bluuebunny/crossref_metadata_2025_split huggingface dataset:
The association between an early diagnosis of dementia and secondary health service use: A retrospective cohort study using electronic health records
Authors: Couch Elyse , Mueller Christoph , Perera Gayan , Lawrence Vanessa , Prina Matthew 
Published: December 2020

AbstractBackgroundThe frequent use of emergency services and unplanned hospitalisations is reflective of fractured dementia care. People living with dementia have a higher risk of hospitalisation and are more likely to use Accident and Emergency (A&E) services more than people of the same age without dementia. It has been proposed that diagnosing dementia early can reduce the risk of harmful hospital admissions or A&E attendances, however there is very little evidence to support this. A diagnosis of Mild Cognitive Impairment (MCI) before dementia can be a helpful proxy to explore early diagnosis. Therefore, the aim of this study was to investigate the association between an early diagnosis of MCI and hospitalisations and A&E attendances.MethodThis study is a retrospective cohort study of electronic health care records from 15,836 patients from a large secondary care database in South London, UK. Participants were divided into two groups: those with a diagnosis of MCI before dementia, to represent an early diagnosis, and those without. Cox regression models were used to compare risk of hospitalisation and A&E attendances after dementia diagnosis. Finally, negative binomial regression models were used to compare the average length of stay and average number of A&E attendances. All models were adjusted for age at diagnosis, gender, ethnicity, levels of comorbid physical conditions, prescription of acetylcholinesterase inhibitors (AChEIs) and, mini‐mental state exam (MMSE) scores at dementia diagnosis.ResultsParticipants with an early diagnosis were more likely to attend A&E after their diagnosis of dementia (HR=1.13), however they did not visit A&E more frequently compared to participants without an early diagnosis (IRR=1.01). There was no difference the risk of hospitalisation or length of stay between the groups.ConclusionThe findings of this study demonstrate that despite the widely held belief that an early diagnosis reduces the likelihood of potentially harmful A&E attendances, patients with an early diagnosis were more likely to visit A&E after their diagnosis. It is possible this may reflect their use of A&E services before dementia. An early diagnosis does not impact the risk of hospitalisation or the length of time spent in hospital.
Association of Apolipoprotein E genetic variation in Alzheimer's disease in a Korean population
Authors: Van Vo Giau , Bagyinszky Eva , An Seong Soo , Kim SangYun 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) is one of the most devastating neurodegenerative diseases. The relationship between Apolipoprotein E (ApoE) genotype and the risk of AD is well described in Caucasians, but less established in other ethnicities.MethodTo examine the association between ApoE polymorphism and the onset of AD in Korean population, we enrolled and examined a total of 1000 Korean patients using polymerase chain reaction. The patients were assessed using the criteria of the National Institute of Neurological and Communicative Disorders and Stroke Alzheimer’ Disease and Related Disorders Association.ResultThe frequency of alleles ε2, ε3 and ε4 were 0.076, 0.784 and 0.292, respectively, in Koreans with AD. Furthermore, we compared our allele frequency data with that from other studies of Asian populations using cluster analysis. APOE genotype was closely related to AD in the Japanese population, which was entirely consistent with results previously reported from Korea.ConclusionThis study confirmed that the subject with at least one ApoE ε4 allele has higher risk suffering from AD than controls in Korean population.
MAPT rs242557 variant is associated with hippocampus tau uptake on 18F‐AV‐1451 PET in non‐demented elders
Authors: Shen Xue‐Ning , Miao Dan , Li Jie‐Qiong , Tan Chen‐Chen , Cao Xi‐Peng , Tan Lan , Yu Jin‐Tai 
Published: December 2020

AbstractBackgroundThe microtubule‐associated protein tau gene rs242557 variant is associated with multiple tauopathies and dementia. This study investigated whether it was correlated with brain tau‐PET uptake in non‐demented elders.MethodNinety non‐demented elders were identified from the Alzheimer's Disease Neuroimaging Initiative cohort. We compared standardized uptake value ratios of tau‐PET tracer 18F‐AV‐1451 between rs242557 variant carriers and non‐carriers in 25 regions of interest.ResultThe minor allele A was associated with increased hippocampus 18F‐AV‐1451 uptake in non‐demented elders (left: β = 0.111, Bonferroni corrected p = 0.035; right: β = 0.103, Bonferroni corrected p = 0.031). Aβ‐positive participants (left: β = 0.206, Bonferroni corrected p = 0.029; right: β = 0.198, Bonferroni corrected p = 0.035) and APOE ε4 non‐carriers (left: β = 0.140, Bonferroni corrected p = 0.006; right: β = 0.134, Bonferroni corrected p = 0.004) exhibited approximately the same findings in hippocampus.ConclusionConsidering no obvious associations in other regions, we confirmed the significant correlation of MAPT rs242557 risk variant with increased hippocampus tau deposition in non‐demented elders. With higher magnitude signals in the hippocampus that is more likely to be uniquely affected in AD, the tau PET ligand 18F‐AV‐1451 seemed to possess a specific binding property for AD‐like tau pathology.
Image‐based modeling of biomechanical factors for risk assessment of developing periventricular white matter hyperintensities
Authors: Tong Yunjie , Diorio Tyler C , Yang Ho‐ching Shawn , Zhou Xiaopeng , Wu Yu‐Chien , Saykin Andrew J. , Rayz Vitaliy 
Published: December 2020

AbstractBackgroundWhite matter lesions, visible as white matter hyperintensities (WMH) on T2‐weighted MR images, have been associated with aging and with cognitive decline. Among WMHs, periventricular WMHs (adjacent to the ventricular system) have preferential associations with cognitive decline/impairment. Despite the prevalence and potential significance in cognitive declines, there is little to no in‐depth knowledge regarding the underlying causes of WMH, except that it is related to small vessel disease. We hypothesize that the development of periventricular WMH is caused by pulsatile stresses exerted on the lateral wall of the ventricles. Elevated stress in regions adjacent to the ventricular wall, coupled with the weakening of the ependymal layer, may trigger the early changes in white‐matter microstructure and surrounding small vessels, eventually causing WMH.MethodWe developed a method to predict stress distribution in the periventricular white matter using patient‐specific brain anatomy and ventricular movement, obtained through MR imaging techniques. Utilizing established tools for image‐based segmentation (ITK Snap), pre‐processing (3D Systems–Geomagic; Altair–Hypermesh), and finite element modeling (ANSYS Workbench), we tested this pipeline on a healthy volunteer. Patient‐specific ventricular wall movement was assessed over the cardiac cycle using fast EPI MRI and utilized as a boundary condition driving displacement on the ventricular walls in the computational model.ResultAs shown in Figure 1, the stress distribution around the lateral ventricles was calculated based on subject specific ventricular geometry. The stress distribution is not uniform, but changes with the curvature of the ventricular wall. Peak stress concentrations were detected around the anterior and posterior horns of the lateral ventricles, where WMHs are commonly found. Initial results provide support for our hypothesis of biomechanical contributions to lesion development.ConclusionWe developed a computational modeling framework based on the ventricular anatomy obtained with structural MR images, and material properties from relevant literature and fast EPI MRI. The periventricular locations with high stresses were correlated with the common WMH topography. In the next step, we will apply the model to patient data to further determine the role of biomechanical factors in forming WMH.
Analyzing the correlation of vitamin D and cognitive function in community elders over 60 years old
Authors: LI Zheng , Yang Yanrong , Hu Tingting , Gao Jing , Wang Yao , Chen Shanping 
Published: December 2020

AbstractBackgroundDementia is a syndrome which describes a decline about cognition severe enough to affect daily living ability. The treatment for dementia is limited; Looking for factors related to cognitive dysfunction, controlling or reducing these factors will help delay the disease.MethodWe collected 190 community elders over 60 years old, used Montreal cognitive assessment (MOCA) to evaluated cognition, and divided into normal cognitive function group and abnormal cognitive function group. And the same time blood samples were collected to measure vitamin D. Compared the vitamin D between the two groups, P<0.05 was significant difference .Pearson's index was used to further compare the vitamin D and a single cognitive domain, P<0.05 was significant statistically.ResultThe incidence of cognition impairment was 77.9%, Comparing to normal cognitive function group and cognitive impairment group, the Vitamin D was significant differences(P<0.05).Further Pearson correlation analysis found that multiple cognitive domains such as executive, calculation, abstraction, visual space, naming, and attention were Positively correlated with vitamin D(P<0.05).ConclusionCognitive function is closely related to vitamin D, especially executive, orientation, calculation, abstraction, visual space, naming, and attention, adequate vitamin D may delay cognitive decline.
Overexpression of novel candidate gene ameliorates dendritic simplification in hippocampal neurons from APP/PS1 mouse model of AD
Authors: Verma Aditi , Gnanabharathi Barathan , Kumar Sunny , Gowaikar Ruturaj , Ramachandran Arathy , Kommaddi Reddy Peera , Rupanagudi Khader Valli , Palkovits Miklos , Renner Eva , Csiba Laszlo , Hortobagyi Tibor , Bennett David A. , Ravindranath Vijayalakshmi 
Published: December 2020

AbstractBackgroundImaging and neuropathological studies have revealed the entorhinal cortex (EC) and hippocampus (HP) circuitry to be affected early on during Alzheimer’s disease (AD) progression. Changes in the EC‐HP circuitry also correlate with the episodic memory deficits that have been reported in AD. Using bulk RNA sequencing, we studied the gene expression changes in the EC and HP of adolescent (1‐month old) and young adult (3‐months old) APPswe/PS1ΔE9 (APP/PS1) mice. The analysis of RNA‐seq data revealed a single common gene, the expression of which was perturbed at both ages and both regions. We further studied the physiological implication of this gene in the transgenic mouse model of AD.MethodTotal RNA was isolated at 1 month and 3 months of age from the EC and HP of male APP/PS1 transgenic (Tg) and wild type (WT) control mice as an input for Illumina paired end sequencing. The reads were aligned to mouse genome after adapter trimming and read counts were generated and normalized using DESeq2 for differential gene expression analysis. qRT‐PCR based validation was performed for the differentially expressed genes. Over‐expression of novel candidate gene on primary hippocampal cultures from Tg and WT APP/PS1 mice was achieved using lentiviral transduction. Imaging of neurons was performed on Zeiss confocal microscope and morphometry and spine analysis was done using Neurolucida software.ResultAPP was found to be upregulated in both EC and HP at 1 month and 3 months of age in APP/PS1 mice, which served as a positive control. A single gene was consistently down‐regulated at both 1 and 3 months of age in both EC and HP, which was validated through qRT‐PCR. Over‐expression of this gene using lentiviral transduction on APP/PS1 Tg hippocampal neurons in vitro rescued the loss of dendritic complexity observed in these neurons but not spine loss. Finally, we show the down‐regulation of this gene in prefrontal cortex from human AD autopsy tissue as compared to controls.ConclusionIn conclusion, our study identified a novel gene candidate that is involved in loss of dendritic complexity in AD pathogenesis early in the disease.
Association between cognition and gait in elderly people: The putamen as a shared substrate
Authors: Li Peixi , Wang Yingzhe , Jiang Yanfeng , Chen Xingdong , Dong Qiang , Cui Mei 
Published: December 2020

AbstractBackgroundCognitive impairment and gait disturbance are both prevalent in elderly people. However, few studies have focused on the underlying mechanisms in the relationship between cognition and gait. The aim of our study is to contrast the strength of correlations between each cognitive domain and gait parameters in a community‐dwelling population, as well as giving a new insight into the shared neuroimaging signature of cognitive impairment and gait disturbance.MethodIn the cross‐sectional population‐based Taizhou Imaging Study, 733 older adults with a mean (SD) age of 63.9 (3.1) years accepted brain MRI, neuropsychological tests and wearable gait tracking devices for quantitative gait analysis. Global cognitive function and individual cognitive domains (memory, executive function, language, visuospatial skill) were assessed using the Mini‐Mental State Examination, auditory verbal learning test (with>6 years of education), modified Fuld Object Memory Evaluation (with≤6 years of education), conflicting instructions task, clock drawing test and animal fluency test. Dementia and mild cognitive impairment (MCI) were diagnosed according to DSM‐5 criteria and the Petersen criteria. The volume of brain regions was analyzed by Freesurfer.ResultOf the 733 participants, 500 (68.2%) were cognitive normal, 182 (24.8%) were diagnosed as MCI, 51 (7.0%) were diagnosed as dementia. Gait parameters, including gait velocity, stride length and cadence, were significantly different among three cognition groups (P<0.001). In fully adjusted linear regression models, global cognitive function and each cognitive domain were significantly associated with gait parameters. Executive function demonstrated the strongest association with gait (β: 0.149‐0.206, P<0.001), which remained significant when adjusted for memory, language and visuospatial skill. The volume of putamen was the only region that was related to both executive function (β=0.103, P=0.007) and gait velocity (β=0.107, P=0.007). Mediation analysis confirmed a mediating role of putaminal atrophy in the association between executive function and gait velocity.ConclusionCognitive function is associated with gait performance in community‐dwelling elderly individuals. Executive function had the strongest association with gait among cognitive domains, which is supported by a shared substrate including putaminal atrophy. Future longitudinal studies with neuroimaging techniques are needed to further confirm our findings.
An association study of Alzheimer’s disease risk genes in a Chinese population
Authors: Xiao Xuewen , Jiao Bin , Yuan Zhenhua , Liao Xinxin , Tang Beisha , Shen Lu 
Published: December 2020

AbstractBackgroundGenome‐wide association studies (GWAS) and whole‐exome sequencing have identified a number of risk genes playing a significant role in the pathogenesis of Alzheimer’s disease (AD). However, most of the genetic studies are from Caucasian populations and relatively rare in Chinese population.MethodWe sequenced 33 AD risk genes using Targeted panel sequencing in 721 AD patients and 365 normal controls in Han population of Southern China. A series of bioinformatic methods including common‐variant (0.01≤MAF≤0.5) based association analysis and gene‐based association analysis on rare variants (MAF<0.01) were performed between AD patients and normal controls.ResultWe identified nine common variants with significant differences, three of them had been reported, including rs429358 in APOE, rs4147929 in ABCA7 and rs3752246 in ABCA7, while other six variants were novel, including rs3752229 in ABCA7, rs4147935 in ABCA7, rs17125497 in SORL1, rs2282647 in SORL1, rs11218355 in SORL1, and rs11682128 in BIN1. The area under the ROC (AUC) of the nine significant loci model was 0.670. Gene‐based association analysis on rare variants showed that the p value of RIN3 was less than 0.05 both in the Sequence Kernel Association Test‐Optimal (SKAT‐O) test and logistic regression analysis (age, gender and APOE ε4 as covariates) between AD patients and normal controls (p = 0.0399, corrected P = 0.0346).ConclusionWe conclude that APOE, ABCA7, SORL1, BIN1 and RIN3 are risk factors for AD in Chinese population.
Sex‐specific differential gene expression changes in young AD transgenic (APPswe/PS1ΔE9) mice through RNA‐seq
Authors: Verma Aditi , Ramachandran Arathy , Rupanagudi Khader Valli , Ravindranath Vijayalakshmi 
Published: December 2020

AbstractBackgroundWomen and men are differently affected in Alzheimer’s disease (AD). However, the factors that contribute to this differential AD epidemiology are not well understood. We, therefore, examined how gene expression changes could work differently in females and males in the APPswe/PS1ΔE9 (APP/PS1) mouse model of AD using RNA sequencing (RNA‐seq).MethodTotal RNA was isolated from EC and HP from 3‐month‐old female and male APP/PS1 transgenic (Tg) and wild type (WT) control mice (n=4). Depletion of ribosomal RNA was performed on the total RNA before cDNA library preparation which was followed by Illumina paired end sequencing. The raw reads were processed to remove reads with low quality and adapters. The reads were then aligned to mouse genome and read counts for all the files were generated from aligned reads using htseq‐count. The counts were then name sorted using samtools and differential gene expression analysis was performed after normalisation using DESeq2 which was followed by pathway analysis using the online application DAVID.ResultIn both EC and HP in the female and male APP/PS1 mice, APP was found to be upregulated. In the EC, we observed that while 55 genes were upregulated in males, 418 genes were upregulated in female Tg mice as compared to WT with only 10 common genes. Further, while 153 genes showed downregulation in males, 152 genes were downregulated in EC in female Tg mice as compared to WT mice with 10 common genes. In HP, 40 genes were found upregulated in males while only 2 genes in females. The number of downregulated genes in male HP was 46, while it was 3 in female HP. Further, biological pathways such as synapse, cell junction, postsynaptic membrane, calmodulin binding, gap junction, cytoskeleton were perturbed in female Tg mice while in male Tg mice the pathways perturbed were synapse, cell junction, SH3 domain, transcription regulation and neurogenesis.ConclusionOur analysis of transcriptomic data reveals a significant difference between male and female APP/PS1 transgenic mice. Our study therefore, highlights the importance of studying sex‐specific mechanisms of AD pathogenesis.
Effect of soluble interleukin‐10 receptor expression in mouse models of Alzheimer’s disease
Authors: Koller Emily J. , De La Cruz Elsa Gonzalez , Weinrich Mary J. , Antezana Gustavo , Ibanez Kristen R. , Ryu Daniel H. , Lewis Jada , Chakrabarty Paramita 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) is a neurodegenerative disease characterized pathologically by intracellular neurofibrillary tangles (NFT), extracellular amyloid β (Aβ) plaques, and neuroinflammation. Interleukin 10 (IL10) is an anti‐inflammatory cytokine released by immune and glial cells. Since IL10 is anti‐inflammatory, it has the potential to be a therapy for neurodegenerative diseases with an inflammatory component. However, contrary to what we expected, an earlier study from our group showed that overexpression of IL10 actually led to an increase in Aβ plaque burden in a mouse model of Aβ plaques. Therefore, we proposed to assess the effect of overexpression of the soluble extracellular portion of the IL10 receptor (sIL10R) on disease pathogenesis in both an Aβ mouse model and tau mouse models. The premise was that this soluble form of the receptor would attenuate IL10 signaling, thus reversing its anti‐inflammatory properties.MethodTo investigate the effect of sIL10R expression on Aβ plaques, we used adeno‐associated virus (AAV) to express sIL10R in neonatal TgCRND8 mice and aged them 3 or 6 months. We next investigated whether sIL10R also affected tau pathology in two tau mouse models: a slowly‐progressing spinal cord tauopathy model (JNPL3) and a rapid model with primarily cortical and hippocampal tauopathy (rTg4510).ResultAssessment of Aβ plaque burden revealed decreased Aβ plaque load in the younger TgCRND8 cohort, but this effect was not observed in the 6 month old mice. We observed a significant reduction of phosphorylated tau and a trend towards reduced p62 levels in the JNPL3 mice. However, we did not observe changes in phosphorylated tau or p62 levels in 4 month old or 6 month old rTg4510 mice. Quantification of neuroinflammatory markers in APP and tau mouse models showed distinct patterns of neuroinflammation specific to each model.ConclusionOur study demonstrates that a decoy receptor may be a potential therapeutic for Alzheimer’s disease and that attenuation of Aβ and tau pathogenesis may occur at different rates and at different disease stages. Future experiments will center around characterizing possible mechanisms underlying these changes.
Intrathecal antibodies against herpes simplex virus are associated with tau pathology in humans with Alzheimer’s disease
Authors: Goldhardt Oliver , Freiberger Robert , Ortner Marion , Müller‐Sarnowski Felix , Förstl Hans , Diehl‐Schmid Janine , Ramirez Alfredo , Magdolen Viktor , Thaler Markus , Grimmer Timo 
Published: December 2020

AbstractBackgroundRecurrent infection with herpes simplex virus type 1 (HSV1) has been discussed as contributing to Alzheimer’s disease (AD) pathology. HSV1 infection has been shown to induce beta‐amyloid (Aβ) accumulation and tau pathology in cell culture and animal models. Aβ limits the activity of the virus and might be part of the innate immune system. Both hyperphosphorylated tau (pTau) and HSV1 are associated with intracellular kinase activity. In this study, we investigated the association of serological HSV biomarkers with CSF biomarkers for Aβ and tau pathology as well as neuronal injury in humans with AD.MethodIn 117 patients at early stages of AD, total Tau (tTau), pTau, Aβ42 and Aβ40 were measured in CSF. All patients were positive for amyloid pathology in amyloid PET or exhibited an Aβ42/Aβ40 ratio <0.05 (in‐house cut‐off). Seral anti‐HSV1‐IgG, anti‐HSV1‐IgM titer and anti‐HSV1/2‐IgG CSF to serum antibody index (HSV‐AI) were determined by ELISA. In HSV1‐seropositives (defined by HSV1‐IgG ≥ 25 U/ml), serological HSV parameters and CSF AD biomarkers were correlated. The association between CSF pTau with serological HSV biomarkers modulated by amyloid was investigated in linear regression models.ResultsIn the HSV1‐positives (n= 92), no serological HSV parameter was significantly correlated with CSF amyloid biomarkers. The HSV‐AI, was significantly correlated with tTau (Rho= 0.276, p= 0.012, n= 82) and pTau concentrations (Rho= 0.296, p= 0.007, n= 82), but not the seral anti‐HSV1‐IgG or IgM titer. In a linear regression model, HSV‐AI significantly and positively predicted pTau variability (adj. R²= 0.140, p<0.001, beta‐coefficient (β) = 0.389). Including Aβ42/Aβ40 ratio in the model increased the explained variability: adj. R²= 0.352, p< 0.001, βHSV‐AI= 0.374 (p< 0.001), βAβ‐Ratio= ‐0.467 (p< 0.001). A significant and negative interaction between the Aβ42/Aβ40 ratio and the HSV‐AI was retrieved (adjusted R²= 0.395, p< 0.001, βHSV‐AI= 1.560 (p =0.001), βAβ‐Ratio= 0.339 (p=0.304), βAβ‐Ratio*HSV‐AI= ‐1.430 (p= 0.013)). All models were controlled for APOE genotype, sex and age.ConclusionIn AD, CSF pTau is associated with intrathecal HSV activity. This association is modulated by Aβ. The results support the hypothesis of HSV infection contributing to AD pathology.