bluuebunny/crossref_metadata_2025_split huggingface dataset:
Simulating the outcome of a clinical intervention from a data‐driven model of Alzheimer's disease progression
Authors: Nader Clement Abi , Ayache Nicholas , Robert Philippe , Lorenzi Marco 
Published: December 2020

AbstractBackgroundThe recent outcomes of clinical trials in Alzheimer's Disease (AD) underline the critical importance of timing for drug intervention, and the need to identify optimal intervention windows along the disease history to maximize cognitive benefit. In this work, we propose a data‐driven progression model of AD allowing simulation of the effect of disease modifying drugs along the entire history of the pathology.MethodWe propose a generative model of disease progression, aimed at identifying the dynamical relationships between multi‐modal clinical and imaging data. Our data consists of AV45‐PET, FDG‐PET, MR images, and clinical scores for 311 ADNI individuals (49 healthy, 113 MCI, 33 MCI converted to AD, and 116 AD patients) for a total of 2188 longitudinal measures. The model is based on a dynamical system relating the multi‐modal information, and is formulated under realistic clinical hypothesis to provide plausible disease progression simulation and predictions.ResultFigure 1 shows the modelled disease progression for grey matter atrophy, glucose hypometabolism, amyloid concentration, and cognitive decline. We notice a global increase of amyloid, while grey matter atrophy and glucose hypometabolism map prevalently temporal and parietal regions. Clinical scores exhibit a non‐linear profile, accelerating during the latest disease stages. The individual disease severity associated to such progression shows significant separation across clinical groups (p<0.01, Figure 2). Finally, our model allows to simulate the intervention outcome of hypothetical modifiers blocking amyloid deposition at a given time. Table 1 shows the values of ADAS11 and MMSE at conversion time, depending on the time at which we simulated amyloid blockage. Mild differences are obtained when complete blockage is performed at least 3 years before conversion, while stronger significant effects appear at intervention time of 10 years before conversion.ConclusionWe presented a model of AD progression, allowing to simulate the effect of disease modifying drugs on the clinical outcome at any stage of the natural history of AD. The model is flexible and future extensions are currently under study, to account for different kind of PET tracers, and for APOE4 genotyping.
Adult hippocampal neurogenesis is impaired in patients with Alzheimer’s disease
Authors: Flor‐García Miguel , Terreros‐Roncal Julia , Moreno‐Jiménez Elena P , Llorens‐Martin María 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) is the most common type of dementia. This devastating disease is characterized by progressive memory impairments and other behavioral alterations. The hippocampus is one of the brain areas mostly affected by AD progression. Importantly, the hippocampus hosts a unique phenomenon that occurs in the mammalian brain, namely the addition of new neurons throughout life. This process, named adult hippocampal neurogenesis (AHN), is involved in hippocampal‐dependent memory and confers an extraordinary degree of plasticity to the entire hippocampal circuitry. AHN has been extensively characterized in rodents and other mammalian species during the last decades. Determining the occurrence of AHN during physiological and pathological aging in humans has an unquestionable therapeutic potential.MethodWe studied AHN in a collection of post‐mortem hippocampal samples obtained from 13 neurologically healthy subjects and 45 AD patients distributed among the six neuropathological Braak stages of the disease. We quantified the presence of various sub‐populations of immature neurons in the hippocampal dentate gyrus (DG) of these subjects. Importantly, we tightly controlled tissue processing methodologies and used state‐of‐the‐art histological procedures.ResultThousands of immature neurons positive for the gold‐standard marker Doublecortin (DCX) were identified in the DG of these subjects up to the tenth decade of life. In contrast, we observed an early and sharp decrease in the number of new neurons in patients with AD. Strikingly, the number of cells further decreased as the disease progressed, even though the number of mature neurons positive for the neuronal nuclei (NeuN) remained unchanged. Accordingly, specific decrease in the ratio between immature/mature neurons was observed along the progression of the disease. Importantly, AHN impairments occurred before the generalized presence of neurofibrillary tangles or senile plaques in the DG.ConclusionOur data demonstrate the persistence of AHN during physiological and pathological aging in humans and provide evidence for impaired neurogenesis as a potentially relevant mechanism underlying memory deficits that occurs in AD. Therefore, the putative detection of AHN impairments by non‐invasive techniques might turn this phenomenon into a relevant biomarker for AD progression.
TREM2 Alzheimer’s variant R47H causes similar transcriptional dysregulation to TREM2 knockout in human IPSC‐derived macrophages
Authors: Roberts Hazel Hall , Agarwal Devika , Daniel Elena Di , Webber Caleb , James William S , Mead Emma , Davis John B , Cowley Sally A 
Published: December 2020

AbstractBackground
TREM2 is a microglia‐specific gene, with mutations linked to Alzheimer’s disease, including R47H (1). In AD mouse models, knockout (KO) of TREM2 impairs microglial clustering around amyloid and prevents microglia from being activated into a “disease‐associated” transcriptional state (2). The R47H mutation has been proposed to reduce ligand binding and therefore reduce TREM2 function (3).MethodWe generated primitive macrophages from human induced pluripotent stem cell (iPSC) harbouring isogenic R47H TREM2 and TREM2 KO mutations gene‐edited onto a healthy genetic background, as a practical, simple model of human microglia. We performed bulk RNA‐seq and compared significant differentially‐expressed genes (DEGs: FDR corrected p<0.05) between the R47H and KO versus WT. Selected hits were validated by qPCR, flow cytometry and western blotting. We also used a bioinformatics approach to predict potential upstream regulators of sets of DEGs.ResultTREM2 KO resulted in a transcriptional signature hallmarked by dysregulation of genes involved with immune processes, calcium homeostasis, cell cycle, cell activation and chemotaxis. Although 3‐fold fewer DEGs were identified for R47H TREM2, 90% of these were also dysregulated in the KO, with directionality preserved. Validation confirmed specific defects in integrin expression in the R47H and KO. A candidate upstream regulator from the bioinformatics analysis was explored in cell assays, to shed more light on the underlying molecular mechanisms linking TREM2 KO to changes in adhesion and motility.ConclusionThe overlap in transcriptional defects between R47H TREM2 and KO (with R47H intermediate between WT and KO) supports the hypothesised partial loss‐of‐function effects of this mutation in humans. Guerriero et. al. (2013) N Engl J Med. 368 (2):117‐27. Krasemann et al. (2017) Immunity 47, 566–581. Kober et al. (2016). eLife, 5, e20391.
Harmonizing the preclinical Alzheimer cognitive composite for multi‐cohort studies
Authors: Hampton Olivia L , Mukherjee Shubhabrata , Properzi Michael J , Schultz Aaron P , Crane Paul K , Gibbons Laura E , Hohman Timothy J , Maruff Paul T , Lim Yen Ying , Amariglio Rebecca , Papp Kathryn V , Johnson Keith A , Rentz Dorene , Sperling Reisa A , Buckley Rachel F 
Published: December 2020

AbstractBackgroundVersions of the Preclinical Alzheimer Cognitive Composite (PACC) and within cohort standardization models have been implemented in multiple observational and clinical trials. Harmonizing PACC data across studies, however, requires modern psychometric approaches to reflect the psychometric, testing, and demographic nuances between cohorts and enable meta‐analyses. We present a method for harmonizing PACC across four cohorts: the Alzheimer’s Disease Neuroimaging Initiative (ADNI), the Anti‐Amyloid Treatment in Asymptomatic Alzheimer’s disease (A4), Harvard Aging Brain Study (HABS), and Australian Imaging, Biomarker & Lifestyle Study of Ageing (AIBL).MethodTables 1 and 2 show the demographic and neuropsychological test data used to form each PACC. The ADNI dataset was defined as the anchor for harmonization. The final visit data were used to set factor score loadings for each PACC (except A4) to maximize cognitive variability in the sample for calibration purposes. First, we used confirmatory factor analysis (CFA) on the ADNI dataset to ascertain raw loadings and thresholds of each test onto a latent PACC factor (lPACC). These loadings were then applied to the longitudinal ADNI dataset (Fig.1). For the other studies, common items (MMSE and Logical Memory) were set as “anchors” to freely estimate unique items. Common items in HABS were set as anchors for A4 (FCsrt and DSST). Longitudinal lPACC scores were generated once all item parameters were estimated for all cohorts. We performed validation analyses to assess the quality of integration using lPACC scores versus within‐cohort standardized PACC (zPACC).ResultLPACC scores largely aligned with zPACC, particularly when examining within‐cohort relationships with baseline demographic variables (Table3) and comparing slope distributions across cohorts (Fig2B). Notable differences between the scores include: a) shifted baseline distributions for lPACC relative to zPACC, reflecting cohort demographic heterogeneity (Fig.2A), and b) constricted slope distribution for lPACC slopes compared with zPACC slopes (Fig.2B), suggesting reduced variability (Fig.2B/C). When the cohorts were combined, the point estimate for strength of association between baseline amyloid and longitudinal cognitive change was higher using the lPACC than the zPACC (Fig.3).ConclusionLPACC scores reflect within cohort patterns, while reducing slope variability. Using advanced psychometrics, a harmonized PACC can be pooled across studies, facilitating robust multi‐cohort analyses.
Instagram live tour: How are COVID‐19 and dementia being faced by healthcare workers in Brazil?
Authors: Peres Fernando Aguzzoli 
Published: December 2020

AbstractBackgroundPromoting live interviews with health workers from all Brazilian regions to address the increased challenges of dementia, quarantine, COVID‐19 and the local specificities of the crisis. The project aims to reach those sheltered in place with positive key content to face misinformation, fear and increasing fake news.MethodInformal "chat" style targeting audiences with different levels of knowledge. Brazil is a continental country with more than 200 million inhabitants, different cultures, demographic factors and several inequalities. Each live sessions have a central topic (e.g. "Self‐care in quarantine times The one‐hour live sessions have a central topic (e.g. "Self‐care in quarantine times") discussed with a professional from that location. The recording is after available in the interviewer's instagram feed with 16,000 followers. The professionals are geriatricians, psychiatrists, psychologists and neurologists, all associated with large institutions such as the Brazilian Alzheimer's Association or the Brazilian Geriatrics and Gerontology society.ResultThe virtual interviews (6 to date) had significant engagement, excellent numbers of attendees during the live session (between 200 and 600 people), queries and comments posted (more than 100 interactions in each session), and views in the subsequent 48‐hour period (between 1,100 and 1,600).ConclusionThe project is cost‐effective, being a collaboration between interviewer and interviewee without any fee, accessible due to the approach chosen, wide‐ranging in knowledge levels, and dynamic due to the interaction with the public. The project also avoid social isolation of those in quarantine, turning into physical distancing.
The impact of ligature‐induced periodontitis on an experimental mouse model of Alzheimer’s disease
Authors: Wang Rachel Pei‐Hsuan , Leung Wai‐Keung , Goto Tetsuya , Ho Janice Yuen Shan , Chang Raymond Chuen‐Chung 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) is the most common form of dementia characterized by the presence of amyloid plaques, neurofibrillary tangles and the activation of the brain immune system. Studies from the public health have shown that activation of the immune cells in the periphery can lead to neuroimmune responses, which can initiate or perpetuate neurodegenerative brain changes that underlie cognitive impairment. One of the common sources of chronic systemic inflammation is periodontitis, which is an inflammatory disease that destroys gums and teeth. We hypothesize that periodontal bone loss due to periodontitis gums may intensify the neuroimmune responses in AD and exacerbate the disease conditions.MethodA 5‐0 silk ligature was placed around the maxillary upper second molars in female 3xTg mice for 5 weeks to induce periodontal bone loss. Open field test was performed to assess the sickness behavior; Spontaneous Y maze and puzzle box test were used to assess the cognitive functions of the mice. Following behavioral testing, the upper maxillary jaws were dissected out and subjected to histological analysis to examine periodontal bone loss. Different brain regions were harvested for biochemical analysis.ResultAfter 5 weeks, ligature‐induced periodontitis led to a significant loss of periodontal bone level in 3xTg mice. It also induced inflammation in the hippocampus and frontal cortex regions. A significant reduction of exploratory motivation was also observed in ligated AD mice compared to WT control. No impairment of short‐term memory was observed in ligated AD mice, but they exhibited significant reduction in the total arm entries, which is also an indicator of a reduction in exploratory behavior. In the puzzle box test, ligature‐induced periodontitis induced long‐term memory impairment in ligated AD miceConclusionAltogether, ligature‐induced periodontitis led to increase neuroimmune responses in the brains of AD mice, a reduction of exploratory motivation as well as long term memory impairment. As bone loss induced by ligation led to increased neuroinflammation. Future work will aim to elucidate the mechanism of how periodontal bone loss and the cytokine innate response lead to neuroimmune response. Acknowledgement: The study is supported by Health and Medical Research Fund (HMRF 04151216) to RCCC.
Laparotomy: A non‐bacterial endotoxin mouse model for investigating the impact of systemic inflammation on neuroinflammation and cognitive functions
Authors: Cheng Wai‐Yin , Ho Yuen‐Shan , Chang Raymond Chuen‐Chung 
Published: December 2020

AbstractBackgroundIncreasing lines of evidence have shown that systemic inflammation may contribute to neuroinflammation and accelerate the progression of neurodegenerative diseases. In this study, a non‐bacterial endotoxin mouse model of laparotomy is adopted to address the systemic inflammation triggered by surgery. We aim at investigating whether laparotomy induces systemic inflammation, neuroinflammation and cellular changes such as tau phosphorylation leading to cognitive dysfunction.MethodMale wild‐type C57BL/6J mice were randomly divided into two groups: control group under sevoflurane anesthesia and laparotomy group under sevoflurane anesthesia. Expression of mRNA for cytokines in the liver, frontal cortex and hippocampus was examined at 4 h and day 1 after laparotomy by quantitative RT‐PCR and tau protein phosphorylation was comparatively determined on post‐operative day (POD) 1 by western blot analysis.ResultFirst, laparotomy induced peripheral inflammation and neuroinflammation. At 4 h after laparotomy, significant increase of interleukin‐1β (IL‐1β) and MCP‐1 were detected in the liver of the laparotomy group (p < 0.05). Expression of IL‐1β was also significantly upregulated in the hippocampus after laparotomy. On POD 1, no significant differences of IL‐1β, IL‐6, TNF‐ α and MCP‐1 mRNA expression were observed at the liver. It implies that the induced systemic inflammation is transient. Meanwhile, the level of IL‐1β remained high in the hippocampus after surgery. Second, on POD 1, there was no significant difference in the total tau protein level between the laparotomy and control groups in the frontal cortex. It could be possible that the changes in protein expression level could not be reflected within a relatively short time period after laparotomy.ConclusionThis study reveals that laparotomy induces systemic and neural inflammation. Further studies will be performed to examine the infiltration of monocytes into the brain and cognitive dysfunction induced by laparotomy. Acknowledgement: The study is supported by General Research Fund (17123217) to RCCC.
Anticoagulant prescribing in atrial fibrillation and risk of incident dementia: A UK population‐based cohort study
Authors: Cadogan Sharon L , Powell Emma , Wong Angel Y , Wing Kevin , Smeeth Liam , Warren‐Gash Charlotte 
Published: December 2020

AbstractBackgroundDementia risk is approximately doubled among patients with atrial fibrillation (AF) 1‐3, who are often recommended to take blood‐thinning drugs (anticoagulants) to prevent stroke. Recent evidence has also shown that taking anticoagulant drugs may help to delay the onset of dementia among individuals with AF4, however, we do not know which types of anticoagulants drugs are most beneficial and for which groups of patients. Hence, the aim of this study was to compare the effect of direct oral anticoagulants (DOACs) versus vitamin K antagonists (VKAs) on risks of incident dementia and mild cognitive impairment (MCI) among patients with newly diagnosed atrial fibrillation (AF).MethodUsing linked electronic health records data from the Clinical Practice Research Datalink (CPRD) in the United Kingdom, we conducted a historical cohort study among first‐time oral anticoagulant users with patients with incident non‐valvular AF diagnosed from 2012 to 2018. Crude incidence rates of dementia and MCI were calculated overall and separately for DOACs and VKAs. Cox proportional hazards regression models were then used to compare the incidence of clinically coded dementia and MCI between patients prescribed VKAs and DOACs, adjusting for sociodemographic and lifestyle factors, clinical comorbidities and medications.ResultOf 39,200 first time oral anticoagulant users (44.6% female, median age 76 years, IQR 68‐83), 20,687 (53%) were prescribed a VKA and 18,513 (47%) a DOAC at baseline. Overall, 1,258 patients (3.2%) had GP‐recorded incident dementia, incidence rate 14.9 per 1,000 person‐years and 1,483 patients (3.9%) received a diagnosis of MCI, incidence rate 19.29 per 1,000‐person years. DOAC treatment for AF was associated with a 15% reduction in dementia risk compared to VKA treatment in the whole cohort (HR 0.85, 95% CI: 0.73, 0.98) and with a 20% reduction in MCI risk (HR 0.80, 95% CI: 0.71‐0.91).ConclusionThe risks of incident EHR‐recorded dementia and MCI were lower among patients prescribed DOACs for new AF compared to those prescribed VKAs. The cognitive risk profile of a patient should help to inform choice of oral anticoagulant treatment for AF among older individuals.
3D neural circuit visualization by neural tracing and tissue clearing for dementia study
Authors: Lai Michael Siu‐Lun , Lee Krit , Sørensen Maja Højvang , Chang Raymond Chuen‐Chung 
Published: December 2020

AbstractBackgroundTo date, different techniques were developed for mapping neural connections, including diffusion tensor imaging (DTI) and neural tracers. DTI allows tracing of connections in macroscale but with low resolution. While neural tracers can allow visualization at single cell level, their signals are usually visualized in 2D sections. This results in missing information from the damages of brain tissues during tissue sectioning and inaccuracy of computation reconstruction. Therefore, we decided to trace neural circuits by using neural tracers in 3D intact tissues instead of 2D sections. In this study, we aim to establish 3D visualization protocol by combining neural tracing and tissue clearing techniques. We tested the potential of this protocol on tracing the neural circuit involved in Parkinson’s disease dementia (PDD) by using both chemical‐based and viral‐based neural tracers. Medial forebrain bundle (MFB) connects striatum, substantia nigra and frontal cortex. We at first focused on dopaminergic pathway projecting from MFB.MethodCholera toxin subunit B (CTB) conjugated with Alexa Fluor‐647 (CTB‐647) or adeno‐associated virus (AAV) expressing nerve growth factor and green fluorescent protein (AAV‐NGF‐GFP) was injected into MFB by stereotaxic injection. The rats were then euthanized by perfusion at different day points (10 days for CTB‐647; 5 weeks for AAV‐NGF‐GFP) after the injection. The brains were treated with 4% sodium dodecyl sulfate (SDS) plus Optical Properties‐adjusting Tissue Clearing agent (OPTIClear) solution for 5 days and then incubated into OPTClear solution for 2 days. The fluorescent signals were visualized by confocal microscopy.ResultCTB‐647 and AAV‐NGF‐GFP signals were detected in striatum. It showed that the CTB‐647 can travel from MFB to striatum through nigrostriatal pathway, while AAV‐NGF‐GFP can be absorbed by the neurons projecting from MFB to striatum to express green fluorescent proteins. It is feasible to trace neural circuits by neural tracing with tissue clearing.ConclusionTaken together, nigrostriatal pathway, connecting substantia nigra and striatum, can be traced by using neural tracers together with tissue clearing. With this protocol, the neural circuits related to the dementia processes in PD can be further studied. Acknowledgement: The study is supported by Seed Funding for Translational and Applied Research (201910160016) to RCCC.