bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plasma biomarkers of inflammation reflect disease state in autosomal dominant forms of familial frontotemporal dementia
Authors: Ljubenkov Peter A. , Staffaroni Adam M. , Casaletto Kaitlin B. , Rojas Julio C. , Vandevrede Lawren , Heuer Hilary W. , Elahi Fanny M. , Brushaber Danielle , Foroud Tatiana M. , Forsberg Leah K. , Karydas Anna M. , Boeve Bradley F. , Rosen Howard J. , Boxer Adam L. , Kramer Joel H. ,   ARTFL and LEFFTDS Consortium Investigators
Published: December 2020

AbstractBackgroundImmune dysregulation may influence disease pathogenesis in familial frontotemporal dementia (fFTD), but the utility of peripheral biomarkers of inflammation remains unclear in this cohort. We sought to investigate candidate plasma biomarkers of immune function within a large cohort of fFTD kindreds from the ARTFL and LEFFTDS Consortia.MethodsWe examined plasma samples from 148 non‐carrier healthy controls and 256 asymptomatic and symptomatic individuals carrying autosomal dominant fFTD‐associated mutations (n=73 MAPT, n=120 C9ORF72, and n=63 GRN). ELISA was used to measure three plasma biomarkers of inflammation (YKL‐40, TNF‐α,IL‐6). We used Mann–Whitney U tests to compare concentrations amongst controls and subgroups of fFTD differing in disease severity, defined by the Clinical Dementia Rating Scale plus National Alzheimer’s Disease Coordinating Center Frontotemporal Lobar Degeneration Behavior and Language Domains (CDR® plus NACC FTLD) global score (asymptomatic=0, early symptomatic=0.5, late symptomatic ≥1). We also used linear mixed models to assess the utility of baseline inflammatory biomarkers in predicting the subsequent annual rate of decline in functional clinical severity (CDR® plus NACC FTLD sum of boxes) and psychomotor speed (Trails A).ResultsPlasma YKL‐40 concentrations were elevated in late symptomatic fFTD (59.3ng/ml [50.1]) relative to controls (32.9ng/ml [24.0]) (p=0.0003) and asymptomatic mutation carriers (30.9ng/ml [25.4], p=0.0001). Plasma TNF‐α concentrations were relatively low in asymptomatic mutation carriers (1.96pg/ml [0.56]) compared to early symptomatic fFTD (2.35pg/ml [0.83], p= 0.009). Amongst mutation carriers (including 140 with follow up clinical data), higher baseline plasma IL‐6 and YKL‐40 concentrations were associated with greater increase in functional clinical severity and declines in psychomotor speed, respectively.ConclusionPlasma biomarkers of inflammation increase with disease severity in fFTD and predict worse clinical trajectories. While the role of inflammation remains unclear in familial FTD, plasma markers of inflammation appear to reflect the processes influencing disease trajectory in patients carrying mutations associated with familial frontotemporal dementia.
Examining the effects of the microglial PLCG2 P522R mutation by transplantation of human stem cell‐derived microglia in chimeric AD mice
Authors: Claes Christel , Danhash Emma , Hasselmann Jonathan , Chadarevian Jean Paul , Shabestari Sepideh Kiani , Lim Tau En , Tu Christina , Silva Jorge , Coburn Morgan A. , Jairaman Amit , Cahalan Michael , Blurton‐Jones Mathew , Davtyan Hayk 
Published: December 2020

AbstractBackgroundGenetic studies have uncovered several Alzheimer’s Disease (AD) risk genes that are highly expressed in microglia, suggesting that immune dysregulation plays a critical role in the development and progression of AD. In line with this, a recently discovered polymorphism (P522R) in the microglia‐expressed gene Phospholipase C‐Gamma 2 (PLCG2) was shown to be protective for AD. Interestingly, PLCG2 codes for a protein that regulates the release of calcium from ER stores and is also a component of the downstream signaling pathway of TREM2, another microglial AD risk gene. This underscores the need to improve our understanding of microglial calcium signaling, the effects of AD risk genes on this pathway, and the impacts of PLCG2 and calcium signaling on human microglial function.MethodsCRISPR gene editing was used to produce isogenic iPSCs that express the AD protective mutation in PLCG2. Several in vitro assays were then performed to examine calcium signaling pathways and phagocytosis. PLCG2‐P522R and WT HPCs were also transplanted directly into xenotransplantation‐compatible mouse pups (MITRG‐5xfAD mice), where they readily differentiated into human microglia, exhibiting typical markers and morphology.. Xenotransplanted human microglia (x‐MG) were then examined by confocal microscopy and isolated from the brain for single‐cell RNA sequencing.ResultsThus far our in vitro studies suggest that the P522R coding mutation increases both basal cytosolic calcium concentrations and amyloid phagocytosis. Additional functional experiments are further examining the interactions between PLCG2 mutations and calcium signaling during the uptake of AD‐relevant substrates. In addition, single cell RNA sequencing studies of chimeric mice reveal that the P522R mutation leads to an increased percentage of human microglia that have adopted a disease‐associated microglial (DAM) phenotype in vivo.ConclusionsBy combining iPSC‐microglia, CRISPR gene editing, and chimeric AD mice these studies have begun to uncover the impact of PLCG2 mutations on human microglial function and reveal that the protective P522R mutation increases Ab phagocytosis and promotes the adoption of a DAM‐like microglial response.
Single nuclear RNA sequencing reveals microglia diversity associated with cognitive resilience in the AD‐BXD mouse model of human Alzheimer’s disease
Authors: Heuer Sarah E. , Zhang Jigang , Samuels Michael , Hadad Niran , Telpoukhovskaia Maria , Ouellette Andrew R. , O'Connell Kristen M.S. , Menon Vilas , Robson Paul , Philip Vivek , Kaczorowski Catherine C. 
Published: December 2020

AbstractBackgroundAn individual’s genetic background plays an important role in governing the risk (or resilience) to developing Alzheimer’s disease (AD) dementia. The goal of this study was to identify the molecular pathways and cell‐types conferring individual differences in cognitive resilience to human familial AD (FAD) mutations that drive high amyloid.MethodA large set of genetically diverse mice harboring familial AD mutations (AD‐BXDs) and their non‐transgenic littermates (Ntg‐BXDs) were tested for short‐ and long‐term memory using contextual fear conditioning at 6m (AD‐BXD n=180, Ntg‐BXD n=174) and 14m (AD‐BXD n=121, Ntg‐BXD n=137). A subset of 14 AD mutation carriers that exhibited extreme resilience (n=7) or susceptibility (n=7) to cognitive decline were selected for hippocampal molecular profiling, along with their Ntg‐BXD littermates, at both 6m and 14m. Data from all hippocampi were aggregated and batch‐corrected using Harmony, and Seurat clustering was employed using the top 2000 variable genes. Known marker genes were used to associate clusters with cell‐types. The fraction of nuclei per sample (cluster composition) and within cell‐type differential gene expression were performed to determine changes in cell quantity and molecular profiles as a function of age, AD mutation carrier status, and resiliency to cognitive decline.ResultThere were no clusters that showed significant change in composition as a function of age. However, AD‐BXD individuals had significantly fewer astrocytes and more microglia than their Ntg‐BXD counterparts. We also found that resilient AD‐BXDs had fewer microglia than susceptible individuals, and the number of microglia at 6m was significantly negatively correlated with cognitive decline in AD‐BXD individuals. Additionally, microglia from resilient individuals showed up‐regulation of mitochondrial respiration and protein translation genes, proposing two pathways that dictate resilience in a microglia‐specific manner.ConclusionOur findings further implicate non‐neuronal cell‐types such as microglia in promoting resilience to cognitive decline in AD, and suggest several pathways by which microglia may be altered in resilient compared to susceptible individuals. We believe that by altering these microglia pathways within susceptible individuals, we can improve how non‐neuronal cells interact with CNS neurons to improve AD cognitive resilience.
MRI‐histopathology correlations of amyloid‐related imaging abnormalities (ARIA) in postmortem human brain samples
Authors: Scherlek Ashley , Kozberg Mariel , Nicoll James A.R. , Bacskai Brian , Greenberg Steven M. , Frosch Matthew P. , Boche Delphine , Veluw Susanne J. 
Published: December 2020

AbstractBackgroundAmyloid‐related imaging abnormalities (ARIA) on MRI are frequently observed adverse advents in the context of anti‐Aβ immunotherapy trials in patients with Alzheimer’s disease (AD). The underlying histopathology and mechanisms of ARIA remain unknown, although coexisting Cerebral Amyloid Angiopathy (CAA) appears to be a risk factor.MethodTen cases were selected from the long‐term follow‐up study of patients who enrolled in the first clinical trial of active Aβ immunization for AD (AN1792; Elan Pharmaceuticals Inc) (iAD cases; mean age at death 81 years, mean survival time from first immunization 107 months). Eleven matched non‐immunized AD cases were used as “controls” (cAD cases; mean age at death 79 years). Formalin‐fixed coronal slabs from the occipital lobe were imaged on a 7T MRI scanner, including a T2*‐weighted gradient echo sequence (voxel size 200 µm3). Samples with and without ARIA were cut in serial sections and stained with Hematoxylin & Eosin (H&E), Perls’ Prussian blue (iron), Von Kossa (calcifications), and immunohistochemistry against Aβ (Dako; clone 6F/3D).ResultOn ex vivo MRI, ARIA were observed in 7/10 iAD cases (including one case with documented ARIA during life) compared to 1/11 cAD cases (p=0.004), in the form of cortical superficial siderosis, hypointense lining of the deeper cortical layers, and white matter rarefaction (arrows in Figure). Histopathologically, ARIA corresponded to intraneuronal, vascular, and extracellular iron depositions and calcifications (Figure). In iAD cases the degree of iron (p=0.0006) and calcium deposits (p<0.0001) was more severe compared to cAD cases. In contrast, Aβ plaque burden was less severe in iAD cases (p=0.0017), confirming the previously reported observation of Aβ plaque removal after immunotherapy. Although the degree of CAA was comparable between iAD and cAD cases, concentric splitting of the walls of leptomeningeal vessels (an advanced stage of CAA severity) was observed in iAD cases in areas with ARIA, but not in areas without ARIA (p=0.055).ConclusionThese findings suggest that ARIA in the context of anti‐Aβ immunotherapy may result in lasting neuropathological alterations (perhaps even in the absence of clinical symptoms) and that advanced CAA likely plays a role in the pathophysiology of ARIA.
Exome sequencing identifies three novel AD‐associated genes
Authors: Holstege Henne , Hulsman Marc , Charbonnier Camille , Grenier‐Boley Benjamin , Quenez Olivier , Ahmad Shahzad , Amin Najaf , van Rooij Jeroen G.J. , Grozeva Detelina , Norsworthy Penny , Hummerich Holger , Kawalia Amit , Mok Kin Y. , Shoai Maryam , Dols‐Icardo Oriol , van Der Flier Wiesje , Sims Rebecca , Amouyel Philippe , Hardy John , Clarimon Jordi , Mead Simon , van Swieten John C. , Ramirez Alfredo , van Duijn Cornelia M. , Williams Julie , Nicolas Gaël , Bellenguez Céline , Lambert Jean‐Charles ,   ADSP Consortium
Published: December 2020

AbstractBackgroundWith the development of next‐generation sequencing technologies, it is possible to identify rare genetic variants that influence the risk of complex disorders. To date, whole exome sequencing (WES) strategies have shown that specific clusters of damaging rare variants in the TREM2, SORL1 and ABCA7 genes are associated with an increased risk of developing Alzheimer’s Disease (AD), reaching odds ratios comparable with the main AD genetic risk factor, the APOE‐ε4 allele. Here, we set out to identify additional AD‐associated genes by a genome‐wide investigation of the burden of rare damaging variants in the genomes of AD cases and cognitively healthy controls, the largest AD‐WES dataset available worldwide.MethodWe integrated the data from 25,982 cases and controls from the European ADES consortium and ADSP consortium from the USA on a single server. We developed a unique bioinformatic pipeline that applies new techniques to homogenize and analyze these data. Carriers of pathogenic variants in genes associated with Mendelian inheritance of AD were excluded. After quality control, we used 12,652 AD cases and 8,693 controls for analysis. Genes were analyzed using a burden analysis, using both non‐synonymous and loss‐of‐function rare variants. Variant impact was prioritized using REVEL.ResultIn our discovery phase, we confirmed and further substantiated that carriership of protein‐damaging genetic variants in TREM2, SORL1 or ABCA7 is a major AD‐risk factor. High‐impact variants in these genes are mostly extremely rare and they are enriched in AD patients with early ages at onset. Furthermore, we identified three additional genes that were significantly associated with AD, in which we identified a similar relationship between very rare, high‐impact variants and an enrichment in AD patients with early ages at onset. We are currently replicating these associations and several additional suggestive findings in independent datasets. The final results will be presented.ConclusionDevelopment of new homogenization methods has enabled the combined analysis of the largest AD‐WES dataset worldwide. With this, we were able to validate and expand on previous findings and to identify new genetic determinants of AD. Together, these genes pinpoint the most relevant pathways in the pathophysiological processes leading to AD.
Amyloid and tau PET in sporadic early‐onset Alzheimer’s disease: Preliminary results from LEADS
Authors: Rabinovici Gil D. , Iaccarino Leonardo , La Joie Renaud , Lesman‐Segev Orit H. , Soleimani‐Meigooni David N. , Provost Karine , Collins Jessica A. , Aisen Paul S. , Borowski Bret J , Eloyan Ani , Fagan Anne , Foroud Tatiana M. , Gatsonis Constantine , Jack Clifford R. , Kramer Joel H. , Saykin Andrew J. , Toga Arthur W. , Vemuri Prashanthi , Day Gregory S. , Graff‐Radford Neil R. , Honig Lawrence S. , Jones David T. , Masdeu Joseph C. , Mendez Mario F. , Onyike Chiadi U. , Rogalski Emily J. , Salloway Stephen P. , Wolk David A. , Wingo Thomas S. , Koeppe Robert A. , Dickerson Brad C. , Carrillo Maria C. , Apostolova Liana G. 
Published: December 2020

AbstractBackgroundPrevious studies have reported that age modifies the distribution and burden of tau (and, to a lesser extent, amyloid) pathology in sporadic Alzheimer’s disease (AD). Here we present preliminary baseline amyloid and tau PET results from the Longitudinal Early‐Onset Alzheimer’s Disease Study (LEADS), a multi‐site longitudinal study of sporadic early‐onset AD.Method135 patients meeting clinical criteria for MCI or probable AD and 50 cognitively normal controls (all age<65 at enrollment) were enrolled at 12 US centers between August 2018 and December 2019 (Table 1). 18F‐Florbetaben amyloid‐PET (FBB) was used to assign patients to EOAD (amyloid‐positive) or EOnonAD (amyloid‐negative) subgroups based on visual rating and semi‐quantification. 130 patients and all controls had 18F‐Flortaucipir tau‐PET (FTP). Regional Standardized Uptake Value Ratios (SUVR) for FBB (whole cerebellum reference) and FTP (inferior cerebellar gray reference) were extracted using co‐registered 3T‐MRI.Result98 patients (72.6%) were amyloid PET‐positive (EOAD) and 37 (27.4%) were amyloid PET‐negative (EOnonAD). Compared to EOAD, EOnonAD patients had higher MMSE, MOCA and CDR sum‐of‐boxes (CDR‐SB) and were more frequently male (Table 1). Patients with EOAD showed elevated FBB and FTP SUVR in temporoparietal and frontal cortex compared to CN and EOnonAD (Figures 1‐2). In EOAD, MMSE, MOCA and CDR‐SB were significantly correlated with FTP SUVR (Figure 3), while no significant correlations were found with FBB SUVR. EOnonAD patients showed variable FTP binding ranging from negative to mildly elevated binding in anterior temporal and frontal cortex and underlying white matter. Two EOnonAD cases showed intense FTP binding comparable to typical EOAD cases, despite visually and quantitatively negative FBB scans.ConclusionPatients with clinically mild, sporadic EOAD typically show an extensive distribution and burden of tau pathology in the setting of positive amyloid PET. Global clinical measures correlate with tau but not amyloid PET. Over 25% of patients meeting clinical criteria for early‐onset MCI/probable AD have negative amyloid PET, suggesting alternative etiologies for cognitive decline. These findings will inform future design of drug trials in this important and under‐studied population.
Examining early‐onset Alzheimer’s disease (EOAD) and late‐onset Alzheimer’s disease to understand the neuropathological substract of typical and atypical AD
Authors: Grinberg Lea Tenenholz , Petersen Cathrine , Nolan Amber L. , Resende Elisa de Paula França , Miller Zachary A. , Spina Salvatore , Miller Bruce L. , Rabinovici Gil D. , Seeley William W. 
Published: December 2020

AbstractBackgroundPathologically proven Alzheimer’s disease (AD) manifest clinically with a broad spectrum of cognitive presentations beyond the classic progressive amnestic‐predominant syndrome pointing to different patterns of selective vulnerability to AD pathology. As atypical clinical variants of AD tend to show a younger age of onset, EOAD cohorts present the best opportunity to understanding differences in the neuropathological substrate of typical vs. atypical AD presentation. Such studies may unveil mechanisms of selective neural vulnerability to AD and inform on novel modifiable pathogenic pathways. To reveal the features and mechanisms underlying the differences between typical and atypical AD, we investigated a sizeable clinicopathological series of sporadic EOAD. We hypothesized that a higher rate of comorbid pathology would explain an atypical AD clinical presentation.MethodWe used the UCSF/Neurodegenerative Disease Brain Bank (NDBB), which is a LEADS neuropathological hub. Neuropathological diagnosis follows internationally accepted research standards. We also employed quantitative neuropathological analysis in a subset for measuring p‐tau burden in neurons and astroglia. Definition of AD pathology required an ADNC ABC score ≥ A2B2C2. Sporadic EOAD cases manifested symptoms when < 65 years and lacked a AD‐associated autosomal dominant mutation.ResultFrom 2009 to 2019, the NDBB performed 113 autopsies with a primary neuropathological diagnosis of EOAD. Of those, (41%) showed an atypical presentation (Figure 1). Typical and atypical EOAD were similar in age and disease duration, but atypical cases were more likely to be female and have less comorbid Lewy body disease (Table 1). In brain areas associated with the most affected cognitive domain, atypical cases demonstrated a higher proportion of neurofibrillary (Table 2), but not of amyloid plaques or age‐related tau astrogliosis.ConclusionOther than greater regional tau burden, no other frequent neurodegenerative changes underlie atypical presentation. LEADS will enable increasing the EOAD neuropathological cohorts to leverage investigation on the factors underlying an atypical AD presentation.
Study on the correlation of depression, cognitive function and living ability in Chongqing, China
Authors: Yang Wenkai , Lü Yang 
Published: December 2020

AbstractBackgroundTo examine the incidence of depression in elderly people over 60 in Chongqing and patients with mild cognitive impairment (MCI) and Alzheimer’s disease (AD) in the Memory Clinic of Department of Geriatrics, The First Affiliated Hospital of Chongqing Medical University.MethodA total of 188 patients with MCI and 275 patients with AD who attended the Memory Clinic of Department of Geriatrics, The First Affiliated Hospital of Chongqing Medical University, from January 2010 to December 2018. 317 community subjects without cognitive impairment were used as control in this study. The neuropsychological examination was conducted for all patients, and the demographics were recorded. In addition, depression and impairment of daily living were evaluated by the Geriatric Depression Scale (GDS‐30) and Activity of Daily Living (ADL) respectively.ResultDepression was identified in 8.83% of subjects without cognitive impairment, 25.53% of patients with MCI, 25.09% of patients with AD. Compared with those without cognitive impairment, patients with cognitive impairment showed different symptoms in dysphoric mood, lack of vitality, worry, self‐evaluation of cognitive function, hopelessness and agitation (p<0.05). Furthermore, lack of vitality and self‐evaluation of cognitive function still remained statistically significant after adjustment for age, sex, and education level by logistic regression analysis [OR(95%CI(=1.312(1.164‐1.478) and 1.482(1.282‐1.714(,p<0.05].In addition, there was a close correlation between depression severity and cognitive function and living ability, that is, the low depression level (the low GDS score) indicates a good cognitive function (a high MMSE score) and living ability (a high ADL score).ConclusionDepressive symptoms show slight difference in patients with cognitive impairment or not. The health promotion for dementia‐related diseases in Chongqing still needs to be further promoted.
Usefulness of the self‐reported Dementia Assessment Sheet for Community‐based Integrated Care System‐21 items (DASC‐21) in the community‐dwelling elderly
Authors: Ono Rei , Uchida Kazuaki , Kawaharada Rika , Kido Yoshiaki , Yasuda Hisafumi , Kowa Hisatomo 
Published: December 2020

AbstractBackgroundThe Dementia Assessment Sheet for Community‐based Integrated Care System‐21 items (DASC‐21) was developed as screening tool to find early dementia. Although it is assessed by trained staff, self‐reported use has expected in community setting. The aim of this study was to examine usefulness to use the self‐reported DASC‐21 in the community dwelling‐elderly.MethodThis study design was cross sectional. We examined 2,140 elderly (≥65 years, mean age: 72.2 ± 4.6 years, females: 1,096) who were registered at Tanba city (Japanese rural area) and attended special health check‐up in 2019. DASC‐21 consisted of 21 items including institutional or basic activity of daily living and cognitive function and each item was indicated by 4‐points scale (21 to 84, ≥31 indicates dementia). Locomotive disorders (LD) were assessed by Geriatric Locomotive Function Scale‐25, which consisted of 25 items and response was graded into a 5‐point scale (0 to 100, ≥7 and ≥16 indicate pre‐LD and LD). Social frailty (SF) was examined using 5 items yes or no questions (0 to 5, 1 and ≥2 indicate SF). Depression was examined using Geriatric Depression Scale (0 to 15, ≥5 and ≥10 indicate moderate and severe depression). We also identified hypertension (systolic blood pressure ≥140mmHg and/or diastolic blood pressure ≥90mmHg), dyslipidemia (serum triglycerides ≥150mg/dL), and hyperglycemia (HbA1c ≥6.5%) from annual health check‐up. We performed statistical analyses using logistic regression, with the presence of dementia as the dependent variable, the presence of LD, SF, depression, hypertension, dyslipidemia, or hyperglycemia as the independent variable, and age, sex and years of education as confounding variables.ResultOf them, 100 participants were identified by DASC‐21 as dementia. In logistic regression analysis, the presence of dementia was associated with the presence of LD [odds ratio (95%CI), 4.2 (2.5 – 7.2) and 10.2 (5.8 – 17.9)], SF [3.7 (2.1 – 6.8) and 9.7 (5.4 – 17.4)], and depression [3.8 (2.5 – 6.0) and 8.5 (4.2 – 17.2)]. However, the other variables were not related.ConclusionUsing self‐reported DASC‐21 in the community‐dwelling elderly included various symptoms.