to discriminate between deposits found in the anterior and posterior of the retina with success rate of 76% (+/‐3%) using 4‐fold cross‐validation.ConclusionIn conclusion, a combination of polarimetric properties and textural features of retinal amyloid deposits can be used to discriminate between anterior and posterior deposits. This suggests that the properties of deposits found in AD (expected in anterior layers) and AMD (expected in posterior layers) can be differentiated. Furthermore, an ability to distinguish these two types of retinal amyloid deposits in live‐eye imaging would assist their differential classification as associated with AD or AMD pathology. This could improve specificity of diagnosis in each of these conditions.
A systematic review on the potential role of APOE genotype as a moderator in the relationship between physical activity, brain health and dementia risk
Authors: de Frutos Jaisalmer , Rodriguez Juan Manuel Serrano , Maestú Fernando , Laws Simon M , Brown Belinda M 
Published: December 2020

AbstractBackgroundPhysical activity (PA) has been associated with decreased dementia risk, reduced Alzheimer’s disease (AD) neuropathological burden, and cognitive decline. On the other hand, the strongest genetic risk factor for AD is the Apolipoprotein E (APOE) ε4 allele, which increases AD‐risk in a dose‐dependent manner. Over the past two decades, researchers around the world have tried to unveil whether APOE ε4 carriage moderates the relationship between PA, brain health and dementia risk (Figure 1). Nevertheless, at present, this findings within this field remain inconsistent.MethodPubmed and Web of Science were searched for entries following the criteria specified in Table 1. The PRISMA guidelines for systematic reviews were followed throughout the process. A final set of 33 studies were considered after abstracts and full‐text articles were screened by two independent researchers. These included studies addressing the protective effect of PA on dementia risk (19 publications) and different markers of brain pathology (14 publications, see Figure 2).ResultStudies with shorter follow‐up periods found PA reduced dementia risk generally found that in both genotype groups; however, studies with longer follow‐ups showed varying results. Midlife PA seems to exert a greater impact on ε4 non‐carriers. Conversely, in neuroimaging studies, mainly ε4 carriers or both groups showed benefits, particularly when group sizes were large. Additionally, the association between PA and amyloid burden is stronger among ε4 carriers.ConclusionAlthough available data appears inconclusive, a close‐up look into the different study designs, methodologies and outcomes utilized can clarify the relationship between dementia and PA. More randomized clinical trials as well as longitudinal neuroimaging studies are need in order to fully elucidate relationship between PA, brain health and dementia risk.