bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reliability assessment of tissue classification algorithms for multi‐center and multi‐scanner data
Authors: Dadar Mahsa , Duchesne Simon 
Published: December 2020

AbstractBackgroundGray and white matter volumes are important imaging markers of pathology and disease progression. Such measures are usually estimated from tissue segmentation maps produced by image processing pipelines. However, the reliability of the produced segmentations when using multi‐center and multi‐scanner data remains understudied. Here, we assess the robustness of six publicly available tissue classification pipelines across images acquired from different scanners models and sites.MethodData included 90 T1‐weighted images of a single individual, scanned in 73 sessions across 27 sites (Duchesne et al., 2019). An average T1‐weighted image template was created out of all scans (Fonov et al., 2009). For each algorithm, their respective segmentation masks on this template was used as a silver standard (Figure 1). Dice Kappa similarity scores between these silver standards and individual segmentations and variability in tissue volumes across segmentations were assessed for Atropos (Avants et al., 2011); BISON (Dadar and Collins, 2019); Classify_Clean (Cocosco et al., 2003); FAST5.0 (Zhang et al., 2001); FreeSurfer6.0.0 (Fischl, 2012); and SPM12 (Penny et al., 2011). We also estimated the sample size necessary to detect a significant 1% volume reduction based on the variability of the estimates from each method within and across scanner models (80% power, 2‐tailed significance).ResultAcross tissue types, BISON had the lowest overall variability in Dice Kappa, followed by SPM12 (Figure 2). For GM, BISON had the highest overall Dice Kappa (0.94±0.01), followed by SPM12 (0.93±0.01) and Atropos (0.92±0.03); while Atropos had the highest overall Dice Kappa for WM (0.94±0.02), followed by BISON (0.93±0.01) and SPM12 (0.93±0.01). BISON had the lowest overall variability in its volumetric estimates (GM:57.60±0.4, WM:34.49±0.4, CSF:7.90±0.3), followed by FreeSurfer (GM: 49.80±0.7, WM: 39.52±0.8, CSF: 10.71±1.2), and SPM12 (GM:57.76±1.3, WM:33.08±1.1, CSF:9.12±0.9, Figure 3). BISON also had the smallest sample size requirement across all scanners and tissue types, followed by FreeSurfer, and SPM12 (Table 1). As expected, the necessary sample sizes decreased when using data from a specific scanner.ConclusionOur comparisons provide a benchmark on the reliability of currently used tissue classification techniques and the amount of variability that can be expected when using large multi‐center and multi‐scanner databases.
Degradation of amyloid beta by multi‐copper oxidases
Authors: Ran Chongzhao , Yang Jing , Ran Kathleen , Lu Ying 
Published: December 2020

AbstractBackgroundThe accumulation of amyloid beta (Aβ) species has been widely considered to be one of the possible causes of the pathology of Alzheimer’s disease (AD). Inhibiting Aβ production to prevent the accumulation and aggregation has been intensively investigated. However, the degradation of Aβ, which can also reduce the accumulation, has received much less attentions.MethodIn this study, we used FAM‐Aβ42, a fluorescent dye conjugated Aβ, to investigate the degradation of Aβ in the presence of various multi‐copper oxidases.ResultWe first discovered that ceruloplasmin (CP), the major copper‐carrying protein in the blood, could degrade Aβs. We then validated the CP‐Aβ interaction using total internal reflection fluorescence (TIRF) microscopy, fluorescence photometer and fluorescence polarization measurement. We further found that the presence of Vitamin C could enhance the degrading effect in a concentration‐dependent manner. Based on the above discovery, we hypothesized that other multi‐copper oxidases (MCO) had similar Aβ‐degrading function. Indeed, we found that other MCOs could induce Aβ cleavage. Remarkably, we revealed that ascorbate oxidase (AO) had the strongest degrading effect amony the tested MCOs. Using iPS‐induced neuron cells, we observed that AO could rescue cell apoptosis and neuron toxicity which induced by Aβ oligmers. In addition, our electrophysiological analysis with brain slides suggested that AO could prevent an Aβ induced deficit in synaptic transmission in the hippocampus.ConclusionTo the best of our knowledge, our report is the first to demonstrate that MCOs could bind to Aβs and mediate cleavage of Aβs. Further investigations are warranted to explore the possible benefits of the Aβ‐degrading function of MCOs.
Multilayer OMICS characterization of APOE‐modulated isogenic hiPSCs elucidates cell‐type–specific mechanisms modified by APOE: A study of the IMI ADAPTED Consortium
Authors: Ried Janina S. , Curado Marco Rocha , Sáez María Eugenia , Bahnassawy Lamiaa , Lee Heyne , Reinhardt Peter , Mohler Eric G. , Madrid Laura , Socorro Alfredo Cabrera , Grezella Clara , Nicolas Armel , Rao Francesco , Ramaswamy Gayathri , Bakker Margot H.M. 
Published: December 2020

AbstractBackgroundAlzheimer’s Disease (AD) is the most common cause of dementia in the elderly and affects over 35 million people worldwide, imposing increasing social and economic burden as the population ages. While it is widely known that the most prominent genetic risk factor for AD is the presence of the Apolipoprotein E (APOE) ε4 allele, the effects of APOE in the development of AD is still poorly understood. As part of the IMI ADAPTED consortium, we aim to clarify the role of APOE as a risk factor in the development of AD. Here we present an in‐depth analysis of the effect of the APOE genotype on the transcriptome of brain cells derived from human‐induced pluripotent stem cells (hiPSCs).MethodIsogenic hiPSC lines were modified to carry different APOE genotypes: ε3/ε3, ε4/ε4, ε3/ε4, ε2/ε2, as well as an APOE knock‐out (KO) cell line. Lines carrying each of these genotypes were differentiated into distinct cell types. Differential gene expression (DGE) and protein expression (DPE) was calculated, followed by gene set enrichment. Clustering approaches were used to identify shared and differing gene signatures across genotypes. We further applied upstream regulator and network analysis on the individual cell‐type results and integrated these results across cell types. The results were compared with DGE and DEP results from an APOE mouse model. Finally, the identified genes and mechanisms were combined with the results of data from postmortem human brain samples of AD cases and controls.ResultsThe observed transcriptional changes confirmed phenotypic observations made for the hiPSCs and refined the insight of genes identified human brain OMICS data. Several genes and pathways were identified, which showed consistent gene expression on transcriptome and proteome level. Further, shared patterns of expressions of genes across genotypes and potential mechanisms involved in this were detected.ConclusionsIn depth transcriptomics and proteomics analysis of APOE modified hiPSCs enabled to study cell type specific effects and contributed with this to the understanding of mechanisms affected by different APOE genotypes.
Socioeconomic status mediating sex and racial differences using the AT(N) framework
Authors: Wisch Julie , Hudson Darrell , Coble Dean W , Xiong Chengjie , Babulal Ganesh M , Gordon Brian A , Flores Shaney E , Dincer Aylin , Benzinger Tammie LS , Morris John C , Ances Beau 
Published: December 2020

AbstractBackgroundPrevious research suggests that women and African Americans are potentially at greater risk for developing Alzheimer disease (AD). Genetic, social, environmental, and cardiovascular factors may increase the risk of AD. (1) Assess neuroimaging biomarkers of amyloid (A), tau (T), and neurodegeneration (N) for potential sex and racial differences. (2) Consider mediating effects of socioeconomic status (SES) and cardiovascular risk factors on observed sex and race differences.MethodImaging measures of AT(N) (amyloid and tau positron emission tomography (PET) structural magnetic resonance imaging, and resting state functional connectivity (rs‐fc)) were collected from African American (n=169) and Caucasian (n=935) participants. Cardiovascular (white matter hyperintensities on MRI, blood pressure, and body mass index) and area‐based socioeconomic status (SES) were assessed as possible mediating factors in a multiple mediation analysis. This analysis assumed nonlinear relationships between the mediation effects and allowed for all four mediators to be considered simultaneously.ResultCompared to Caucasian participants, African American participants had lower amyloid PET burden but greater neurodegeneration, as measured by decreased cortical volumes and decreased AD global rs‐fc signature. African American participants were substantially more likely to be female (64%) compared to Caucasian participants (55% female). Female participants had greater tau burden and decreased AD cortical signature volume; but no significant race by sex interactions were observed. African Americans had lower area‐based SES and higher blood pressure, BMI, and white matter hyperintensity volumes. These proposed mediators significantly influenced associations between race and cortical amyloid PET accumulation, AD cortical signature volume, and AD global rs‐fc signature. Area‐level SES in particular was a significant mediating factor, and BMI had a significant effect on amyloid burden.ConclusionObserved racial differences in AD are not primarily due to immutable, genetic differences, but rather modifiable factors fueled by differences in social contexts and resources, particularly area‐level SES. Future studies should emphasize collection of relevant psychosocial factors in addition to the development of intentional diversity and inclusion efforts to improve the racial/ethnic and socioeconomic representativeness of AD studies.
Multi‐channel IIT and Rush University Aging (MIITRA) Atlas: Development and evaluation of multimodal templates of the older adult brain
Authors: Wu Yingjuan , Ridwan Abdur Raquib , Qi Xiaoxiao , Zhang Shengwei , Bennett David A , Arfanakis Konstantinos 
Published: December 2020

AbstractBackgroundRecent years have seen an increasing demand for multimodal MRI templates of the older adult brain. As part of the Multi‐channel IIT and Rush university Aging (MIITRA) atlas, this work aimed to develop high quality multi‐modal T1‐weighted (T1w) and diffusion tensor imaging (DTI) templates of the older adult brain. This was accomplished through a proposed iterative multimodal template construction strategy.MethodTemplate construction: T1w and DTI data on 202 non‐demented older adults (50% male,65.2‐94.9 yrs) from Rush MAP were used. DTI data were aligned to the raw T1w images. In the proposed approach, each iteration includes two steps(Fig.1). In step1, a temporary T1w template is generated and the resulting transformations are also applied to the DTI data. In step2, a temporary DTI template is generated and the resulting transformations are also applied to the T1w data. The template quality at each iteration was assessed through the spatial matching of deformed data. The T1w and DTI template spatial matching was assessed by the overlap between the white matter tissue probability map and the FA map. Comparison to other templates: For the evaluation, T1w and DTI data on 202 non‐demented older adults from ADNI3 were used. The new MIITRA templates generated through the proposed approach were compared with study‐specific template(constructed using evaluation data) and other standardized templates including older adults in terms of inter‐subject spatial normalization accuracy and inter‐modality spatial matching when used as reference for normalization of evaluation data.ResultsFigure 2 demonstrates that the spatial normalization of the T1w and DTI data used to construct the templates improves(p<10‐10) and the spatial matching between the T1w and DTI templates also improves(p<10‐10), suggesting better quality of the templates with more iterations. Figure 4 to 6 show that the new MIITRA templates allow higher spatial normalization accuracy of data from older adults compared to other available templates(p<10‐10).ConclusionThis work proposed a new multimodal templates construction approach and generated new MIITRA T1w and DTI templates of the older adult brain in the same space, which allow better spatial normalization of T1w and DTI data from older adults compared to other available templates.
Brain transcriptomes and plasma proteins reveal upregulation of a proinflammatory signature in APOE e4 carriers
Authors: Das Sudeshna , Serrano‐Pozo Alberto , Li Zhaozhi , Kivisäkk Pia , Carlyle Becky C. , Arnold Steven E , Hyman Bradley T. 
Published: December 2020

AbstractBackground
APOE e4 —the main genetic risk factor for Alzheimer’s disease (AD)—is associated with an increased Aβ plaque burden. Aβ plaques are surrounded by activated microglia, but whether APOE influences microglial responses to plaques in human brains has not yet been extensively studied. In this study, we investigated whether APOE alleles are associated with differences in microglial gene expression—either in concert with, or independent of, AD neuropathological changes—and with plasma protein levels.MethodWe analyzed brain transcriptomics data from the Mount Sinai Brain Bank (MSBB) and the Rush Religious Orders Study and Memory and Aging Project (ROSMAP). We performed integrative analysis to evaluate microglia gene expression across all APOE alleles: e4+ (e3/e4, e4/e4), e2+ (e2/e2, e2/e3) and e3/e3 (reference), adjusting for Braak neurofibrillary tangle (NFT) stage and CERAD neuritic plaque (NP) score. Additionally, we investigated the effect of the e4 allele on the plasma levels of 400 proteins in 34 cognitively normal subjects, measured using the OlinkTMProximity Extension Assay (PEA) panels.ResultMore than a third of the microglial genes were significantly upregulated in e4+ individuals controlling for CERAD NP score. Sensitivity analysis using Braak NFT stage yielded similar results. These genes included complement factors (C3, PLAU, PLAUR), Toll‐like receptor (TLR2, TLR5, TLR7, SPP1), and chemokines (CCL2,CCR5, CCR10). Of note, ∼20% of these genes were significantly increased even in cognitively normal e4+ subjects with low AD neuropathological changes at autopsy (none or sparse NP and Braak NFT stage 0‐II), suggesting e4 is associated with an enhanced baseline inflammatory pattern. A similar pro‐inflammatory profile was also observed in the plasma of cognitively normal e4+ carriers.ConclusionOur brain transcriptomic analyses and multiplexed quantification of plasma proteins indicate that carrying the APOE e4 allele is associated with a pro‐inflammatory program compared to the APOE e3/e3 reference group. This differential effect of the APOE e4 allele was observed in brains of individuals with low AD neuropathological changes at autopsy, suggesting that it is not just mediated through its effects on amyloid plaques. Thus, APOE e4 may prime microglia toward a pro‐inflammatory phenotype before plaques and tangles develop.
Characterizing MRI biomarkers for early prediction of amnestic mild cognitive impairment among the community‐dwelling Chinese
Authors: Yue Ling , Pan Yongsheng , Wang Tao , Liu Mingxia , Shen Dinggang , Xiao Shifu 
Published: December 2020

AbstractBackgroundIdentifying subjects at the preclinical amnestic mild cognitive impairment (pre‐MCI), is fundamental for early intervention of Alzheimer's disease. Extensive studies have shown that structural magnetic resonance imaging (MRI) provides objective biomarkers for automated diagnosis of Alzheimer’s disease and its prodromal stage (i.e., aMCI). This study aims to investigate a deep‐learning‐based framework for predicting the progression from normal control (NC) to MCI, by characterizing imaging biomarkers in structural MRI data.MethodMotivated by previous disease diagnosis systems with MRI, we create a unique deep‐learning framework for pre‐MCI conversion prediction, by evaluating the discriminative capability of single region‐of‐interest (ROI) or multiple ROIs in the brain. Our framework includes 2 steps: 1) a single‐ROI‐based network (SRNet) for locating the informative regions in the brain, and 2) a multi‐ROI‐based network (MRNet) for pre‐MCI conversion prediction (see Fig 1). We use 845 subjects with baseline MRI in ADNI‐1 to train SRNet and MRNet. To balance the sample size in each category, we use both AD and progressive MCI (within 3 years) patients as positive samples, while NC and stable MCI (within 3 years) samples as negative samples. We then apply the model trained on ADNI‐1 to our private dataset from the Chinese Longitudinal Aging Study (CLAS). The dataset of CLAS included 109 subjects with a baseline NC diagnosis and a 7‐year follow‐up diagnosis. Among these subjects, 40 NC are absolutely converted to aMCI within 7 years (pNC) and 69 NC remain cognitively normal (sNC).ResultWe illustrate the predicted scores of all testing subjects derived by our method, where the subjects are roughly sorted by their stages. We further compared these two groups by logistic analysis while controlled for age, gender, education level, depression symptoms, anxiety symptom, physical disease and baseline cognitive score, pNC individuals remained significant higher predicted score than sNC (see table 1).ConclusionThis study develops an ROI‐based deep‐learning framework to predict the progression from cognitive normal to aMCI. Experimental results suggest that our method can discriminate the cognitive normal individuals who would be diagnosed with MCI 7 years later, which is helpful for early diagnosis.
Implementation of an interprofessional approach to assessment and care planning in ambulatory older adults with cognitive impairment
Authors: Osbaugh Nicole A , Pearson Scott M , Fixen Danielle R , Hartley Kirbie , Parnes Bennett L , Linnebur Sunny A 
Published: December 2020

AbstractBackgroundMedicare‐reimbursed assessment and care planning for cognitive impairment and associated functional decline requires a comprehensive approach that may be challenging for medical practices to implement. An interprofessional team approach to this service utilizes unique strengths of team members to optimize care.MethodsThe University of Colorado Health Seniors Clinic developed an interprofessional “Memory Clinic,” in May 2017 to meet these needs. The team includes geriatricians, clinical pharmacists, a social worker, and medical assistants who are part of the larger Seniors Clinic team. Patients referred to the “clinic” are scheduled for a 40‐minute appointment with a geriatrician for medical, cognitive and functional assessment; receive a pharmacist‐provided cognition‐focused medication, lab, and recreational drug review; and visit with the social worker for functional and caregiver support and resources. Medical assistants assess vital signs and perform depression screening prior to the physician appointment. Medicare Part B is billed for the visit using CPT code 99483.ResultsA review of the electronic medical record identified 112 patients referred to the “clinic” through early December 2019. The mean patient age was 82 years (range 71‐96 years) and all patients received a pharmacist review. 94 (84%) were seen by a geriatrician, and 51 (46%) met separately with a social worker. The majority of patients evaluated by the geriatrician were assessed with the MOCA test (86%, mean score 17.9/30) and the FAST (95%, most common stages 2 and 4). Almost two‐thirds of patients had documented advance directives and a majority had caregivers present at the visit (72%). The pharmacist review identified a mean 2.4 medications per patient that could contribute to cognitive impairment and additional laboratory assessment needed in approximately 50% of patients. FDA‐approved pharmacologic treatments for dementia were prescribed in 17 (15%) patients. A small number of patients stated they regularly ingested marijuana (n=3), applied it topically (n=2), or drank alcohol excessively (n=11).ConclusionsAn interprofessional team‐based approach to cognitive impairment screening and care planning was successfully implemented in a University‐based ambulatory geriatrics clinic. Evaluated patients were found to most often be mildly impaired and have several medications that could be impacting their cognition.
Neuropathological correlates of cortical superficial siderosis in cerebral amyloid angiopathy
Authors: van Veluw Susanne J. , Charidimou Andreas , Frosch Matthew P. , Greenberg Steven M 
Published: December 2020

AbstractBackgroundCortical superficial siderosis (cSS) is an established hemorrhagic neuroimaging marker of cerebral amyloid angiopathy (CAA) and emerging as a strong independent risk factor for future lobar intracerebral hemorrhage. However, the underlying neuropathological correlates and pathophysiological mechanisms of cSS remain elusive.MethodFourteen autopsy cases with CAA (mean age at death 73 years, 9 males) and three controls (mean age at death 91 years, 1 male) were included. Intact formalin‐fixed cerebral hemispheres were scanned on a 3 tesla MRI scanner. cSS was assessed on ex vivo gradient echo and turbo spin echo MRI sequences and compared to findings on available in vivo MRI. Subsequently, eleven representative areas in four cases with available in vivo MRI scans were sampled for histopathological verification of MRI‐defined cSS. In addition, samples were taken from pre‐defined standard areas of the brain, blinded to MRI findings. Serial sections were stained for H&E and Perls’ Prussian blue, and immunohistochemistry was performed against Aβ and GFAP.ResultcSS was present on ex vivo MRI in 8/14 cases and 0/3 controls. Histopathologically, cSS corresponded to Iron‐positive hemosiderin deposits in the subarachnoid space and superficial cortical layers, indicative of chronic bleeding events originating from the leptomeningeal vessels (Figure 1). Increased severity of cSS was associated with upregulation of reactive astrocytes. Next, cSS and CAA pathology were assessed on a total of 65 sections from MRI‐targeted and untargeted samples. Moderate‐to‐severe cSS was associated with concentric splitting (an advanced form of CAA‐related vascular damage) of the walls of leptomeningeal vessels (p<0.0001), but reduced CAA severity in cortical vessels (p=0.048). Moderate‐to‐severe cSS was associated with the presence of microinfarcts (p=0.025), though not microbleeds (p=0.973).ConclusioncSS on MRI corresponds to Iron‐positive depositions in the superficial cortical layers, representing the chronic manifestation of bleeding episodes from leptomeningeal vessels. cSS appears to be the result predominantly of advanced CAA of the leptomeningeal vessels and may trigger secondary ischemic injury in affected areas.